Abstract:
A tansdermal delivery device for effectively treating seasonal allergic rhinitis and chronic idiopathic urticariain in humans is disclosed and methods thereof.

Description:
This application claims the benefit of U.S. Provisional Application No. 60/242,514, filed Oct. 23, 2000, hereby incorporated by reference. 
    
    
     BACKGROUND OF THE INVENTION 
     It is the intent of all sustained-release pharmaceutical preparations to provide a longer period of pharmacologic effect after the administration of a drug than is ordinarily experienced after the administration of immediate release preparations of the same drug. Such longer periods of efficacy can provide many inherent therapeutic benefits that are not achieved with corresponding immediate release preparations. The benefits of prolonged treatment of the nasal and non-nasal symptoms of seasonal allergic rhinitis or chronic idiopathic urticaria afforded by sustained release oral preparations have become universally recognized and oral sustained-release preparations are commercially available. 
     Another approach to sustained delivery of a therapeutically active agent is transdermal delivery systems, such as transdermal patches. Generally, transdermal patches contain a therapeutically active agent, a reservoir or matrix containing the active ingredient(s) and an adhesive which allows the transdermal device to adhere to the skin, allowing for the passage of the active agent from the device through the skin of the patient. Once the active agent has penetrated the skin layer, the drug is absorbed into the blood stream where it can exert a desired pharmacotherapeutic effect. 
     In spite of the known art related to transdermal therapy, there exists a need for the transdermal delivery of a beneficial agent for the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria. 
     Loratadine, commercially available as Claritin® in the U.S. from Schering Corporation (Kenilworth, N.J. 07033, U.S.A.), is a long-acting tricyclic antihistamine with selective peripheral histamine H1-receptor antagonistic activity, with the chemical name, ethyl 4-(8-chloro-5,6-dihydro-11H-benzo cyclohepta pyridin-11-ylidene)-1-piperidinecarboxylate, and it is used mainly for treating nasal and non-nasal symptoms of seasonal allergic rhinitis, but may also be used in the treatment of chronic idiopathic urticaria, a common skin disorder . It is in the form of a white to off white powder, not soluble in water, but very soluble in organic solvents. Loratadine inhibits the activity of the substance, histamine, thus reducing the allergic effects caused by this substance such as itching, sneezing, runny nose and watery eyes. Loratadine is preferable to other antihistamines because it is nonsedating and does not cause cardiac arrhythmias brought on by use of some other antihistamines. The recommended oral dosage of loratadine for adults and children 12 years old or older is 10 mg once daily. In patients with liver or renal problems, the initial oral dosage of loratadine should be 10 mg every other day. 
     Seasonal allergic rhinitis (hay fever) is a term used to describe the symptoms caused seasonally by an allergic reaction that occurs in the eyes, nose, and throat in response to airborne allergens such as pollen from trees, grasses, and weeds. Other possible allergens include dust mites, molds, and animal dander. The allergens produce an allergic response by misleading the immune into thinking that the allergen is a harmful substance, thereby causing the immune system to produce antibodies to this specific allergen. When that allergen enters the immune system again, a reaction occurs between the allergen and IgE antibodies triggering the release of substances such as histamine from mast cells and other cells, producing symptoms such as runny nose, watery eyes, sneezing, and itching. 
     Chronic urticaria is an allergic skin disorder characterized by hives, e.g. red welts or small bumps, on the skin which are very itchy. Patients with chronic urticaria have hives that last longer than six months. This skin disorder is caused by an antigen-antibody reaction in which histamine and other substances such as acetyl choline are released from mast cells and other cells causing symptoms such as swelling, itching, pain, and rash. There are also cases in which there are no known causes for the hives (chronic idiopathic urticaria). As with chronic urticaria, antihistamines are used for treating chronic idiopathic urticaria. 
     Symptoms of seasonal allergic rhinitis and chronic idiopathic urticaria are improved by treatment with nonsedating antihistamines. Nonsedating antihistamines such as loratadine (The Merck Index, 11 th  Edition, Merck &amp; Co., Inc., Rahway, N.J. U.S.A. 1989, hereby incorporated by reference) act as an antagonist to the peripheral histamine H 1  receptor by selectively binding to this receptor, thereby blocking histamine from being released from the immune system and thus preventing histamines unwanted effects. (Goodman and Gillmans, The Pharmacological Basis of Therapeutics, 9 th  Edition, hereby incorporated by reference). 
     Following oral administration, loratadine is rapidly absorbed, fast acting, and undergoes extensive first pass metabolism to the active metabolite descarboethoxyloratadine. Food delays absorption, so loratadine should be taken on an empty stomach. Pharmacokinetic studies have revealed that the onset of antihistamine activity occurs within 1-3 hours following administration of loratadine, reaching a maximum at 8-12 hours and lasting in excess of 24 hours. There was no evidence of tolerance to this effect after 28 days of dosing with loratadine. After 10 days of dosing, a mean peak plasma concentration of 1.3 hours and 2.3 hours (T max ) was observed in loratadine and the active metabolite, respectively. The mean elimination half-life observed in normal adults was 8.4 hours for loratadine and 28 hours for active metabolite. In patients with chronic liver disease, a mean half-life for loratadine and descarboethoxyloratadine of 24 hours and 37 hours were observed, respectively. Within 10 days of dosing, approximately 80% of the total loratadine administered were found in equal proportions between the urine and feces in the form of metabolic products. Finally, loratadine is 97% plasma-protein bound. 
     The most common adverse side effects of loratadine therapy include headache, somnolence, fatigue, and dry mouth. Less common or rare side effects may include altered lacrimination, altered salivation, flushing, hypoesthesia, impotence, increased sweating, thirst, angioneurotic edema, asthenia, back pain, blurred vision, chest pain, earache, eye pain, fever, leg cramps, malaise, rigors, tinnitus, viral infection, weight gain, hypertension, hypotension, palpitations, superventricular tachyarrhythmias, syncope, tachycardia, blepharospasm, dizziness, dysphonia, hypertonia, migraine, paresthesia, tremor, vertigo, altered taste, anorexia, constipation, diarrhea, dyspepsia, flatulence, gastritis, hiccup, increased appetite, nausea, stomatitis, toothache, vomiting, arthraglia, myalgia, agitation, amnesia, anxiety, confusion, decreased libido, depression, impaired concentration, insomnia, irritability, paroniria, breast pain, dysmenorrhea, menorrhagia, vaginitis, bronchitis, bronchospasm, coughing, dyspnea, epistaxis, hemoptysis, laryngitis, nasal dryness, pharyngitis, sinusitis, sneezing, dermatitis, dry hair, dry skin, photosensitivity reaction, pruritis, purpura, rash, urticaria, altered micturition, urinary discoloration, urinary incontinence, urinary retention. Further, the following spontaneous adverse effects were rarely reported for loratadine: abnormal hepatic function, including jaundice, hepatitis, and hepatic necrosis, alopecia, anaphylaxis, breast enlargement, erythema multiforme, peripheral edema, and seizures. (Physicians&#39; Desk Reference, 53rd Edition, 1999, hereby incorporated by reference). 
     Despite advances in the art, there remains a need for methods of treating patients with seasonal allergic rhinitis and chronic idiopathic urticaria with an agent that provides effective levels of loratadine for prolonged periods of time, preferably while eliminating or minimizing the symptoms of seasonal allergic rhinitis or chronic idiopathic urticaria, and/or any of the other above mentioned side effects, thus providing a safe and effective method of management of such allergic reactions and skin disorders. 
     OBJECTS AND SUMMARY OF THE INVENTION 
     It is an object of the present invention to provide a continuous plasma loratadine concentration in mammals, preferably humans patients suffering from seasonal allergic rhinitis and/or chronic idiopathic urticaria. 
     It is an object of certain embodiments of the present invention to provide a method for treating patients suffering from seasonal allergic rhinitis and chronic idiopathic urticaria which achieves prolonged and effective management of these conditions, while at the same time provides the opportunity to reduce possible side effects, e.g., which patients may experience when subjected to prolonged oral therapy. 
     It is an object of certain embodiments of the present invention to provide a method for the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria disorders in patients by utilizing a transdermal delivery system which contains loratadine. 
     It is an object of certain embodiments of the present invention to provide a method for the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria disorders in patients which maximizes the dosage interval, i.e., the interval during which the transdermal delivery system is maintained in contact with the skin, and minimizes the plasma concentrations and or fluctuations in plasma concentrations in the patients during the dosage interval, while surprisingly maintaining effective management of seasonal allergic rhinitis and chronic idiopathic urticaria. 
     It is an object of certain embodiments of the present invention to provide a method for lessening the dry mouth associated with the oral administration of loratadine. 
     In certain embodiments, the present invention is directed to a method of effectively treating seasonal allergic rhinitus, chronic idiopathic urticaria, or both conditions in a human patient, comprising 
     administering loratadine transdermally to the human patient by applying a transdermal delivery system containing loratadine to the skin of a patient, and maintaining the transdermal delivery system in contact with the skin of the patient for at least 3 days, the transdermal delivery system maintaining an effective mean relative release rate to provide a therapeutic blood level of the loratadine within 36 hours from the initiation of the dosing interval, and thereafter maintaining a therapeutic blood level until the end of at least the three-day dosing interval. 
     In certain embodiments, the present invention is directed to a method of effectively treating seasonal allergic rhinitus, chronic idiopathic urticaria, or both conditions in a human patient, comprising 
     administering loratadine transdermally to the human patient by applying a transdermal delivery system containing loratadine to the skin of a patient, and maintaining the transdermal delivery system in contact with the skin of the patient for at least 5 days, the transdermal delivery system maintaining an effective mean relative release rate to provide a therapeutic blood level of the loratadine within three days from the initiation of the dosing interval, and thereafter maintaining a therapeutic blood level until the end of at least the five-day dosing interval. 
     In certain embodiments, the present invention is directed to a method for lessening the incidence of side-effects in a patient associated with the oral administration of loratadine, wherein the method comprises administering the loratadine in a transdermal delivery system over at least twenty-four hours and thereby lessening the incidence of side effects. 
     In certain embodiments, the above methods can further comprise providing a mean relative release rate of loratadine from a transdermal delivery system to provide a plasma level of loratadine of at least about 0.1 ng/ml within about 6 hours, 3 hours, 2 hours, 1 hour or 0.5 hours after after application of the transdermal delivery system onto the skin of the patient. 
     In certain embodiments, the above methods can further comprise providing a loratadine transdermal delivery system which maintains a plasma level of loratadine at steady-state from about 1 to about 3 ng/ml. 
     In certain embodiments, the above methods can further comprise maintaining a therapeutic plasma level from about 0.1 ng/ml to about 3.3 ng/ml during the dosing interval for the transdermal delivery system. 
     In certain embodiments, the above methods can further comprise having the transdermal delivery system having a mean relative release rate from 1.0 μm/hour/cm 2  to about 30.0 μm/hour/cm 2  or about 1.8 μm/hour/cm 2  to about 17 μm/hour/cm 2 . 
     In certain other embodiments, the above methods can further comprise having the transdermal delivery system having a mean relative release rate from 2.0 μm/hour/cm 2  to about 10.0 μm/hour/cm 2 . 
     In certain other embodiments, the above methods can further comprise having the transdermal delivery system having a mean relative release rate from 2.0 μm/hour/cm 2  to about 5.0 μm/hour/cm 2 . 
     In certain embodiments, the above methods can further comprise having the transdermal delivery system having a mean relative release rate from about 2.8 μg/cm 2 /hr to about 16.2 μg/cm 2 /hr at 24 hours;
         from about 2.3 μg/cm 2 /hr to about 13.7 μg/cm 2 /hr at 48 hours; and   from about 2.0 μg/cm 2 /hr to about 11.9 μg/cm 2 /hr at 72 hours; as determined via an in-vitro permeation test utilizing a Valia-Chien cell where the membrane is a human cadaver skin and the cell has a receptor chamber containing a 40:60 mixture of ethanol:water.       

     In certain embodiments, the above methods can further comprise having the transdermal delivery system to provide an in-vitro cumulative amount of permeation of from about 63 μg/cm 2  to about 388 μg/cm 2  at 24 hours; from about 105 μg/cm 2  to about 660 μg/cm 2  at 48 hours; and from about 139 μg/cm 2  to about 854 μg/cm 2  at 72 hours, as determined via an in-vitro permeation test utilizing a Valia-Chien cell where the membrane is a human cadaver skin and the cell has a receptor chamber containing a 40:60 mixture of ethanol:water. 
     In certain embodiments, the above methods can further comprise having the plasma level of loratadine at 48 hours not decrease by more than 30% over the next 72 hours. 
     In certain embodiments, the above methods can further comprise maintaining an effective mean relative release rate of the transdermal delivery system to provide a substantially first order plasma level increase of loratadine from the initiation of the dosing interval until about 48 to about 72 hours after the initiation of the dosing interval; and thereafter providing an effective mean relative release rate to provide a substantially zero order plasma level fluctuation of loratadine until the end of at least the five-day dosing interval. 
     In certain embodiments, the above methods can further comprise administering the loratadine in a transdermal delivery system applied to the skin of a human patient for about 3 to about 5 days. 
     In certain embodiments, the invention is directed to a transdermal device containing loratadine which provides effective blood plasma levels of loratadine when the device is applied to the skin of a mammal, preferably a human. 
     In certain embodiments, the invention is directed to a transdermal device containing loratadine which provides effective treatment of seasonal allergic rhinitis and chronic idiopathic urticaria disorders in patients. 
     In certain embodiments, the invention is directed to a transdermal delivery device comprising loratadine or a pharmaceutically acceptable salt thereof which maintains an effective mean relative release rate to provide a therapeutic blood level of the loratadine within three days from the initiation of the dosing interval, and thereafter maintaining a therapeutic blood level until the end of at least the five-day dosing interval. 
     In certain embodiments, the invention is directed to a transdermal device containing loratadine for the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria disorders in patients which maximizes the dosage interval, i.e., the interval during which the transdermal delivery system is maintained in contact with the skin, and minimizes the plasma concentrations and or fluctuations in plasma concentrations in the patients during the dosage interval, while surprisingly maintaining effective management of seasonal allergic rhinitis and chronic idiopathic urticaria. 
     In certain embodiments, the invention is directed to a transdermal delivery system containing loratadine or a pharmaceutically acceptable salt thereof which provides a mean relative release rate from about 1.0 μm/hour/cm 2  to about 30.0 μm/hour/cm 2  or about 1.8 μm/hour/cm 2  to about 17 μm/hour/cm 2  of the transdermal delivery system; a plasma level of loratadine of at least about 0.1 ng/ml within about 6 hours, 3 hours, 2 hours, 1 hour or 0.5 hours after application of the transdermal delivery system onto the skin of the patient; and a plasma level of loratadine at steady-state from about 0.1 to about 3.3 ng/ml. 
     In certain embodiments, the transdermal delivery system provides a mean relative release rate from about 2.8 μg/cm 2 /hr to about 16.2 μg/cm 2 /hr at 24 hours; from about 2.3 μg/cm 2 /hr to about 13.7 μg/cm 2 /hr at 48 hours; and from about 2.0 μg/cm 2 /hr to about 11.9 μg/cm 2 /hr at 72 hours; as determined via an in-vitro permeation test utilizing a Valia-Chien cell where the membrane is a human cadaver skin and the cell has a receptor chamber containing a 40:60 mixture of ethanol:water. 
     In certain embodiments, the transdermal delivery system provides an in-vitro cumulative amount of permeation of from about 63 μg/cm 2  to about 388 μg/cm 2  at 24 hours; from about 105 μg/cm 2  to about 660 μg/cm at 48 hours; and from about 139 μg/cm 2  to about 854 μg/cm at 72 hours, as determined via an in-vitro permeation test utilizing a Valia-Chien cell where the membrane is a human cadaver skin and the cell has a receptor chamber containing a 40:60 mixture of ethanol:water. 
     In certain embodiments, the transdermal delivery system maintains a plasma level of loratadine at steady-state from about 1 to about 3 ng/ml. 
     In certain embodiments, the transdermal delivery system maintains an effective mean relative release rate to provide a therapeutic blood level of the loratadine within three days from the initiation of the dosing interval, and thereafter maintaining a therapeutic blood level until the end of at least the five-day dosing interval. 
     In certain embodiments, the transdermal delivery system provides a mean relative release rate of loratadine effective to provide a plasma level of loratadine of at least about 0.1 ng/ml within about 6 hours, 3 hours, 2 hours, 1 hour or 0.5 hours after application of the transdermal delivery system onto the skin of the patient. 
     In certain embodiments, the transdermal delivery system maintains a plasma level of loratadine at steady-state from about 1 to about 3 ng/ml. 
     In certain embodiments, the transdermal delivery system maintains a therapeutic plasma level from about 0.1 ng/ml to about 3.3 ng/ml during the dosing interval for the transdermal delivery system. 
     In certain embodiments, the transdermal delivery system provides a mean relative release rate from about 1.0 μm/hour/cm 2  to about 30.0 μm/hour/cm 2  or about 1.8 μg/hour/cm 2  to about 17 μg/hour/cm 2  of the transdermal delivery system. 
     In certain embodiments, the transdermal delivery system provides a mean relative release rate from about 2.8 μg/cm 2 /hr to about 16.2 μg/cm 2 /hr at 24 hours; from about 2.3 μg/cm 2 /hr to about 13.7 μg/cm 2 /hr at 48 hours; and from about 2.0 μg/cm 2 /hr to about 11.9 μg/cm 2 /hr at 72 hours; and from about 1.8 μg/cm 2 /hr to about 9.9 μg/cm 2  /hr at 96 hours; as determined via an in-vitro permeation test utilizing a Valia-Chien cell where the membrane is a human cadaver skin and the cell has a receptor chamber containing a 40:60 mixture of ethanol:water. 
     In certain embodiments, the transdermal delivery system provides an in-vitro cumulative amount of permeation of from about 63 μg/cm to about 388 μg/cm 2  at 24 hours; from about 105 μg/cm 2  to about 660 μg/cm 2  at 48 hours; and from about 139 μg/cm 2  to about 854 μg/cm 2  a 72 hours; and from about 162 μg/cm 2  to about 955 μg/cm 2  at 96 hours; as determined via an in-vitro permeation test utilizing a Valia-Chien cell where the membrane is a human cadaver skin and the cell has a receptor chamber containing a 40:60 mixture of ethanol:water. 
     In further embodiments, the invention is directed to a transdermal device and method which, when applied to the skin of a mammal such as a human patient, provides therapeutically effective blood plasma levels of loratadine to effectively treat seasonal allergic rhinitis, chronic idiopathic urticaria, or both conditions in a human patient, wherein the transdermal device is maintained in contact with the patient&#39;s skin for at least 5 days, the transdermal delivery system maintaining an effective mean relative release rate to provide a therapeutic blood level of the loratadine within three days from the initiation of the dosing interval, and thereafter maintaining a therapeutic blood level until the end of at least the five-day dosing interval. 
     The invention is further directed to a transdermal loratadine device for the effective treatment of seasonal allergic rhinitis, chronic idiopathic urticaria, or both conditions in a human patient, which device, when applied to the skin of a patient maintained in contact with the patient&#39;s skin for at least 3 days, has an effective mean relative release rate to provide a therapeutic blood level of the loratadine within 36 hours from the initiation of the dosing interval, and thereafter maintains a therapeutic blood level until the end of at least the three-day dosing interval. 
     The invention is further directed in part to a transdermal loratadine device for the treatment of chronic allergic rhinitis and chronic idiopathic urticaria which provides substantially zero order pharmacokinetics over a significant portion of the dosage interval. 
     The invention is further directed to a transdermal device and a method of effectively treating seasonal allergic rhinitis, chronic idiopathic urticaria, or both conditions in a human patient, comprising applying the transdermal loratadine device to the skin of the patient and maintaining the transdermal delivery system in contact with the skin of a patient for at least 5 days, the transdermal delivery system maintaining an effective mean relative release rate to provide a substantially first order plasma level increase of loratadine from the initiation of the dosing interval until about 48 to about 72 hours after the initiation of the dosing interval; and thereafter providing an effective mean relative release rate to provide a substantially zero order plasma level fluctuation of loratadine until the end of at least the five-day dosing interval. 
     The invention is further directed to a transdermal loratadine device which when applied to the skin of a patient and maintained in contact with the patient&#39;s skin for at least 3 days, has an effective mean relative release rate to provide a substantially first order plasma level increase of loratadine from the initiation of the dosing interval until about 24 hours after the initiation of the dosing interval; and thereafter provides an effective mean relative release rate to provide a substantially zero order plasma level fluctuation of loratadine until the end of at least the three-day dosing interval. 
     The invention is further directed to a transdermal loratadine device and a method for lessening the incidence of side-effects in a patient associated with the oral administration of loratadine, wherein the method comprises administering the loratadine in a transdermal dosage form over at least twenty-four hours and thereby lessening the incidence of side effects. 
     The invention is further directed to a transdermal loratadine device and method which provides for reduced side-effects and for avoids peak plasma concentrations of loratadine in a patient associated with the oral administration of loratadine (i.e., reduces the peak plasma level relative to immediate release orally delivered loratadine), via the administration of loratadine in a transdermal dosage form over at least twenty-four hours, thereby lessening the incidence of side effects and avoiding the peak plasma concentrations of loratadine. 
     In certain embodiments, the invention is directed to transdermal delivery devices which are suitable for attaining any of the above methods. 
     For example, the above methods can be achieved utilizing a transdermal therapeutic system for the administration of loratadine to the skin comprising a backing layer which is impermeable to the active substance, a pressure-sensitive adhesive reservoir layer, and optionally a removable protective layer, the reservoir layer by weight comprising 20 to 90% of a polymeric matrix, 0.1 to 30% of a softening agent, 0.1 to 20% of loratadine base or of a pharmaceutically acceptable salt thereof and 0.1 to 30% of a solvent for the loratadine or salt thereof. 
     Another alternative is to utilize a laminated composite for administering loratadine or a pharmaceutically acceptable salt thereof to an individual transdermally comprising
         (a) a polymer backing layer that is substantially impermeable to loratadine or the pharmaceutically acceptable salt thereof; and   (b) a reservoir layer comprising an acrylate or silicone pressure-sensitive adhesive, 0.1 to 20% of loratadine base or of a pharmaceutically acceptable salt thereof, 0.1 to 30% of an ester of a carboxylic acid acting as a softening agent and 0.1 to 30% of a solvent for loratadine having at least one acidic group.       

