# Patent

## Title
Loratadine transdermal device and methods

## Abstract

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

## Background
This application claims the benefit of U.S. Provisional Application No. 60/242,514, filed Oct. 23, 2000, hereby incorporated by reference.


BACKGROUND OF THE INVENTION
It is the intent of all sustained-release pharmaceutical preparations to provide a longer period of pharmacologic effect after the administration of a drug than is ordinarily experienced after the administration of immediate release preparations of the same drug. Such longer periods of efficacy can provide many inherent therapeutic benefits that are not achieved with corresponding immediate release preparations. The benefits of prolonged treatment of the nasal and non-nasal symptoms of seasonal allergic rhinitis or chronic idiopathic urticaria afforded by sustained release oral preparations have become universally recognized and oral sustained-release preparations are commercially available.
Another approach to sustained delivery of a therapeutically active agent is transdermal delivery systems, such as transdermal patches. Generally, transdermal patches contain a therapeutically active agent, a reservoir or matrix containing the active ingredient(s) and an adhesive which allows the transdermal device to adhere to the skin, allowing for the passage of the active agent from the device through the skin of the patient. Once the active agent has penetrated the skin layer, the drug is absorbed into the blood stream where it can exert a desired pharmacotherapeutic effect.
In spite of the known art related to transdermal therapy, there exists a need for the transdermal delivery of a beneficial agent for the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria.
Loratadine, commercially available as Claritin® in the U.S. from Schering Corporation (Kenilworth, N.J. 07033, U.S.A.), is a long-acting tricyclic antihistamine with selective peripheral histamine H1-receptor antagonistic activity, with the chemical name, ethyl 4-(8-chloro-5,6-dihydro-11H-benzo cyclohepta pyridin-11-ylidene)-1-piperidinecarboxylate, and it is used mainly for treating nasal and non-nasal symptoms of seasonal allergic rhinitis, but may also be used in the treatment of chronic idiopathic urticaria, a common skin disorder . It is in the form of a white to off white powder, not soluble in water, but very soluble in organic solvents. Loratadine inhibits the activity of the substance, histamine, thus reducing the allergic effects caused by this substance such as itching, sneezing, runny nose and watery eyes. Loratadine is preferable to other antihistamines because it is nonsedating and does not cause cardiac arrhythmias brought on by use of some other antihistamines. The recommended oral dosage of loratadine for adults and children 12 years old or older is 10 mg once daily. In patients with liver or renal problems, the initial oral dosage of loratadine should be 10 mg every other day.
Seasonal allergic rhinitis (hay fever) is a term used to describe the symptoms caused seasonally by an allergic reaction that occurs in the eyes, nose, and throat in response to airborne allergens such as pollen from trees, grasses, and weeds. Other possible allergens include dust mites, molds, and animal dander. The allergens produce an allergic response by misleading the immune into thinking that the allergen is a harmful substance, thereby causing the immune system to produce antibodies to this specific allergen. When that allergen enters the immune system again, a reaction occurs between the allergen and IgE antibodies triggering the release of substances such as histamine from mast cells and other cells, producing symptoms such as runny nose, watery eyes, sneezing, and itching.
Chronic urticaria is an allergic skin disorder characterized by hives, e.g. red welts or small bumps, on the skin which are very itchy. Patients with chronic urticaria have hives that last longer than six months. This skin disorder is caused by an antigen-antibody reaction in which histamine and other substances such as acetyl choline are released from mast cells and other cells causing symptoms such as swelling, itching, pain, and rash. There are also cases in which there are no known causes for the hives (chronic idiopathic urticaria). As with chronic urticaria, antihistamines are used for treating chronic idiopathic urticaria.
Symptoms of seasonal allergic rhinitis and chronic idiopathic urticaria are improved by treatment with nonsedating antihistamines. Nonsedating antihistamines such as loratadine (The Merck Index, 11th Edition, Merck & Co., Inc., Rahway, N.J. U.S.A. 1989, hereby incorporated by reference) act as an antagonist to the peripheral histamine H1 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, 9th Edition, hereby incorporated by reference).
Following oral administration, loratadine is rapidly absorbed, fast acting, and undergoes extensive first pass metabolism to the active metabolite descarboethoxyloratadine. Food delays absorption, so loratadine should be taken on an empty stomach. Pharmacokinetic studies have revealed that the onset of antihistamine activity occurs within 1-3 hours following administration of loratadine, reaching a maximum at 8-12 hours and lasting in excess of 24 hours. There was no evidence of tolerance to this effect after 28 days of dosing with loratadine. After 10 days of dosing, a mean peak plasma concentration of 1.3 hours and 2.3 hours (Tmax) was observed in loratadine and the active metabolite, respectively. The mean elimination half-life observed in normal adults was 8.4 hours for loratadine and 28 hours for active metabolite. In patients with chronic liver disease, a mean half-life for loratadine and descarboethoxyloratadine of 24 hours and 37 hours were observed, respectively. Within 10 days of dosing, approximately 80% of the total loratadine administered were found in equal proportions between the urine and feces in the form of metabolic products. Finally, loratadine is 97% plasma-protein bound.
The most common adverse side effects of loratadine therapy include headache, somnolence, fatigue, and dry mouth. Less common or rare side effects may include altered lacrimination, altered salivation, flushing, hypoesthesia, impotence, increased sweating, thirst, angioneurotic edema, asthenia, back pain, blurred vision, chest pain, earache, eye pain, fever, leg cramps, malaise, rigors, tinnitus, viral infection, weight gain, hypertension, hypotension, palpitations, superventricular tachyarrhythmias, syncope, tachycardia, blepharospasm, dizziness, dysphonia, hypertonia, migraine, paresthesia, tremor, vertigo, altered taste, anorexia, constipation, diarrhea, dyspepsia, flatulence, gastritis, hiccup, increased appetite, nausea, stomatitis, toothache, vomiting, arthraglia, myalgia, agitation, amnesia, anxiety, confusion, decreased libido, depression, impaired concentration, insomnia, irritability, paroniria, breast pain, dysmenorrhea, menorrhagia, vaginitis, bronchitis, bronchospasm, coughing, dyspnea, epistaxis, hemoptysis, laryngitis, nasal dryness, pharyngitis, sinusitis, sneezing, dermatitis, dry hair, dry skin, photosensitivity reaction, pruritis, purpura, rash, urticaria, altered micturition, urinary discoloration, urinary incontinence, urinary retention. Further, the following spontaneous adverse effects were rarely reported for loratadine: abnormal hepatic function, including jaundice, hepatitis, and hepatic necrosis, alopecia, anaphylaxis, breast enlargement, erythema multiforme, peripheral edema, and seizures. (Physicians' Desk Reference, 53rd Edition, 1999, hereby incorporated by reference).
Despite advances in the art, there remains a need for methods of treating patients with seasonal allergic rhinitis and chronic idiopathic urticaria with an agent that provides effective levels of loratadine for prolonged periods of time, preferably while eliminating or minimizing the symptoms of seasonal allergic rhinitis or chronic idiopathic urticaria, and/or any of the other above mentioned side effects, thus providing a safe and effective method of management of such allergic reactions and skin disorders.
OBJECTS AND SUMMARY OF THE INVENTION
It is an object of the present invention to provide a continuous plasma loratadine concentration in mammals, preferably humans patients suffering from seasonal allergic rhinitis and/or chronic idiopathic urticaria.
It is an object of certain embodiments of the present invention to provide a method for treating patients suffering from seasonal allergic rhinitis and chronic idiopathic urticaria which achieves prolonged and effective management of these conditions, while at the same time provides the opportunity to reduce possible side effects, e.g., which patients may experience when subjected to prolonged oral therapy.
It is an object of certain embodiments of the present invention to provide a method for the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria disorders in patients by utilizing a transdermal delivery system which contains loratadine.
It is an object of certain embodiments of the present invention to provide a method for the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria disorders in patients which maximizes the dosage interval, i.e., the interval during which the transdermal delivery system is maintained in contact with the skin, and minimizes the plasma concentrations and or fluctuations in plasma concentrations in the patients during the dosage interval, while surprisingly maintaining effective management of seasonal allergic rhinitis and chronic idiopathic urticaria.
It is an object of certain embodiments of the present invention to provide a method for lessening the dry mouth associated with the oral administration of loratadine.
In certain embodiments, the present invention is directed to a method of effectively treating seasonal allergic rhinitus, chronic idiopathic urticaria, or both conditions in a human patient, comprising
administering loratadine transdermally to the human patient by applying a transdermal delivery system containing loratadine to the skin of a patient, and maintaining the transdermal delivery system in contact with the skin of the patient for at least 3 days, the transdermal delivery system maintaining an effective mean relative release rate to provide a therapeutic blood level of the loratadine within 36 hours from the initiation of the dosing interval, and thereafter maintaining a therapeutic blood level until the end of at least the three-day dosing interval.
In certain embodiments, the present invention is directed to a method of effectively treating seasonal allergic rhinitus, chronic idiopathic urticaria, or both conditions in a human patient, comprising
administering loratadine transdermally to the human patient by applying a transdermal delivery system containing loratadine to the skin of a patient, and maintaining the transdermal delivery system in contact with the skin of the patient for at least 5 days, the transdermal delivery system maintaining an effective mean relative release rate to provide a therapeutic blood level of the loratadine within three days from the initiation of the dosing interval, and thereafter maintaining a therapeutic blood level until the end of at least the five-day dosing interval.
In certain embodiments, the present invention is directed to a method for lessening the incidence of side-effects in a patient associated with the oral administration of loratadine, wherein the method comprises administering the loratadine in a transdermal delivery system over at least twenty-four hours and thereby lessening the incidence of side effects.
In certain embodiments, the above methods can further comprise providing a mean relative release rate of loratadine from a transdermal delivery system to provide a plasma level of loratadine of at least about 0.1 ng/ml within about 6 hours, 3 hours, 2 hours, 1 hour or 0.5 hours after after application of the transdermal delivery system onto the skin of the patient.
In certain embodiments, the above methods can further comprise providing a loratadine transdermal delivery system which maintains a plasma level of loratadine at steady-state from about 1 to about 3 ng/ml.
In certain embodiments, the above methods can further comprise maintaining a therapeutic plasma level from about 0.1 ng/ml to about 3.3 ng/ml during the dosing interval for the transdermal delivery system.
In certain embodiments, the above methods can further comprise having the transdermal delivery system having a mean relative release rate from 1.0 μm/hour/cm2 to about 30.0 μm/hour/cm2 or about 1.8 μm/hour/cm2 to about 17 μm/hour/cm2.
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/cm2 to about 10.0 μm/hour/cm2.
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/cm2 to about 5.0 μm/hour/cm2.
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/cm2/hr to about 16.2 μg/cm2/hr at 24 hours;

    
    
        from about 2.3 μg/cm2/hr to about 13.7 μg/cm2/hr at 48 hours; and
        from about 2.0 μg/cm2/hr to about 11.9 μg/cm2/hr at 72 hours; as determined via an in-vitro permeation test utilizing a Valia-Chien cell where the membrane is a human cadaver skin and the cell has a receptor chamber containing a 40:60 mixture of ethanol:water.
    
    


