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

Description:
[0001]    This application claims the benefit of U.S. Provisional Application No. 60/242,514, filed Oct. 23, 2001, hereby incorporated by reference. 
     
    
     
       BACKGROUND OF THE INVENTION  
         [0002]    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.  
           [0003]    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.  
           [0004]    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.  
           [0005]    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[5,6]cyclohepta [1,2-b]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.  
           [0006]    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.  
           [0007]    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.  
           [0008]    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).  
           [0009]    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.  
           [0010]    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).  
           [0011]    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  
         [0012]    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.  
           [0013]    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.  
           [0014]    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.  
           [0015]    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.  
           [0016]    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.  
           [0017]    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  
           [0018]    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.  
           [0019]    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  
           [0020]    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.  
           [0021]    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.  
           [0022]    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.  
           [0023]    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.  
           [0024]    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.  
           [0025]    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 .  
           [0026]    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 .  
           [0027]    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 .  
           [0028]    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;  
           [0029]    from about 2.3 μg/cm 2 /hr to about 13.7 μg/cm 2 /hr at 48 hours; and  
           [0030]    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.  
           [0031]    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.  
           [0032]    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.  
           [0033]    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.  
           [0034]    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.  
           [0035]    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.  
           [0036]    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.  
           [0037]    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.  
           [0038]    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.  
           [0039]    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.  
           [0040]    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.  
           [0041]    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.  
           [0042]    In certain embodiments, the transdermal delivery system maintains a plasma level of loratadine at steady-state from about 1 to about 3 ng/ml.  
           [0043]    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.  
           [0044]    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.  
           [0045]    In certain embodiments, the transdermal delivery system maintains a plasma level of loratadine at steady-state from about 1 to about 3 ng/ml.  
           [0046]    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.  
           [0047]    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.  
           [0048]    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 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.  
           [0049]    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.  
           [0050]    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.  
           [0051]    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.  
           [0052]    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.  
           [0053]    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.  
           [0054]    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.  
           [0055]    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.  
           [0056]    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.  
           [0057]    In certain embodiments, the invention is directed to transdermal delivery devices which are suitable for attaining any of the above methods.  
           [0058]    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.  
           [0059]    Another alternative is to utilize a laminated composite for administering loratadine or a pharmaceutically acceptable salt thereof to an individual transdermally comprising  
           [0060]    (a) a polymer backing layer that is substantially impermeable to loratadine or the pharmaceutically acceptable salt thereof; and  
           [0061]    (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.  
           [0062]    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:  
           [0063]    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.  
           [0064]    Drug release from membrane-controlled systems may be defined as follows: 
           Amount released per area unit  Q =const (zero order kinetics) 
           [0065]    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”.  
           [0066]    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.  
           [0067]    The term “steady state” means that the blood plasma concentration curve for a given drug has been substantially repeated from dose to dose.  
           [0068]    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.  
           [0069]    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.  
           [0070]    The term “first order” pharmacokinetics is defined as plasma concentrations which increase over a specified time period.  
           [0071]    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.  
           [0072]    Drug release from membrane-controlled systems may be defined as follows: 
           Amount released per area unit  Q =const (zero order kinetics) 
           [0073]    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”.  
           [0074]    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.  
           [0075]    The term “steady state” means that the blood plasma concentration curve for a given drug has been substantially repeated from dose to dose.  
           [0076]    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.  
           [0077]    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.  
           [0078]    For purposes of the present invention, the terms “transdermal delivery device” and “transdermal delivery system” are interchangeable.  
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0079]    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.  
         [0080]    [0080]FIG. 1 is a graphical representation of the cumulative amounts of loratadine resulting from 3 permeation tests of Example 1 through human cadaver skin.  
         [0081]    [0081]FIG. 2 is a graphical representation of the average loratadine permeation rate (flux rate) of Example 2 through human cadaver skin.  
         [0082]    [0082]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.  
         [0083]    [0083]FIG. 4 is a graphical representation of the cumulative amounts of loratadine resulting from 3 permeation tests of Example 3 through human cadaver skin.  
         [0084]    [0084]FIG. 5 is a graphical representation of the cumulative amounts of loratadine resulting from 3 permeation tests of Example 4 through human cadaver skin.  
         [0085]    [0085]FIG. 6 is graphical representation of the average loratadine permeation rates (flux rates) of Examples 5, 6, and 7 through human cadaver skin.  
         [0086]    [0086]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.  
         [0087]    [0087]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.  
         [0088]    [0088]FIG. 9 is a graphical representation of the average loratadine permeation rates (flux rates) of Examples 8, 9, and 10 through human cadaver skin.  
         [0089]    [0089]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.  
         [0090]    [0090]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.  
         [0091]    [0091]FIG. 12 is a graphical representation of the average loratadine permeation rates (flux rates) of Examples 13 and 14 through human cadaver skin.  
         [0092]    [0092]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.  
         [0093]    [0093]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  
       [0094]    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 
     