     The methods of the present invention are described in further detail in the following sections. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. However, it should be understood that for purposes of the present invention, the following terms have the following meanings: 
     The term “effective treatment of seasonal allergic rhinitis or chronic idiopathic urticaria” is defined for purposes of the present invention as a satisfactory reduction in or elimination of the symptoms associated with seasonal allergic rhinitis and chronic idiopathic urticaria, along with the process of a tolerable level of side effects, as determined by the human patient. 
     Drug release from membrane-controlled systems may be defined as follows:
 
Amount released per area unit  Q =const (zero order kinetics)
 
     The term “mean relative release rate” is determined from the amount of drug released per unit time from the transdermal delivery system through the skin and into the bloodstream of a human patient. Mean relative release rate may be expressed, e.g., as μg/cm 2 /hr. For example, a transdermal delivery system that releases 10 mg of loratadine over a time period of 24 hours is considered to have a relative release rate of 420 μg/hr. For purposes of the invention, it is understood that relative release rates may change between any particular time points within a particular dosing interval, and the term therefore only reflects the overall release rate during the particular dosing interval. For purposes of the present invention, relative release rate should be considered synonymous with the term “flux rate”. 
     The term “sustained release” is defined for purposes of the present invention as the release of the drug (loratadine) from the transdermal formulation at such a rate that blood (e.g., plasma) concentrations (levels) are maintained within the therapeutic range (above the minimum effective concentration) but below the upper limit of the therapeutic window over a period of time of about 3 days or longer. 
     The term “steady state” means that the blood plasma concentration curve for a given drug has been substantially repeated from dose to dose. 
     The term “minimum effective concentration” is defined for purposes of this invention as the minimum effective therapeutic blood plasma level of the drug at which at least some therapeutic effect in treating seasonal allergic rhinitis or chronic idiopathic urticaria is achieved in a given patient. 
     The term “overage” means for the purposes of the present invention the amount of loratadine contained in a transdermal delivery system which is not delivered to the patient. The overage is necessary for creating a concentration gradient by means of which the active agent (e.g., loratadine) migrates through the layers of the transdermal dosage form to the desired site on a patient&#39;s skin. 
     The term “first order” pharmacokinetics is defined as plasma concentrations which increase over a specified time period. 
     The term “zero order” pharmacokinetics contemplates an amount of drug released from a loratadine formulation which substantially maintains plasma concentrations at a relatively constant level. For purposes of the present invention, a relatively constant plasma concentration is defined as a concentration which does not decrease more than about 30% over a 48 hour time period. 
     Drug release from membrane-controlled systems may be defined as follows:
 
Amount released per area unit  Q =const (zero order kinetics)
 
     The term “mean relative release rate” is determined from the amount of drug released per unit time from the transdermal delivery system through the skin and into the bloodstream of a human patient. Mean relative release rate may be expressed, e.g, as μg/cm 2 /hr. For example, a transdermal delivery system that releases 10 mg of loratadine over a time period of 24 hours is considered to have a relative release rate of 4.1×10 −4  μg/hr. For purposes of the invention, it is understood that relative release rates may change between any particular time points within a particular dosing interval, and the term therefore only reflects the overall release rate during the particular dosing interval. For purposes of the present invention, relative release rate should be considered synonymous with the term “flux rate”. 
     The term “sustained release” is defined for purposes of the present invention as the release of the drug from the transdermal formulation at such a rate that blood (e.g., plasma) concentrations (levels) are maintained within the therapeutic range (above the minimum effective drug concentration or “MEDC”) but below toxic levels over a period of time of about 3 days or longer. 
     The term “steady state” means that the blood plasma concentration curve for a given drug has been substantially repeated from dose to dose. 
     The term “minimum effective concentration” is defined for purposes of this invention as the minimum effective therapeutic blood plasma level of the drug at which at least some relief of the seasonal allergic rhinitis or chronic idiopathic urticaria symptoms is achieved in a given patient. 
     For purposes of the present invention, the term “loratadine” shall include loratadine base, pharmaceutically acceptable salts thereof, stereoisomers thereof, enantiomers thereof, ethers thereof, and mixtures thereof. 
     For purposes of the present invention, the terms “transdermal delivery device” and “transdermal delivery system” are interchangeable. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The following drawings are illustrative of embodiments of the invention and are not meant to limit the scope of the invention as encompassed by the claims. 
         FIG. 1  is a graphical representation of the cumulative amounts of loratadine resulting from 3 permeation tests of Example 1 through human cadaver skin. 
         FIG. 2  is a graphical representation of the average loratadine permeation rate (flux rate) of Example 2 through human cadaver skin. 
         FIG. 3  is a graphical representation of the average cumulative amount of loratadine resulting from 4 permeation tests of Example 2 through human cadaver skin. 
         FIG. 4  is a graphical representation of the cumulative amounts of loratadine resulting from 3 permeation tests of Example 3 through human cadaver skin. 
         FIG. 5  is a graphical representation of the cumulative amounts of loratadine resulting from 3 permeation tests of Example 4 through human cadaver skin. 
         FIG. 6  is graphical representation of the average loratadine permeation rates (flux rates) of Examples 5, 6, and 7 through human cadaver skin. 
         FIG. 7  is a graphical representation of the average cumulative amounts of loratadine resulting from permeation tests of Examples 5, 6, and 7 through human cadaver skin. 
         FIG. 8  is a graphical representation of the average cumulative amounts of loratadine resulting from permeation tests of Examples 8, 9, and 10 through human cadaver skin. 
         FIG. 9  is a graphical representation of the average loratadine permeation rates (flux rates) of Examples 8, 9, and 10 through human cadaver skin. 
         FIG. 10  is a graphical representation of the average cumulative amounts of loratadine resulting from permeation tests of Examples 11, 12, and 9 through human cadaver skin. 
         FIG. 11  is a graphical representation of the average cumulative amounts of loratadine resulting from permeation tests of Examples 13 and 14 through human cadaver skin. 
         FIG. 12  is a graphical representation of the average loratadine permeation rates (flux rates) of Examples 13 and 14 through human cadaver skin. 
         FIG. 13  is a graphical representation of the average cumulative amounts of loratadine resulting from permeation tests of Examples 15 and 16 through human cadaver skin. 
         FIG. 14  is a graphical representation of the average loratadine permeation rates (flux rates) of Examples 15 and 16 through human cadaver skin. 
     
    
    
     DETAILED DESCRIPTION 
     Transdermal delivery of active agents is measured in terms of “relative release rate” or “flux”, i.e., the rate of penetration of the active agent through the skin of an individual. Skin flux may be generally determined from the following equation:
 
 dm/dT=J=P*C  
 
where J is the skin flux, P is the permeability coefficient and C is the concentration gradient across the membrane, assumed to be the same as the donor concentration. M represents the amount of drug entering the blood stream. The variable dm/dT represents the change in the amount of drug entering the blood stream over time.
 