In certain embodiments, the above methods can further comprise having the transdermal delivery system to provide an in-vitro cumulative amount of permeation of from about 63 μg/cm2 to about 388 μg/cm2 at 24 hours; from about 105 μg/cm2 to about 660 μg/cm2 at 48 hours; and from about 139 μg/cm2 to about 854 μg/cm2 at 72 hours, as determined via an in-vitro permeation test utilizing a Valia-Chien cell where the membrane is a human cadaver skin and the cell has a receptor chamber containing a 40:60 mixture of ethanol:water.
In certain embodiments, the above methods can further comprise having the plasma level of loratadine at 48 hours not decrease by more than 30% over the next 72 hours.
In certain embodiments, the above methods can further comprise maintaining an effective mean relative release rate of the transdermal delivery system to provide a substantially first order plasma level increase of loratadine from the initiation of the dosing interval until about 48 to about 72 hours after the initiation of the dosing interval; and thereafter providing an effective mean relative release rate to provide a substantially zero order plasma level fluctuation of loratadine until the end of at least the five-day dosing interval.
In certain embodiments, the above methods can further comprise administering the loratadine in a transdermal delivery system applied to the skin of a human patient for about 3 to about 5 days.
In certain embodiments, the invention is directed to a transdermal device containing loratadine which provides effective blood plasma levels of loratadine when the device is applied to the skin of a mammal, preferably a human.
In certain embodiments, the invention is directed to a transdermal device containing loratadine which provides effective treatment of seasonal allergic rhinitis and chronic idiopathic urticaria disorders in patients.
In certain embodiments, the invention is directed to a transdermal delivery device comprising loratadine or a pharmaceutically acceptable salt thereof which maintains an effective mean relative release rate to provide a therapeutic blood level of the loratadine within three days from the initiation of the dosing interval, and thereafter maintaining a therapeutic blood level until the end of at least the five-day dosing interval.
In certain embodiments, the invention is directed to a transdermal device containing loratadine for the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria disorders in patients which maximizes the dosage interval, i.e., the interval during which the transdermal delivery system is maintained in contact with the skin, and minimizes the plasma concentrations and or fluctuations in plasma concentrations in the patients during the dosage interval, while surprisingly maintaining effective management of seasonal allergic rhinitis and chronic idiopathic urticaria.
In certain embodiments, the invention is directed to a transdermal delivery system containing loratadine or a pharmaceutically acceptable salt thereof which provides a mean relative release rate from about 1.0 μm/hour/cm2 to about 30.0 μm/hour/cm2 or about 1.8 μm/hour/cm2 to about 17 μm/hour/cm2 of the transdermal delivery system; a plasma level of loratadine of at least about 0.1 ng/ml within about 6 hours, 3 hours, 2 hours, 1 hour or 0.5 hours after application of the transdermal delivery system onto the skin of the patient; and a plasma level of loratadine at steady-state from about 0.1 to about 3.3 ng/ml.
In certain embodiments, the transdermal delivery system provides a mean relative release rate from about 2.8 μg/cm2/hr to about 16.2 μg/cm2/hr at 24 hours; from about 2.3 μg/cm2/hr to about 13.7 μg/cm2/hr at 48 hours; and from about 2.0 μg/cm2/hr to about 11.9 μg/cm2/hr at 72 hours; as determined via an in-vitro permeation test utilizing a Valia-Chien cell where the membrane is a human cadaver skin and the cell has a receptor chamber containing a 40:60 mixture of ethanol:water.
In certain embodiments, the transdermal delivery system provides an in-vitro cumulative amount of permeation of from about 63 μg/cm2 to about 388 μg/cm2 at 24 hours; from about 105 μg/cm2 to about 660 μg/cm at 48 hours; and from about 139 μg/cm2 to about 854 μg/cm at 72 hours, as determined via an in-vitro permeation test utilizing a Valia-Chien cell where the membrane is a human cadaver skin and the cell has a receptor chamber containing a 40:60 mixture of ethanol:water.
In certain embodiments, the transdermal delivery system maintains a plasma level of loratadine at steady-state from about 1 to about 3 ng/ml.
In certain embodiments, the transdermal delivery system maintains an effective mean relative release rate to provide a therapeutic blood level of the loratadine within three days from the initiation of the dosing interval, and thereafter maintaining a therapeutic blood level until the end of at least the five-day dosing interval.
In certain embodiments, the transdermal delivery system provides a mean relative release rate of loratadine effective to provide a plasma level of loratadine of at least about 0.1 ng/ml within about 6 hours, 3 hours, 2 hours, 1 hour or 0.5 hours after application of the transdermal delivery system onto the skin of the patient.
In certain embodiments, the transdermal delivery system maintains a plasma level of loratadine at steady-state from about 1 to about 3 ng/ml.
In certain embodiments, the transdermal delivery system maintains a therapeutic plasma level from about 0.1 ng/ml to about 3.3 ng/ml during the dosing interval for the transdermal delivery system.
In certain embodiments, the transdermal delivery system provides a mean relative release rate from about 1.0 μm/hour/cm2 to about 30.0 μm/hour/cm2 or about 1.8 μg/hour/cm2 to about 17 μg/hour/cm2 of the transdermal delivery system.
In certain embodiments, the transdermal delivery system provides a mean relative release rate from about 2.8 μg/cm2/hr to about 16.2 μg/cm2/hr at 24 hours; from about 2.3 μg/cm2/hr to about 13.7 μg/cm2/hr at 48 hours; and from about 2.0 μg/cm2/hr to about 11.9 μg/cm2/hr at 72 hours; and from about 1.8 μg/cm2/hr to about 9.9 μg/cm2 /hr at 96 hours; as determined via an in-vitro permeation test utilizing a Valia-Chien cell where the membrane is a human cadaver skin and the cell has a receptor chamber containing a 40:60 mixture of ethanol:water.
In certain embodiments, the transdermal delivery system provides an in-vitro cumulative amount of permeation of from about 63 μg/cm to about 388 μg/cm2 at 24 hours; from about 105 μg/cm2 to about 660 μg/cm2 at 48 hours; and from about 139 μg/cm2 to about 854 μg/cm2 a 72 hours; and from about 162 μg/cm2 to about 955 μg/cm2 at 96 hours; as determined via an in-vitro permeation test utilizing a Valia-Chien cell where the membrane is a human cadaver skin and the cell has a receptor chamber containing a 40:60 mixture of ethanol:water.
In further embodiments, the invention is directed to a transdermal device and method which, when applied to the skin of a mammal such as a human patient, provides therapeutically effective blood plasma levels of loratadine to effectively treat seasonal allergic rhinitis, chronic idiopathic urticaria, or both conditions in a human patient, wherein the transdermal device is maintained in contact with the patient's skin for at least 5 days, the transdermal delivery system maintaining an effective mean relative release rate to provide a therapeutic blood level of the loratadine within three days from the initiation of the dosing interval, and thereafter maintaining a therapeutic blood level until the end of at least the five-day dosing interval.
The invention is further directed to a transdermal loratadine device for the effective treatment of seasonal allergic rhinitis, chronic idiopathic urticaria, or both conditions in a human patient, which device, when applied to the skin of a patient maintained in contact with the patient's skin for at least 3 days, has an effective mean relative release rate to provide a therapeutic blood level of the loratadine within 36 hours from the initiation of the dosing interval, and thereafter maintains a therapeutic blood level until the end of at least the three-day dosing interval.
The invention is further directed in part to a transdermal loratadine device for the treatment of chronic allergic rhinitis and chronic idiopathic urticaria which provides substantially zero order pharmacokinetics over a significant portion of the dosage interval.
The invention is further directed to a transdermal device and a method of effectively treating seasonal allergic rhinitis, chronic idiopathic urticaria, or both conditions in a human patient, comprising applying the transdermal loratadine device to the skin of the patient and maintaining the transdermal delivery system in contact with the skin of a patient for at least 5 days, the transdermal delivery system maintaining an effective mean relative release rate to provide a substantially first order plasma level increase of loratadine from the initiation of the dosing interval until about 48 to about 72 hours after the initiation of the dosing interval; and thereafter providing an effective mean relative release rate to provide a substantially zero order plasma level fluctuation of loratadine until the end of at least the five-day dosing interval.
The invention is further directed to a transdermal loratadine device which when applied to the skin of a patient and maintained in contact with the patient's skin for at least 3 days, has an effective mean relative release rate to provide a substantially first order plasma level increase of loratadine from the initiation of the dosing interval until about 24 hours after the initiation of the dosing interval; and thereafter provides an effective mean relative release rate to provide a substantially zero order plasma level fluctuation of loratadine until the end of at least the three-day dosing interval.
The invention is further directed to a transdermal loratadine device and a method for lessening the incidence of side-effects in a patient associated with the oral administration of loratadine, wherein the method comprises administering the loratadine in a transdermal dosage form over at least twenty-four hours and thereby lessening the incidence of side effects.
The invention is further directed to a transdermal loratadine device and method which provides for reduced side-effects and for avoids peak plasma concentrations of loratadine in a patient associated with the oral administration of loratadine (i.e., reduces the peak plasma level relative to immediate release orally delivered loratadine), via the administration of loratadine in a transdermal dosage form over at least twenty-four hours, thereby lessening the incidence of side effects and avoiding the peak plasma concentrations of loratadine.
In certain embodiments, the invention is directed to transdermal delivery devices which are suitable for attaining any of the above methods.
For example, the above methods can be achieved utilizing a transdermal therapeutic system for the administration of loratadine to the skin comprising a backing layer which is impermeable to the active substance, a pressure-sensitive adhesive reservoir layer, and optionally a removable protective layer, the reservoir layer by weight comprising 20 to 90% of a polymeric matrix, 0.1 to 30% of a softening agent, 0.1 to 20% of loratadine base or of a pharmaceutically acceptable salt thereof and 0.1 to 30% of a solvent for the loratadine or salt thereof.
Another alternative is to utilize a laminated composite for administering loratadine or a pharmaceutically acceptable salt thereof to an individual transdermally comprising

    
    
        (a) a polymer backing layer that is substantially impermeable to loratadine or the pharmaceutically acceptable salt thereof; and
        (b) a reservoir layer comprising an acrylate or silicone pressure-sensitive adhesive, 0.1 to 20% of loratadine base or of a pharmaceutically acceptable salt thereof, 0.1 to 30% of an ester of a carboxylic acid acting as a softening agent and 0.1 to 30% of a solvent for loratadine having at least one acidic group.
    
    


The methods of the present invention are described in further detail in the following sections. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. However, it should be understood that for purposes of the present invention, the following terms have the following meanings:
The term “effective treatment of seasonal allergic rhinitis or chronic idiopathic urticaria” is defined for purposes of the present invention as a satisfactory reduction in or elimination of the symptoms associated with seasonal allergic rhinitis and chronic idiopathic urticaria, along with the process of a tolerable level of side effects, as determined by the human patient.
Drug release from membrane-controlled systems may be defined as follows:

Amount released per area unit Q=const (zero order kinetics)

The term “mean relative release rate” is determined from the amount of drug released per unit time from the transdermal delivery system through the skin and into the bloodstream of a human patient. Mean relative release rate may be expressed, e.g., as μg/cm2/hr. For example, a transdermal delivery system that releases 10 mg of loratadine over a time period of 24 hours is considered to have a relative release rate of 420 μg/hr. For purposes of the invention, it is understood that relative release rates may change between any particular time points within a particular dosing interval, and the term therefore only reflects the overall release rate during the particular dosing interval. For purposes of the present invention, relative release rate should be considered synonymous with the term “flux rate”.
The term “sustained release” is defined for purposes of the present invention as the release of the drug (loratadine) from the transdermal formulation at such a rate that blood (e.g., plasma) concentrations (levels) are maintained within the therapeutic range (above the minimum effective concentration) but below the upper limit of the therapeutic window over a period of time of about 3 days or longer.
The term “steady state” means that the blood plasma concentration curve for a given drug has been substantially repeated from dose to dose.
The term “minimum effective concentration” is defined for purposes of this invention as the minimum effective therapeutic blood plasma level of the drug at which at least some therapeutic effect in treating seasonal allergic rhinitis or chronic idiopathic urticaria is achieved in a given patient.
The term “overage” means for the purposes of the present invention the amount of loratadine contained in a transdermal delivery system which is not delivered to the patient. The overage is necessary for creating a concentration gradient by means of which the active agent (e.g., loratadine) migrates through the layers of the transdermal dosage form to the desired site on a patient's skin.
The term “first order” pharmacokinetics is defined as plasma concentrations which increase over a specified time period.
The term “zero order” pharmacokinetics contemplates an amount of drug released from a loratadine formulation which substantially maintains plasma concentrations at a relatively constant level. For purposes of the present invention, a relatively constant plasma concentration is defined as a concentration which does not decrease more than about 30% over a 48 hour time period.
Drug release from membrane-controlled systems may be defined as follows:

Amount released per area unit Q=const (zero order kinetics)

The term “mean relative release rate” is determined from the amount of drug released per unit time from the transdermal delivery system through the skin and into the bloodstream of a human patient. Mean relative release rate may be expressed, e.g, as μg/cm2/hr. For example, a transdermal delivery system that releases 10 mg of loratadine over a time period of 24 hours is considered to have a relative release rate of 4.1×10−4 μg/hr. For purposes of the invention, it is understood that relative release rates may change between any particular time points within a particular dosing interval, and the term therefore only reflects the overall release rate during the particular dosing interval. For purposes of the present invention, relative release rate should be considered synonymous with the term “flux rate”.
The term “sustained release” is defined for purposes of the present invention as the release of the drug from the transdermal formulation at such a rate that blood (e.g., plasma) concentrations (levels) are maintained within the therapeutic range (above the minimum effective drug concentration or “MEDC”) but below toxic levels over a period of time of about 3 days or longer.
The term “steady state” means that the blood plasma concentration curve for a given drug has been substantially repeated from dose to dose.
The term “minimum effective concentration” is defined for purposes of this invention as the minimum effective therapeutic blood plasma level of the drug at which at least some relief of the seasonal allergic rhinitis or chronic idiopathic urticaria symptoms is achieved in a given patient.
For purposes of the present invention, the term “loratadine” shall include loratadine base, pharmaceutically acceptable salts thereof, stereoisomers thereof, enantiomers thereof, ethers thereof, and mixtures thereof.
For purposes of the present invention, the terms “transdermal delivery device” and “transdermal delivery system” are interchangeable.



BRIEF DESCRIPTION OF THE DRAWINGS
The following drawings are illustrative of embodiments of the invention and are not meant to limit the scope of the invention as encompassed by the claims.
FIG. 1 is a graphical representation of the cumulative amounts of loratadine resulting from 3 permeation tests of Example 1 through human cadaver skin.
FIG. 2 is a graphical representation of the average loratadine permeation rate (flux rate) of Example 2 through human cadaver skin.
FIG. 3 is a graphical representation of the average cumulative amount of loratadine resulting from 4 permeation tests of Example 2 through human cadaver skin.
FIG. 4 is a graphical representation of the cumulative amounts of loratadine resulting from 3 permeation tests of Example 3 through human cadaver skin.
FIG. 5 is a graphical representation of the cumulative amounts of loratadine resulting from 3 permeation tests of Example 4 through human cadaver skin.
FIG. 6 is graphical representation of the average loratadine permeation rates (flux rates) of Examples 5, 6, and 7 through human cadaver skin.
FIG. 7 is a graphical representation of the average cumulative amounts of loratadine resulting from permeation tests of Examples 5, 6, and 7 through human cadaver skin.
FIG. 8 is a graphical representation of the average cumulative amounts of loratadine resulting from permeation tests of Examples 8, 9, and 10 through human cadaver skin.
FIG. 9 is a graphical representation of the average loratadine permeation rates (flux rates) of Examples 8, 9, and 10 through human cadaver skin.
FIG. 10 is a graphical representation of the average cumulative amounts of loratadine resulting from permeation tests of Examples 11, 12, and 9 through human cadaver skin.
FIG. 11 is a graphical representation of the average cumulative amounts of loratadine resulting from permeation tests of Examples 13 and 14 through human cadaver skin.
FIG. 12 is a graphical representation of the average loratadine permeation rates (flux rates) of Examples 13 and 14 through human cadaver skin.
FIG. 13 is a graphical representation of the average cumulative amounts of loratadine resulting from permeation tests of Examples 15 and 16 through human cadaver skin.
FIG. 14 is a graphical representation of the average loratadine permeation rates (flux rates) of Examples 15 and 16 through human cadaver skin.