         [0095]    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.  
         [0096]    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.  
         [0097]    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.  
         [0098]    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  
       [0099]    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.  
         [0100]    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.  
         [0101]    The polymer matrix layer may optionally include a pharmaceutically acceptable cross-linking agent. Suitable crosslinking agents include, e.g., tetrapropoxy silane.  
         [0102]    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.  
         [0103]    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.  
         [0104]    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.  
         [0105]    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.  
         [0106]    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.  
         [0107]    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.  
         [0108]    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.  
         [0109]    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.  
         [0110]    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.  
         [0111]    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.  
         [0112]    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.  
         [0113]    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.  
         [0114]    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  
       [0115]    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:  
         [0116]    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.  
         [0117]    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.  
         [0118]    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.  
         [0119]    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.  
         [0120]    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.  
         [0121]    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.  
         [0122]    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.  
         [0123]    The pharmacokinetic information for loratadine is available in the literature. 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 steady state concentration 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 9.8 mcg/hour/cm 2  of transdermal patch surface area.  
         [0124]    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  
       [0125]    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  
       [0126]    The following general method is used in the following examples in which the transdermal device tested is a matrix system (device):  
         [0127]    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.  
         [0128]    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.  
         [0129]    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  
       [0130]    The following general method is used in the following examples in which the transdermal device tested is a reservoir system (device):  
         [0131]    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.  
         [0132]    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.  
         [0133]    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.  
         [0134]    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  
       [0135]    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.  
         [0136]    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:  
         [0137]    J=CV/At where:  
         [0138]    J=micrograms/cm 2 -hr  
         [0139]    C=micrograms/ml  
         [0140]    V=ml  
         [0141]    A=cm 2    
         [0142]    t=hr  
         [0143]    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  
       [0144]    [0144]                                       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  
       [0145]    [0145]                                                                         Column   Altima C8, 5 um, 4.6 mm × 15 cm           Mobile phase   Acetonitrile/Buffer 70/30           Buffer:   0.01 M 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  
       [0146]    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                      
 
         [0147]    The formulation of Table 1A was prepared and incorporated into a permeation testing apparatus according to the following procedure:  
         [0148]    1. Loratadine is dissolved with ethanol and water and the solution is placed into the donor cell.  
         [0149]    2. The ethylvinylacetate membrane is placed against the donor cell.  
         [0150]    3. Thereafter, the human cadaver skin is placed between the membrane and the receptor cell and the apparatus is secured.  
         [0151]    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   120.23   4   480.932   4   480.932   189.956   670.888   1054.524               3       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   113.29   4   453.192   4   453.192   154.148   607.340   945.637               8       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   107.97   4   431.896   4   431.896   144.720   576.616   906.344               4                  
 
         [0152]    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  
       [0153]    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                      
 
         [0154]    The formulation of Table 2A was prepared and incorporated into a permeation testing apparatus according to the following procedure:  
         [0155]    1. Loratadine is dissolved with ethanol and water and the solution is placed into the donor cell.  
         [0156]    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.  
         [0157]    3. Thereafter, the human cadaver skin is placed between the adhesive coated polyethylene membrane and the receptor cell and the apparatus is secured.  
         [0158]    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                  
 
         [0159]    Based on the permeation results of Example 2, listed in Table 2B, the following flux 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  
       [0160]    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                      
 
         [0161]    The formulation of Table 3A was prepared and incorporated into a permeation testing apparatus according to the following procedure:  
         [0162]    1. Loratadine is dispersed in the requisite amount of ethyl acetate and adhesive solution to form the active drug/adhesive matrix.  
         [0163]    2. The active drug/adhesive matrix is applied to a backing layer and dried.  
         [0164]    3. Thereafter, the patch is applied to the human cadaver skin affixed to the receptor cell.  
         [0165]    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                  
 
         [0166]    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  
       [0167]    A Loratadine active drug/adhesive matrix formulation was prepared having the 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                      
 
         [0168]    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.  
         [0169]    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                  
 
         [0170]    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  
       [0171]    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                      
 
         [0172]    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.  
         [0173]    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                  
 
         [0174]    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                  
 
         [0175]    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  
       [0176]    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                      
 
         [0177]    The formulation of Table 6A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3.  
         [0178]    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                  
 