     It is well understood in the art of transdermal delivery systems that in order to maintain a desired flux rate for a desired dosing period, it is necessary to include an overage of active agent in the transdermal delivery system in an amount that is substantially greater than the amount to be delivered to the patient over the desired time period. For example, to maintain the desired flux rate for a three day time period, it is considered necessary to include much greater than 100% of a three-day dose of an active agent in a transdermal delivery system. This overage is necessary for creating a concentration gradient by means of which the active agent migrates through the layers of the transdermal delivery system to the desired site on a patient&#39;s skin. The remainder of the active agent remains in the transdermal delivery system. It is only the portion of active agent that exits the transdermal delivery system that becomes available for absorption into the skin. The total amount of active agent absorbed into the patient&#39;s blood stream is less than the total amount available. The amount of overage to be included in a transdermal delivery system is dependent on these and other factors known to the skilled artisan. 
     It has been found that it is possible to treat seasonal allergic rhinitis and chronic idiopathic urticaria according to the present invention by providing a transdermal delivery system containing a sufficient amount of loratadine to provide a desired relative release rate for at least about 3 days, and after single administration (application) of the transdermal dosage form, leaving the dosage form on the skin for approximately a 3 to 8 day time period, thereby resulting in the flux being maintained over the prolonged period and effective blood plasma levels and management of seasonal allergic rhinitis or chronic idiopathic urticaria being maintained over the prolonged period. Preferably, the desired flux is maintained at least about 5, preferably at least about 7 days after application of the transdermal delivery system. 
     Transdermal dosage forms used in accordance with the invention preferably include a backing layer made of pharmaceutically acceptable material which is impermeable to loratadine. The backing layer preferably serves as a protective cover for the active agent, e.g. loratadine and may also provide a support function. Examples of materials suitable for making the backing layer are films of high and low density polyethylene, polypropylene, polyvinylchloride, polyurethane, polyesters such as poly(ethylene terephthalate), metal foils, metal foil laminates of such suitable polymer films, textile fabrics, if the components of the reservoir cannot penetrate the fabric due to their physical properties and the like. Preferably, the materials used for the backing layer are laminates of such polymer films with a metal foil such as aluminum foil. The backing layer can be any appropriate thickness which will provide the desired protective and support functions. A suitable thickness will be from about 10 to about 200 microns. Desirable materials and thickness will be apparent to the skilled artisan. 
     Matrix Systems 
     In certain preferred embodiments, the transdermal dosage forms used in accordance with the invention contain a polymer matrix layer. Generally, the polymers used to form the biologically acceptable polymer matrix are those capable of forming thin walls or coatings through which pharmaceuticals can pass at a controlled rate. A non-limiting list of exemplary materials for inclusion in the polymer matrix includes polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethylacrylate copolymers, ethylene vinyl acetate copolymers, silicones, rubber, rubber-like synthetic homo-, co- or block polymers, polyacrylic esters and the copolymers thereof, polyurethanes, polyisobutylene, chlorinated polyethylene, polyvinylchloride, vinyl chloride-vinyl acetate copolymer, polymethacrylate polymer (hydrogel), polyvinylidene chloride, poly(ethylene terephthalate), ethylene-vinyl alcohol copolymer, ethylene-vinyloxyethanol copolymer, silicones including silicone copolymers such as polysiloxane-polymethacrylate copolymers, cellulose polymers (e.g., ethyl cellulose, and cellulose esters), polycarbonates, polytetrafluoroethylene and mixtures thereof. 
     Preferred materials for inclusion in the polymer matrix layer are silicone elastomers of the general polydimethylsiloxane structures, (e.g., silicone polymers). Preferred silicone polymers cross-link and are pharmaceutically acceptable. Other preferred materials for inclusion in the polymer matrix layer include: silicone polymers that are cross-linkable copolymers having dimethyl and/or dimethylvinyl siloxane units which can be crosslinked using a suitable peroxide catalyst. Also preferred are those polymers consisting of block copolymers based on styrene and 1,3-dienes (particularly linear styrene-isoprene-block copolymers of styrene-butadiene-block copolymers), polyisobutylenes, polymers based on acrylate and/or methacrylate. 
     The polymer matrix layer may optionally include a pharmaceutically acceptable cross-linking agent. Suitable crosslinking agents include, e.g., tetrapropoxy silane. 
     Preferred transdermal delivery systems used in accordance with the methods of the present invention include an adhesive layer to affix the dosage form to the skin of the patient for a desired period of administration, e.g., about 3 to about 8 days. If the adhesive layer of the dosage form fails to provide adhesion for the desired period of time, it is possible to maintain contact between the dosage form with the skin by, for instance, affixing the dosage form to the skin of the patient with an adhesive tape, e.g, surgical tape. It is not critical for purposes of the present invention whether adhesion of the dosage form to the skin of the patient is achieved solely by the adhesive layer of the dosage form or in connection with a peripheral adhesive source, such as surgical tape, provided that the dosage form is adhered to the patient&#39;s skin for the requisite administration period. 
     The adhesive layer preferably includes using any adhesive known in the art that is pharmaceutically compatible with the dosage form and preferably hypoallergenic, such as polyacrylic adhesive polymers, acrylate copolymers (e.g., polyacrylate) and polyisobutylene adhesive polymers. In other preferred embodiments of the invention, the adhesive is a pressure-sensitive contact adhesive, which is preferably hypoallergenic. 
     The transdermal dosage forms which can be used in accordance with the present invention may optionally include a permeation enhancing agent. Permeation enhancing agents are compounds which promote penetration and/or absorption of the loratadine into the blood stream of the patient. A non-limiting list of permeation enhancing agents includes polyethylene glycols, surfactants, and the like. 
     Alternatively, permeation of loratadine may be enhanced by occlusion of the dosage form after application to the desired site on the patient with, e.g. an occlusive bandage. Permeation may also be enhanced by removing hair from the application site by, e.g. clipping, shaving or use of a depilatory agent. Another permeation enhancer is heat. It is thought that heat enhancement can be induced by, among other things, using a radiating heat form, such as an infrared lamp, onto the application site after application of the transdermal dosage form. Other means of enhancing permeation of loratadine such as the use of iontophoretic means are also contemplated to be within the scope of the present invention. 
     A preferred transdermal dosage form which may be used in accordance with the present invention includes a non-permeable backing layer made, for example, of polyester; an adhesive layer made, for example of a polyacrylate; and a matrix containing the loratadine and other desirable pharmaceutical aids such as softeners, permeability enhancers, viscosity agents and the like. 
     The active agent may be included in the device in a drug reservoir, drug matrix or drug/adhesive layer. Preferably, the active agent is loratadine or a pharmaceutically acceptable salt thereof. 
     Certain preferred transdermal delivery systems also include a softening agent. Suitable softening agents include higher alcohols such as dodecanol, undecanol, octanol, esters of carboxylic acids, wherein the alcohol component may also be a polyethoxylated alcohol, diesters of dicarboxylic acids, such as di-n-butyladiapate, and triglycerides particularly medium-chain triglycerides of the caprylic/capric acids or coconut oil, have proved to be particularly suitable. Further examples of suitable softeners are multivalent alcohols, for example, levulinic acid, cocprylic acids glycerol and 1,2-propanediol which can also be etherified by polyethylene glycols. 
     A loratadine solvent may also be included in the transdermal delivery systems of the present invention. Preferably, the solvents dissolve the loratadine to a sufficient extent thereby avoiding complete salt formation. A non-limiting list of suitable solvents include those with at least one acidic group. Particularly suitable are monoesters of dicarboxylic acids such as monomethylglutarate and monomethyladipate. 
     Other pharmaceutically acceptable compounds which may be included in the reservoir or matrix include: solvents, for example alcohols such as isopropanol; permeation enhancing agents such as those described above; and viscosity agents, such as cellulose derivatives, natural or synthetic gums, such as guar gum, and the like. 
     In preferred embodiments, the transdermal dosage form includes a removable protective layer. The removable protective layer is removed prior to application, and consists of the materials used for the production of the backing layer described above provided that they are rendered removable, for example, by a silicone treatment. Other removable protective layers, for example, are polyltetra-fluoroethylene, treated paper, allophane, polyvinyl chloride, and the like. Generally, the removable protective layer is in contact with the adhesive layer and provides a convenient means of maintaining the integrity of the adhesive layer until the desired time of application. 
     The composition of the transdermal dosage forms used in accordance with the invention and the type of device used are not considered critical to the method of the invention, provided that the device delivers the active agent, e.g. loratadine, for the desired time period and at the desired flux rate and/or the desired delivery rate of the transdermal dosage form. 
     Certain transdermal dosage forms for use in accordance with the present invention are described in U.S. Pat. No. 5,240,711 (Hille, et. al.; assigned to LTS Lohmann Therapie-Systeme GmbH &amp; Co.), hereby incorporated by reference. Such transdermal delivery systems may be a laminated composite having an impermeable backing layer containing loratadine, e.g., instead of buprenorphine, and optionally a permeation enhancer combined with a pressure-sensitive adhesive. A preferred transdermal dosage form in accordance with the &#39;711 patent includes: (i) a polyester backing layer which is impermeable to the drug; (ii) a polyacrylate adhesive layer; (iii) a separating polyester layer; and (iv) a matrix containing loratadine, a solvent for the loratadine, a softener and a polyacrylate adhesive. The loratadine solvent may or may not be present in the final formulation. The transdermal delivery device described therein includes a backing layer which is impermeable to the active substance, a pressure-sensitive adhesive reservoir layer and optionally, a removable protective layer. Preferably, the reservoir layer includes about 10 to about 95%-wt polymeric material, about 0.1 to about 40%-wt softener, about 0.1 to about 30%-wt loratadine. A solvent for the loratadine base or pharmaceutically acceptable salt thereof may be included as about 0.1 to about 30%-wt. 
     The transdermal delivery system may also be prepared in accordance with the disclosure of International Patent Application No. WO 96/19975 (Hille, et. al.; assigned to LTS Lohmann Therapie-Systeme GMBH), hereby incorporated by reference, where loratadine is substituted for buprenorphine as an active agent. In this device, the loratadine transdermal delivery device contains resorption-promoting auxiliary substances. The resorption-promoting auxiliary substance forms an undercooled mass. The delivery system contains 10% loratadine base, 10-15% acid (such as levulinic acid), about 10% softener (such as oleyoleate); 55-70% polyacrylate; and 0-10% polyvinylpyrollidone (PVP). 
     Reservoir Devices 
     Alternatively, the transdermal device may be a reservoir system. A reservoir system transdermal drug delivery patch comprises several different components. An exemplary construction includes a backing layer, an active drug and optional permeation enhancing solvent gel, a membrane, a skin contact adhesive layer, and a protective release coated liner film. Characteristics of each component are set forth below: 
     Backing Film: This layer is exposed to the external environment when the system is worn on the skin surface. It is impervious to penetration of the active drug contained within the system preventing the escape of the active drug through the backing film. The backing film serves as barrier layer. Moisture, soaps, lotions and other elements are prevented from entering the system and diluting the active ingredients or altering the release characteristics of the system. The active drug and solvent are contained within the system to perform its designated function. The backing film also forms one half of the chamber which contains the active drug reservoir. The backing film must be capable of being suitably attached to the membrane in order to form the reservoir chamber. Typical attachment methods include thermal, ultrasonic polymer heat seal or welding, and adhesive bonding. Necessary mechanical properties include a low compliance for conformability to the skin surface and elasticity to allow for movement with the skin surface. Typical thickness is in the range of 0.5-25.0 mil. A wide range of homogenous, woven, and non-woven polymer or composite materials are suitable as backing films. 
     Membrane: The membrane in combination with the backing film forms the chamber which contains the active drug reservoir. The membrane is attached to the backing film, and provides a support surface for the skin contact adhesive. The membrane can be a homogenous polymer film, or a material with a porous structure. The membrane may also be designed to control the transport rate of the active drug and/or the permeation enhancing solvent. Necessary mechanical properties include a low compliance for conformability to the skin surface and elasticity to allow for movement with the skin surface. Typical thickness is in the range of 0.25-30.0 mil and more preferably in the range of 0.5 to 25.0 mils. A wide range of homogenous, porous, woven, and non-woven polymer or composite materials are suitable as membranes and known in the art. 
     Active Drug Reservoir: The active drug is combined with a liquid vehicle to fill the reservoir chamber. A range of solvents can be used for the liquid vehicle. The solvents can be chosen to optimize skin permeation of the active (enhancers) or to optimize the permeation characteristics of the membrane or the adhesion of the skin contact adhesive. A viscosity increasing agent is often included in the vehicle to aid in the handling and system manufacturing process. The composition of the vehicle must be compatible with the other components of the system. The vehicle may be in the form of a solution, suspension, cream, lotion, gel, physical mixture or emulsion. This list is not meant to be exhaustive. 
     Skin Contact Adhesive: The system is affixed to the skin with a skin contact adhesive. The adhesive may cover the entire surface of the system membrane, be applied in an intermittent pattern, or only to the perimeter of the system. The adhesive composition must be of materials suitable for skin contact without creating intolerable adverse effects such as excessive skin irritation or sensitization. Adequate adhesion to the membrane and skin are also necessary. The adhesive must also possess enough cohesive integrity to remain completely on the membrane upon removal of the system. The adhesive is applied in a thickness to provide a weight of 0.025 to 50.0 mg/cm 2 , more preferably 0.25 to 1.0 mg/cm 2  and most preferably 0.3 to 0.6 mg/cm 2 . Typical materials include silicone, polyisobutylene (PIB), and acrylates dissolved in organic solvents, aqueous emulsions, or directly applied by hot melt processing. 
     Release Coated Liner Film: The liner film is removed from the system before application to the skin surface. The liner film serves the function as a protective barrier to the skin contact adhesive prior to use. The coating on the liner provides a release capability for the adhesive, allowing separation of the liner from the adhesive. A coating is not necessary if the liner material is readily removed from the adhesive without disrupting the reservoir system. Typical thickness is in the range of 0.5-25.0 mil. A wide range of homogenous, woven, and non-woven paper, polymer or composite materials are suitable as liner films. Release coatings are typically composed of paraffin, polyethylene, silicone or fluorocarbons. 
     In other embodiments, the transdermal delivery system may be a plaster such as that described in U.S. Pat. No. 5,225,199 to Hidaka et al., hereby incorporated by reference. Such plasters include a film layer including a polyester film of about 0.5 to about 4.9 μm thickness, about 8 to about 85 g/mm strength, respectively in the two directions intersecting substantially at right angles, about 30 to about 150% elongation, in the two directions intersecting substantially at right angles and an elongation ratio of A to B of about 1:0 to about 5.0, wherein A and B represent data in two directions intersecting at right angles, and A is greater than B and wherein the polyester film includes about 0.01 to about 1.0% by weight, based on the total weight of the polyester film, of solid fine particles in which the average particle size is about 0.001 to about 3.0 μm and an adhesive layer which is composed of an adhesive containing transdermally absorbable drugs; wherein the adhesive layer is laminated on the film layer over the surface in about 2 to about 60 μm thickness. The average particle size is substantially not more than 1.5 times the thickness of the polyester film. 
     The transdermal delivery system used in the present invention may also be prepared in accordance with U.S. Pat. No. 5,879,701, issued Mar. 9, 1999 to Audett, et al., hereby incorporated by reference, wherein solubilization enhancer compositions are provided which facilitate transdermal administration of basic drugs from transdermal systems composed of nonpolar adhesive materials. The solubilization enhancing composition is particularly useful in facilitating the administration of basic drugs using transdermal systems worn for at least four days containing drug reservoirs comprised of nonpolar materials such as polyisobutylene adhesives or the like. The solubilizing enhancing composition itself is preferably a liquid which is an isomeric acid mixture. Examples of suitable solubilizers include, but are not limited to, oleic acid dimer and neodecanoic acid, with oleic acid dimer particularly preferred. The solubilizer constitutes at least about 0.10 wt. % of the reservoir, and preferably represents on the order of 0.25 wt. % to 1.0 wt. % of the reservoir. The amount of enhancer composition present in the drug formulation will depend on a number of factors, e.g., the strength of the particular enhancer composition, the desired increase in skin permeability, and the amount of drug which is necessary to deliver. 
     The adult oral dosage for loratadine is 10 mg/day. The bioavailability for the drug is 20%, expressed as fraction, 0.20 of the oral dose made available to the blood stream from gastrointestinal absorption. A release rate for a loratadine transdermal delivery system was calculated from this data. 0.20 of the oral 10 mg daily dose provides 2.0 mg of loratadine available into the blood stream. Therefore, an equal dose is required to be delivered transdermally. 2.0 mg/day is converted to 2000 mcg/24 hours. This would require delivery of 83.3 mcg/hour. The largest desirable surface area for a transdermal patch is about 40 cm 2 . Dividing 83.3 mcg/hour/40 cm 2  by 40, yields a release rate of 2.1 mcg/hour/cm 2  of transdermal patch surface area. To account for drug elimination, further pharmacokinetic data and physiological data was required. The plasma concentration at steady state for loratadine is 0.002 mcg/ml. The physiological clearance rate is 196,000 ml/hour. The dosing rate is obtained from the product of the steady state concentration of loratadine and a representative clearance rate. This product is 392 mcg/hour. The largest desirable surface area for a transdermal patch is about 40 cm 2 . Dividing 392 mcg/hour/40 cm 2  by 40, yields a release rate of 9.8 mcg/hour/cm 2  of transdermal patch surface area. One of skill would expect a larger input rate or flux to maintain a steady state concentration in consideration of the loss of drug in the plasma due to elimination. A confirmatory calculation for flux requires further pharmacokinetic parameters. The volume of distribution for loratadine is 1,660,000 ml and the half-life is 8.4 hours. The elimination rate constant is 0.693/half-life. The product of steady state concentration, volume of distribution and elimination rate constant yields a rate of 274 mcg/hour. The largest desirable surface area for a transdermal patch is about 40 cm 2 . Dividing 274 mcg/hour/40 cm 2  by 40, yields a release rate of 6.85 mcg/hour/cm 2  of transdermal patch surface area. 
     Any type of transdermal delivery system may be used in accordance with the methods of the present invention so long as the desired pharmacokinetic and pharmacodynamic response(s) are attained over at least 3 days, e.g., from about 5 to about 8 days. Preferable transdermal delivery systems include e.g., transdermal patches, transdermal plasters, transdermal discs, iontophoretic transdermal devices and the like. 
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The following examples illustrate various aspects of the present invention. They are not to be construed to limit the claims in any manner whatsoever. 
     Overview of Method of Manufacture: Matrix System 
     The following general method is used in the following examples in which the transdermal device tested is a matrix system (device): 
     Step 1: Preparation of the active drug vehicle/solvent/adhesive matrix. Active drug is combined with the liquid vehicle components and the adhesive components using appropriate mixing techniques well known in the art. Simple mechanical mixers, motionless mixers, homogenizers, high shear mixers, and magnetic mixing devices can be employed. 
     Step 2: Preparation of the active drug/adhesive matrix coated liner. Active drug/adhesive matrix coating is done with continuous web based equipment on a commercial scale. Small sheet batches can be made readily in the lab manually. A mechanism for applying a controlled thickness coating of the active drug/adhesive matrix onto the liner is employed. If solvent-based adhesives are used, a procedure for driving off the solvent and drying the active drug/adhesive matrix is employed. The open surface of the active drug/adhesive matrix on the liner must be protected during processing. A second intermediate liner can be used to cover this active drug/adhesive matrix surface. 
     Step 3: Laminating of the membrane to active drug/adhesive and/or liner. The membrane is typically applied on line after solvent removal on a commercial scale. This avoids the need for a second liner. A separate web and a heat and/or pressure lamination station bonds the two layers. The membrane provides a non-stick surface to the open side of the adhesive and allows for further processing in a roll form. 
     Overview of the Manufacture of Reservoir Devices 
     The following general method is used in the following examples in which the transdermal device tested is a reservoir system (device): 
     Step 1: Preparation of the adhesive coated liner. Adhesive coating is done with continuous web based equipment on a commercial scale. Small sheet batches can be made readily in the lab manually. A mechanism for applying a controlled thickness coating of the adhesive onto the liner is employed. If solvent-based adhesives are used, a procedure for driving off the solvent and drying the adhesive is employed. The open surface of the adhesive on the liner must be protected during processing. A second intermediate liner can be used to cover this adhesive surface. 
     Step 2: Laminating of the membrane to adhesive and/or liner. The membrane is typically applied on line after solvent removal on a commercial scale. This avoids the need for a second liner. A separate web and a heat and/or pressure lamination station bonds the two layers. The membrane provides a non-stick surface to the open side of the adhesive and allows for further processing in a roll form. 
     Step 3: Preparation of the active vehicle/solvent combination. Active drug is combined with the liquid vehicle components using appropriate mixing techniques well known in the art. Simple mechanical mixers, motionless mixers, homogenizers, high shear mixers, and magnetic mixing devices can be employed. Other ingredients are also incorporated at this time. These may include permeation enhancers and viscosity thickeners, for example. 
     Step 4: Finalizing the delivery system utilizing the form, fill and seal process incorporating the reservoir and backing film. This process can be carried out in either a horizontal or vertical plane. The horizontal mode requires a thickened viscosity of the reservoir vehicle, while the vertical mode can handle liquid vehicles of minimal viscosity. In the horizontal mode a dispensing head places a fixed volume drop of the drug vehicle onto the surface of the membrane. The backing film is then placed over the drop of vehicle, and then bound to the membrane to enclose the active/vehicle. A heated die is commonly used to form a heat seal welded bond. In web based systems a die cutting and packaging station often follows. 
     In-vitro Skin Permeation Test Method 
     The test methods utilized in the following examples involves the use of a permeation cell. Several permeation cell designs are available for in-vitro permeation testing. These include “Franz cells”, “Valia-Chien cells”, and “Bronaugh cells”. Each cell design shares several common characteristics. All cells are made with a definable surface area for permeation. All cells contain two chambers and a clamping mechanism to hold the test membrane positioned between the two cell chambers. Several exemplary test membranes include mouse skin and human cadaver skin. The membrane may be oriented in either the horizontal or vertical plane based on the cell special arrangement. One chamber serves as a reservoir (donor) for the drug to be tested, the second is a place where the permeated drug is accumulated (receptor). The receptor is often chosen to mimic the physiological conditions found beneath the membrane in-vivo. In the case where a complete transdermal system is the donor, it is clamped between the two chambers and only the receptor chamber is filled. 
     Calculation of the permeation rate (J) requires knowledge of the concentration (C) of the drug in the receptor chamber, the permeation area (A), sampling interval (t) and the receptor volume (V). The equation below is typical: 
     J=CV/At where:
         J=micrograms/cm 2 -hr   C=micrograms/ml   V=ml   A=cm 2      t=hr       

     Only the drug concentration and testing time vary in typical experiments. The drug concentration is determined by any appropriate analytical technique such as high performance liquid chromatograpy, gas chromatograpy, or ultraviolet spectrophotometry. Other considerations in the testing system may include temperature control systems, receptor stirring systems, flow through receptor chambers, and automated sampling equipment utilizing pumps and fraction collectors. Partial receptor sampling protocols have been used in situations where the sensitivity of the analytical method for determining the drug concentration was less than optimal. 
     Sample Testing Protocols for Loratadine Follow. 
                                     Cells   Valia Chien       Membrane   Human cadaver skin       A (cm2)   0.636       V (ml)   4.0       receptor   Ethanol/water 40/60       sampling points   6, 24, 48, 72, 120, 144, 168 hours       sampling mode:   partial, 0.6 ml per point, replace with fresh receptor.                    
HPLC Conditions for Determination of Drug Concentration
 
     
       
         
               
               
               
             
           
               
                   
               
             
             
               
                   
                 Column 
                 Altima C8, 5 um, 4.6 mm × 15 cm 
               
               
                   
                 Mobile phase 
                 Acetonitrile/Buffer 70/30 
               
               
                   
                 Buffer: 
                 0.01M phosphate at pH 4.5 
               
               
                   
                 Flow rate 
                 1 ml/min 
               
               
                   
                 UV detection 
                 205 nm 
               
               
                   
                 Injection volume 
                 20 microliters 
               
               
                   
                 Retention time 
                 5.0 minutes 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 1 
     A Loratadine drug reservoir formulation was prepared having the formulation set forth in Table 1A below: 
     
       
         
               
               
               
             
           
               
                 TABLE 1A 
               
               
                   
               
               
                   
                 Ingredient 
                 Amount (gm) 
               
               
                   
               
             
             
               
                   
                 Loratadine 
                  0.5 
               
               
                   
                 Ethanol 
                 12.2 
               
               
                   
                 Water 
                 15   
               
               
                   
                 Total 
                 27.7 
               
               
                   
                 Ethylvinylacetate membrane 
               
               
                   
               
             
          
         
       
     
     The formulation of Table 1A was prepared and incorporated into a permeation testing apparatus according to the following procedure:
         1. Loratadine is dissolved with ethanol and water and the solution is placed into the donor cell.   2. The ethylvinylacetate membrane is placed against the donor cell.   3. Thereafter, the human cadaver skin is placed between the membrane and the receptor cell and the apparatus is secured.       