DETAILED DESCRIPTION
Transdermal delivery of active agents is measured in terms of “relative release rate” or “flux”, i.e., the rate of penetration of the active agent through the skin of an individual. Skin flux may be generally determined from the following equation:

dm/dT=J=P*C 

where J is the skin flux, P is the permeability coefficient and C is the concentration gradient across the membrane, assumed to be the same as the donor concentration. M represents the amount of drug entering the blood stream. The variable dm/dT represents the change in the amount of drug entering the blood stream over time.

It is well understood in the art of transdermal delivery systems that in order to maintain a desired flux rate for a desired dosing period, it is necessary to include an overage of active agent in the transdermal delivery system in an amount that is substantially greater than the amount to be delivered to the patient over the desired time period. For example, to maintain the desired flux rate for a three day time period, it is considered necessary to include much greater than 100% of a three-day dose of an active agent in a transdermal delivery system. This overage is necessary for creating a concentration gradient by means of which the active agent migrates through the layers of the transdermal delivery system to the desired site on a patient'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's blood stream is less than the total amount available. The amount of overage to be included in a transdermal delivery system is dependent on these and other factors known to the skilled artisan.
It has been found that it is possible to treat seasonal allergic rhinitis and chronic idiopathic urticaria according to the present invention by providing a transdermal delivery system containing a sufficient amount of loratadine to provide a desired relative release rate for at least about 3 days, and after single administration (application) of the transdermal dosage form, leaving the dosage form on the skin for approximately a 3 to 8 day time period, thereby resulting in the flux being maintained over the prolonged period and effective blood plasma levels and management of seasonal allergic rhinitis or chronic idiopathic urticaria being maintained over the prolonged period. Preferably, the desired flux is maintained at least about 5, preferably at least about 7 days after application of the transdermal delivery system.
Transdermal dosage forms used in accordance with the invention preferably include a backing layer made of pharmaceutically acceptable material which is impermeable to loratadine. The backing layer preferably serves as a protective cover for the active agent, e.g. loratadine and may also provide a support function. Examples of materials suitable for making the backing layer are films of high and low density polyethylene, polypropylene, polyvinylchloride, polyurethane, polyesters such as poly(ethylene terephthalate), metal foils, metal foil laminates of such suitable polymer films, textile fabrics, if the components of the reservoir cannot penetrate the fabric due to their physical properties and the like. Preferably, the materials used for the backing layer are laminates of such polymer films with a metal foil such as aluminum foil. The backing layer can be any appropriate thickness which will provide the desired protective and support functions. A suitable thickness will be from about 10 to about 200 microns. Desirable materials and thickness will be apparent to the skilled artisan.
Matrix Systems
In certain preferred embodiments, the transdermal dosage forms used in accordance with the invention contain a polymer matrix layer. Generally, the polymers used to form the biologically acceptable polymer matrix are those capable of forming thin walls or coatings through which pharmaceuticals can pass at a controlled rate. A non-limiting list of exemplary materials for inclusion in the polymer matrix includes polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethylacrylate copolymers, ethylene vinyl acetate copolymers, silicones, rubber, rubber-like synthetic homo-, co- or block polymers, polyacrylic esters and the copolymers thereof, polyurethanes, polyisobutylene, chlorinated polyethylene, polyvinylchloride, vinyl chloride-vinyl acetate copolymer, polymethacrylate polymer (hydrogel), polyvinylidene chloride, poly(ethylene terephthalate), ethylene-vinyl alcohol copolymer, ethylene-vinyloxyethanol copolymer, silicones including silicone copolymers such as polysiloxane-polymethacrylate copolymers, cellulose polymers (e.g., ethyl cellulose, and cellulose esters), polycarbonates, polytetrafluoroethylene and mixtures thereof.
Preferred materials for inclusion in the polymer matrix layer are silicone elastomers of the general polydimethylsiloxane structures, (e.g., silicone polymers). Preferred silicone polymers cross-link and are pharmaceutically acceptable. Other preferred materials for inclusion in the polymer matrix layer include: silicone polymers that are cross-linkable copolymers having dimethyl and/or dimethylvinyl siloxane units which can be crosslinked using a suitable peroxide catalyst. Also preferred are those polymers consisting of block copolymers based on styrene and 1,3-dienes (particularly linear styrene-isoprene-block copolymers of styrene-butadiene-block copolymers), polyisobutylenes, polymers based on acrylate and/or methacrylate.
The polymer matrix layer may optionally include a pharmaceutically acceptable cross-linking agent. Suitable crosslinking agents include, e.g., tetrapropoxy silane.
Preferred transdermal delivery systems used in accordance with the methods of the present invention include an adhesive layer to affix the dosage form to the skin of the patient for a desired period of administration, e.g., about 3 to about 8 days. If the adhesive layer of the dosage form fails to provide adhesion for the desired period of time, it is possible to maintain contact between the dosage form with the skin by, for instance, affixing the dosage form to the skin of the patient with an adhesive tape, e.g, surgical tape. It is not critical for purposes of the present invention whether adhesion of the dosage form to the skin of the patient is achieved solely by the adhesive layer of the dosage form or in connection with a peripheral adhesive source, such as surgical tape, provided that the dosage form is adhered to the patient's skin for the requisite administration period.
The adhesive layer preferably includes using any adhesive known in the art that is pharmaceutically compatible with the dosage form and preferably hypoallergenic, such as polyacrylic adhesive polymers, acrylate copolymers (e.g., polyacrylate) and polyisobutylene adhesive polymers. In other preferred embodiments of the invention, the adhesive is a pressure-sensitive contact adhesive, which is preferably hypoallergenic.
The transdermal dosage forms which can be used in accordance with the present invention may optionally include a permeation enhancing agent. Permeation enhancing agents are compounds which promote penetration and/or absorption of the loratadine into the blood stream of the patient. A non-limiting list of permeation enhancing agents includes polyethylene glycols, surfactants, and the like.
Alternatively, permeation of loratadine may be enhanced by occlusion of the dosage form after application to the desired site on the patient with, e.g. an occlusive bandage. Permeation may also be enhanced by removing hair from the application site by, e.g. clipping, shaving or use of a depilatory agent. Another permeation enhancer is heat. It is thought that heat enhancement can be induced by, among other things, using a radiating heat form, such as an infrared lamp, onto the application site after application of the transdermal dosage form. Other means of enhancing permeation of loratadine such as the use of iontophoretic means are also contemplated to be within the scope of the present invention.
A preferred transdermal dosage form which may be used in accordance with the present invention includes a non-permeable backing layer made, for example, of polyester; an adhesive layer made, for example of a polyacrylate; and a matrix containing the loratadine and other desirable pharmaceutical aids such as softeners, permeability enhancers, viscosity agents and the like.
The active agent may be included in the device in a drug reservoir, drug matrix or drug/adhesive layer. Preferably, the active agent is loratadine or a pharmaceutically acceptable salt thereof.
Certain preferred transdermal delivery systems also include a softening agent. Suitable softening agents include higher alcohols such as dodecanol, undecanol, octanol, esters of carboxylic acids, wherein the alcohol component may also be a polyethoxylated alcohol, diesters of dicarboxylic acids, such as di-n-butyladiapate, and triglycerides particularly medium-chain triglycerides of the caprylic/capric acids or coconut oil, have proved to be particularly suitable. Further examples of suitable softeners are multivalent alcohols, for example, levulinic acid, cocprylic acids glycerol and 1,2-propanediol which can also be etherified by polyethylene glycols.
A loratadine solvent may also be included in the transdermal delivery systems of the present invention. Preferably, the solvents dissolve the loratadine to a sufficient extent thereby avoiding complete salt formation. A non-limiting list of suitable solvents include those with at least one acidic group. Particularly suitable are monoesters of dicarboxylic acids such as monomethylglutarate and monomethyladipate.
Other pharmaceutically acceptable compounds which may be included in the reservoir or matrix include: solvents, for example alcohols such as isopropanol; permeation enhancing agents such as those described above; and viscosity agents, such as cellulose derivatives, natural or synthetic gums, such as guar gum, and the like.
In preferred embodiments, the transdermal dosage form includes a removable protective layer. The removable protective layer is removed prior to application, and consists of the materials used for the production of the backing layer described above provided that they are rendered removable, for example, by a silicone treatment. Other removable protective layers, for example, are polyltetra-fluoroethylene, treated paper, allophane, polyvinyl chloride, and the like. Generally, the removable protective layer is in contact with the adhesive layer and provides a convenient means of maintaining the integrity of the adhesive layer until the desired time of application.
The composition of the transdermal dosage forms used in accordance with the invention and the type of device used are not considered critical to the method of the invention, provided that the device delivers the active agent, e.g. loratadine, for the desired time period and at the desired flux rate and/or the desired delivery rate of the transdermal dosage form.
Certain transdermal dosage forms for use in accordance with the present invention are described in U.S. Pat. No. 5,240,711 (Hille, et. al.; assigned to LTS Lohmann Therapie-Systeme GmbH & 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 '711 patent includes: (i) a polyester backing layer which is impermeable to the drug; (ii) a polyacrylate adhesive layer; (iii) a separating polyester layer; and (iv) a matrix containing loratadine, a solvent for the loratadine, a softener and a polyacrylate adhesive. The loratadine solvent may or may not be present in the final formulation. The transdermal delivery device described therein includes a backing layer which is impermeable to the active substance, a pressure-sensitive adhesive reservoir layer and optionally, a removable protective layer. Preferably, the reservoir layer includes about 10 to about 95%-wt polymeric material, about 0.1 to about 40%-wt softener, about 0.1 to about 30%-wt loratadine. A solvent for the loratadine base or pharmaceutically acceptable salt thereof may be included as about 0.1 to about 30%-wt.
The transdermal delivery system may also be prepared in accordance with the disclosure of International Patent Application No. WO 96/19975 (Hille, et. al.; assigned to LTS Lohmann Therapie-Systeme GMBH), hereby incorporated by reference, where loratadine is substituted for buprenorphine as an active agent. In this device, the loratadine transdermal delivery device contains resorption-promoting auxiliary substances. The resorption-promoting auxiliary substance forms an undercooled mass. The delivery system contains 10% loratadine base, 10-15% acid (such as levulinic acid), about 10% softener (such as oleyoleate); 55-70% polyacrylate; and 0-10% polyvinylpyrollidone (PVP).
Reservoir Devices
Alternatively, the transdermal device may be a reservoir system. A reservoir system transdermal drug delivery patch comprises several different components. An exemplary construction includes a backing layer, an active drug and optional permeation enhancing solvent gel, a membrane, a skin contact adhesive layer, and a protective release coated liner film. Characteristics of each component are set forth below:
Backing Film: This layer is exposed to the external environment when the system is worn on the skin surface. It is impervious to penetration of the active drug contained within the system preventing the escape of the active drug through the backing film. The backing film serves as barrier layer. Moisture, soaps, lotions and other elements are prevented from entering the system and diluting the active ingredients or altering the release characteristics of the system. The active drug and solvent are contained within the system to perform its designated function. The backing film also forms one half of the chamber which contains the active drug reservoir. The backing film must be capable of being suitably attached to the membrane in order to form the reservoir chamber. Typical attachment methods include thermal, ultrasonic polymer heat seal or welding, and adhesive bonding. Necessary mechanical properties include a low compliance for conformability to the skin surface and elasticity to allow for movement with the skin surface. Typical thickness is in the range of 0.5-25.0 mil. A wide range of homogenous, woven, and non-woven polymer or composite materials are suitable as backing films.
Membrane: The membrane in combination with the backing film forms the chamber which contains the active drug reservoir. The membrane is attached to the backing film, and provides a support surface for the skin contact adhesive. The membrane can be a homogenous polymer film, or a material with a porous structure. The membrane may also be designed to control the transport rate of the active drug and/or the permeation enhancing solvent. Necessary mechanical properties include a low compliance for conformability to the skin surface and elasticity to allow for movement with the skin surface. Typical thickness is in the range of 0.25-30.0 mil and more preferably in the range of 0.5 to 25.0 mils. A wide range of homogenous, porous, woven, and non-woven polymer or composite materials are suitable as membranes and known in the art.
Active Drug Reservoir: The active drug is combined with a liquid vehicle to fill the reservoir chamber. A range of solvents can be used for the liquid vehicle. The solvents can be chosen to optimize skin permeation of the active (enhancers) or to optimize the permeation characteristics of the membrane or the adhesion of the skin contact adhesive. A viscosity increasing agent is often included in the vehicle to aid in the handling and system manufacturing process. The composition of the vehicle must be compatible with the other components of the system. The vehicle may be in the form of a solution, suspension, cream, lotion, gel, physical mixture or emulsion. This list is not meant to be exhaustive.
Skin Contact Adhesive: The system is affixed to the skin with a skin contact adhesive. The adhesive may cover the entire surface of the system membrane, be applied in an intermittent pattern, or only to the perimeter of the system. The adhesive composition must be of materials suitable for skin contact without creating intolerable adverse effects such as excessive skin irritation or sensitization. Adequate adhesion to the membrane and skin are also necessary. The adhesive must also possess enough cohesive integrity to remain completely on the membrane upon removal of the system. The adhesive is applied in a thickness to provide a weight of 0.025 to 50.0 mg/cm2, more preferably 0.25 to 1.0 mg/cm2 and most preferably 0.3 to 0.6 mg/cm2. Typical materials include silicone, polyisobutylene (PIB), and acrylates dissolved in organic solvents, aqueous emulsions, or directly applied by hot melt processing.
Release Coated Liner Film: The liner film is removed from the system before application to the skin surface. The liner film serves the function as a protective barrier to the skin contact adhesive prior to use. The coating on the liner provides a release capability for the adhesive, allowing separation of the liner from the adhesive. A coating is not necessary if the liner material is readily removed from the adhesive without disrupting the reservoir system. Typical thickness is in the range of 0.5-25.0 mil. A wide range of homogenous, woven, and non-woven paper, polymer or composite materials are suitable as liner films. Release coatings are typically composed of paraffin, polyethylene, silicone or fluorocarbons.
In other embodiments, the transdermal delivery system may be a plaster such as that described in U.S. Pat. No. 5,225,199 to Hidaka et al., hereby incorporated by reference. Such plasters include a film layer including a polyester film of about 0.5 to about 4.9 μm thickness, about 8 to about 85 g/mm strength, respectively in the two directions intersecting substantially at right angles, about 30 to about 150% elongation, in the two directions intersecting substantially at right angles and an elongation ratio of A to B of about 1:0 to about 5.0, wherein A and B represent data in two directions intersecting at right angles, and A is greater than B and wherein the polyester film includes about 0.01 to about 1.0% by weight, based on the total weight of the polyester film, of solid fine particles in which the average particle size is about 0.001 to about 3.0 μm and an adhesive layer which is composed of an adhesive containing transdermally absorbable drugs; wherein the adhesive layer is laminated on the film layer over the surface in about 2 to about 60 μm thickness. The average particle size is substantially not more than 1.5 times the thickness of the polyester film.
The transdermal delivery system used in the present invention may also be prepared in accordance with U.S. Pat. No. 5,879,701, issued Mar. 9, 1999 to Audett, et al., hereby incorporated by reference, wherein solubilization enhancer compositions are provided which facilitate transdermal administration of basic drugs from transdermal systems composed of nonpolar adhesive materials. The solubilization enhancing composition is particularly useful in facilitating the administration of basic drugs using transdermal systems worn for at least four days containing drug reservoirs comprised of nonpolar materials such as polyisobutylene adhesives or the like. The solubilizing enhancing composition itself is preferably a liquid which is an isomeric acid mixture. Examples of suitable solubilizers include, but are not limited to, oleic acid dimer and neodecanoic acid, with oleic acid dimer particularly preferred. The solubilizer constitutes at least about 0.10 wt. % of the reservoir, and preferably represents on the order of 0.25 wt. % to 1.0 wt. % of the reservoir. The amount of enhancer composition present in the drug formulation will depend on a number of factors, e.g., the strength of the particular enhancer composition, the desired increase in skin permeability, and the amount of drug which is necessary to deliver.
The adult oral dosage for loratadine is 10 mg/day. The bioavailability for the drug is 20%, expressed as fraction, 0.20 of the oral dose made available to the blood stream from gastrointestinal absorption. A release rate for a loratadine transdermal delivery system was calculated from this data. 0.20 of the oral 10 mg daily dose provides 2.0 mg of loratadine available into the blood stream. Therefore, an equal dose is required to be delivered transdermally. 2.0 mg/day is converted to 2000 mcg/24 hours. This would require delivery of 83.3 mcg/hour. The largest desirable surface area for a transdermal patch is about 40 cm2. Dividing 83.3 mcg/hour/40 cm2 by 40, yields a release rate of 2.1 mcg/hour/cm2 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 cm2. Dividing 392 mcg/hour/40 cm2 by 40, yields a release rate of 9.8 mcg/hour/cm2 of transdermal patch surface area. One of skill would expect a larger input rate or flux to maintain a steady state concentration in consideration of the loss of drug in the plasma due to elimination. A confirmatory calculation for flux requires further pharmacokinetic parameters. The volume of distribution for loratadine is 1,660,000 ml and the half-life is 8.4 hours. The elimination rate constant is 0.693/half-life. The product of steady state concentration, volume of distribution and elimination rate constant yields a rate of 274 mcg/hour. The largest desirable surface area for a transdermal patch is about 40 cm2. Dividing 274 mcg/hour/40 cm2 by 40, yields a release rate of 6.85 mcg/hour/cm2 of transdermal patch surface area.
Any type of transdermal delivery system may be used in accordance with the methods of the present invention so long as the desired pharmacokinetic and pharmacodynamic response(s) are attained over at least 3 days, e.g., from about 5 to about 8 days. Preferable transdermal delivery systems include e.g., transdermal patches, transdermal plasters, transdermal discs, iontophoretic transdermal devices and the like.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following examples illustrate various aspects of the present invention. They are not to be construed to limit the claims in any manner whatsoever.
Overview of Method of Manufacture: Matrix System
The following general method is used in the following examples in which the transdermal device tested is a matrix system (device):
Step 1: Preparation of the active drug vehicle/solvent/adhesive matrix. Active drug is combined with the liquid vehicle components and the adhesive components using appropriate mixing techniques well known in the art. Simple mechanical mixers, motionless mixers, homogenizers, high shear mixers, and magnetic mixing devices can be employed.
Step 2: Preparation of the active drug/adhesive matrix coated liner. Active drug/adhesive matrix coating is done with continuous web based equipment on a commercial scale. Small sheet batches can be made readily in the lab manually. A mechanism for applying a controlled thickness coating of the active drug/adhesive matrix onto the liner is employed. If solvent-based adhesives are used, a procedure for driving off the solvent and drying the active drug/adhesive matrix is employed. The open surface of the active drug/adhesive matrix on the liner must be protected during processing. A second intermediate liner can be used to cover this active drug/adhesive matrix surface.
Step 3: Laminating of the membrane to active drug/adhesive and/or liner. The membrane is typically applied on line after solvent removal on a commercial scale. This avoids the need for a second liner. A separate web and a heat and/or pressure lamination station bonds the two layers. The membrane provides a non-stick surface to the open side of the adhesive and allows for further processing in a roll form.
Overview of the Manufacture of Reservoir Devices
The following general method is used in the following examples in which the transdermal device tested is a reservoir system (device):
Step 1: Preparation of the adhesive coated liner. Adhesive coating is done with continuous web based equipment on a commercial scale. Small sheet batches can be made readily in the lab manually. A mechanism for applying a controlled thickness coating of the adhesive onto the liner is employed. If solvent-based adhesives are used, a procedure for driving off the solvent and drying the adhesive is employed. The open surface of the adhesive on the liner must be protected during processing. A second intermediate liner can be used to cover this adhesive surface.
Step 2: Laminating of the membrane to adhesive and/or liner. The membrane is typically applied on line after solvent removal on a commercial scale. This avoids the need for a second liner. A separate web and a heat and/or pressure lamination station bonds the two layers. The membrane provides a non-stick surface to the open side of the adhesive and allows for further processing in a roll form.
Step 3: Preparation of the active vehicle/solvent combination. Active drug is combined with the liquid vehicle components using appropriate mixing techniques well known in the art. Simple mechanical mixers, motionless mixers, homogenizers, high shear mixers, and magnetic mixing devices can be employed. Other ingredients are also incorporated at this time. These may include permeation enhancers and viscosity thickeners, for example.
Step 4: Finalizing the delivery system utilizing the form, fill and seal process incorporating the reservoir and backing film. This process can be carried out in either a horizontal or vertical plane. The horizontal mode requires a thickened viscosity of the reservoir vehicle, while the vertical mode can handle liquid vehicles of minimal viscosity. In the horizontal mode a dispensing head places a fixed volume drop of the drug vehicle onto the surface of the membrane. The backing film is then placed over the drop of vehicle, and then bound to the membrane to enclose the active/vehicle. A heated die is commonly used to form a heat seal welded bond. In web based systems a die cutting and packaging station often follows.
In-vitro Skin Permeation Test Method
The test methods utilized in the following examples involves the use of a permeation cell. Several permeation cell designs are available for in-vitro permeation testing. These include “Franz cells”, “Valia-Chien cells”, and “Bronaugh cells”. Each cell design shares several common characteristics. All cells are made with a definable surface area for permeation. All cells contain two chambers and a clamping mechanism to hold the test membrane positioned between the two cell chambers. Several exemplary test membranes include mouse skin and human cadaver skin. The membrane may be oriented in either the horizontal or vertical plane based on the cell special arrangement. One chamber serves as a reservoir (donor) for the drug to be tested, the second is a place where the permeated drug is accumulated (receptor). The receptor is often chosen to mimic the physiological conditions found beneath the membrane in-vivo. In the case where a complete transdermal system is the donor, it is clamped between the two chambers and only the receptor chamber is filled.
Calculation of the permeation rate (J) requires knowledge of the concentration (C) of the drug in the receptor chamber, the permeation area (A), sampling interval (t) and the receptor volume (V). The equation below is typical:
J=CV/At where:

    
    
        J=micrograms/cm2-hr
        C=micrograms/ml
        V=ml
        A=cm2 
        t=hr
    
    


Only the drug concentration and testing time vary in typical experiments. The drug concentration is determined by any appropriate analytical technique such as high performance liquid chromatograpy, gas chromatograpy, or ultraviolet spectrophotometry. Other considerations in the testing system may include temperature control systems, receptor stirring systems, flow through receptor chambers, and automated sampling equipment utilizing pumps and fraction collectors. Partial receptor sampling protocols have been used in situations where the sensitivity of the analytical method for determining the drug concentration was less than optimal.
Sample Testing Protocols for Loratadine Follow.













Cells
Valia Chien


Membrane
Human cadaver skin


A (cm2)
0.636


V (ml)
4.0


receptor
Ethanol/water 40/60


sampling points
6, 24, 48, 72, 120, 144, 168 hours


sampling mode:
partial, 0.6 ml per point, replace with fresh receptor.









HPLC Conditions for Determination of Drug Concentration
















Column
Altima C8, 5 um, 4.6 mm × 15 cm



Mobile phase
Acetonitrile/Buffer 70/30



Buffer:
0.01M phosphate at pH 4.5



Flow rate
1 ml/min



UV detection
205 nm



Injection volume
20 microliters



Retention time
5.0 minutes









EXAMPLE 1
A Loratadine drug reservoir formulation was prepared having the formulation set forth in Table 1A below:









TABLE 1A






Ingredient
Amount (gm)








Loratadine
 0.5



Ethanol
12.2



Water
15  



Total
27.7



Ethylvinylacetate membrane









The formulation of Table 1A was prepared and incorporated into a permeation testing apparatus according to the following procedure:

    
    
        1. Loratadine is dissolved with ethanol and water and the solution is placed into the donor cell.
        2. The ethylvinylacetate membrane is placed against the donor cell.
        3. Thereafter, the human cadaver skin is placed between the membrane and the receptor cell and the apparatus is secured.
    
    


The formulation of Example 1 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (1-1, 1-2, 1-3) were conducted giving the results listed in Table 1B below:
















TABLE 1B











Drug











Loss due


Amount



Sam-

Recep-

Sam-
to

Cumulative
Per-



pling
Drug
tor
Drug
pling
Sam-
Cumulative
Amount
meated


Test
Time
Conc.
Volume
amount
Volume
pling
Drug Loss
Permeated
per cm2


#
(Hours)
(μg/ml)
(ml)
(μg)
(ml)
(μg)
(μg)
(μg)
(μg/cm2)
























1-1
1
0.000
4
0.000
4
0.000
0.000
0.000
0.000



2
0.177
4
0.708
4
0.708
0.000
0.708
1.113



16
14.449
4
57.796
4
57.796
0.708
58.504
91.959



17
0.914
4
3.656
4
3.656
58.504
62.160
97.705



24
6.666
4
26.664
4
26.664
62.160
88.824
139.616



42
18.644
4
74.576
4
74.576
88.824
163.400
256.837



48
6.639
4
26.556
4
26.556
163.400
189.956
298.579



168
120.233
4
480.932
4
480.932
189.956
670.888
1054.524


1-2
1
0.000
4
0.000
4
0.000
0.000
0.000
0.000



2
0.154
4
0.616
4
0.616
0.000
0.616
0.968



16
11.703
4
46.812
4
46.812
0.616
41.428
74.549



17
0.433
4
1.732
4
1.732
47.428
49.160
77.271



24
5.388
4
21.552
4
21.552
49.160
70.712
111.147



42
15.636
4
62.544
4
62.544
70.712
133.256
209.456



48
5.223
4
20.892
4
20.892
133.256
154.148
242.295



168
113.298
4
453.192
4
453.192
154.148
607.340
945.637


1-3
1
0.000
4
0.000
4
0.000
0.000
0.000
0.000



2
0.019
4
0.076
4
0.076
0.000
0.076
0.119



16
10.734
4
42.936
4
42.936
0.076
43.012
67.608



17
0.547
4
2.188
4
2.188
43.012
45.200
71.047



24
4.741
4
18.964
4
18.964
45.200
64.064
100.855



42
15.189
4
60.756
4
60.756
64.164
124.920
196.353



48
4.950
4
19.800
4
19.800
124.920
144.720
227.476



168
107.974
4
431.896
4
431.896
144.720
576.616
906.344









Based on the permeation results of Example 1, listed in Table 1B, the averages of the three calculated and the flux results listed in Table 1C below were obtained:













TABLE 1C









Avg. of








all 3




Hours
Test 1-1
Test 1-2
Test 1-3
tests
Std Dev
μg/cm2/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


F4-76
6.435
5.245
4.957
5.546
0.784



CORR
1.000
1.000
0.999
1.000









EXAMPLE 2
A Loratadine reservoir and adhesive formulation was prepared having the formulation set forth in Table 2A below:









TABLE 2A






Ingredient
Amount (gm)








Loratadine
 1.0



Ethanol
22.0



Water
27.0



Total
50.0



Polyethylene membrane




Silicone adhesive









The formulation of Table 2A was prepared and incorporated into a permeation testing apparatus according to the following procedure:

    
    
        1. Loratadine is dissolved with ethanol and water and the solution is placed into the donor cell.
        2. The polyethylene membrane is coated with a silicone adhesive and placed against the donor cell. The adhesive coated membrane is positioned opposite from the donor cell.
        3. Thereafter, the human cadaver skin is placed between the adhesive coated polyethylene membrane and the receptor cell and the apparatus is secured.
    