         [0179]    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  
       [0180]    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                      
 
         [0181]    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.  
         [0182]    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                  
 
         [0183]    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  
       [0184]    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                      
 
         [0185]    The formulation of Table 8A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3.  
         [0186]    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                  
 
         [0187]    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  
       [0188]    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                      
 
         [0189]    The formulation of Table 9A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3.  
         [0190]    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                  
 
         [0191]    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       COR   0.962   0.959   0.962   0.961   0.002       R                  
 
       EXAMPLE 10  
       [0192]    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                      
 
         [0193]    The formulation of Table 10A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3.  
         [0194]    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                  
 
         [0195]    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  
       [0196]    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                      
 
         [0197]    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.  
         [0198]    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                  
 
         [0199]    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                  
 
         [0200]    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  
       [0201]    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                      
 
         [0202]    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.  
         [0203]    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                  
 
         [0204]    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                  
 
         [0205]    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  
       [0206]    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                      
 
         [0207]    The formulation of Table 13A was prepared and incorporated into a permeation testing apparatus according to the following procedure:  
         [0208]    1. Loratadine is dissolved with ethanol and water and the solution is placed into the donor cell.  
         [0209]    2. Loratadine is dispersed in the adhesive solution and ethyl acetate solvent to form the active drug/adhesive matrix.  
         [0210]    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.  
         [0211]    4. Thereafter, the human cadaver skin is placed between the coated membrane surface and the receptor cell and the apparatus is secured.  
         [0212]    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                  
 
         [0213]    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                  
 
         [0214]    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           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  
       [0215]    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*                                  
 
         [0216]    The formulation of Example 14 was prepared and incorporated into a permeation testing apparatus according to the procedure as in Example 13.  
         [0217]    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                  
 
         [0218]    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                  
 
         [0219]    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  
       [0220]    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                      
 
         [0221]    The formulation of Table 15A was prepared and incorporated into a permeation testing apparatus according to the following procedure:  
         [0222]    1. Loratadine is dissolved with ethanol and water, Klucel HF is added and the solution is placed into the donor cell.  
         [0223]    2. Loratadine is dispersed in the adhesive solution and ethyl acetate solvent to form the active drug/adhesive matrix.  
         [0224]    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.  
         [0225]    4. Thereafter, the human cadaver skin is placed between the coated membrane surface and the receptor cell and the apparatus is secured.  
         [0226]    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                  
 
         [0227]    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-   6   4.550   13   59.150   1   4.550   0.000   59.150   33.475       3           24   13.85   13   180.10   1   13.854   4.550   184.652   104.500               4       2           30   14.92   13   194.02   1   14.925   18.404   212.429   120.220               5       5           48   22.44   13   291.72   1   22.440   33.329   325.049   183.955               0       0           54   23.32   13   303.16   1   23.320   55.769   358.929   203.129               0       0           72   32.21   13   418.78   1   32.214   79.089   497.871   281.761               4       2           78   32.62   13   424.09   1   32.623   111.303   535.402   303.001               3       9           96   40.99   13   532.93   1   40.995   143.926   676.861   383.057               5       5           120   54.75   13   711.82   1   54.756   184.921   896.749   507.498               6       8           144   67.38   13   875.97   1   67.383   239.677   1115.656   631.384               3       9           168   75.62   13   983.60   1   75.662   307.060   1290.666   730.428               2       6                  
 
         [0228]    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  
       [0229]    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                      
 
         [0230]    The formulation of Example 16 was prepared and incorporated into a permeation testing apparatus according to the procedure as in Example 15.  
         [0231]    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                  
 
         [0232]    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-   6   4.977   13   64.701   1   4.977   0.000   64.701   36.616       3           24   14.57   13   189.47   1   14.575   4.977   194.452   110.046               5       5           30   15.63   13   203.28   1   15.637   19.552   222.833   126.108               7       1           48   22.46   13   292.00   1   22.462   35.189   327.195   185.170               2       6           54   23.28   13   302.66   1   23.282   57.651   360.317   203.915               2       6           72   29.97   13   389.72   1   29.979   80.933   470.660   266.361               9       7           78   28.97   13   376.72   1   28.979   110.912   487.639   275.970               9       7           96   35.83   13   465.82   1   35.833   139.891   605.720   342.796               3       9           120   47.64   13   619.42   1   47.648   175.724   795.148   449.999               8       4           144   55.31   13   719.08   1   55.314   223.372   942.454   533.364               4       2           168   61.07   13   794.02   1   61.079   278.686   1072.713   607.081               9       7                  
 
         [0233]    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                  
 
         [0234]    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.  
         [0235]    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.