     The formulation of Example 1 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (1-1, 1-2, 1-3) were conducted giving the results listed in Table 1B below: 
     
       
         
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 1B 
               
               
                   
               
               
                   
                   
                   
                   
                   
                   
                 Drug 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Loss due 
                   
                   
                 Amount 
               
               
                   
                 Sam- 
                   
                 Recep- 
                   
                 Sam- 
                 to 
                   
                 Cumulative 
                 Per- 
               
               
                   
                 pling 
                 Drug 
                 tor 
                 Drug 
                 pling 
                 Sam- 
                 Cumulative 
                 Amount 
                 meated 
               
               
                 Test 
                 Time 
                 Conc. 
                 Volume 
                 amount 
                 Volume 
                 pling 
                 Drug Loss 
                 Permeated 
                 per cm 2   
               
               
                 # 
                 (Hours) 
                 (μg/ml) 
                 (ml) 
                 (μg) 
                 (ml) 
                 (μg) 
                 (μg) 
                 (μg) 
                 (μg/cm 2 ) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1-1 
                 1 
                 0.000 
                 4 
                 0.000 
                 4 
                 0.000 
                 0.000 
                 0.000 
                 0.000 
               
               
                   
                 2 
                 0.177 
                 4 
                 0.708 
                 4 
                 0.708 
                 0.000 
                 0.708 
                 1.113 
               
               
                   
                 16 
                 14.449 
                 4 
                 57.796 
                 4 
                 57.796 
                 0.708 
                 58.504 
                 91.959 
               
               
                   
                 17 
                 0.914 
                 4 
                 3.656 
                 4 
                 3.656 
                 58.504 
                 62.160 
                 97.705 
               
               
                   
                 24 
                 6.666 
                 4 
                 26.664 
                 4 
                 26.664 
                 62.160 
                 88.824 
                 139.616 
               
               
                   
                 42 
                 18.644 
                 4 
                 74.576 
                 4 
                 74.576 
                 88.824 
                 163.400 
                 256.837 
               
               
                   
                 48 
                 6.639 
                 4 
                 26.556 
                 4 
                 26.556 
                 163.400 
                 189.956 
                 298.579 
               
               
                   
                 168 
                 120.233 
                 4 
                 480.932 
                 4 
                 480.932 
                 189.956 
                 670.888 
                 1054.524 
               
               
                 1-2 
                 1 
                 0.000 
                 4 
                 0.000 
                 4 
                 0.000 
                 0.000 
                 0.000 
                 0.000 
               
               
                   
                 2 
                 0.154 
                 4 
                 0.616 
                 4 
                 0.616 
                 0.000 
                 0.616 
                 0.968 
               
               
                   
                 16 
                 11.703 
                 4 
                 46.812 
                 4 
                 46.812 
                 0.616 
                 41.428 
                 74.549 
               
               
                   
                 17 
                 0.433 
                 4 
                 1.732 
                 4 
                 1.732 
                 47.428 
                 49.160 
                 77.271 
               
               
                   
                 24 
                 5.388 
                 4 
                 21.552 
                 4 
                 21.552 
                 49.160 
                 70.712 
                 111.147 
               
               
                   
                 42 
                 15.636 
                 4 
                 62.544 
                 4 
                 62.544 
                 70.712 
                 133.256 
                 209.456 
               
               
                   
                 48 
                 5.223 
                 4 
                 20.892 
                 4 
                 20.892 
                 133.256 
                 154.148 
                 242.295 
               
               
                   
                 168 
                 113.298 
                 4 
                 453.192 
                 4 
                 453.192 
                 154.148 
                 607.340 
                 945.637 
               
               
                 1-3 
                 1 
                 0.000 
                 4 
                 0.000 
                 4 
                 0.000 
                 0.000 
                 0.000 
                 0.000 
               
               
                   
                 2 
                 0.019 
                 4 
                 0.076 
                 4 
                 0.076 
                 0.000 
                 0.076 
                 0.119 
               
               
                   
                 16 
                 10.734 
                 4 
                 42.936 
                 4 
                 42.936 
                 0.076 
                 43.012 
                 67.608 
               
               
                   
                 17 
                 0.547 
                 4 
                 2.188 
                 4 
                 2.188 
                 43.012 
                 45.200 
                 71.047 
               
               
                   
                 24 
                 4.741 
                 4 
                 18.964 
                 4 
                 18.964 
                 45.200 
                 64.064 
                 100.855 
               
               
                   
                 42 
                 15.189 
                 4 
                 60.756 
                 4 
                 60.756 
                 64.164 
                 124.920 
                 196.353 
               
               
                   
                 48 
                 4.950 
                 4 
                 19.800 
                 4 
                 19.800 
                 124.920 
                 144.720 
                 227.476 
               
               
                   
                 168 
                 107.974 
                 4 
                 431.896 
                 4 
                 431.896 
                 144.720 
                 576.616 
                 906.344 
               
               
                   
               
             
          
         
       
     
     Based on the permeation results of Example 1, listed in Table 1B, the averages of the three calculated and the flux results listed in Table 1C below were obtained: 
     
       
         
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 1C 
               
               
                   
               
               
                   
                   
                   
                   
                 Avg. of 
                   
                   
               
               
                   
                   
                   
                   
                 all 3 
                   
                   
               
               
                 Hours 
                 Test 1-1 
                 Test 1-2 
                 Test 1-3 
                 tests 
                 Std Dev 
                 μg/cm 2 /hr 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 0.000 
                 0.000 
                 0.000 
                 0.000 
                 0.000 
                 0.000 
               
               
                 2 
                 1.113 
                 0.968 
                 0.119 
                 0.733 
                 0.537 
                 0.367 
               
               
                 16 
                 91.959 
                 74.549 
                 67.608 
                 78.039 
                 12.545 
                 4.877 
               
               
                 17 
                 97.705 
                 77.271 
                 71.047 
                 82.008 
                 13.946 
                 4.824 
               
               
                 24 
                 139.616 
                 111.147 
                 100.855 
                 117.206 
                 20.078 
                 4.884 
               
               
                 42 
                 256.837 
                 209.456 
                 196.353 
                 220.882 
                 31.820 
                 5.259 
               
               
                 48 
                 298.579 
                 242.295 
                 227.476 
                 256.117 
                 37.513 
                 5.336 
               
               
                 168 
                 1054.524 
                 954.637 
                 906.344 
                 971.835 
                 75.572 
                 5.785 
               
               
                 F 4-76   
                 6.435 
                 5.245 
                 4.957 
                 5.546 
                 0.784 
                   
               
               
                 CORR 
                 1.000 
                 1.000 
                 0.999 
                 1.000 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 2 
     A Loratadine reservoir and adhesive formulation was prepared having the formulation set forth in Table 2A below: 
     
       
         
               
               
               
             
           
               
                 TABLE 2A 
               
               
                   
               
               
                   
                 Ingredient 
                 Amount (gm) 
               
               
                   
               
             
             
               
                   
                 Loratadine 
                  1.0 
               
               
                   
                 Ethanol 
                 22.0 
               
               
                   
                 Water 
                 27.0 
               
               
                   
                 Total 
                 50.0 
               
               
                   
                 Polyethylene membrane 
                   
               
               
                   
                 Silicone adhesive 
               
               
                   
               
             
          
         
       
     
     The formulation of Table 2A was prepared and incorporated into a permeation testing apparatus according to the following procedure:
         1. Loratadine is dissolved with ethanol and water and the solution is placed into the donor cell.   2. The polyethylene membrane is coated with a silicone adhesive and placed against the donor cell. The adhesive coated membrane is positioned opposite from the donor cell.   3. Thereafter, the human cadaver skin is placed between the adhesive coated polyethylene membrane and the receptor cell and the apparatus is secured.       

     The formulation of Example 2 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (2-1, 2-2, 2-3) were conducted giving the results listed in Table 2B below: 
     
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 2B 
               
             
             
               
                   
               
               
                 μg/cm 2   
               
             
          
           
               
                   
                   
                   
                   
                   
                 Avg. of 
                   
               
               
                   
                   
                   
                   
                   
                 all 4 
                   
               
               
                 Hours 
                 Test 2-1 
                 Test 2-2 
                 Test 2-3 
                 Test 2-4 
                 tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 5.608 
                 7.362 
                 6.344 
                 4.231 
                 5.886 
                 1.317 
               
               
                 24 
                 87.325 
                 83.930 
                 66.665 
                 66.771 
                 76.173 
                 11.005 
               
               
                 30 
                 125.489 
                 120.132 
                 91.229 
                 92.763 
                 107.406 
                 17.936 
               
               
                 48 
                 228.840 
                 220.207 
                 158.202 
                 165.954 
                 193.307 
                 36.363 
               
               
                 54 
                 271.600 
                 262.829 
                 183.313 
                 193.688 
                 227.858 
                 45.783 
               
               
                 72 
                 381.257 
                 368.375 
                 249.607 
                 269.632 
                 317.218 
                 67.215 
               
               
                 78 
                 425.099 
                 409.871 
                 273.618 
                 297.447 
                 351.509 
                 77.053 
               
               
                 96 
                 544.508 
                 521.226 
                 343.427 
                 375.668 
                 446.207 
                 101.375 
               
               
                 102 
                 592.644 
                 565.193 
                 368.375 
                 404.470 
                 482.671 
                 112.669 
               
               
                 120 
                 715.385 
                 675.064 
                 436.674 
                 483.691 
                 577.704 
                 138.037 
               
               
                 144 
                 892.983 
                 836.158 
                 536.473 
                 598.510 
                 716.031 
                 174.924 
               
               
                 168 
                 1046.419 
                 982.364 
                 627.249 
                 701.572 
                 839.401 
                 205.994 
               
               
                   
               
             
          
         
       
     
     Based on the permeation results of Example 2, listed in Table 2B, the following flux results listed in Table 2C below were obtained: 
     
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 2C 
               
             
             
               
                   
               
               
                 μg/cm 2 /hr 
               
             
          
           
               
                   
                   
                   
                   
                   
                 Avg. of 
                   
               
               
                 Hours 
                 Test 2-1 
                 Test 2-2 
                 Test 2-3 
                 Test 2-4 
                 all 4 tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 0.935 
                 1.224 
                 1.057 
                 0.705 
                 0.981 
                 0.220 
               
               
                 24 
                 3.639 
                 3.497 
                 2.778 
                 2.782 
                 3.174 
                 0.459 
               
               
                 30 
                 4.183 
                 4.004 
                 3.041 
                 3.092 
                 3.580 
                 0.598 
               
               
                 48 
                 4.768 
                 4.588 
                 3.296 
                 3.457 
                 4.027 
                 0.758 
               
               
                 54 
                 5.030 
                 4.867 
                 3.395 
                 3.587 
                 4.220 
                 0.848 
               
               
                 72 
                 5.295 
                 5.116 
                 3.467 
                 3.745 
                 4.406 
                 0.934 
               
               
                 78 
                 5.450 
                 5.255 
                 3.508 
                 3.813 
                 4.507 
                 0.988 
               
               
                 96 
                 5.672 
                 5.429 
                 3.577 
                 3.913 
                 4.648 
                 1.056 
               
               
                 102 
                 5.810 
                 5.541 
                 3.612 
                 3.965 
                 4.732 
                 1.105 
               
               
                 120 
                 5.962 
                 5.626 
                 3.639 
                 4.031 
                 4.814 
                 1.150 
               
               
                 144 
                 6.201 
                 5.807 
                 3.726 
                 4.156 
                 4.972 
                 1.215 
               
               
                 168 
                 6.229 
                 5.847 
                 3.734 
                 4.176 
                 4.996 
                 1.226 
               
               
                 F 6-96   
                 6.066 
                 5.815 
                 3.770 
                 4.173 
                 4.956 
                 1.153 
               
               
                 CORR 
                 0.998 
                 0.998 
                 1.000 
                 0.999 
                 0.999 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 3 
     A Loratadine active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 3A below: 
     
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 3A 
               
               
                   
               
               
                   
                 Ingredient 
                 Amount (gm) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Loratadine 
                 0.23 
               
               
                   
                 Ethyl Acetate 
                 1.77 
               
               
                   
                 BIO PSA 7-4302 (adhesive solution) 
                 16.3 
               
               
                   
                 containing 9.8 gm silicone adhesive 
                   
               
               
                   
                 (60% solids) 
                   
               
               
                   
                 Total 
                 18.3 
               
               
                   
               
             
          
         
       
     
     The formulation of Table 3A was prepared and incorporated into a permeation testing apparatus according to the following procedure:
         1. Loratadine is dispersed in the requisite amount of ethyl acetate and adhesive solution to form the active drug/adhesive matrix.   2. The active drug/adhesive matrix is applied to a backing layer and dried.   3. Thereafter, the patch is applied to the human cadaver skin affixed to the receptor cell.       

     The formulation of Example 3 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was ethanol:water (40:60) and the membrane was a human cadaver skin membrane. Three permeation tests (3-1, 3-2, 3-3) were conducted giving the results listed in Table 3B below: 
     
       
         
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 3B 
               
               
                   
               
               
                   
                   
                   
                   
                   
                   
                 Drug 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Loss due 
                   
                   
                 Amount 
               
               
                   
                 Sam- 
                   
                 Recep- 
                   
                 Sam- 
                 to 
                   
                 Cumulative 
                 Per- 
               
               
                   
                 pling 
                 Drug 
                 tor 
                 Drug 
                 pling 
                 Sam- 
                 Cumulative 
                 Amount 
                 meated 
               
               
                 Test 
                 Time 
                 Conc. 
                 Volume 
                 amount 
                 Volume 
                 pling 
                 Drug Loss 
                 Permeated 
                 per cm 2   
               
               
                 # 
                 (Hours) 
                 (μg/ml) 
                 (ml) 
                 (μg) 
                 (ml) 
                 (μg) 
                 (μg) 
                 (μg) 
                 (μg/cm 2 ) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 3-1 
                  4 
                 3.220 
                 13 
                 41.860 
                 1 
                 3.220 
                 0.000 
                 41.860 
                 23.690 
               
               
                   
                 24 
                 34.978 
                 13 
                 454.714 
                 1 
                 34.978 
                 3.220 
                 457.934 
                 259.159 
               
               
                   
                 28 
                 35.903 
                 13 
                 466.739 
                 1 
                 35.903 
                 38.198 
                 504.937 
                 285.759 
               
               
                   
                 48 
                 55.584 
                 13 
                 722.592 
                 1 
                 55.584 
                 74.101 
                 796.693 
                 450.873 
               
               
                   
                 52 
                 49.609 
                 13 
                 644.917 
                 1 
                 49.609 
                 129.685 
                 774.602 
                 438.371 
               
               
                   
                 72 
                 60.990 
                 13 
                 792.870 
                 1 
                 60.990 
                 179.294 
                 972.164 
                 550.178 
               
               
                   
                 76 
                 54.504 
                 13 
                 708.552 
                 1 
                 54.504 
                 240.284 
                 948.836 
                 536.976 
               
               
                   
                 96 
                 61.080 
                 13 
                 794.040 
                 1 
                 61.080 
                 294.788 
                 1088.828 
                 616.201 
               
               
                 3-2 
                  4 
                 4.782 
                 13 
                 62.166 
                 1 
                 4.782 
                 0.000 
                 62.166 
                 35.182 
               
               
                   
                 24 
                 37.018 
                 13 
                 481.234 
                 1 
                 37.018 
                 4.782 
                 486.016 
                 275.051 
               
               
                   
                 28 
                 38.489 
                 13 
                 500.357 
                 1 
                 38.489 
                 41.800 
                 542.157 
                 306.823 
               
               
                   
                 48 
                 54.826 
                 13 
                 712.738 
                 1 
                 54.826 
                 80.289 
                 793.027 
                 448.799 
               
               
                   
                 52 
                 54.818 
                 13 
                 712.634 
                 1 
                 54.818 
                 135.115 
                 847.749 
                 479.767 
               
               
                   
                 72 
                 61.280 
                 13 
                 796.640 
                 1 
                 61.280 
                 189.933 
                 986.573 
                 558.332 
               
               
                   
                 76 
                 59.295 
                 13 
                 770.835 
                 1 
                 59.295 
                 251.213 
                 1022.048 
                 578.409 
               
               
                   
                 96 
                 60.455 
                 13 
                 785.915 
                 1 
                 60.455 
                 310.508 
                 1096.423 
                 620.500 
               
               
                 3-3 
                  4 
                 2.418 
                 13 
                 31.434 
                 1 
                 2.418 
                 0.000 
                 31.434 
                 17.789 
               
               
                   
                 24 
                 30.875 
                 13 
                 401.375 
                 1 
                 30.875 
                 2.418 
                 403.793 
                 228.519 
               
               
                   
                 28 
                 33.696 
                 13 
                 438.048 
                 1 
                 33.696 
                 33.293 
                 471.341 
                 266.746 
               
               
                   
                 48 
                 51.182 
                 13 
                 665.366 
                 1 
                 51.182 
                 66.989 
                 732.355 
                 414.462 
               
               
                   
                 52 
                 50.819 
                 13 
                 660.647 
                 1 
                 50.819 
                 118.171 
                 778.818 
                 440.757 
               
               
                   
                 72 
                 59.651 
                 13 
                 775.463 
                 1 
                 59.651 
                 168.990 
                 944.453 
                 534.495 
               
               
                   
                 76 
                 55.812 
                 13 
                 725.556 
                 1 
                 55.812 
                 228.641 
                 954.197 
                 540.010 
               
               
                   
                 96 
                 63.094 
                 13 
                 820.222 
                 1 
                 63.094 
                 284.453 
                 1104.675 
                 625.170 
               
               
                   
               
             
          
         
       
     
     Based on the permeation results of Example 3, listed in Table 3B, the averages of all three calculated and the flux results listed in Table 3C below were obtained: 
     
       
         
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 3C 
               
               
                   
               
               
                   
                   
                   
                   
                 Avg. of 
                   
                   
               
               
                   
                   
                   
                   
                 all 3 
                   
                   
               
               
                 Hours 
                 Test 3-1 
                 Test 3-2 
                 Test 3-3 
                 tests 
                 Std Dev 
                 μg/cm 2 /hr 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                  4 
                 23.690 
                 35.182 
                 17.789 
                 25.554 
                 8.845 
                 6.388 
               
               
                 24 
                 259.159 
                 275.051 
                 228.519 
                 254.243 
                 23.652 
                 10.593 
               
               
                 28 
                 285.759 
                 306.823 
                 266.746 
                 286.443 
                 20.047 
                 10.230 
               
               
                 48 
                 450.873 
                 448.799 
                 414.462 
                 438.045 
                 20.449 
                 9.123 
               
               
                 52 
                 438.371 
                 479.767 
                 440.757 
                 452.965 
                 23.242 
                 8.711 
               
               
                 72 
                 550.178 
                 558.332 
                 534.495 
                 547.668 
                 12.115 
                 7.607 
               
               
                 76 
                 536.946 
                 578.409 
                 540.010 
                 551.798 
                 23.095 
                 7.261 
               
               
                 96 
                 616.201 
                 620.500 
                 625.170 
                 620.624 
                 4.486 
                 6.465 
               
               
                 F 4-76   
                 6.917 
                 7.120 
                 7.069 
                 7.036 
                 0.015 
                   
               
               
                 CORR 
                 0.970 
                 0.975 
                 0.982 
                 0.976 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 4 
     A Loratadine active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 4A below: 
     
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 4A 
               
               
                   
               
               
                   
                 Ingredient 
                 Amount (gm) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Loratadine 
                 0.23 
               
               
                   
                 Ethyl Acetate 
                 1.77 
               
               
                   