    


The formulation of Example 2 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (2-1, 2-2, 2-3) were conducted giving the results listed in Table 2B below:







TABLE 2B







μg/cm2


















Avg. of








all 4



Hours
Test 2-1
Test 2-2
Test 2-3
Test 2-4
tests
Std Dev
















6
5.608
7.362
6.344
4.231
5.886
1.317


24
87.325
83.930
66.665
66.771
76.173
11.005


30
125.489
120.132
91.229
92.763
107.406
17.936


48
228.840
220.207
158.202
165.954
193.307
36.363


54
271.600
262.829
183.313
193.688
227.858
45.783


72
381.257
368.375
249.607
269.632
317.218
67.215


78
425.099
409.871
273.618
297.447
351.509
77.053


96
544.508
521.226
343.427
375.668
446.207
101.375


102
592.644
565.193
368.375
404.470
482.671
112.669


120
715.385
675.064
436.674
483.691
577.704
138.037


144
892.983
836.158
536.473
598.510
716.031
174.924


168
1046.419
982.364
627.249
701.572
839.401
205.994









Based on the permeation results of Example 2, listed in Table 2B, the following flux results listed in Table 2C below were obtained:







TABLE 2C







μg/cm2/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


F6-96
6.066
5.815
3.770
4.173
4.956
1.153


CORR
0.998
0.998
1.000
0.999
0.999









EXAMPLE 3
A Loratadine active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 3A below:









TABLE 3A






Ingredient
Amount (gm)


















Loratadine
0.23



Ethyl Acetate
1.77



BIO PSA 7-4302 (adhesive solution)
16.3



containing 9.8 gm silicone adhesive




(60% solids)




Total
18.3









The formulation of Table 3A was prepared and incorporated into a permeation testing apparatus according to the following procedure:

    
    
        1. Loratadine is dispersed in the requisite amount of ethyl acetate and adhesive solution to form the active drug/adhesive matrix.
        2. The active drug/adhesive matrix is applied to a backing layer and dried.
        3. Thereafter, the patch is applied to the human cadaver skin affixed to the receptor cell.
    
    


The formulation of Example 3 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was ethanol:water (40:60) and the membrane was a human cadaver skin membrane. Three permeation tests (3-1, 3-2, 3-3) were conducted giving the results listed in Table 3B below:
















TABLE 3B











Drug











Loss due


Amount



Sam-

Recep-

Sam-
to

Cumulative
Per-



pling
Drug
tor
Drug
pling
Sam-
Cumulative
Amount
meated


Test
Time
Conc.
Volume
amount
Volume
pling
Drug Loss
Permeated
per cm2


#
(Hours)
(μg/ml)
(ml)
(μg)
(ml)
(μg)
(μg)
(μg)
(μg/cm2)
























3-1
 4
3.220
13
41.860
1
3.220
0.000
41.860
23.690



24
34.978
13
454.714
1
34.978
3.220
457.934
259.159



28
35.903
13
466.739
1
35.903
38.198
504.937
285.759



48
55.584
13
722.592
1
55.584
74.101
796.693
450.873



52
49.609
13
644.917
1
49.609
129.685
774.602
438.371



72
60.990
13
792.870
1
60.990
179.294
972.164
550.178



76
54.504
13
708.552
1
54.504
240.284
948.836
536.976



96
61.080
13
794.040
1
61.080
294.788
1088.828
616.201


3-2
 4
4.782
13
62.166
1
4.782
0.000
62.166
35.182



24
37.018
13
481.234
1
37.018
4.782
486.016
275.051



28
38.489
13
500.357
1
38.489
41.800
542.157
306.823



48
54.826
13
712.738
1
54.826
80.289
793.027
448.799



52
54.818
13
712.634
1
54.818
135.115
847.749
479.767



72
61.280
13
796.640
1
61.280
189.933
986.573
558.332



76
59.295
13
770.835
1
59.295
251.213
1022.048
578.409



96
60.455
13
785.915
1
60.455
310.508
1096.423
620.500


3-3
 4
2.418
13
31.434
1
2.418
0.000
31.434
17.789



24
30.875
13
401.375
1
30.875
2.418
403.793
228.519



28
33.696
13
438.048
1
33.696
33.293
471.341
266.746



48
51.182
13
665.366
1
51.182
66.989
732.355
414.462



52
50.819
13
660.647
1
50.819
118.171
778.818
440.757



72
59.651
13
775.463
1
59.651
168.990
944.453
534.495



76
55.812
13
725.556
1
55.812
228.641
954.197
540.010



96
63.094
13
820.222
1
63.094
284.453
1104.675
625.170









Based on the permeation results of Example 3, listed in Table 3B, the averages of all three calculated and the flux results listed in Table 3C below were obtained:













TABLE 3C









Avg. of








all 3




Hours
Test 3-1
Test 3-2
Test 3-3
tests
Std Dev
μg/cm2/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


F4-76
6.917
7.120
7.069
7.036
0.015



CORR
0.970
0.975
0.982
0.976









EXAMPLE 4
A Loratadine active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 4A below:









TABLE 4A






Ingredient
Amount (gm)


















Loratadine
0.23



Ethyl Acetate
1.77



DURO-TAK 87-6430 (adhesive
32.6



solution) containing 9.8 gm




Polyisobutylene adhesive (30%




solids)




Total
34.6









The formulation of Table 4A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3, using DURO-TAK 87-6430 as the adhesive solution.
the formulation of Example 4 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was ethanol:water (40:60). Three permeation tests (4-1, 4-2, 4-3) were conducted giving the results listed in Table 4B below:
















TABLE 4B











Drug











Loss due


Amount



Sam-

Recep-

Sam-
to

Cumulative
Per-



pling
Drug
tor
Drug
pling
Sam-
Cumulative
Amount
meated


Test
Time
Conc.
Volume
amount
Volume
pling
Drug Loss
Permeated
per cm2


#
(Hours)
(μg/ml)
(ml)
(μg)
(ml)
(μg)
(μg)
(μg)
(μg/cm2)
























4-1
 4
0.750
13
9.750
1
0.750
0.000
9.750
5.518



24
8.590
13
111.670
1
8.590
0.750
112.420
63.622



28
9.430
13
122.590
1
9.430
9.340
131.930
74.663



48
13.706
13
178.178
1
13.706
18.770
196.945
111.459



52
12.916
13
167.908
1
12.916
32.476
200.384
113.404



72
15.903
13
206.739
1
15.903
45.392
252.131
142.689



76
15.470
13
201.110
1
15.470
61.295
262.405
148.503



96
16.762
13
217.906
1
16.762
76.765
294.671
166.763


4-2
 4
0.468
13
6.084
1
0.468
0.000
6.084
3.443



24
8.485
13
110.305
1
8.485
0.468
110.773
62.690



28
8.718
13
113.334
1
8.718
8.953
122.287
69.206



48
12.944
13
168.272
1
12.944
17.671
185.943
105.231



52
11.946
13
155.298
1
11.946
30.615
185.913
105.214



72
15.568
13
202.384
1
15.568
42.561
244.945
138.622



76
14.784
13
192.192
1
14.784
58.129
250.321
141.664



96
16.423
13
213.499
1
16.423
72.913
286.412
162.089


4-3
 4
0.660
13
8.580
1
0.660
0.000
8.580
4.856



24
9.734
13
126.542
1
9.734
0.660
127.202
71.988



28
9.973
13
129.649
1
9.973
10.394
140.043
79.255



48
14.864
13
193.232
1
14.864
20.367
213.599
120.882



52
13.830
13
179.790
1
13.830
35.231
215.021
121.687



72
17.243
13
224.159
1
17.243
49.061
273.220
154.624



76
16.208
13
210.704
1
16.208
66.304
277.008
156.767



96
18.495
13
240.435
1
18.495
82.512
322.947
182.766









Based on the permeation results of Example 4, listed in Table 4B, the averages of all three test were calculated and the flux results listed in Table 4C below were obtained:













TABLE 4C









Avg. of








all 3
Std



Hours
Test 4-1
Test 4-2
Test 4-3
tests
Dev
μg/cm2/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


F4-76
1.881
1.820
2.006
1.902
0.095



CORR
0.983
0.984
0.979
0.982









EXAMPLE 5
A Loratadine active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 5A below:









TABLE 5A






Ingredient
Amount (gm)


















Loratadine
0.23



Ethyl Acetate
1.77



DURO-TAK 87-8298 (adhesive
28.8



solution) containing 9.8 gm acrylate




adhesive (38.5% solids)




Total
30.8









The formulation of Table 5A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3, using DURO-TAK 87-8298 as the adhesive solution.
The formulation of Example 5 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Two permeation tests (5-1, 5-2) were conducted giving the results listed in Table 5B below:
















TABLE 5B











Drug











Loss due


Amount



Sam-

Recep-

Sam-
to

Cumulative
Per-



pling
Drug
tor
Drug
pling
Sam-
Cumulative
Amount
meated


Test
Time
Conc.
Volume
amount
Volume
pling
Drug Loss
Permeated
per cm2


#
(Hours)
(μg/ml)
(ml)
(μg)
(ml)
(μg)
(μg)
(μg)
(μg/cm2)
























5-1
6
1.828
12
21.936
1
1.828
0.000
21.936
12.414



24
11.188
12
134.256
1
11.188
1.828
136.08
77.014



48
22.197
12
266.364
1
22.197
13.016
279.38
157.110



72
30.850
12
370.200
1
30.850
35.213
405.41
229.436



96
36.048
12
432.576
1
36.048
66.063
498.64
282.195



120
39.128
12
469.536
1
39.128
102.111
571.65
323.513



148
39.190
12
470.280
1
39.190
141.239
611.52
346.078



168
39.347
12
472.164
1
39.347
180.429
652.59
369.323


5-2
6
0.767
12
9.204
1
0.767
0.000
9.20
5.209



24
6.015
12
72.180
1
6.015
0.767
72.95
41.283



48
12.141
12
145.692
1
12.141
6.782
152.47
86.290



72
17.910
12
214.920
1
17.910
18.923
233.84
132.339



96
21.591
12
259.092
1
21.591
36.833
295.93
167.473



120
24.647
12
295.764
1
24.647
58.424
354.19
200.446



148
27.851
12
334.212
1
27.851
83.071
417.28
236.153



168
29.933
12
359.196
1
29.933
110.922
470.12
266.054









The average of the two permeation tests of Example 5 was calculated and is listed in Table 5C







TABLE 5C







μg/cm2














Average of two



Hours
Test 5-1
Test 5-2
tests
Std Dev














6
12.414
5.209
8.812
5.095


24
77.014
41.283
59.149
25.266


48
158.110
86.290
122.200
50.784


72
229.436
132.339
180.888
68.658


96
282.195
167.473
224.834
81.121


120
323.513
200.446
261.980
87.022


148
346.078
236.153
291.116
77.729


168
369.323
266.054
317.689
73.022









Based on the permeation results of Example 5, listed in Table 5B, the following flux results listed in Table 5D below were obtained:







TABLE 5D







μg/cm2/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


F6-96
3.025
1.820
2.423
0.853


CORR
0.996
0.999
0.997
0.002









EXAMPLE 6
A Loratadine active matrix/adhesive matrix formulation was prepared having the formulation set forth in Table 6A below:









TABLE 6A






Ingredient
Amount (gm)


















Loratadine
0.36



Ethyl Acetate
2.67



BIO PSA 7-4302 (adhesive solution)
19.93



containing 11.96 gm silicone




adhesive (60% solids)




Total
22.96









The formulation of Table 6A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3.
The formulation of Example 6 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (6-1, 6-2, and 6-3) were conducted giving the results listed in Table 6B below:







TABLE 6B







μg/cm2
















Average of



Hours
Test 6-1
Test 6-2
Test 6-3
three tests
Std Dev















6
103.382
105.542
89.338
99.421
8.798


24
385.736
387.593
348.952
374.094
21.793


48
637.848
659.757
591.666
629.757
34.759


72
832.501
854.233
769.620
818.785
43.942


96
897.573
954.671
857.260
903.168
48.946


124
972.628
1026.660
933.732
977.673
46.669


144
1041.228
1107.161
1003.008
1050.466
52.687


168
1051.728
1140.184
1036.631
1076.181
55.940









Based on the permeation results of Example 6, listed in Table 6B, the following flux results listed in Table 6C below were obtained:







TABLE 6C







μg/cm2/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


F6-96
8.831
9.407
8.499
8.912
0.459


CORR
0.970
0.977
0.976
0.974
0.004









EXAMPLE 7
A Loratadine active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 7A below:









TABLE 7A






Ingredient
Amount (gm)


















Loratadine
0.24



Polyisobutylene (adhesive)




MA-24 + mineral oil (adhesive
28.62



solution) (25% solids)




Total
28.86









The formulation of Table 7A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3, using MA-24+ mineral oil as the adhesive solution and without the use of ethyl acetate.
The formulation of Example 7 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (7-1, 7-2, and 7-3) were conducted giving the results listed in Table 7B below:







TABLE 7B







μg/cm2
















Average of



Hours
Test 7-1
Test 7-2
Test 7-3
three tests
Std Dev















6
16.075
2.405
15.945
11.475
7.855


24
99.938
67.530
113.135
93.534
23.467


48
214.922
184.259
249.768
216.316
32.777


72
310.962
294.490
354.921
320.124
32.240


96
334.402
323.299
388.632
348.778
34.958


124
350.720
342.504
415.032
369.419
39.715


144
360.886
352.968
420.276
378.043
36.788


168
359.021
358.228
421.273
379.507
36.172









Based on the permeation results of Example 7, listed in Table 7B, the following flux results listed in Table 7C below were obtained:







TABLE 7C







μg/cm2/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


F6-96
3.697
3.802
4.305
3.934
0.325


CORR
0.979
0.985
0.981
0.981
0.003









EXAMPLE 8
A active drug/adhesive matrix formulation was prepared having the formulation set forth in table 8A below:










TABLE 8A






Ingredient
Amount (gm)




















Loratadine
0.12




Ethyl Acetate
0.89




Silicone (adhesive)
11.49
(60% solids)



BIO PSA 7-4302 (adhesive solution)
19.14




Total
20.15









The formulation of Table 8A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3.
The formulation of Example 8A was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (8-1, 8-2, and 8-3) were conducted giving the results listed in Table 8B below:







TABLE 8B







μg/cm2
















Average of



Hours
Test 8-1
Test 8-2
Test 8-3
three tests
Std Dev















6
49.508
21.195
21.589
30.764
16.234


24
245.430
189.040
202.444
212.305
29.460


48
358.829
323.036
321.963
334.609
20.982


72
420.138
393.948
379.922
398.003
20.412


96
435.580
418.582
401.711
418.624
16.935


124
435.805
432.793
415.518
428.039
10.947


144
444.518
443.853
441.285
443.219
1.707


168
442.115
451.107
436.680
443.301
7.286









Based on the permeation results of Example 8, listed in Table 8B, the following flux results listed in Table 8C below were obtained:







TABLE 8C







μg/cm2/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


F6-96
4.069
4.317
4.037
4.141
0.154


CORR
0.920
0.945
0.930
0.932
0.013









EXAMPLE 9
A active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 9A below:









TABLE 9A






Ingredient
Amount (gm)


















Loratadine
0.24



Ethyl Acetate
1.78



BIO PSA 7-4302 (adhesive solution)
19.38



containing 11.63 silicone adhesive




(60% solids)




Total
21.4









The formulation of Table 9A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3.
The formulation of Example 9A was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (9-1, 9-2, and 9-3) were conducted giving the results listed in Table 9B below:







TABLE 9B







μg/cm2
















Average of



Hours
Test 9-1
Test 9-2
Test 9-3
three tests
Std Dev















6
70.513
52.306
34.329
52.383
18.092


24
325.937
331.333
293.360
316.877
20.544


48
639.013
547.878
503.103
563.331
69.260


72
809.531
697.645
650.643
719.273
81.622


96
856.208
750.846
704.606
770.553
77.699


124
892.737
784.874
746.189
807.933
75.947


144
928.925
836.425
766.745
844.032
81.357


168
919.161
849.990
812.193
860.448
54.245









Based on the permeation results of Example 9, listed in Table 9B, the following flux results listed in Table 9C below were obtained:







TABLE 9C







μg/cm2/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


F6-96
8.921
7.631
7.353
7.968
0.836


CORR
0.962
0.959
0.962
0.961
0.002









EXAMPLE 10
A active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 10A below:









TABLE 10A






Ingredient
Amount (gm)


















Loratadine
0.36



Ethyl Acetate
2.67



BIO PSA 7-4302 (adhesive solution)
19.93



containing 11.96 gm silicone




adhesive (60% solids)




Total
22.96









The formulation of Table 10A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3.
The formulation of Example 10A was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (10-1, 10-2, and 10-3) were conducted giving the results listed in Table 10B below:







TABLE 10B







μg/cm2
















Average of



Hours
Test 10-1
Test 10-2
Test 10-3
three tests
Std Dev















6
103.382
105.542
89.338
99.421
8.798


24
385.736
387.593
348.592
374.094
21.793


48
637.848
659.757
591.666
629.757
34.759


72
832.501
854.233
769.620
818.785
43.942


96
897.573
954.671
857.260
903.168
48.946


124
972.628
1026.660
933.732
977.679
46.669


144
1041.228
1107.161
1003.008
1050.466
52.687


168
1051.728
1140.184
1036.631
1076.181
55.940









Based on the permeation results of Example 10, listed in Table 10B, the following flux results listed in Table 10C below were obtained:







TABLE 10C







μg/cm2/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


F6-96
8.831
9.407
8.499
8.912
0.459


CORR
0.970
0.977
0.976
0.974
0.004









EXAMPLE 11
A active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 11A below:









TABLE 11A






Ingredient
Amount (gm)


















Loratadine
0.4



Ethyl Acetate
3.0



BIO PSA 7-4302 (adhesive solution)
29.3



containing 17.6 gm silicone adhesive




(60% solids)




Transcutol P (solvent)
2.0



Total
34.7









The formulation of Table 11A was prepared and incorporated into a permeation testing apparatus according to the same procedure as in Example 3 using Transcutol P as an additional solvent.
The formulation of Example 11A was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (11-1, 11-2, and 11-3) were conducted giving the results listed in Table 11B below:







TABLE 11B







μg/cm2
















Average of



Hours
Test 11-1
Test 11-2
Test 11-3
three tests
Std Dev















6
133.990
155.952
140.876
143.606
11.233


24
515.838
553.145
539.020
536.001
18.836


30
555.286
591.475
589.167
578.643
20.260


48
683.414
725.466
718.901
709.260
22.623


54
695.520
751.848
742.940
730.103
30.279


72
783.265
845.732
833.738
820.912
33.150


78
782.751
837.382
845.070
821.734
33.979


99
868.499
913.301
877.658
886.486
23.670


120
918.598
970.121
944.529
944.416
25.762


144
946.115
1004.137
964.594
971.615
29.641


150
936.874
984.544
961.619
961.012
23.841


168
951.645
1006.483
993.268
983.799
28.619









Table 11C lists further data with respect to Test 11-3.
















TABLE 11C











Drug Loss






Sam-
Drug


Sam-
due to

Cumulative
Amount



pling
Conc.
Receptor
Drug
pling
Sam-
Cumulative
Amount
Permeated


Test
Time
(μg/
Volume
Amount
Volume
pling
Drug Loss
Permeated
per cm2


#
(Hours)
ml)
(ml)
(μg)
(ml)
(μg)
(μg)
(μg)
(μg/cm2)
























11-3
6
20.744
12
248.928
1
20.744
0.00
248.928
140.876



24
77.642
12
931.704
1
77.642
20.744
952.448
539.020



30
78.556
12
942.672
1
78.556
98.386
1041.058
589.167



48
91.113
12
1093.356
1
91.113
176.942
1270.298
718.901



54
87.060
12
1044.720
1
87.060
268.055
1312.775
742.940



72
93.175
12
1118.100
1
93.175
355.115
1473.215
833.738



78
87.079
12
1044.948
1
87.079
448.290
1493.238
845.070



99
84.621
12
1015.452
1
84.621
535.369
1550.821
877.658



120
87.416
12
1048.992
1
87.416
619.990
1668.982
944.529



144
83.086
12
997.032
1
83.086
707.406
1704.438
964.594



150
75.724
12
908.688
1
75.724
790.492
1699.180
961.619



168
74.074
12
888.888
1
74.074
866.216
1755.104
993.268









Based on the permeation results of Example 11, listed in Table 11B, the averages of the permeation tests were calculated and the flux results listed in Table 11D below were obtained:







TABLE 11D







μg/cm2/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


F6-99
6.851
7.164
7.071
7.029
0.161


CORR
0.914
0.913
0.902
0.910



F6-168
3.958
4.094
3.969
4.007
0.076


CORR
0.882
0.878
0.867
0.876









EXAMPLE 12
A active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 12A below:









TABLE 12A






Ingredient
Amount (gm)


















Loratadine
0.4



Ethyl Acetate
3.0



BIO PSA 7-4302 (adhesive solution)
29.3



containing 17.6 gm silicone adhesive




(60% solids)




Lauryl Acohol (solvent)
2.0



Total
34.7









The formulation of Table 12A was prepared and incorporated into a permeation testing us according to the same procedure as in Example 3 using lauryl alcohol as an additional solvent.
The formulation of Example 12A was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (12-1, 12-2, and 12-3) were conducted giving the results listed in Table 12B below:







TABLE 12B







μg/cm2
















Average of



Hours
Test 12-1
Test 12-2
Test 12-3
three tests
Std Dev















6
171.613
167.470
145.806
161.630
13.859


24
603.924
573.643
553.767
577.111
25.258


30
648.367
661.962
595.567
935.299
35.074


48
803.563
770.051
738.869
770.828
32.354


54
832.797
779.924
749.892
787.538
41.974


72
932.645
881.734
847.836
887.405
42.688


78
937.072
895.118
853.752
895.314
41.660


99
978.713
946.745
921.427
948.962
28.707


120
1019.499
994.321
969.105
994.308
25.197


144
1072.582
1013.288
1009.257
1031.709
35.454


150
1046.531
1027.470
989.674
1021.225
28.938


168
1064.410
1030.903
1035.502
1043.605
18.164









Table 12C lists further data with respect to Test 12-3.
















TABLE 12C











Drug Loss

Cumulative
Amount



Sampling
Drug
Receptor
Drug
Sampling
due to
Cumulative
Amount
Permeated


Test
Time
Conc.
Volume
Amount
Volume
Sampling
Drug Loss
Permeated
per cm2


#
(Hours)
(μg/ml)
(ml)
(μg)
(ml)
(μg)
(μg)
(μg)
(μg/cm2)
























12-3
6
21.470
12
257.640
1
21.470
0.000
257.640
145.806



24
79.753
12
957.036
1
79.753
21.470
978.506
553.767



30
79.262
12
951.144
1
79.262
101.223
1052.367
595.567



48
93.758
12
1125.096
1
93.758
180.485
1305.581
738.869



54
87.568
12
1050.816
1
87.568
274.243
1325.059
749.892



72
94.693
12
1136.316
1
94.693
361.811
1498.127
847.836



78
87.673
12
1052.076
1
87.673
456.504
1508.580
853.752



99
90.332
12
1083.984
1
90.332
544.177
1628.161
921.427



120
89.825
12
1077.900
1
89.825
634.509
1712.409
969.105



144
88.252
12
1059.024
1
88.252
724.334
1783.358
1009.257



150
78.014
12
936.168
1
78.014
812.586
1748.754
989.674



168
78.261
12
939.132
1
78.261
890.600
1829.732
1035.502









Based on the permeation results of Example 12, listed in Table 12B, the averages of the permeation tests were calculated and the flux results listed in Table 12D below were obtained:







TABLE 12D







μg/cm2/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


F6-99
7.791
7.344
7.339
7.492
0.260


CORR
0.905
0.902
0.912
0.906



F6-168
4.176
4.036
4.197
4.136
0.088


CORR
0.852
0.859
0.879
0.863









EXAMPLE 13
A Loratadine reservoir and active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 13A below:










TABLE 13A






Ingredient
Amount (gm)




















Donor Solution





Loratadine
0.35




Ethanol
22.0
(95%)



Water
27.0




Total
49.35












Membrane
Polyethylene












Active Drug/Adhesive Matrix





Loratadine
0.12
gm



BIO PSA 7-4302 (adhesive solution)
19.14
gm



containing 11.49 gm silicone





adhesive (60% solids)





Ethyl acetate solvent
0.89
gm



Total
20.15
gm









The formulation of Table 13A was prepared and incorporated into a permeation testing apparatus according to the following procedure:

    
    
        1. Loratadine is dissolved with ethanol and water and the solution is placed into the donor cell.
        2. Loratadine is dispersed in the adhesive solution and ethyl acetate solvent to form the active drug/adhesive matrix.
        3. The polyethylene membrane is coated with active drug/adhesive matrix and placed against the donor cell and dried. The coated surface of the membrane is positioned opposite from the donor cell.
        4. Thereafter, the human cadaver skin is placed between the coated membrane surface and the receptor cell and the apparatus is secured.
    
