WO1991005529A1 - Drug delivery systems and matrix therefor - Google Patents

Abstract

A drug delivery system that contains an active ingredient-containing adhesive matrix coextensive with a backing layer is described. The adhesive matrix contains an anhydrous, hydratable pressure-sensitive adhesive, a non-aromatic terpene alcohol or an ester thereof, an absorption promoter and a drug, such as a steroid, capable of transdermal or transcutaneous administration. The non-aromatic terpen alcohol preferably is alpha-terpineol. A dosage form such as a transdermal patch is disclosed, as well as a method for long-term administration of a drug to a mammal.

Description

DRUG DELIVERY SYSTEMS AND MATRIX THEREFOR

Technical Field This invention relates to a pressure-sensitive adhesive drug delivery system with restricted moisture vapor permeability for the transdermal and transcutaneous administration of therapeutic agents. Background of the Invention The delivery of drugs by transdermal or transcutaneous routes of administration have been described in U.S. Patents Nos. 3,598,122, 3,598,123, 3,731,683, 3,742,951, and 3,797,494 to Zaffaroni; Nos. 3,946,106, 3,992,518, and 4,053,580 to Chien et al.; Nos. 4,201,211 and 4,286,592 to Chandrasekaran; and Nos. 4,289,749, 4,470,962, 4,466,953, 4,292,301, 4,294,820, and 4,321,252 to Keith. These particular systems are classified as adhesive devices, monolithic devices with or without skin contact adhesives and reservoir devices with or without skin contact adhesives. The adhesive polymers utilized in these devices are pressure- sensitive and include copolymers of acrylic acid, acrylamide, isobutylene, vinyl acetate and esters of acrylic acid. Particular commercialized transdermal drug delivery systems are well known, such as Transderm Scop^® for scopolamine (CIBA-Geigy, Ardsley, New York) , Nitro- Disc* for nitroglycerin (G.D. Searle, Skokie, IL) , Catapress^® TTS for clonidine (Boehringer-Ingelheim, Ingelheim am Rhein, Fed. Rep. of Germany) and Estraderm^® TTS for 17-beta-estradiol (CIBA-Geigy, Ardsley, New York) . These devices have been designed and developed with an occlusive backing such as aluminum foil or an aluminumized laminate film which serves as an occlusive backing for the drug delivery matrix or is present on a reservoir device.

It is recognized in the pharmaceutical sciences and dermatology that occlusion of the skin with a moisture impermeable membrane or film improves the permeability of the skin. This occurs as a result of improved hydration and retention of moisture vapor into the stratum corneum, the outermost horny layer of the skin. However, such occlusion for a prolonged period of time produces skin damage such as irritation, redness, itching, burning and disruption of the balance of anaerobic and aerobic bacteria covering the skin surface. Consequently, occluded transdermal drug delivery systems have a limited scope with regard to their application time and optimal use for therapeutic benefit, compliance and convenience. In particular, current therapeutic transdermal delivery systems are indicated for skin application for a period of only 1 to 3 days depending on the drug and clinical response. Furthermore, drug delivery systems with pressure- sensitive adhesive and occlusive backings have a tendency to lose adhesive strength due to moisture build-up in the delivery system, particularly, in the adhesive matrix. The build-up of moisture leads to reduction of adhesive strength and results in poor adhesion of the system. This causes problems of wear such as edge lift-off during the wear period. The non- conformable nature of backing materials such as aluminumized laminates result in premature falling off of the delivery system or application periods which are very short.

Moisture vapor-permeable polymeric sheet materials have been used for medical purposes as illustrated in Great Britain Patent No. 1,280,631 to Smith et al. In U.S. Patent No. 4,340,043 to Smith et al. an adhesive-coated polyetherurethane sheet material is disclosed for incorporating antibacterial substances in the adhesive matrix. These adhesive-coated films are used as surgical, medical or wound dressings. In Japanese Patent No. JP 63-21647, assigned to Fuji Photo Film KK, fluoropolymer film is disclosed in a transdermal tape which is permeable to moisture released from the skin. The transdermal tape is utilized to incorporate antibiotics, antihistamines, topical corticosteriods, coronary vasodilators and the like in an adhesive which is laminated on the fluoropolymer film, and this tape is used for topical therapy.

Another problem encountered with current transdermal drug delivery systems is that of diminution of drug delivery due to drug metabolism in the skin.

This is common with some drugs such as 17-beta-estradiol and nitroglycerin.