                 DURO-TAK 87-6430 (adhesive 
                 32.6 
               
               
                   
                 solution) containing 9.8 gm 
                   
               
               
                   
                 Polyisobutylene adhesive (30% 
                   
               
               
                   
                 solids) 
                   
               
               
                   
                 Total 
                 34.6 
               
               
                   
               
             
          
         
       
     
     The formulation of Table 4A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3, using DURO-TAK 87-6430 as the adhesive solution. 
     the formulation of Example 4 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was ethanol:water (40:60). Three permeation tests (4-1, 4-2, 4-3) were conducted giving the results listed in Table 4B below: 
     
       
         
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 4B 
               
               
                   
               
               
                   
                   
                   
                   
                   
                   
                 Drug 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Loss due 
                   
                   
                 Amount 
               
               
                   
                 Sam- 
                   
                 Recep- 
                   
                 Sam- 
                 to 
                   
                 Cumulative 
                 Per- 
               
               
                   
                 pling 
                 Drug 
                 tor 
                 Drug 
                 pling 
                 Sam- 
                 Cumulative 
                 Amount 
                 meated 
               
               
                 Test 
                 Time 
                 Conc. 
                 Volume 
                 amount 
                 Volume 
                 pling 
                 Drug Loss 
                 Permeated 
                 per cm 2   
               
               
                 # 
                 (Hours) 
                 (μg/ml) 
                 (ml) 
                 (μg) 
                 (ml) 
                 (μg) 
                 (μg) 
                 (μg) 
                 (μg/cm 2 ) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 4-1 
                  4 
                 0.750 
                 13 
                 9.750 
                 1 
                 0.750 
                 0.000 
                 9.750 
                 5.518 
               
               
                   
                 24 
                 8.590 
                 13 
                 111.670 
                 1 
                 8.590 
                 0.750 
                 112.420 
                 63.622 
               
               
                   
                 28 
                 9.430 
                 13 
                 122.590 
                 1 
                 9.430 
                 9.340 
                 131.930 
                 74.663 
               
               
                   
                 48 
                 13.706 
                 13 
                 178.178 
                 1 
                 13.706 
                 18.770 
                 196.945 
                 111.459 
               
               
                   
                 52 
                 12.916 
                 13 
                 167.908 
                 1 
                 12.916 
                 32.476 
                 200.384 
                 113.404 
               
               
                   
                 72 
                 15.903 
                 13 
                 206.739 
                 1 
                 15.903 
                 45.392 
                 252.131 
                 142.689 
               
               
                   
                 76 
                 15.470 
                 13 
                 201.110 
                 1 
                 15.470 
                 61.295 
                 262.405 
                 148.503 
               
               
                   
                 96 
                 16.762 
                 13 
                 217.906 
                 1 
                 16.762 
                 76.765 
                 294.671 
                 166.763 
               
               
                 4-2 
                  4 
                 0.468 
                 13 
                 6.084 
                 1 
                 0.468 
                 0.000 
                 6.084 
                 3.443 
               
               
                   
                 24 
                 8.485 
                 13 
                 110.305 
                 1 
                 8.485 
                 0.468 
                 110.773 
                 62.690 
               
               
                   
                 28 
                 8.718 
                 13 
                 113.334 
                 1 
                 8.718 
                 8.953 
                 122.287 
                 69.206 
               
               
                   
                 48 
                 12.944 
                 13 
                 168.272 
                 1 
                 12.944 
                 17.671 
                 185.943 
                 105.231 
               
               
                   
                 52 
                 11.946 
                 13 
                 155.298 
                 1 
                 11.946 
                 30.615 
                 185.913 
                 105.214 
               
               
                   
                 72 
                 15.568 
                 13 
                 202.384 
                 1 
                 15.568 
                 42.561 
                 244.945 
                 138.622 
               
               
                   
                 76 
                 14.784 
                 13 
                 192.192 
                 1 
                 14.784 
                 58.129 
                 250.321 
                 141.664 
               
               
                   
                 96 
                 16.423 
                 13 
                 213.499 
                 1 
                 16.423 
                 72.913 
                 286.412 
                 162.089 
               
               
                 4-3 
                  4 
                 0.660 
                 13 
                 8.580 
                 1 
                 0.660 
                 0.000 
                 8.580 
                 4.856 
               
               
                   
                 24 
                 9.734 
                 13 
                 126.542 
                 1 
                 9.734 
                 0.660 
                 127.202 
                 71.988 
               
               
                   
                 28 
                 9.973 
                 13 
                 129.649 
                 1 
                 9.973 
                 10.394 
                 140.043 
                 79.255 
               
               
                   
                 48 
                 14.864 
                 13 
                 193.232 
                 1 
                 14.864 
                 20.367 
                 213.599 
                 120.882 
               
               
                   
                 52 
                 13.830 
                 13 
                 179.790 
                 1 
                 13.830 
                 35.231 
                 215.021 
                 121.687 
               
               
                   
                 72 
                 17.243 
                 13 
                 224.159 
                 1 
                 17.243 
                 49.061 
                 273.220 
                 154.624 
               
               
                   
                 76 
                 16.208 
                 13 
                 210.704 
                 1 
                 16.208 
                 66.304 
                 277.008 
                 156.767 
               
               
                   
                 96 
                 18.495 
                 13 
                 240.435 
                 1 
                 18.495 
                 82.512 
                 322.947 
                 182.766 
               
               
                   
               
             
          
         
       
     
     Based on the permeation results of Example 4, listed in Table 4B, the averages of all three test were calculated and the flux results listed in Table 4C below were obtained: 
     
       
         
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 4C 
               
               
                   
               
               
                   
                   
                   
                   
                 Avg. of 
                   
                   
               
               
                   
                   
                   
                   
                 all 3 
                 Std 
                   
               
               
                 Hours 
                 Test 4-1 
                 Test 4-2 
                 Test 4-3 
                 tests 
                 Dev 
                 μg/cm 2 /hr 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                  4 
                 5.518 
                 3.443 
                 4.856 
                 4.606 
                 1.060 
                 1.151 
               
               
                 24 
                 63.622 
                 62.690 
                 71.988 
                 66.100 
                 5.120 
                 2.754 
               
               
                 28 
                 74.663 
                 69.206 
                 79.255 
                 74.375 
                 5.031 
                 2.656 
               
               
                 48 
                 111.459 
                 105.231 
                 120.882 
                 112.524 
                 7.880 
                 2.344 
               
               
                 52 
                 113.404 
                 105.214 
                 121.687 
                 113.435 
                 8.237 
                 2.181 
               
               
                 72 
                 142.689 
                 138.622 
                 154.624 
                 145.312 
                 8.317 
                 2.018 
               
               
                 76 
                 148.503 
                 141.664 
                 156.767 
                 148.978 
                 7.563 
                 1.960 
               
               
                 96 
                 166.763 
                 162.089 
                 182.766 
                 170.539 
                 10.843 
                 1.776 
               
               
                 F 4-76   
                 1.881 
                 1.820 
                 2.006 
                 1.902 
                 0.095 
                   
               
               
                 CORR 
                 0.983 
                 0.984 
                 0.979 
                 0.982 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 5 
     A Loratadine active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 5A below: 
     
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 5A 
               
               
                   
               
               
                   
                 Ingredient 
                 Amount (gm) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Loratadine 
                 0.23 
               
               
                   
                 Ethyl Acetate 
                 1.77 
               
               
                   
                 DURO-TAK 87-8298 (adhesive 
                 28.8 
               
               
                   
                 solution) containing 9.8 gm acrylate 
                   
               
               
                   
                 adhesive (38.5% solids) 
                   
               
               
                   
                 Total 
                 30.8 
               
               
                   
               
             
          
         
       
     
     The formulation of Table 5A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3, using DURO-TAK 87-8298 as the adhesive solution. 
     The formulation of Example 5 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Two permeation tests (5-1, 5-2) were conducted giving the results listed in Table 5B below: 
     
       
         
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 5B 
               
               
                   
               
               
                   
                   
                   
                   
                   
                   
                 Drug 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Loss due 
                   
                   
                 Amount 
               
               
                   
                 Sam- 
                   
                 Recep- 
                   
                 Sam- 
                 to 
                   
                 Cumulative 
                 Per- 
               
               
                   
                 pling 
                 Drug 
                 tor 
                 Drug 
                 pling 
                 Sam- 
                 Cumulative 
                 Amount 
                 meated 
               
               
                 Test 
                 Time 
                 Conc. 
                 Volume 
                 amount 
                 Volume 
                 pling 
                 Drug Loss 
                 Permeated 
                 per cm 2   
               
               
                 # 
                 (Hours) 
                 (μg/ml) 
                 (ml) 
                 (μg) 
                 (ml) 
                 (μg) 
                 (μg) 
                 (μg) 
                 (μg/cm 2 ) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 5-1 
                 6 
                 1.828 
                 12 
                 21.936 
                 1 
                 1.828 
                 0.000 
                 21.936 
                 12.414 
               
               
                   
                 24 
                 11.188 
                 12 
                 134.256 
                 1 
                 11.188 
                 1.828 
                 136.08 
                 77.014 
               
               
                   
                 48 
                 22.197 
                 12 
                 266.364 
                 1 
                 22.197 
                 13.016 
                 279.38 
                 157.110 
               
               
                   
                 72 
                 30.850 
                 12 
                 370.200 
                 1 
                 30.850 
                 35.213 
                 405.41 
                 229.436 
               
               
                   
                 96 
                 36.048 
                 12 
                 432.576 
                 1 
                 36.048 
                 66.063 
                 498.64 
                 282.195 
               
               
                   
                 120 
                 39.128 
                 12 
                 469.536 
                 1 
                 39.128 
                 102.111 
                 571.65 
                 323.513 
               
               
                   
                 148 
                 39.190 
                 12 
                 470.280 
                 1 
                 39.190 
                 141.239 
                 611.52 
                 346.078 
               
               
                   
                 168 
                 39.347 
                 12 
                 472.164 
                 1 
                 39.347 
                 180.429 
                 652.59 
                 369.323 
               
               
                 5-2 
                 6 
                 0.767 
                 12 
                 9.204 
                 1 
                 0.767 
                 0.000 
                 9.20 
                 5.209 
               
               
                   
                 24 
                 6.015 
                 12 
                 72.180 
                 1 
                 6.015 
                 0.767 
                 72.95 
                 41.283 
               
               
                   
                 48 
                 12.141 
                 12 
                 145.692 
                 1 
                 12.141 
                 6.782 
                 152.47 
                 86.290 
               
               
                   
                 72 
                 17.910 
                 12 
                 214.920 
                 1 
                 17.910 
                 18.923 
                 233.84 
                 132.339 
               
               
                   
                 96 
                 21.591 
                 12 
                 259.092 
                 1 
                 21.591 
                 36.833 
                 295.93 
                 167.473 
               
               
                   
                 120 
                 24.647 
                 12 
                 295.764 
                 1 
                 24.647 
                 58.424 
                 354.19 
                 200.446 
               
               
                   
                 148 
                 27.851 
                 12 
                 334.212 
                 1 
                 27.851 
                 83.071 
                 417.28 
                 236.153 
               
               
                   
                 168 
                 29.933 
                 12 
                 359.196 
                 1 
                 29.933 
                 110.922 
                 470.12 
                 266.054 
               
               
                   
               
             
          
         
       
     
     The average of the two permeation tests of Example 5 was calculated and is listed in Table 5C 
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 5C 
               
             
             
               
                   
               
               
                 μg/cm 2   
               
             
          
           
               
                   
                   
                   
                 Average of two 
                   
               
               
                 Hours 
                 Test 5-1 
                 Test 5-2 
                 tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 12.414 
                 5.209 
                 8.812 
                 5.095 
               
               
                 24 
                 77.014 
                 41.283 
                 59.149 
                 25.266 
               
               
                 48 
                 158.110 
                 86.290 
                 122.200 
                 50.784 
               
               
                 72 
                 229.436 
                 132.339 
                 180.888 
                 68.658 
               
               
                 96 
                 282.195 
                 167.473 
                 224.834 
                 81.121 
               
               
                 120 
                 323.513 
                 200.446 
                 261.980 
                 87.022 
               
               
                 148 
                 346.078 
                 236.153 
                 291.116 
                 77.729 
               
               
                 168 
                 369.323 
                 266.054 
                 317.689 
                 73.022 
               
               
                   
               
             
          
         
       
     
     Based on the permeation results of Example 5, listed in Table 5B, the following flux results listed in Table 5D below were obtained: 
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 5D 
               
             
             
               
                   
               
               
                 μg/cm 2 /hr 
               
             
          
           
               
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 5-1 
                 Test 5-2 
                 two tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 2.069 
                 0.868 
                 1.469 
                 0.846 
               
               
                 24 
                 3.209 
                 1.720 
                 2.465 
                 1.053 
               
               
                 48 
                 3.294 
                 1.798 
                 2.546 
                 1.058 
               
               
                 72 
                 3.187 
                 1.838 
                 2.512 
                 0.954 
               
               
                 96 
                 2.940 
                 1.745 
                 2.342 
                 0.845 
               
               
                 120 
                 2.696 
                 1.670 
                 2.183 
                 0.725 
               
               
                 148 
                 2.338 
                 1.596 
                 1.967 
                 0.525 
               
               
                 168 
                 2.198 
                 1.584 
                 1.891 
                 0.435 
               
               
                 F 6-96   
                 3.025 
                 1.820 
                 2.423 
                 0.853 
               
               
                 CORR 
                 0.996 
                 0.999 
                 0.997 
                 0.002 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 6 
     A Loratadine active matrix/adhesive matrix formulation was prepared having the formulation set forth in Table 6A below: 
     
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 6A 
               
               
                   
               
               
                   
                 Ingredient 
                 Amount (gm) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Loratadine 
                 0.36 
               
               
                   
                 Ethyl Acetate 
                 2.67 
               
               
                   
                 BIO PSA 7-4302 (adhesive solution) 
                 19.93 
               
               
                   
                 containing 11.96 gm silicone 
                   
               
               
                   
                 adhesive (60% solids) 
                   
               
               
                   
                 Total 
                 22.96 
               
               
                   
               
             
          
         
       
     
     The formulation of Table 6A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3. 
     The formulation of Example 6 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (6-1, 6-2, and 6-3) were conducted giving the results listed in Table 6B below: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 6B 
               
             
             
               
                   
               
               
                 μg/cm 2   
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 6-1 
                 Test 6-2 
                 Test 6-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 103.382 
                 105.542 
                 89.338 
                 99.421 
                 8.798 
               
               
                 24 
                 385.736 
                 387.593 
                 348.952 
                 374.094 
                 21.793 
               
               
                 48 
                 637.848 
                 659.757 
                 591.666 
                 629.757 
                 34.759 
               
               
                 72 
                 832.501 
                 854.233 
                 769.620 
                 818.785 
                 43.942 
               
               
                 96 
                 897.573 
                 954.671 
                 857.260 
                 903.168 
                 48.946 
               
               
                 124 
                 972.628 
                 1026.660 
                 933.732 
                 977.673 
                 46.669 
               
               
                 144 
                 1041.228 
                 1107.161 
                 1003.008 
                 1050.466 
                 52.687 
               
               
                 168 
                 1051.728 
                 1140.184 
                 1036.631 
                 1076.181 
                 55.940 
               
               
                   
               
             
          
         
       
     
     Based on the permeation results of Example 6, listed in Table 6B, the following flux results listed in Table 6C below were obtained: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 6C 
               
             
             
               
                   
               
               
                 μg/cm 2 /hr 
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 6-1 
                 Test 6-2 
                 Test 6-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                  6 
                 17.230 
                 17.590 
                 14.890 
                 16.570 
                 1.466 
               
               
                 24 
                 16.072 
                 16.150 
                 14.540 
                 15.587 
                 0.908 
               
               
                 48 
                 13.289 
                 13.745 
                 12.326 
                 13.120 
                 0.724 
               
               
                 72 
                 11.563 
                 11.864 
                 10.689 
                 11.372 
                 0.610 
               
               
                 96 
                 9.350 
                 9.944 
                 8.930 
                 9.408 
                 0.510 
               
               
                 124  
                 7.844 
                 8.280 
                 7.530 
                 7.884 
                 0.376 
               
               
                 144  
                 7.231 
                 7.689 
                 6.965 
                 7.295 
                 0.366 
               
               
                 168  
                 6.260 
                 6.787 
                 6.170 
                 6.406 
                 0.333 
               
               
                 F 6-96   
                 8.831 
                 9.407 
                 8.499 
                 8.912 
                 0.459 
               
               
                 CORR 
                 0.970 
                 0.977 
                 0.976 
                 0.974 
                 0.004 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 7 
     A Loratadine active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 7A below: 
     
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 7A 
               
               
                   
               
               
                   
                 Ingredient 
                 Amount (gm) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Loratadine 
                 0.24 
               
               
                   
                 Polyisobutylene (adhesive) 
                   
               
               
                   
                 MA-24 + mineral oil (adhesive 
                 28.62 
               
               
                   
                 solution) (25% solids) 
                   
               
               
                   
                 Total 
                 28.86 
               
               
                   
               
             
          
         
       
     
     The formulation of Table 7A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3, using MA-24+ mineral oil as the adhesive solution and without the use of ethyl acetate. 
     The formulation of Example 7 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (7-1, 7-2, and 7-3) were conducted giving the results listed in Table 7B below: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 7B 
               
             
             
               
                   
               
               
                 μg/cm 2   
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 7-1 
                 Test 7-2 
                 Test 7-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 16.075 
                 2.405 
                 15.945 
                 11.475 
                 7.855 
               
               
                 24 
                 99.938 
                 67.530 
                 113.135 
                 93.534 
                 23.467 
               
               
                 48 
                 214.922 
                 184.259 
                 249.768 
                 216.316 
                 32.777 
               
               
                 72 
                 310.962 
                 294.490 
                 354.921 
                 320.124 
                 32.240 
               
               
                 96 
                 334.402 
                 323.299 
                 388.632 
                 348.778 
                 34.958 
               
               
                 124 
                 350.720 
                 342.504 
                 415.032 
                 369.419 
                 39.715 
               
               
                 144 
                 360.886 
                 352.968 
                 420.276 
                 378.043 
                 36.788 
               
               
                 168 
                 359.021 
                 358.228 
                 421.273 
                 379.507 
                 36.172 
               
               
                   
               
             
          
         
       
     
     Based on the permeation results of Example 7, listed in Table 7B, the following flux results listed in Table 7C below were obtained: 
     
       
         
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 7C 
               
             
             
               
                   
               
               
                 μg/cm 2 /hr 
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 7-1 
                 Test 7-2 
                 Test 7-3 
                 three tests 
                 Std Dev 
               