    


The formulation of Example 13 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (13-1, 13-2, and 13-3) were conducted giving the results listed in Table 13B below:







TABLE 13B







μg/cm2
















Average of



Hours
Test 13-1
Test 13-2
Test 13-3
three tests
Std Dev















6
72.594
58.406
69.079
66.694
7.387


24
217.680
175.542
197.278
196.833
21.073


30
255.681
203.923
227.740
229.115
25.906


48
348.695
283.263
310.261
314.073
32.882


54
385.778
308.526
336.586
343.630
39.105


72
487.268
391.914
419.969
433.050
49.004


78
523.816
419.585
446.677
463.359
54.081


96
629.393
505.149
532.631
555.721
65.262


102
662.817
528.167
555.429
582.138
71.188


120
762.760
613.895
634.252
671.302
80.061


144
920.453
741.930
759.623
807.335
98.361


168
1068.287
865.187
872.726
935.400
115.145









Table 13C lists further data with respect to Test 13-3.
















TABLE 13C











Drug Loss






Sam-
Drug


Sam-
due to

Cumulative
Amount



pling
Conc.
Receptor
Drug
pling
Sam-
Cumulative
Amount
Permeated


Test
Time
(μg/
Volume
amount
Volume
pling
Drug Loss
Permeated
per cm2


#
(Hours)
ml)
(ml)
(μg)
(ml)
(μg)
(μg)
(μg)
(μg/cm2)
























13-3
6
10.987
4
43.948
4
43.948
0.000
43.948
69.079



24
20.390
4
81.560
4
81.560
43.948
125.508
197.278



30
4.845
4
19.380
4
19.380
125.508
144.888
227.740



48
13.125
4
42.500
4
52.500
144.888
197.388
310.261



54
4.187
4
16.748
4
16.748
197.388
214.136
336.586



72
13.262
4
53.048
4
53.048
214.136
267.184
419.969



78
4.248
4
16.992
4
16.992
267.184
284.176
446.677



96
13.671
4
54.684
4
54.684
284.176
338.860
532.631



102
3.626
4
14.504
4
14.504
338.860
353.364
555.429



120
13.014
4
52.056
4
52.056
353.364
405.420
637.252



144
19.463
4
77.852
4
77.852
405.420
483.272
759.623



168
17.989
4
71.956
4
71.956
483.272
555.228
872.726









Based on the permeation results of Example 13, listed in Table 13B, the averages of the permeation test were calculated and the flux results listed in Table 13D below were obtained:







TABLE 13D







μ/cm2/hr
















Average of



Hours
Test 13-1
Test 13-2
Test 13-3
three tests
Std Dev















6
12.099
9.735
11.513
11.116
1.231


24
9.070
7.314
8.220
8.201
0.878


30
8.523
6.797
7.591
7.637
0.864


48
7.264
5.901
6.464
6.543
0.685


54
7.144
5.713
6.233
6.364
0.724


72
6.768
5.443
5.833
6.015
0.681


78
6.716
5.379
5.727
5.941
0.693


96
6.556
5.262
5.548
5.789
0.680


102
6.498
5.178
5.445
5.707
0.698


120
6.356
5.116
5.310
5.594
0.667


144
6.392
5.152
5.275
5.606
0.683


168
6.359
5.150
5.195
5.568
0.685









EXAMPLE 14
A Loratadine reservoir and active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 14A below:










TABLE 14A






Ingredient
Amount (gm)




















Donor Solution





Loratadine
0.35




Ethanol
22.0
(95%)



Water
27.0




Total
49.35












Membrane
Polyethylene












Active Drug/Adhesive Matrix





Loratadine
0.24
gm



BIO PSA 7-4302 (adhesive solution)
19.38
gm



containing 11.63 gm silicone





adhesive (60% solids)





Ethyl acetate solvent
1.78
gm



Total
21.4
gm*





*Reflects removal of solvent from formulation upon drying






The formulation of Example 14 was prepared and incorporated into a permeation testing apparatus according to the procedure as in Example 13.
The formulation of Example 14 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (14-1, 14-2, and 14-3) were conducted giving the results listed in Table 14B below:







TABLE 14B







μg/cm2
















Average of



Hours
Test 14-1
Test 14-2
Test 14-3
three tests
Std Dev















6
99.616
93.914
65.244
86.258
18.421


24
289.299
264.313
215.108
256.240
37.749


30
329.217
303.791
247.476
293.495
41.832


48
407.865
397.793
316.888
374.182
49.873


54
434.033
430.324
339.025
401.127
53.814


72
510.588
523.829
405.564
479.994
64.797


78
536.221
556.542
427.281
506.681
69.509


96
617.391
654.782
494.782
588.985
83.697


102
638.743
684.929
511.311
611.661
89.922


120
713.411
777.743
574.052
688.402
104.123


144
828.802
914.128
671.500
804.810
123.080


168
935.549
1041.830
761.138
912.839
141.717









Table 14C lists further data with respect to Test 14-3.
















TABLE 14C











Drug Loss






Sam-
Drug


Sam-
due to

Cumulative
Amount



pling
Conc.
Receptor
Drug
pling
Sam-
Cumulative
Amount
Permeated


Test
Time
(μg/
Volume
amount
Volume
pling
Drug Loss
Permeated
per cm2


#
(Hours)
ml)
(ml)
(μg)
(ml)
(μg)
(μg)
(μg)
(μg/cm2)
























14-3
6
10.377
1
41.508
4
41.508
0.000
41.508
65.244



24
23.836
4
95.344
4
95.344
41.508
136.852
215.108



30
5.148
4
20.592
4
20.592
136.852
157.444
247.476



48
11.040
4
44.160
4
44.160
157.444
201.604
316.888



54
3.521
4
14.084
4
14.084
201.604
215.688
339.025



72
10.583
4
42.332
4
42.332
215.688
258.020
405.564



78
3.454
4
13.816
4
13.816
258.020
271.836
427.281



96
10.736
4
42.944
4
42.944
271.836
314.780
494.782



102
2.629
4
10.516
4
10.516
314.780
325.296
511.311



120
9.979
4
39.916
4
39.916
325.296
365.212
574.052



144
15.499
4
61.996
4
61.996
365.212
427.208
671.500



168
14.257
4
57.028
4
57.028
427.208
484.236
761.138









Based on the permeation results of Example 14, listed in Table 14B, the averages of the permeation tests were calculated and the flux results listed in Table 14D below were obtained:







TABLE 14D







μg/cm2/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


F6-96
5.283
5.906
4.439
5.209
0.736


CORR
0.979
0.992
0.983









EXAMPLE 15
A Loratadine reservoir and active drug/adhesive matrix formulation was prepared having the formulation set forth in Table 15A below:










TABLE 15A






Ingredient
Amount (gm)




















Donor Solution





Loratadine
0.17




Ethanol
10.93
(95%)



Water
13.4




Klucel HF (gelling agent/enhancer)
0.50




Total
25.0
gm











Membrane
Polyethylene












Active Drug/Adhesive Matrix





Loratadine
0.12
gm



BIO PSA 7-4302 (adhesive solution)
19.14
gm



containing 11.49 gm silicone





adhesive (60% solids)





Ethyl acetate solvent
0.89
gm



Total
20.15
gm









The formulation of Table 15A was prepared and incorporated into a permeation testing apparatus according to the following procedure:

    
    
        1. Loratadine is dissolved with ethanol and water, Klucel HF is added and the solution is placed into the donor cell.
        2. Loratadine is dispersed in the adhesive solution and ethyl acetate solvent to form the active drug/adhesive matrix.
        3. The polyethylene membrane is coated with active drug/adhesive matrix and placed against the donor cell and dried. The coated surface of the membrane is positioned opposite from the donor cell.
        4. Thereafter, the human cadaver skin is placed between the coated membrane surface and the receptor cell and the apparatus is secured.
    
    


The formulation of Example 15 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (15-1, 15-2, and 15-3) were conducted giving the results listed in Table 15B below:







TABLE 15B







μg/cm2
















Average of



Hours
Test 15-1
Test 15-2
Test 15-3
three tests
Std Dev















6
30.400
31.356
33.475
31.744
1.574


24
113.504
96.723
104.500
104.909
8.398


30
138.050
114.351
120.220
124.207
12.342


48
220.527
176.029
183.955
193.504
23.736


54
245.590
194.380
203.129
214.366
27.392


72
336.788
265.985
281.761
294.845
37.171


78
359.116
286.556
303.001
316.224
38.044


96
450.921
350.096
383.057
394.691
51.410


120
591.832
455.829
507.498
518.386
68.652


144
685.488
556.102
631.384
624.325
64.981


168
780.272
635.766
730.428
715.489
73.402









Table 15C lists further data with respect to Test 15-3.
















TABLE 15C











Drug











Loss due

Cumulative
Amount



Sampling
Drug
Receptor
Drug
Sampling
to
Cumulative
Amount
Permeated


Test
Time
Conc.
Volume
Amount
Volume
Sampling
Drug Loss
Permeated
per cm2


#
(Hours)
(μg/ml)
(ml)
(μg)
(ml)
(μg)
(μg)
(μg)
(μg/cm2)
























15-3
6
4.550
13
59.150
1
4.550
0.000
59.150
33.475



24
13.854
13
180.102
1
13.854
4.550
184.652
104.500



30
14.925
13
194.025
1
14.925
18.404
212.429
120.220



48
22.440
13
291.720
1
22.440
33.329
325.049
183.955



54
23.320
13
303.160
1
23.320
55.769
358.929
203.129



72
32.214
13
418.782
1
32.214
79.089
497.871
281.761



78
32.623
13
424.099
1
32.623
111.303
535.402
303.001



96
40.995
13
532.935
1
40.995
143.926
676.861
383.057



120
54.756
13
711.828
1
54.756
184.921
896.749
507.498



144
67.383
13
875.979
1
67.383
239.677
1115.656
631.384



168
75.622
13
983.606
1
75.662
307.060
1290.666
730.428









Based on the permeation results of Example 15, listed in Table 15B, the averages of the permeation tests were calculated and the flux results listed in Table 15D below were obtained:







TABLE 15D







μg/cm2/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


F6-96
4.651
3.544
3.830
4.008
0.575


CORR
1.000
1.000
0.998









EXAMPLE 16
A Loratadine reservoir and active drug/adhesive matrix formulation was prepared having the formulation of Table 16A below:










TABLE 16A






Ingredient
Amount (gm)




















Donor Solution





Loratadine
0.17




Ethanol
10.93
(95%)



Water
13.4




Klucel HF (gelling agent/enhancer)
0.50




Total
25.0
gm











Membrane
Polyethylene












Active Drug/Adhesive Matrix





Loratadine
0.24
gm



BIO PSA 7-4302 (adhesive solution)
19.38
gm



containing 11.63 gm silicone





adhesive (60% solids)





Ethyl acetate solvent
1.78
gm



Total
21.4
gm









The formulation of Example 16 was prepared and incorporated into a permeation testing apparatus according to the procedure as in Example 15.
The formulation of Example 16 was tested using a permeation cell with a definable surface area for permeation. The receptor of the permeation cell was Ethanol:water (40:60). Three permeation tests (16-1, 16-2, and 16-3) were conducted giving the results listed in Table 16B below:







TABLE 16B







μg/cm2
















Average of



Hours
Test 16-1
Test 16-2
Test 16-3
three tests
Std Dev















6
36.962
56.230
36.616
43.269
11.226


24
123.022
152.233
110.046
128.434
21.608


30
144.736
172.600
126.108
147.815
23.398


48
219.344
253.782
185.170
219.432
34.306


54
248.951
275.052
203.915
242.639
35.986


72
341.293
369.066
266.361
325.573
53.126


78
367.063
390.341
275.970
344.458
60.444


96
469.268
481.973
342.796
431.346
76.949


120
624.439
618.731
449.999
564.390
99.106


144
748.033
737.652
533.364
673.016
121.054


168
854.492
842.808
607.081
768.127
139.592









Table 16C lists further data with respect to Test 16-3.
















TABLE 16C











Drug











Loss due

Cumulative
Amount



Sampling
Drug
Receptor
Drug
Sampling
to
Cumulative
Amount
Permeated


Test
Time
Conc.
Volume
Amount
Volume
Sampling
Drug Loss
Permeated
per cm2


#
(Hours)
(μg/ml)
(ml)
(μg)
(ml)
(μg)
(μg)
(μg)
(μg/cm2)
























16-3
6
4.977
13
64.701
1
4.977
0.000
64.701
36.616



24
14.575
13
189.475
1
14.575
4.977
194.452
110.046



30
15.637
13
203.281
1
15.637
19.552
222.833
126.108



48
22.462
13
292.006
1
22.462
35.189
327.195
185.170



54
23.282
13
302.666
1
23.282
57.651
360.317
203.915



72
29.979
13
389.727
1
29.979
80.933
470.660
266.361



78
28.979
13
376.727
1
28.979
110.912
487.639
275.970



96
35.833
13
465.829
1
35.833
139.891
605.720
342.796



120
47.648
13
619.424
1
47.648
175.724
795.148
449.999



144
55.314
13
719.082
1
55.314
223.372
942.454
533.364



168
61.079
13
794.027
1
61.079
278.686
1072.713
607.081









Based on the permeation results of Example 16, listed in Table 16B, the averages of the permeation tests were calculated and the flux results listed in Table 16D below were obtained:







TABLE 16D







μg/cm2/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


F6-96
4.722
4.647
3.318
4.229
0.790


CORR
0.998
0.999
0.999









In vitro skin permeation studies with cadaver skin quantitatively predict the pharmacokinetics and extent of drug absorption from the transdermal delivery dosage form. Matching in vitro skin donors to the in vivo population improves the correlation. Further improvements in this correlation are achieved by matching application sites.
it will be readily apparent that various modifications to the invention may be made by those killed in the art without departing from the scope of this invention. For example, many different transdermal delivery systems may be utilized in order to obtain the relative release rates and plasma levels described herein. Further, it is possible that mean values for plasma concentrations over a particular patient population for a particular described time point along the dosing interval may vary from the plasma concentration ranges described herein for that time point. Such obvious modifications are considered to be within the scope of the appended claims.