For drugs with poor solubility due to their hydrophobic nature and a low partition coefficient into the stratum corneum, transdermal flux is improved by the use of penetrant aids or absorption promoters such as ethanol. In U.S. Patent No. 4,379,454 to Campbell et al., the use of ethanol in the transdermal delivery of 17-beta-estradiol is disclosed. However, ethanol increases the transepidermal loss of water from the skin and cannot be used in non-reservoir devices, such as solvent- or emulsion-based pressure-sensitive adhesives that require oven drying procedures for device fabrication. A further problem with the use of alkanols as penetrant enhancers is that these compounds extract intercellular lipids from the stratum corneum. The occlusion of alkanols such as ethanol on the skin can lead to skin dehydration, irritation and delipidization. In order to overcome, or at least mitigate, the above-stated problems, the present invention contemplates a transdermal and transcutaneous drug delivery system which contains a backing layer coextensive with an adhesive matrix that contains a non- aromatic terpene alcohol. Summary of the Invention

The present invention contemplates an anhydrous, hydratable pressure-sensitive adhesive matrix that contains a terpene alcohol. This matrix is supported by a backing layer which is coextensive with the adhesive matrix. In a drug dosage form, the adhesive matrix of the present invention contains a pressure-sensitive adhesive, a non-aromatic terpene alcohol, an absorption promoter and a drug which is capable of transdermal or transcutaneous administration. The adhesive matrix is a monolithic mono- or multi- laminated matrix. The non-aromatic terpene alcohol is a high boiling non-aromatic and relatively hydrophobic terpene alcohol, such as alpha-terpineol, that is present in sufficient amount to promote drug release from the matrix. It is particularly preferred that the terpene alcohol is present in combination with a hydrophilic absorption promoter, such as propylene glycol, in suitable proportions to provide a balanced binary combination of a lipophilic vehicle and a hydrophilic vehicle which together impart desirable adhesion characteristics to the adhesive matrix. This binary combination provides improved absorption of relatively lipophilic drugs such as estrogens, androgens, progestins, and the like. The adhesive matrix is coextensive with a backing layer having restricted moisture vapor permeability, such as a polyetherurethane film or ethylene vinyl acetate film. In a preferred embodiment the backing layer is reinforced with a nylon scrim which improves the physical strength and performance of the backing layer. The backing layer can allow variable gas permeability and moisture vapor transmission, depending upon whether local or systemic drug delivery is preferred, through the drug delivery system. A dosage form for the administration of drugs to a mammal is also contemplated by the present invention. This dosage form is attached to the skin of the mammal by means of a pressure-sensitive adhesive, and the drug is administered to the mammal through the adhesive layer. This dosage form includes an adhesive matrix which is capable of attachment to the skin of the mammal through the pressure-sensitive adhesive as well as a backing layer. The adhesive matrix comprises a medical-grade pressure-sensitive adhesive, a non- aromatic terpene alcohol such as alpha-terpineol, an absorption promoter such as propylene glycol or polyethylene glycol 400, and a drug to be administered. The present invention further contemplates a method for the long-term administration of a drug to a mammal. In this method, a pressure-sensitive adhesive drug delivery system (dosage form) is attached to the skin of a mammal by contact with the adhesive and the desired drug, present in the drug delivery system (dosage form) , is absorbed by the mammal through the adhesive attachment site during the period of attachment.

The pressure-sensitive adhesive drug delivery system of this invention is capable of extended wear without the detrimental moisture build-up and irritation which is encountered with the current systems. The present system permits a longer wear time- with comfort, convenience and maximum therapeutic benefit, all without the need for removal and replacement of the system every few days. Brief Description of Figures

FIGURE 1 is a graph of the transdermal flux of 17-beta-estradiol across excized Yucatan pig skin where either an Estraderm^® 0.05 patch (+) or a 17.5 cm² patch of the present invention containing 0.6 meg/cm² of 17- beta-estradiol (X) was applied.

FIGURE 2 is a bar plot illustrating the comparative serum levels of estradiol in the pig following the application of one of the following treatments: an Estraderm^® 0.05 patch for 3 days (Q) , a single estradiol dosage form of the present invention (4 mg of 17-beta-estradiol/dosage form) for 6 days (0) _/ °r two estradiol dosage forms of the present invention (4 mg/dosage form for 6 days __ ) .

FIGURE 3 is a bar plot illustrating comparative serum levels of estrone in the pig following application of one of the following treatments: an Estraderm^® 0.05 patch for 3 days (__ ) , a single estradiol dosage form of the present invention

(4 mg estradiol/dosage form) for 6 days (0) ^{or two} estradiol dosage forms of the present invention (4 mg/dosage form) for 6 days (__) .

FIGURE 4 is an illustrative transdermal patch embodying the present invention.

FIGURE 5 is a graph of the in vitro penetration of estradiol from transdermal patches having different backing films: reinforced polyether urethane (£S0, polyether-polyethylene (^) , occlusive tetra- laminate (A) and Estraderm^® 0.05 (A).