               
                   
               
               
                  6 
                 2.679 
                 0.401 
                 2.658 
                 1.913 
                 1.309 
               
               
                 24 
                 4.164 
                 2.814 
                 4.714 
                 3.897 
                 0.978 
               
               
                 48 
                 4.478 
                 3.839 
                 5.204 
                 4.507 
                 0.683 
               
               
                 72 
                 4.319 
                 4.090 
                 4.929 
                 4.446 
                 0.434 
               
               
                 96 
                 3.483 
                 3.368 
                 4.048 
                 3.633 
                 0.364 
               
               
                 124  
                 2.828 
                 2.762 
                 3.347 
                 2.979 
                 0.320 
               
               
                 144  
                 2.506 
                 2.451 
                 2.919 
                 2.625 
                 0.255 
               
               
                 168  
                 2.137 
                 2.132 
                 2.508 
                 2.259 
                 0.215 
               
               
                 F 6-96   
                 3.697 
                 3.802 
                 4.305 
                 3.934 
                 0.325 
               
               
                 CORR 
                 0.979 
                 0.985 
                 0.981 
                 0.981 
                 0.003 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 8 
     A active drug/adhesive matrix formulation was prepared having the formulation set forth in table 8A below: 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 8A 
               
               
                   
               
               
                   
                 Ingredient 
                 Amount (gm) 
                   
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Loratadine 
                 0.12 
                   
               
               
                   
                 Ethyl Acetate 
                 0.89 
                   
               
               
                   
                 Silicone (adhesive) 
                 11.49 
                 (60% solids) 
               
               
                   
                 BIO PSA 7-4302 (adhesive solution) 
                 19.14 
                   
               
               
                   
                 Total 
                 20.15 
               
               
                   
               
             
          
         
       
     
     The formulation of Table 8A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3. 
     The formulation of Example 8A was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (8-1, 8-2, and 8-3) were conducted giving the results listed in Table 8B below: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 8B 
               
             
             
               
                   
               
               
                 μg/cm 2   
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 8-1 
                 Test 8-2 
                 Test 8-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 49.508 
                 21.195 
                 21.589 
                 30.764 
                 16.234 
               
               
                 24 
                 245.430 
                 189.040 
                 202.444 
                 212.305 
                 29.460 
               
               
                 48 
                 358.829 
                 323.036 
                 321.963 
                 334.609 
                 20.982 
               
               
                 72 
                 420.138 
                 393.948 
                 379.922 
                 398.003 
                 20.412 
               
               
                 96 
                 435.580 
                 418.582 
                 401.711 
                 418.624 
                 16.935 
               
               
                 124 
                 435.805 
                 432.793 
                 415.518 
                 428.039 
                 10.947 
               
               
                 144 
                 444.518 
                 443.853 
                 441.285 
                 443.219 
                 1.707 
               
               
                 168 
                 442.115 
                 451.107 
                 436.680 
                 443.301 
                 7.286 
               
               
                   
               
             
          
         
       
     
     Based on the permeation results of Example 8, listed in Table 8B, the following flux results listed in Table 8C below were obtained: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 8C 
               
             
             
               
                   
               
               
                 μg/cm 2 /hr 
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 8-1 
                 Test 8-2 
                 Test 8-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                  6 
                 8.251 
                 3.533 
                 3.598 
                 5.127 
                 2.706 
               
               
                 24 
                 10.226 
                 7.877 
                 8.435 
                 8.846 
                 1.227 
               
               
                 48 
                 7.476 
                 6.730 
                 6.708 
                 6.971 
                 0.437 
               
               
                 72 
                 5.835 
                 5.472 
                 5.277 
                 5.528 
                 0.284 
               
               
                 96 
                 4.537 
                 4.360 
                 4.184 
                 4.361 
                 0.176 
               
               
                 124  
                 3.515 
                 3.490 
                 3.351 
                 3.452 
                 0.088 
               
               
                 144  
                 3.087 
                 3.082 
                 3.064 
                 3.078 
                 0.012 
               
               
                 168  
                 2.632 
                 2.685 
                 2.599 
                 2.639 
                 0.043 
               
               
                 F 6-96   
                 4.069 
                 4.317 
                 4.037 
                 4.141 
                 0.154 
               
               
                 CORR 
                 0.920 
                 0.945 
                 0.930 
                 0.932 
                 0.013 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 9 
     A active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 9A below: 
     
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 9A 
               
               
                   
               
               
                   
                 Ingredient 
                 Amount (gm) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Loratadine 
                 0.24 
               
               
                   
                 Ethyl Acetate 
                 1.78 
               
               
                   
                 BIO PSA 7-4302 (adhesive solution) 
                 19.38 
               
               
                   
                 containing 11.63 silicone adhesive 
                   
               
               
                   
                 (60% solids) 
                   
               
               
                   
                 Total 
                 21.4 
               
               
                   
               
             
          
         
       
     
     The formulation of Table 9A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3. 
     The formulation of Example 9A was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (9-1, 9-2, and 9-3) were conducted giving the results listed in Table 9B below: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 9B 
               
             
             
               
                   
               
               
                 μg/cm 2   
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 9-1 
                 Test 9-2 
                 Test 9-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 70.513 
                 52.306 
                 34.329 
                 52.383 
                 18.092 
               
               
                 24 
                 325.937 
                 331.333 
                 293.360 
                 316.877 
                 20.544 
               
               
                 48 
                 639.013 
                 547.878 
                 503.103 
                 563.331 
                 69.260 
               
               
                 72 
                 809.531 
                 697.645 
                 650.643 
                 719.273 
                 81.622 
               
               
                 96 
                 856.208 
                 750.846 
                 704.606 
                 770.553 
                 77.699 
               
               
                 124 
                 892.737 
                 784.874 
                 746.189 
                 807.933 
                 75.947 
               
               
                 144 
                 928.925 
                 836.425 
                 766.745 
                 844.032 
                 81.357 
               
               
                 168 
                 919.161 
                 849.990 
                 812.193 
                 860.448 
                 54.245 
               
               
                   
               
             
          
         
       
     
     Based on the permeation results of Example 9, listed in Table 9B, the following flux results listed in Table 9C below were obtained: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 9C 
               
             
             
               
                   
               
               
                 μg/cm 2 /hr 
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 9-1 
                 Test 9-2 
                 Test 9-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                  6 
                 11.752 
                 8.718 
                 5.722 
                 8.730 
                 3.015 
               
               
                 24 
                 13.581 
                 13.806 
                 12.223 
                 13.203 
                 0.856 
               
               
                 48 
                 13.313 
                 11.414 
                 10.481 
                 11.736 
                 1.443 
               
               
                 72 
                 11.243 
                 9.690 
                 9.037 
                 9.990 
                 1.134 
               
               
                 96 
                 8.919 
                 7.821 
                 7.340 
                 8.027 
                 0.809 
               
               
                 124  
                 7.199 
                 6.330 
                 6.018 
                 6.516 
                 0.612 
               
               
                 144  
                 6.451 
                 5.809 
                 5.325 
                 5.861 
                 0.565 
               
               
                 168  
                 5.471 
                 5.059 
                 4.834 
                 5.122 
                 0.323 
               
               
                 F 6-96   
                 8.921 
                 7.631 
                 7.353 
                 7.968 
                 0.836 
               
               
                 CORR 
                 0.962 
                 0.959 
                 0.962 
                 0.961 
                 0.002 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 10 
     A active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 10A below: 
     
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 10A 
               
               
                   
               
               
                   
                 Ingredient 
                 Amount (gm) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Loratadine 
                 0.36 
               
               
                   
                 Ethyl Acetate 
                 2.67 
               
               
                   
                 BIO PSA 7-4302 (adhesive solution) 
                 19.93 
               
               
                   
                 containing 11.96 gm silicone 
                   
               
               
                   
                 adhesive (60% solids) 
                   
               
               
                   
                 Total 
                 22.96 
               
               
                   
               
             
          
         
       
     
     The formulation of Table 10A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3. 
     The formulation of Example 10A was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (10-1, 10-2, and 10-3) were conducted giving the results listed in Table 10B below: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 10B 
               
             
             
               
                   
               
               
                 μg/cm 2   
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 10-1 
                 Test 10-2 
                 Test 10-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 103.382 
                 105.542 
                 89.338 
                 99.421 
                 8.798 
               
               
                 24 
                 385.736 
                 387.593 
                 348.592 
                 374.094 
                 21.793 
               
               
                 48 
                 637.848 
                 659.757 
                 591.666 
                 629.757 
                 34.759 
               
               
                 72 
                 832.501 
                 854.233 
                 769.620 
                 818.785 
                 43.942 
               
               
                 96 
                 897.573 
                 954.671 
                 857.260 
                 903.168 
                 48.946 
               
               
                 124 
                 972.628 
                 1026.660 
                 933.732 
                 977.679 
                 46.669 
               
               
                 144 
                 1041.228 
                 1107.161 
                 1003.008 
                 1050.466 
                 52.687 
               
               
                 168 
                 1051.728 
                 1140.184 
                 1036.631 
                 1076.181 
                 55.940 
               
               
                   
               
             
          
         
       
     
     Based on the permeation results of Example 10, listed in Table 10B, the following flux results listed in Table 10C below were obtained: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 10C 
               
             
             
               
                   
               
               
                 μg/cm 2 /hr 
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 10-1 
                 Test 10-2 
                 Test 10-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                  6 
                 17.230 
                 17.590 
                 14.890 
                 16.570 
                 1.466 
               
               
                 24 
                 16.072 
                 16.150 
                 14.540 
                 15.587 
                 0.908 
               
               
                 48 
                 13.289 
                 13.745 
                 12.326 
                 13.120 
                 0.724 
               
               
                 72 
                 11.563 
                 11.864 
                 10.689 
                 11.372 
                 0.610 
               
               
                 96 
                 9.350 
                 9.944 
                 8.930 
                 9.408 
                 0.510 
               
               
                 124  
                 7.844 
                 8.280 
                 7.530 
                 7.884 
                 0.376 
               
               
                 144  
                 7.231 
                 7.689 
                 6.965 
                 7.295 
                 0.366 
               
               
                 168  
                 6.260 
                 6.787 
                 6.170 
                 6.406 
                 0.333 
               
               
                 F 6-96   
                 8.831 
                 9.407 
                 8.499 
                 8.912 
                 0.459 
               
               
                 CORR 
                 0.970 
                 0.977 
                 0.976 
                 0.974 
                 0.004 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 11 
     A active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 11A below: 
     
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 11A 
               
               
                   
               
               
                   
                 Ingredient 
                 Amount (gm) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Loratadine 
                 0.4 
               
               
                   
                 Ethyl Acetate 
                 3.0 
               
               
                   
                 BIO PSA 7-4302 (adhesive solution) 
                 29.3 
               
               
                   
                 containing 17.6 gm silicone adhesive 
                   
               
               
                   
                 (60% solids) 
                   
               
               
                   
                 Transcutol P (solvent) 
                 2.0 
               
               
                   
                 Total 
                 34.7 
               
               
                   
               
             
          
         
       
     
     The formulation of Table 11A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3 using Transcutol P as an additional solvent. 
     The formulation of Example 11A was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (11-1, 11-2, and 11-3) were conducted giving the results listed in Table 11B below: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 11B 
               
             
             
               
                   
               
               
                 μg/cm 2   
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 11-1 
                 Test 11-2 
                 Test 11-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 133.990 
                 155.952 
                 140.876 
                 143.606 
                 11.233 
               
               
                 24 
                 515.838 
                 553.145 
                 539.020 
                 536.001 
                 18.836 
               
               
                 30 
                 555.286 
                 591.475 
                 589.167 
                 578.643 
                 20.260 
               
               
                 48 
                 683.414 
                 725.466 
                 718.901 
                 709.260 
                 22.623 
               
               
                 54 
                 695.520 
                 751.848 
                 742.940 
                 730.103 
                 30.279 
               
               
                 72 
                 783.265 
                 845.732 
                 833.738 
                 820.912 
                 33.150 
               
               
                 78 
                 782.751 
                 837.382 
                 845.070 
                 821.734 
                 33.979 
               
               
                 99 
                 868.499 
                 913.301 
                 877.658 
                 886.486 
                 23.670 
               
               
                 120 
                 918.598 
                 970.121 
                 944.529 
                 944.416 
                 25.762 
               
               
                 144 
                 946.115 
                 1004.137 
                 964.594 
                 971.615 
                 29.641 
               
               
                 150 
                 936.874 
                 984.544 
                 961.619 
                 961.012 
                 23.841 
               
               
                 168 
                 951.645 
                 1006.483 
                 993.268 
                 983.799 
                 28.619 
               
               
                   
               
             
          
         
       
     
     Table 11C lists further data with respect to Test 11-3. 
     
       
         
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 11C 
               
               
                   
               
               
                   
                   
                   
                   
                   
                   
                 Drug Loss 
                   
                   
                   
               
               
                   
                 Sam- 
                 Drug 
                   
                   
                 Sam- 
                 due to 
                   
                 Cumulative 
                 Amount 
               
               
                   
                 pling 
                 Conc. 
                 Receptor 
                 Drug 
                 pling 
                 Sam- 
                 Cumulative 
                 Amount 
                 Permeated 
               
               
                 Test 
                 Time 
                 (μg/ 
                 Volume 
                 Amount 
                 Volume 
                 pling 
                 Drug Loss 
                 Permeated 
                 per cm 2   
               
               
                 # 
                 (Hours) 
                 ml) 
                 (ml) 
                 (μg) 
                 (ml) 
                 (μg) 
                 (μg) 
                 (μg) 
                 (μg/cm 2 ) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 11-3 
                 6 
                 20.744 
                 12 
                 248.928 
                 1 
                 20.744 
                 0.00 
                 248.928 
                 140.876 
               
               
                   
                 24 
                 77.642 
                 12 
                 931.704 
                 1 
                 77.642 
                 20.744 
                 952.448 
                 539.020 
               
               
                   
                 30 
                 78.556 
                 12 
                 942.672 
                 1 
                 78.556 
                 98.386 
                 1041.058 
                 589.167 
               
               
                   
                 48 
                 91.113 
                 12 
                 1093.356 
                 1 
                 91.113 
                 176.942 
                 1270.298 
                 718.901 
               
               
                   
                 54 
                 87.060 
                 12 
                 1044.720 
                 1 
                 87.060 
                 268.055 
                 1312.775 
                 742.940 
               
               
                   
                 72 
                 93.175 
                 12 
                 1118.100 
                 1 
                 93.175 
                 355.115 
                 1473.215 
                 833.738 
               
               
                   
                 78 
                 87.079 
                 12 
                 1044.948 
                 1 
                 87.079 
                 448.290 
                 1493.238 
                 845.070 
               
               
                   
                 99 
                 84.621 
                 12 
                 1015.452 
                 1 
                 84.621 
                 535.369 
                 1550.821 
                 877.658 
               
               
                   
                 120 
                 87.416 
                 12 
                 1048.992 
                 1 
                 87.416 
                 619.990 
                 1668.982 
                 944.529 
               
               
                   
                 144 
                 83.086 
                 12 
                 997.032 
                 1 
                 83.086 
                 707.406 
                 1704.438 
                 964.594 
               
               
                   
                 150 
                 75.724 
                 12 
                 908.688 
                 1 
                 75.724 
                 790.492 
                 1699.180 
                 961.619 
               
               
                   
                 168 
                 74.074 
                 12 
                 888.888 
                 1 
                 74.074 
                 866.216 
                 1755.104 
                 993.268 
               
               
                   
               
             
          
         
       
     
     Based on the permeation results of Example 11, listed in Table 11B, the averages of the permeation tests were calculated and the flux results listed in Table 11D below were obtained: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 11D 
               
             
             
               
                   
               
               
                 μg/cm 2 /hr 
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 11-1 
                 Test 11-2 
                 Test 11-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 22.332 
                 25.992 
                 23.479 
                 23.934 
                 1.872 
               
               
                 24 
                 21.493 
                 23.048 
                 22.459 
                 22.333 
                 0.785 
               
               
                 30 
                 18.510 
                 19.716 
                 19.639 
                 19.288 
                 0.675 
               
               
                 48 
                 14.238 
                 15.114 
                 14.977 
                 14.776 
                 0.471 
               
               
                 54 
                 12.880 
                 13.923 
                 13.758 
                 13.520 
                 0.561 
               
               
                 72 
                 10.879 
                 11.746 
                 11.580 
                 11.402 
                 0.460 
               
               
                 78 
                 10.035 
                 10.736 
                 10.834 
                 10.535 
                 0.436 
               
               
                 99 
                 8.773 
                 9.225 
                 8.865 
                 8.954 
                 0.239 
               
               
                 120 
                 7.655 
                 8.084 
                 7.871 
                 7.870 
                 0.215 
               
               
                 144 
                 6.570 
                 6.973 
                 6.699 
                 6.747 
                 0.206 
               
               
                 150 
                 6.246 
                 6.564 
                 6.411 
                 6.407 
                 0.159 
               
               
                 168 
                 5.665 
                 5.991 
                 5.912 
                 5.856 
                 0.170 
               
               
                 F 6-99   
                 6.851 
                 7.164 
                 7.071 
                 7.029 
                 0.161 
               
               
                 CORR 
                 0.914 
                 0.913 
                 0.902 
                 0.910 
                   
               
               
                 F 6-168   
                 3.958 
                 4.094 
                 3.969 
                 4.007 
                 0.076 
               
               
                 CORR 
                 0.882 
                 0.878 
                 0.867 
                 0.876 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 12 
     A active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 12A below: 
     
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 12A 
               
               
                   
               
               
                   
                 Ingredient 
                 Amount (gm) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Loratadine 
                 0.4 
               
               
                   
                 Ethyl Acetate 
                 3.0 
               
               
                   
                 BIO PSA 7-4302 (adhesive solution) 
                 29.3 
               
               
                   
                 containing 17.6 gm silicone adhesive 
                   
               
               
                   
                 (60% solids) 
                   
               
               
                   
                 Lauryl Acohol (solvent) 
                 2.0 
               
               
                   
                 Total 
                 34.7 
               
               
                   
               
             
          
         
       
     
     The formulation of Table 12A was prepared and incorporated into a permeation testing us according to the same procedure as in Example 3 using lauryl alcohol as an additional solvent. 
     The formulation of Example 12A was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (12-1, 12-2, and 12-3) were conducted giving the results listed in Table 12B below: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 12B 
               
             
             
               
                   
               
               
                 μg/cm 2   
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 12-1 
                 Test 12-2 
                 Test 12-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 171.613 
                 167.470 
                 145.806 
                 161.630 
                 13.859 
               
               
                 24 
                 603.924 
                 573.643 
                 553.767 
                 577.111 
                 25.258 
               
               
                 30 
                 648.367 
                 661.962 
                 595.567 
                 935.299 
                 35.074 
               
               
                 48 
                 803.563 
                 770.051 
                 738.869 
                 770.828 
                 32.354 
               
               
                 54 
                 832.797 
                 779.924 
                 749.892 
                 787.538 
                 41.974 
               
               
                 72 
                 932.645 
                 881.734 
                 847.836 
                 887.405 
                 42.688 
               
               
                 78 
                 937.072 
                 895.118 
                 853.752 
                 895.314 
                 41.660 
               
               
                 99 
                 978.713 
                 946.745 
                 921.427 
                 948.962 
                 28.707 
               
               
                 120 
                 1019.499 
                 994.321 
                 969.105 
                 994.308 
                 25.197 
               
               
                 144 
                 1072.582 
                 1013.288 
                 1009.257 
                 1031.709 
                 35.454 
               
               
                 150 
                 1046.531 
                 1027.470 
                 989.674 
                 1021.225 
                 28.938 
               
               
                 168 
                 1064.410 
                 1030.903 
                 1035.502 
                 1043.605 
                 18.164 
               
               
                   
               
             
          
         
       
     
     Table 12C lists further data with respect to Test 12-3. 
     