## Claims

1. A method of effectively treating seasonal allergic rhinitus, chronic idiopathic urticaria, or both conditions in a human patient, comprising administering loratadine transdermally to the human patient by applying a transdermal delivery system comprising (i) an active agent consisting of loratadine or a pharmaceutically acceptable salt thereof, (ii) a polymer, (iii) a softening agent; and (iv) a solvent, to the skin of a patient, and maintaining said transdermal delivery system in contact with the skin of the patient for at least 5 days, said transdermal delivery system maintaining an effective mean relative release rate to provide a therapeutic blood level of said 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, said transdermal delivery device maintaining a plasma level of loratadine at steady state of about 3 ng/ml;
said transdermal delivery system having a mean relative release rate of from about 2.8 μg/cm2/hr to about 16.2 μg/cm2/hr of the transdermal delivery system surface area at 24 hours;
from about 2.3 μg/cm2/hr to about 13.7 μg/cm2/hr of the transdermal delivery system surface area at 48 hours;
from about 2.0 μg/cm2/hr to about 11.9 μg/cm2/hr of the transdermal delivery system surface area at 72 hours;
and a mean relative release rate of from about 1.8 μg/cm2/hr to about 9.9 μg/cm2/hr of the transdermal delivery system surface area at 96 hours; as determined via an in-vitro permeation test utilizing a Valia-Chien cell where the membrane is a human cadaver skin, said cell having a receptor chamber containing a 40:60 mixture of ethanol:water.

2. The method of claim 1 wherein the plasma level of loratadine at 48 hours does not decrease by more than 30% over the next 72 hours.

3. The method of claim 1, further comprising maintaining an effective mean relative release rate of said 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.

4. The method of claim 1, further comprising providing a mean relative release rate of loratadine from said transdermal delivery system to provide a plasma level of loratadine of at least about 0.1 ng/ml within about 6 hours after application of said transdermal delivery system onto the skin of the patient.

5. The method of claim 1, wherein said therapeutic plasma level is maintained from about 0.1 ng/ml to about 3.3 ng/ml during the dosing interval for said transdermal delivery system.

6. The method of claim 1, wherein said transdermal delivery system has a mean relative release rate from about 1.0 μg/hour/cm2 to about 30.0 μg/hour/cm2.

7. The method of claim 1, wherein said transdermal delivery system provides an in-vitro cumulative amount of permeation of from about 63 μg/cm2 to about 388 μg/cm2 of the transdermal delivery system surface area at 24 hours; from about 105 μg/cm2 to about 660 μg/cm2 of the transdermal delivery system surface area at 48 hours; and from about 139 μg/cm2 to about 854 μg/cm2 of the transdermal delivery system surface area at 72 hours; and from about 162 μg/cm2 to about 955 μg/cm2 of the transdermal delivery system surface area 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 said cell has a receptor chamber containing a 40:60 mixture of ethanol:water.

8. A transdermal delivery system comprising (i) an active agent consisting of loratadine or a pharmaceutically acceptable salt thereof, (ii) a polymer, (iii) a softening agent; and (iv) a solvent,
the transdermal delivery system provides a mean relative release rate of from about 2.8 μg/cm2/hr to about 16.2 μg/cm2/hr of the transdermal delivery system surface area at 24 hours;
from about 2.3 μg/cm2/hr to about 13.7 μg/cm2/hr of the transdermal delivery system surface area at 48 hours;
from about 2.0 μg/cm2/hr to about 11.9 μg/cm2/hr of the transdermal delivery system surface area at 72 hours; and
from about 1.8 μg/cm2/hr to about 9.9 μg/cm2/hr of the transdermal delivery system surface area 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 said cell having a receptor chamber containing a 40:60 mixture of ethanol:water; said transdermal delivery system maintaining an effective mean relative release rate to provide a therapeutic blood level of said loratadine within 36 hours from the initiation of the dosing interval, and a plasma level of loratadine of at least about 0.1 ng/ml by about 6 hours after application of said transdermal delivery system onto the skin of a human patient; said transdermal delivery system maintaining a therapeutic blood level until the end of at least a five-day dosing interval and a plasma level of loratadine at steady state of about 3 ng/ml.

9. The transdermal delivery system of claim 8, which provides an in-vitro cumulative amount of permeation of from about 63 μg/cm2 to about 388 μg/cm2 of the transdermal delivery system surface area at 24 hours; from about 105 μg/cm2 to about 660 μg/cm2 of the transdermal delivery system surface area at 48 hours; and from about 139 μg/cm2 to about 854 μg/cm2 of the transdermal delivery system surface area 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 said cell has a receptor chamber containing a 40:60 mixture of ethanol:water.

10. The transdermal delivery system of claim 8, 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.

11. The transdermal delivery system of claim 8, which is a laminated composite comprising (a) a polymer backing layer that is substantially impermeable to loratadine or the pharmaceutically acceptable salt thereat and (b) a reservoir layer comprising an acrylate or silicone based 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.

12. The transdermal delivery system of claim 8, wherein said therapeutic plasma level is maintained from about 0.1 ng/ml to about 3.3 ng/ml during the dosing interval for said transdermal delivery system.

13. The transdermal delivery system of claim 8, wherein said transdermal delivery system has a mean relative release rate from about 1.0 μg/hour/cm2 to about 30.0 μg/hour/cm2of the transdermal delivery system surface area.

14. The transdermal delivery system of claim 8, wherein said transdermal delivery system provides an in-vitro cumulative amount of permeation of from about 63 μg/cm2 to about 388 μg/cm2 of the transdermal delivery system surface area at 24 hours; from about 105 μg/cm2 to about 660 μg/cm2 of the transdermal delivery system surface area at 48 hours; and from about 139 μg/cm2 to about 854 μg/cm2 of the transdermal delivery system surface area at 72 hours; and from about 162 μg/cm2 to about 955 μg/cm2 of the transdermal delivery system surface area 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 said cell has a receptor chamber containing a 40:60 mixture of ethanol:water.

15. The transdermal delivery system according to claim 10, wherein the backing layer is composed of a flexible material.

16. The transdermal delivery system according to claim 10, wherein the backing layer is selected from the group consisting of a flexible material, an inflexible material, and an aluminum foil.

17. The transdermal delivery system according to claim 10, wherein the polymeric matrix is at least one of rubber, a synthetic homo-, co- or blockpolymer, a urethane and silicone.

18. The transdermal delivery system according to claim 10, wherein the softening agent is at least one of dodecanol, undecanol, octanol, a glycol and glycanol.

19. The transdermal delivery system according to claim 10, wherein the solvent is a monoester of a dicarboxylic acid.

20. The transdermal delivery system according to claim 10, wherein the solvent is at least one of monomethyl glutarate and monomethyl adipate.

21. The transdermal delivery system according to claim 10, wherein by weight the polymer is present in about 55%, the loratadine in about 10%, the solvent in about 10% and the softener in about 15%.

22. The transdermal delivery system according to claim 10, wherein the solvent is present in from about 25 to 100% the weight of the loratadine.

23. The transdermal delivery system according to claim 10, which also comprises a removable protective layer.

24. The transdermal delivery system according to claim 10, wherein the pressure-sensitive adhesive reservoir layer comprises a polymer based on an acrylate, a methacrylate, a silicone compound or a combination thereof.

25. The transdermal delivery system according to claim 10, wherein the softening agent is a medium-chain triglyceride of the caprylic/capric acids of coconut oil.

26. The transdermal delivery system according to claim 10, wherein the solvent has at least one acidic group.

27. A method of effectively treating seasonal allergic rhinitus, chronic idiopathic urticaria, or both conditions in a human patient, comprising administering loratadine transdermally to the human patient by applying a transdermal delivery system containing loratadine or a pharmaceutically acceptable salt thereof to the skin of a patient, and maintaining said transdermal delivery system in contact with the skin of the patient for at least 5 days, said transdermal delivery system maintaining an effective mean relative release rate to provide a therapeutic blood level of said 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, said transdermal delivery device maintaining a plasma level of loratadine at steady state of about 3 ng/ml;
said transdermal delivery device comprising a backing layer which is substantially impermeable to the loratadine or pharmaceutically acceptable salt thereof; and a reservoir layer consisting essentially of 20 to 90% by weight of a polymeric matrix, 0.1 to 30% by weight of a softening agent; 0.1 to 20% by weight of loratadine base or of a pharmaceutically acceptable salt thereof and 0.1 to 30% by weight of a solvent, for the loratadine or salt thereaof;
said transdermal delivery system having a mean relative release rate of from about 2.8 μg/cm2/hr to about 16.2 μg/cm2/hr of the transdermal delivery system surface area at 24 hours;
from about 2.3 μg/cm2/hr to about 13.7 μg/cm2/hr of the transdermal delivery system surface area at 48 hours;
from about 2.0 μg/cm2/hr to about 11.9 μg/cm2/hr of the transdermal delivery system surface area at 72 hours;
and a mean relative release rate of from about 1.8 μg/cm2/hr to about 9.9 μg/cm2/hr of the transdermal delivery system surface area at 96 hours; as determined via an in-vitro permeation test utilizing a Valia-Chien cell where the membrane is a human cadaver skin, said cell having a receptor chamber containing a 40:60 mixture of ethanol:water.

28. The method of claim 1, wherein said transdermal delivery system has a mean relative release rate of from about 1.5 μg/cm2/hr to about 8.5 μg/cm2/hr of the transdermal delivery system surface area at 120 hours;
from about 2.4 μg/cm2/hr to about 7.7 μg/cm2/hr of the transdermal delivery system surface area at 144 hours;
and from about 1.5 μg/cm2/hr to about 6.7 μg/cm2/hr of the transdermal delivery system surface area at 168 hours; as determined via an in-vitro permeation test utilizing a Valia-Chien cell where the membrane is a human cadaver skin, said cell having a receptor chamber containing a 40:60 mixture of ethanol:water.

29. The transdermal delivery system of claim 8, wherein said transdermal delivery system has a mean relative release rate of from about 1.5 μg/cm2/hr to about 8.5 μg/cm2/hr of the transdermal delivery system surface area at 120 hours;
from about 2.4 μg/cm2/hr to about 7.7 μg/cm2/hr of the transdermal delivery system surface area at 144 hours;
and from about 1.5 μg/cm2/hr to about 6.7 μg/cm2/hr of the transdermal delivery system surface area at 168 hours; as determined via an in-vitro permeation test utilizing a Valia-Chien cell where the membrane is a human cadaver skin, said cell having a receptor chamber containing a 40:60 mixture of ethanol:water.

30. The method of claim 27, wherein said transdermal delivery system has a mean relative release rate of from about 1.5 μg/cm2/hr to about 8.5 μg/cm2/hr of the transdermal delivery system surface area at 120 hours;
from about 2.4 μg/cm2/hr to about 7.7 μg/cm2/hr of the transdermal delivery system surface area at 144 hours;
and from about 1.5 μg/cm2/hr to about 6.7 μg/cm2/hr of the transdermal delivery system surface area at 168 hours; as determined via an in-vitro permeation test utilizing a Valia-Chien cell where the membrane is a human cadaver skin, said cell having a receptor chamber containing a 40:60 mixture of ethanol:water.

31. The method of claim 1, wherein a softening agent is selected from the group consisting of dodecanol, undecanol, octanol, a glycol, glycanol and a medium-chain triglyceride of the caprylic/capric acids of coconut oil; and the solvent is selected from the group consisting of a monoester of a dicarboxylic acid, monomethyl glutarate and monomethyl adipate.

32. The transdermal delivery system of claim 8, wherein a softening agent is selected from the group consisting of dodecanol, undecanol, octanol, a glycol, glycanol and a medium-chain triglyceride of the caprylic/capric acids of coconut oil; and the solvent is selected from the group consisting of a monoester of a dicarboxylic acid, monomethyl glutarate and monomethyl adipate.

33. The method of claim 27, wherein a softening agent is selected from the group consisting of dodecanol, undecanol, octanol, a glycol, glycanol and a medium-chain triglyceride of the caprylic/capric acids of coconut oil; and the solvent is selected from the group consisting of a monoester of a dicarboxylic acid, monomethyl glutarate and monomethyl adipate.

34. The method of claim 1, wherein the transdermal delivery system comprises a solution of the loratadine or a pharmaceutically acceptable salt thereof.

35. The transdermal delivery system of claim 8, wherein the transdermal delivery system comprises a solution of the loratadine or a pharmaceutically acceptable salt thereof.

36. The method of claim 27, wherein the transdermal delivery system comprises a solution of the loratadine or a pharmaceutically acceptable salt thereof.

37. The method of claim 1, wherein said loratadine is the only active agent in the transdermal delivery system.

38. The transdermal delivery system of claim 8, wherein said loratadine is the only active agent in the transdermal delivery system.

39. The method of claim 27, wherein said loratadine is the only active agent in the transdermal delivery system.