       
         
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 12C 
               
               
                   
               
               
                   
                   
                   
                   
                   
                   
                 Drug Loss 
                   
                 Cumulative 
                 Amount 
               
               
                   
                 Sampling 
                 Drug 
                 Receptor 
                 Drug 
                 Sampling 
                 due to 
                 Cumulative 
                 Amount 
                 Permeated 
               
               
                 Test 
                 Time 
                 Conc. 
                 Volume 
                 Amount 
                 Volume 
                 Sampling 
                 Drug Loss 
                 Permeated 
                 per cm 2   
               
               
                 # 
                 (Hours) 
                 (μg/ml) 
                 (ml) 
                 (μg) 
                 (ml) 
                 (μg) 
                 (μg) 
                 (μg) 
                 (μg/cm 2 ) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 12-3 
                 6 
                 21.470 
                 12 
                 257.640 
                 1 
                 21.470 
                 0.000 
                 257.640 
                 145.806 
               
               
                   
                 24 
                 79.753 
                 12 
                 957.036 
                 1 
                 79.753 
                 21.470 
                 978.506 
                 553.767 
               
               
                   
                 30 
                 79.262 
                 12 
                 951.144 
                 1 
                 79.262 
                 101.223 
                 1052.367 
                 595.567 
               
               
                   
                 48 
                 93.758 
                 12 
                 1125.096 
                 1 
                 93.758 
                 180.485 
                 1305.581 
                 738.869 
               
               
                   
                 54 
                 87.568 
                 12 
                 1050.816 
                 1 
                 87.568 
                 274.243 
                 1325.059 
                 749.892 
               
               
                   
                 72 
                 94.693 
                 12 
                 1136.316 
                 1 
                 94.693 
                 361.811 
                 1498.127 
                 847.836 
               
               
                   
                 78 
                 87.673 
                 12 
                 1052.076 
                 1 
                 87.673 
                 456.504 
                 1508.580 
                 853.752 
               
               
                   
                 99 
                 90.332 
                 12 
                 1083.984 
                 1 
                 90.332 
                 544.177 
                 1628.161 
                 921.427 
               
               
                   
                 120 
                 89.825 
                 12 
                 1077.900 
                 1 
                 89.825 
                 634.509 
                 1712.409 
                 969.105 
               
               
                   
                 144 
                 88.252 
                 12 
                 1059.024 
                 1 
                 88.252 
                 724.334 
                 1783.358 
                 1009.257 
               
               
                   
                 150 
                 78.014 
                 12 
                 936.168 
                 1 
                 78.014 
                 812.586 
                 1748.754 
                 989.674 
               
               
                   
                 168 
                 78.261 
                 12 
                 939.132 
                 1 
                 78.261 
                 890.600 
                 1829.732 
                 1035.502 
               
               
                   
               
             
          
         
       
     
     Based on the permeation results of Example 12, listed in Table 12B, the averages of the permeation tests were calculated and the flux results listed in Table 12D below were obtained: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 12D 
               
             
             
               
                   
               
               
                 μg/cm 2 /hr 
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 12-1 
                 Test 12-2 
                 Test 12-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 28.602 
                 27.912 
                 24.301 
                 26.938 
                 2.310 
               
               
                 24 
                 25.164 
                 23.902 
                 23.074 
                 24.046 
                 1.052 
               
               
                 30 
                 21.612 
                 22.065 
                 19.852 
                 21.177 
                 1.169 
               
               
                 48 
                 16.741 
                 16.043 
                 15.393 
                 16.059 
                 0.674 
               
               
                 54 
                 15.422 
                 14.443 
                 13.887 
                 14.584 
                 0.777 
               
               
                 72 
                 12.953 
                 12.246 
                 11.776 
                 12.325 
                 0.593 
               
               
                 78 
                 12.014 
                 11.476 
                 10.946 
                 11.478 
                 0.534 
               
               
                 99 
                 9.886 
                 9.563 
                 9.307 
                 9.585 
                 0.290 
               
               
                 120 
                 8.496 
                 8.286 
                 8.076 
                 8.286 
                 0.210 
               
               
                 144 
                 7.448 
                 7.037 
                 7.009 
                 7.165 
                 0.246 
               
               
                 150 
                 6.977 
                 6.850 
                 6.598 
                 6.808 
                 0.193 
               
               
                 168 
                 6.336 
                 6.136 
                 6.164 
                 6.212 
                 0.108 
               
               
                 F 6-99   
                 7.791 
                 7.344 
                 7.339 
                 7.492 
                 0.260 
               
               
                 CORR 
                 0.905 
                 0.902 
                 0.912 
                 0.906 
                   
               
               
                 F 6-168   
                 4.176 
                 4.036 
                 4.197 
                 4.136 
                 0.088 
               
               
                 CORR 
                 0.852 
                 0.859 
                 0.879 
                 0.863 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 13 
     A Loratadine reservoir and active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 13A below: 
     
       
         
               
               
               
               
             
               
               
               
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 13A 
               
               
                   
               
               
                   
                 Ingredient 
                 Amount (gm) 
                   
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Donor Solution 
                   
                   
               
               
                   
                 Loratadine 
                 0.35 
                   
               
               
                   
                 Ethanol 
                 22.0 
                 (95%) 
               
               
                   
                 Water 
                 27.0 
                   
               
               
                   
                 Total 
                 49.35 
                   
               
             
          
           
               
                   
                 Membrane 
                 Polyethylene 
                   
               
             
          
           
               
                   
                 Active Drug/Adhesive Matrix 
                   
                   
               
               
                   
                 Loratadine 
                 0.12 
                 gm 
               
               
                   
                 BIO PSA 7-4302 (adhesive solution) 
                 19.14 
                 gm 
               
               
                   
                 containing 11.49 gm silicone 
                   
                   
               
               
                   
                 adhesive (60% solids) 
                   
                   
               
               
                   
                 Ethyl acetate solvent 
                 0.89 
                 gm 
               
               
                   
                 Total 
                 20.15 
                 gm 
               
               
                   
               
             
          
         
       
     
     The formulation of Table 13A was prepared and incorporated into a permeation testing apparatus according to the following procedure:
         1. Loratadine is dissolved with ethanol and water and the solution is placed into the donor cell.   2. Loratadine is dispersed in the adhesive solution and ethyl acetate solvent to form the active drug/adhesive matrix.   3. The polyethylene membrane is coated with active drug/adhesive matrix and placed against the donor cell and dried. The coated surface of the membrane is positioned opposite from the donor cell.   4. Thereafter, the human cadaver skin is placed between the coated membrane surface and the receptor cell and the apparatus is secured.       

     The formulation of Example 13 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (13-1, 13-2, and 13-3) were conducted giving the results listed in Table 13B below: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 13B 
               
             
             
               
                   
               
               
                 μg/cm 2   
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 13-1 
                 Test 13-2 
                 Test 13-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 72.594 
                 58.406 
                 69.079 
                 66.694 
                 7.387 
               
               
                 24 
                 217.680 
                 175.542 
                 197.278 
                 196.833 
                 21.073 
               
               
                 30 
                 255.681 
                 203.923 
                 227.740 
                 229.115 
                 25.906 
               
               
                 48 
                 348.695 
                 283.263 
                 310.261 
                 314.073 
                 32.882 
               
               
                 54 
                 385.778 
                 308.526 
                 336.586 
                 343.630 
                 39.105 
               
               
                 72 
                 487.268 
                 391.914 
                 419.969 
                 433.050 
                 49.004 
               
               
                 78 
                 523.816 
                 419.585 
                 446.677 
                 463.359 
                 54.081 
               
               
                 96 
                 629.393 
                 505.149 
                 532.631 
                 555.721 
                 65.262 
               
               
                 102 
                 662.817 
                 528.167 
                 555.429 
                 582.138 
                 71.188 
               
               
                 120 
                 762.760 
                 613.895 
                 634.252 
                 671.302 
                 80.061 
               
               
                 144 
                 920.453 
                 741.930 
                 759.623 
                 807.335 
                 98.361 
               
               
                 168 
                 1068.287 
                 865.187 
                 872.726 
                 935.400 
                 115.145 
               
               
                   
               
             
          
         
       
     
     Table 13C lists further data with respect to Test 13-3. 
     
       
         
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 13C 
               
               
                   
               
               
                   
                   
                   
                   
                   
                   
                 Drug Loss 
                   
                   
                   
               
               
                   
                 Sam- 
                 Drug 
                   
                   
                 Sam- 
                 due to 
                   
                 Cumulative 
                 Amount 
               
               
                   
                 pling 
                 Conc. 
                 Receptor 
                 Drug 
                 pling 
                 Sam- 
                 Cumulative 
                 Amount 
                 Permeated 
               
               
                 Test 
                 Time 
                 (μg/ 
                 Volume 
                 amount 
                 Volume 
                 pling 
                 Drug Loss 
                 Permeated 
                 per cm 2   
               
               
                 # 
                 (Hours) 
                 ml) 
                 (ml) 
                 (μg) 
                 (ml) 
                 (μg) 
                 (μg) 
                 (μg) 
                 (μg/cm 2 ) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 13-3 
                 6 
                 10.987 
                 4 
                 43.948 
                 4 
                 43.948 
                 0.000 
                 43.948 
                 69.079 
               
               
                   
                 24 
                 20.390 
                 4 
                 81.560 
                 4 
                 81.560 
                 43.948 
                 125.508 
                 197.278 
               
               
                   
                 30 
                 4.845 
                 4 
                 19.380 
                 4 
                 19.380 
                 125.508 
                 144.888 
                 227.740 
               
               
                   
                 48 
                 13.125 
                 4 
                 42.500 
                 4 
                 52.500 
                 144.888 
                 197.388 
                 310.261 
               
               
                   
                 54 
                 4.187 
                 4 
                 16.748 
                 4 
                 16.748 
                 197.388 
                 214.136 
                 336.586 
               
               
                   
                 72 
                 13.262 
                 4 
                 53.048 
                 4 
                 53.048 
                 214.136 
                 267.184 
                 419.969 
               
               
                   
                 78 
                 4.248 
                 4 
                 16.992 
                 4 
                 16.992 
                 267.184 
                 284.176 
                 446.677 
               
               
                   
                 96 
                 13.671 
                 4 
                 54.684 
                 4 
                 54.684 
                 284.176 
                 338.860 
                 532.631 
               
               
                   
                 102 
                 3.626 
                 4 
                 14.504 
                 4 
                 14.504 
                 338.860 
                 353.364 
                 555.429 
               
               
                   
                 120 
                 13.014 
                 4 
                 52.056 
                 4 
                 52.056 
                 353.364 
                 405.420 
                 637.252 
               
               
                   
                 144 
                 19.463 
                 4 
                 77.852 
                 4 
                 77.852 
                 405.420 
                 483.272 
                 759.623 
               
               
                   
                 168 
                 17.989 
                 4 
                 71.956 
                 4 
                 71.956 
                 483.272 
                 555.228 
                 872.726 
               
               
                   
               
             
          
         
       
     
     Based on the permeation results of Example 13, listed in Table 13B, the averages of the permeation test were calculated and the flux results listed in Table 13D below were obtained: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 13D 
               
             
             
               
                   
               
               
                 μ/cm 2 /hr 
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 13-1 
                 Test 13-2 
                 Test 13-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 12.099 
                 9.735 
                 11.513 
                 11.116 
                 1.231 
               
               
                 24 
                 9.070 
                 7.314 
                 8.220 
                 8.201 
                 0.878 
               
               
                 30 
                 8.523 
                 6.797 
                 7.591 
                 7.637 
                 0.864 
               
               
                 48 
                 7.264 
                 5.901 
                 6.464 
                 6.543 
                 0.685 
               
               
                 54 
                 7.144 
                 5.713 
                 6.233 
                 6.364 
                 0.724 
               
               
                 72 
                 6.768 
                 5.443 
                 5.833 
                 6.015 
                 0.681 
               
               
                 78 
                 6.716 
                 5.379 
                 5.727 
                 5.941 
                 0.693 
               
               
                 96 
                 6.556 
                 5.262 
                 5.548 
                 5.789 
                 0.680 
               
               
                 102 
                 6.498 
                 5.178 
                 5.445 
                 5.707 
                 0.698 
               
               
                 120 
                 6.356 
                 5.116 
                 5.310 
                 5.594 
                 0.667 
               
               
                 144 
                 6.392 
                 5.152 
                 5.275 
                 5.606 
                 0.683 
               
               
                 168 
                 6.359 
                 5.150 
                 5.195 
                 5.568 
                 0.685 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 14 
     A Loratadine reservoir and active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 14A below: 
     
       
         
               
               
               
               
             
               
               
               
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 14A 
               
               
                   
               
               
                   
                 Ingredient 
                 Amount (gm) 
                   
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Donor Solution 
                   
                   
               
               
                   
                 Loratadine 
                 0.35 
                   
               
               
                   
                 Ethanol 
                 22.0 
                 (95%) 
               
               
                   
                 Water 
                 27.0 
                   
               
               
                   
                 Total 
                 49.35 
                   
               
             
          
           
               
                   
                 Membrane 
                 Polyethylene 
                   
               
             
          
           
               
                   
                 Active Drug/Adhesive Matrix 
                   
                   
               
               
                   
                 Loratadine 
                 0.24 
                 gm 
               
               
                   
                 BIO PSA 7-4302 (adhesive solution) 
                 19.38 
                 gm 
               
               
                   
                 containing 11.63 gm silicone 
                   
                   
               
               
                   
                 adhesive (60% solids) 
                   
                   
               
               
                   
                 Ethyl acetate solvent 
                 1.78 
                 gm 
               
               
                   
                 Total 
                 21.4 
                 gm* 
               
               
                   
               
               
                 *Reflects removal of solvent from formulation upon drying 
               
             
          
         
       
     
     The formulation of Example 14 was prepared and incorporated into a permeation testing apparatus according to the procedure as in Example 13. 
     The formulation of Example 14 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (14-1, 14-2, and 14-3) were conducted giving the results listed in Table 14B below: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 14B 
               
             
             
               
                   
               
               
                 μg/cm 2   
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 14-1 
                 Test 14-2 
                 Test 14-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 99.616 
                 93.914 
                 65.244 
                 86.258 
                 18.421 
               
               
                 24 
                 289.299 
                 264.313 
                 215.108 
                 256.240 
                 37.749 
               
               
                 30 
                 329.217 
                 303.791 
                 247.476 
                 293.495 
                 41.832 
               
               
                 48 
                 407.865 
                 397.793 
                 316.888 
                 374.182 
                 49.873 
               
               
                 54 
                 434.033 
                 430.324 
                 339.025 
                 401.127 
                 53.814 
               
               
                 72 
                 510.588 
                 523.829 
                 405.564 
                 479.994 
                 64.797 
               
               
                 78 
                 536.221 
                 556.542 
                 427.281 
                 506.681 
                 69.509 
               
               
                 96 
                 617.391 
                 654.782 
                 494.782 
                 588.985 
                 83.697 
               
               
                 102 
                 638.743 
                 684.929 
                 511.311 
                 611.661 
                 89.922 
               
               
                 120 
                 713.411 
                 777.743 
                 574.052 
                 688.402 
                 104.123 
               
               
                 144 
                 828.802 
                 914.128 
                 671.500 
                 804.810 
                 123.080 
               
               
                 168 
                 935.549 
                 1041.830 
                 761.138 
                 912.839 
                 141.717 
               
               
                   
               
             
          
         
       
     
     Table 14C lists further data with respect to Test 14-3. 
     
       
         
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 14C 
               
               
                   
               
               
                   
                   
                   
                   
                   
                   
                 Drug Loss 
                   
                   
                   
               
               
                   
                 Sam- 
                 Drug 
                   
                   
                 Sam- 
                 due to 
                   
                 Cumulative 
                 Amount 
               
               
                   
                 pling 
                 Conc. 
                 Receptor 
                 Drug 
                 pling 
                 Sam- 
                 Cumulative 
                 Amount 
                 Permeated 
               
               
                 Test 
                 Time 
                 (μg/ 
                 Volume 
                 amount 
                 Volume 
                 pling 
                 Drug Loss 
                 Permeated 
                 per cm 2   
               
               
                 # 
                 (Hours) 
                 ml) 
                 (ml) 
                 (μg) 
                 (ml) 
                 (μg) 
                 (μg) 
                 (μg) 
                 (μg/cm 2 ) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 14-3 
                 6 
                 10.377 
                 1 
                 41.508 
                 4 
                 41.508 
                 0.000 
                 41.508 
                 65.244 
               
               
                   
                 24 
                 23.836 
                 4 
                 95.344 
                 4 
                 95.344 
                 41.508 
                 136.852 
                 215.108 
               
               
                   
                 30 
                 5.148 
                 4 
                 20.592 
                 4 
                 20.592 
                 136.852 
                 157.444 
                 247.476 
               
               
                   
                 48 
                 11.040 
                 4 
                 44.160 
                 4 
                 44.160 
                 157.444 
                 201.604 
                 316.888 
               
               
                   
                 54 
                 3.521 
                 4 
                 14.084 
                 4 
                 14.084 
                 201.604 
                 215.688 
                 339.025 
               
               
                   
                 72 
                 10.583 
                 4 
                 42.332 
                 4 
                 42.332 
                 215.688 
                 258.020 
                 405.564 
               
               
                   
                 78 
                 3.454 
                 4 
                 13.816 
                 4 
                 13.816 
                 258.020 
                 271.836 
                 427.281 
               
               
                   
                 96 
                 10.736 
                 4 
                 42.944 
                 4 
                 42.944 
                 271.836 
                 314.780 
                 494.782 
               
               
                   
                 102 
                 2.629 
                 4 
                 10.516 
                 4 
                 10.516 
                 314.780 
                 325.296 
                 511.311 
               
               
                   
                 120 
                 9.979 
                 4 
                 39.916 
                 4 
                 39.916 
                 325.296 
                 365.212 
                 574.052 
               
               
                   
                 144 
                 15.499 
                 4 
                 61.996 
                 4 
                 61.996 
                 365.212 
                 427.208 
                 671.500 
               
               
                   
                 168 
                 14.257 
                 4 
                 57.028 
                 4 
                 57.028 
                 427.208 
                 484.236 
                 761.138 
               
               
                   
               
             
          
         
       
     
     Based on the permeation results of Example 14, listed in Table 14B, the averages of the permeation tests were calculated and the flux results listed in Table 14D below were obtained: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 14D 
               
             
             
               
                   
               
               
                 μg/cm 2 /hr 
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 14-1 
                 Test 14-2 
                 Test 14-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 16.603 
                 15.652 
                 10.874 
                 14.376 
                 3.070 
               
               
                 24 
                 12.054 
                 11.013 
                 8.963 
                 10.677 
                 1.573 
               
               
                 30 
                 10.974 
                 10.126 
                 8.249 
                 9.783 
                 1.394 
               
               
                 48 
                 8.497 
                 8.287 
                 6.602 
                 7.795 
                 1.039 
               
               
                 54 
                 8.038 
                 7.969 
                 6.278 
                 7.428 
                 0.997 
               
               
                 72 
                 7.092 
                 7.275 
                 5.633 
                 6.667 
                 0.900 
               
               
                 78 
                 6.875 
                 7.135 
                 5.478 
                 6.496 
                 0.891 
               
               
                 96 
                 6.431 
                 6.821 
                 5.154 
                 6.135 
                 0.872 
               
               
                 102 
                 6.262 
                 6.715 
                 5.013 
                 5.997 
                 0.882 
               
               
                 120 
                 5.945 
                 6.481 
                 4.784 
                 5.737 
                 0.868 
               
               
                 144 
                 5.756 
                 6.348 
                 4.663 
                 5.589 
                 0.855 
               
               
                 168 
                 5.569 
                 6.201 
                 4.531 
                 5.434 
                 0.844 
               
               
                 F 6-96   
                 5.283 
                 5.906 
                 4.439 
                 5.209 
                 0.736 
               
               
                 CORR 
                 0.979 
                 0.992 
                 0.983 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 15 
     A Loratadine reservoir and active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 15A below: 
     
       
         
               
               
               
               
             
               
               
               
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 15A 
               
               
                   
               
               
                   
                 Ingredient 
                 Amount (gm) 
                   
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Donor Solution 
                   
                   
               
               
                   
                 Loratadine 
                 0.17 
                   
               
               
                   
                 Ethanol 
                 10.93 
                 (95%) 
               
               
                   
                 Water 
                 13.4 
                   
               
               
                   
                 Klucel HF (gelling agent/enhancer) 
                 0.50 
                   
               
               
                   
                 Total 
                 25.0 
                 gm 
               
             
          
           
               
                   
                 Membrane 
                 Polyethylene 
                   
               
             
          
           
               
                   
                 Active Drug/Adhesive Matrix 
                   
                   
               
               
                   
                 Loratadine 
                 0.12 
                 gm 
               
               
                   
                 BIO PSA 7-4302 (adhesive solution) 
                 19.14 
                 gm 
               
               
                   
                 containing 11.49 gm silicone 
                   
                   
               
               
                   
                 adhesive (60% solids) 
                   
                   
               
               
                   
                 Ethyl acetate solvent 
                 0.89 
                 gm 
               
               
                   
                 Total 
                 20.15 
                 gm 
               
               
                   
               
             
          
         
       
     
     The formulation of Table 15A was prepared and incorporated into a permeation testing apparatus according to the following procedure:
         1. Loratadine is dissolved with ethanol and water, Klucel HF is added and the solution is placed into the donor cell.   2. Loratadine is dispersed in the adhesive solution and ethyl acetate solvent to form the active drug/adhesive matrix.   3. The polyethylene membrane is coated with active drug/adhesive matrix and placed against the donor cell and dried. The coated surface of the membrane is positioned opposite from the donor cell.   4. Thereafter, the human cadaver skin is placed between the coated membrane surface and the receptor cell and the apparatus is secured.       

     The formulation of Example 15 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (15-1, 15-2, and 15-3) were conducted giving the results listed in Table 15B below: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 15B 
               
             
             
               
                   
               
               
                 μg/cm 2   
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 15-1 
                 Test 15-2 
                 Test 15-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 30.400 
                 31.356 
                 33.475 
                 31.744 
                 1.574 
               
               
                 24 
                 113.504 
                 96.723 
                 104.500 
                 104.909 
                 8.398 
               
               
                 30 
                 138.050 
                 114.351 
                 120.220 
                 124.207 
                 12.342 
               
               
                 48 
                 220.527 
                 176.029 
                 183.955 
                 193.504 
                 23.736 
               
               
                 54 
                 245.590 
                 194.380 
                 203.129 
                 214.366 
                 27.392 
               
               
                 72 
                 336.788 
                 265.985 
                 281.761 
                 294.845 
                 37.171 
               
               
                 78 
                 359.116 
                 286.556 
                 303.001 
                 316.224 
                 38.044 
               
               
                 96 
                 450.921 
                 350.096 
                 383.057 
                 394.691 
                 51.410 
               
               
                 120 
                 591.832 
                 455.829 
                 507.498 
                 518.386 
                 68.652 
               
               
                 144 
                 685.488 
                 556.102 
                 631.384 
                 624.325 
                 64.981 
               
               
                 168 
                 780.272 
                 635.766 
                 730.428 
                 715.489 
                 73.402 
               
               
                   
               
             
          
         
       
     
     Table 15C lists further data with respect to Test 15-3. 
     
       
         
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 15C 
               
               
                   
               
               
                   
                   
                   
                   
                   
                   
                 Drug 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Loss due 
                   
                 Cumulative 
                 Amount 
               
               
                   
                 Sampling 
                 Drug 
                 Receptor 
                 Drug 
                 Sampling 
                 to 
                 Cumulative 
                 Amount 
                 Permeated 
               
               
                 Test 
                 Time 
                 Conc. 
                 Volume 
                 Amount 
                 Volume 
                 Sampling 
                 Drug Loss 
                 Permeated 
                 per cm 2   
               
               
                 # 
                 (Hours) 
                 (μg/ml) 
                 (ml) 
                 (μg) 
                 (ml) 
                 (μg) 
                 (μg) 
                 (μg) 
                 (μg/cm 2 ) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 15-3 
                 6 
                 4.550 
                 13 
                 59.150 
                 1 
                 4.550 
                 0.000 
                 59.150 
                 33.475 
               
               
                   
                 24 
                 13.854 
                 13 
                 180.102 
                 1 
                 13.854 
                 4.550 
                 184.652 
                 104.500 
               
               
                   
                 30 
                 14.925 
                 13 
                 194.025 
                 1 
                 14.925 
                 18.404 
                 212.429 
                 120.220 
               
               
                   
                 48 
                 22.440 
                 13 
                 291.720 
                 1 
                 22.440 
                 33.329 
                 325.049 
                 183.955 
               
               
                   
                 54 
                 23.320 
                 13 
                 303.160 
                 1 
                 23.320 
                 55.769 
                 358.929 
                 203.129 
               
               
                   
                 72 
                 32.214 
                 13 
                 418.782 
                 1 
                 32.214 
                 79.089 
                 497.871 
                 281.761 
               
               
                   
                 78 
                 32.623 
                 13 
                 424.099 
                 1 
                 32.623 
                 111.303 
                 535.402 
                 303.001 
               
               
                   
                 96 
                 40.995 
                 13 
                 532.935 
                 1 
                 40.995 
                 143.926 
                 676.861 
                 383.057 
               
               
                   
                 120 
                 54.756 
                 13 
                 711.828 
                 1 
                 54.756 
                 184.921 
                 896.749 
                 507.498 
               
               
                   
                 144 
                 67.383 
                 13 
                 875.979 
                 1 
                 67.383 
                 239.677 
                 1115.656 
                 631.384 
               
               
                   
                 168 
                 75.622 
                 13 
                 983.606 
                 1 
                 75.662 
                 307.060 
                 1290.666 
                 730.428 
               
               
                   
               
             
          
         
       
     
     Based on the permeation results of Example 15, listed in Table 15B, the averages of the permeation tests were calculated and the flux results listed in Table 15D below were obtained: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 15D 
               
             
             
               
                   
               
               
                 μg/cm 2 /hr 
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 15-1 
                 Test 15-2 
                 Test 15-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 5.067 
                 5.226 
                 5.579 
                 5.291 
                 0.262 
               
               
                 24 
                 4.729 
                 4.030 
                 4.354 
                 4.371 
                 0.350 
               
               
                 30 
                 4.602 
                 3.812 
                 4.007 
                 4.140 
                 0.411 
               
               
                 48 
                 4.594 
                 3.667 
                 3.832 
                 4.031 
                 0.495 
               
               
                 54 
                 4.548 
                 3.600 
                 3.762 
                 3.970 
                 0.507 
               
               
                 72 
                 4.678 
                 3.694 
                 3.913 
                 4.095 
                 0.516 
               
               
                 78 
                 4.604 
                 3.674 
                 3.885 
                 4.054 
                 0.488 
               
               
                 96 
                 4.697 
                 3.647 
                 3.990 
                 4.111 
                 0.536 
               
               
                 120 
                 4.932 
                 3.799 
                 4.229 
                 4.320 
                 0.572 
               
               
                 144 
                 4.760 
                 3.862 
                 4.385 
                 4.336 
                 0.451 
               
               
                 168 
                 4.644 
                 3.784 
                 4.348 
                 4.259 
                 0.437 
               
               
                 F 6-96   
                 4.651 
                 3.544 
                 3.830 
                 4.008 
                 0.575 
               
               
                 CORR 
                 1.000 
                 1.000 
                 0.998 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 16 
     A Loratadine reservoir and active drug/adhesive matrix formulation was prepared having the formulation of Table 16A below: 
     
       
         
               
               
               
               
             
               
               
               
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 16A 
               
               
                   
               
               
                   
                 Ingredient 
                 Amount (gm) 
                   
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Donor Solution 
                   
                   
               
               
                   
                 Loratadine 
                 0.17 
                   
               
               
                   
                 Ethanol 
                 10.93 
                 (95%) 
               
               
                   
                 Water 
                 13.4 
                   
               
               
                   
                 Klucel HF (gelling agent/enhancer) 
                 0.50 
                   
               
               
                   
                 Total 
                 25.0 
                 gm 
               
             
          
           
               
                   
                 Membrane 
                 Polyethylene 
                   
               
             
          
           
               
                   
                 Active Drug/Adhesive Matrix 
                   
                   
               
               
                   
                 Loratadine 
                 0.24 
                 gm 
               
               
                   
                 BIO PSA 7-4302 (adhesive solution) 
                 19.38 
                 gm 
               
               
                   
                 containing 11.63 gm silicone 
                   
                   
               
               
                   
                 adhesive (60% solids) 
                   
                   
               
               
                   
                 Ethyl acetate solvent 
                 1.78 
                 gm 
               
               
                   
                 Total 
                 21.4 
                 gm 
               
               
                   
               
             
          
         
       
     
     The formulation of Example 16 was prepared and incorporated into a permeation testing apparatus according to the procedure as in Example 15. 
     The formulation of Example 16 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (16-1, 16-2, and 16-3) were conducted giving the results listed in Table 16B below: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 16B 
               
             
             
               
                   
               
               
                 μg/cm 2   
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 16-1 
                 Test 16-2 
                 Test 16-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 36.962 
                 56.230 
                 36.616 
                 43.269 
                 11.226 
               
               
                 24 
                 123.022 
                 152.233 
                 110.046 
                 128.434 
                 21.608 
               
               
                 30 
                 144.736 
                 172.600 
                 126.108 
                 147.815 
                 23.398 
               
               
                 48 
                 219.344 
                 253.782 
                 185.170 
                 219.432 
                 34.306 
               
               
                 54 
                 248.951 
                 275.052 
                 203.915 
                 242.639 
                 35.986 
               
               
                 72 
                 341.293 
                 369.066 
                 266.361 
                 325.573 
                 53.126 
               
               
                 78 
                 367.063 
                 390.341 
                 275.970 
                 344.458 
                 60.444 
               
               
                 96 
                 469.268 
                 481.973 
                 342.796 
                 431.346 
                 76.949 
               
               
                 120 
                 624.439 
                 618.731 
                 449.999 
                 564.390 
                 99.106 
               
               
                 144 
                 748.033 
                 737.652 
                 533.364 
                 673.016 
                 121.054 
               
               
                 168 
                 854.492 
                 842.808 
                 607.081 
                 768.127 
                 139.592 
               
               
                   
               
             
          
         
       
     
     Table 16C lists further data with respect to Test 16-3. 
     
       
         
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 16C 
               
               
                   
               
               
                   
                   
                   
                   
                   
                   
                 Drug 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Loss due 
                   
                 Cumulative 
                 Amount 
               
               
                   
                 Sampling 
                 Drug 
                 Receptor 
                 Drug 
                 Sampling 
                 to 
                 Cumulative 
                 Amount 
                 Permeated 
               
               
                 Test 
                 Time 
                 Conc. 
                 Volume 
                 Amount 
                 Volume 
                 Sampling 
                 Drug Loss 
                 Permeated 
                 per cm 2   
               
               
                 # 
                 (Hours) 
                 (μg/ml) 
                 (ml) 
                 (μg) 
                 (ml) 
                 (μg) 
                 (μg) 
                 (μg) 
                 (μg/cm 2 ) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 16-3 
                 6 
                 4.977 
                 13 
                 64.701 
                 1 
                 4.977 
                 0.000 
                 64.701 
                 36.616 
               
               
                   
                 24 
                 14.575 
                 13 
                 189.475 
                 1 
                 14.575 
                 4.977 
                 194.452 
                 110.046 
               
               
                   
                 30 
                 15.637 
                 13 
                 203.281 
                 1 
                 15.637 
                 19.552 
                 222.833 
                 126.108 
               
               
                   
                 48 
                 22.462 
                 13 
                 292.006 
                 1 
                 22.462 
                 35.189 
                 327.195 
                 185.170 
               
               
                   
                 54 
                 23.282 
                 13 
                 302.666 
                 1 
                 23.282 
                 57.651 
                 360.317 
                 203.915 
               
               
                   
                 72 
                 29.979 
                 13 
                 389.727 
                 1 
                 29.979 
                 80.933 
                 470.660 
                 266.361 
               
               
                   
                 78 
                 28.979 
                 13 
                 376.727 
                 1 
                 28.979 
                 110.912 
                 487.639 
                 275.970 
               
               
                   
                 96 
                 35.833 
                 13 
                 465.829 
                 1 
                 35.833 
                 139.891 
                 605.720 
                 342.796 
               
               
                   
                 120 
                 47.648 
                 13 
                 619.424 
                 1 
                 47.648 
                 175.724 
                 795.148 
                 449.999 
               
               
                   
                 144 
                 55.314 
                 13 
                 719.082 
                 1 
                 55.314 
                 223.372 
                 942.454 
                 533.364 
               
               
                   
                 168 
                 61.079 
                 13 
                 794.027 
                 1 
                 61.079 
                 278.686 
                 1072.713 
                 607.081 
               
               
                   
               
             
          
         
       
     
     Based on the permeation results of Example 16, listed in Table 16B, the averages of the permeation tests were calculated and the flux results listed in Table 16D below were obtained: 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 16D 
               
             
             
               
                   
               
               
                 μg/cm 2 /hr 
               
             
          
           
               
                   
                   
                   
                   
                 Average of 
                   
               
               
                 Hours 
                 Test 16-1 
                 Test 16-2 
                 Test 16-3 
                 three tests 
                 Std Dev 
               
               
                   
               
             
          
           
               
                 6 
                 6.160 
                 9.372 
                 6.103 
                 7.212 
                 1.871 
               
               
                 24 
                 5.126 
                 6.343 
                 4.585 
                 5.351 
                 0.900 
               
               
                 30 
                 4.825 
                 5.753 
                 4.204 
                 4.927 
                 0.780 
               
               
                 48 
                 4.570 
                 5.287 
                 3.858 
                 4.572 
                 0.715 
               
               
                 54 
                 4.610 
                 5.094 
                 3.776 
                 4.493 
                 0.666 
               
               
                 72 
                 4.740 
                 5.126 
                 3.699 
                 4.522 
                 0.738 
               
               
                 78 
                 4.706 
                 5.004 
                 3.583 
                 4.416 
                 0.775 
               
               
                 96 
                 4.888 
                 5.021 
                 3.571 
                 4.493 
                 0.802 
               
               
                 120 
                 5.204 
                 5.156 
                 3.750 
                 4.703 
                 0.826 
               
               
                 144 
                 5.195 
                 5.123 
                 3.704 
                 4.674 
                 0.841 
               
               
                 168 
                 5.086 
                 5.017 
                 3.614 
                 4.572 
                 0.831 
               
               
                 F 6-96   
                 4.722 
                 4.647 
                 3.318 
                 4.229 
                 0.790 
               
               
                 CORR 
                 0.998 
                 0.999 
                 0.999 
               
               
                   
               
             
          
         
       
     
     In vitro skin permeation studies with cadaver skin quantitatively predict the pharmacokinetics and extent of drug absorption from the transdermal delivery dosage form. Matching in vitro skin donors to the in vivo population improves the correlation. Further improvements in this correlation are achieved by matching application sites. 
     it will be readily apparent that various modifications to the invention may be made by those killed in the art without departing from the scope of this invention. For example, many different transdermal delivery systems may be utilized in order to obtain the relative release rates and plasma levels described herein. Further, it is possible that mean values for plasma concentrations over a particular patient population for a particular described time point along the dosing interval may vary from the plasma concentration ranges described herein for that time point. Such obvious modifications are considered to be within the scope of the appended claims.