FIGURE 6 is a graph of the plasma concentration of estradiol ( Q ) and estrone (#) over a period of 7 days in subjects following application of a patch of the present invention for 7 days (Panel A) and following application of an Estraderm^® 0.1 patch for 3 days (Panel B) .

Description of Preferred Embodiments

The present invention contemplates an anhydrous, but hydratable monolithic mono- or multi- laminated pressure-sensitive adhesive matrix. The matrix includes, among other things, a high boiling non- aromatic and relatively hydrophobic terpene alcohol that is present in sufficient amount to promote drug release from the monolithic matrix.

Specifically, the use of alpha-terpineol, a non-aromatic terpene alcohol, which also has antiseptic properties, to reduce the likelihood of bacterial growth and infection, in combination with other inert ingredients in the monolithic matrix, is particularly preferred in that it provides a unique system with extended application periods and high tolerance on the skin for long-term transdermal or transcutaneous therapy. Drugs, particularly those which exhibit absorption and irritation problems by the gastro¬ intestinal route due to solubility limitations, pH or enzymatic degradation and/or extensive first pass metabolism by the liver, are particularly well suited for use in combination with the present therapeutic carrier system. These drugs can be hydrophilic, hydrophobic or amphiphilic in nature, and can belong to specific therapeutic classes. Illustrative of such drugs are compounds that are useful in wound therapy, cardiovascular treatment, bronchodilation, growth stimulation, memory maintenance, memory retention or enhancement, immunomodulation and appetite modulation. Exemplary drugs include estrogens, androgens, antidepressants, anticonvulsants, antimicrobials, nutritional supplements, vitamins, and drugs useful in the treatment of specific disorders such as anxiety, diabetes, gastrointestinal problems and parkinsonism, as well as biotechnology-derived drugs and hormones. Particularly preferred hydrophilic drugs include nitroglycerin, phenylephrine and the like.

Particularly preferred hydrophobic, or lipophilic, drugs include 17-beta-estradiol, dehydroepiandrosterone (DHEA) , nifedipine, diltiazem, ti olol, bupranolol, fentanyl, testosterone, progesterone, norethindrone, norethisterone, norgestrel, levonorgesterel, oxandrolone, piroxicam, ketoprofen, flurbiprofen, mestranol, cromoglycolic acid, ethinyl estradiol, triamcinolone, beclomethasone, corticosteroids, prostaglandins and the like. Particularly preferred amphiphilic drugs include fentanyl and the like. The terpene alcohol or ester thereof in combination with a hydrophilic excipient or absorption promoter, such as propylene glycol, in suitable proportions, also provides a balanced binary combination of a lipophilic and a hydrophilic vehicle which imparts desirable adhesion and drug penetration characteristics to the adhesive matrix. This binary combination is particularly well suited for the transdermal delivery of relatively lipophilic drugs such as estrogens, androgens, progestins, contraceptives, cardiovascular agents, and the like, at controlled rates.

The mono- or multi-laminated monolithic matrix, in a preferred embodiment, is affixed onto a thin non-occlusive backing. The non-occlusive backing, such as a thin polyetherurethane film, can be reinforced with a nylon scrim which improves its physical strength.

As used herein, a "backing layer" is a film which has variable permeability to moisture vapor and gases such as oxygen and carbon dioxide, and includes semi-occlusive material such as a polyetherurethane or polyesterurethane film, and a polyester/polyethylene copolymer film, and occlusive material such as a tri- laminate film of polyethylene/aluminum/polyester. Semi- occlusive backing layers have a relatively high moisture vapor transmission rate (MVTR) of the order of about 0.3 to about 12 grams/centimeters²/24 hr. (g/cm²/24 hr.), a relatively high liquid barrier property and mechanical flexibility, as well as stability. An occlusive backing film has an MVTR of less than 0.3 g/cm²/24 hr.

As used herein, "transdermal administration" means that the drug permeates the skin, enters the blood and combines with drug receptor sites that are at organs remote from the application site. The drug thus remains in equilibrium with the blood that carries the drug from the skin at the absorption site.

As used herein, "transcutaneous administration" means that the drug permeates through the skin and perfuses the subdermal tissue that needs it for a beneficial pharmacological response in the vicinity of the site of application.

The backing layer which is attached to the pressure-sensitive adhesive matrix of the drug delivery system of the present invention is preferably a semi- occlusive film with a nylon scrim reinforcement. This semi-occlusive film with nylon scrim provides a barrier for external aqueous washes as well as a barrier for internal liquid components of the composition. It also provides conformance, flexibility and ease of lamination for the dosage form of the present invention. This enables die cutting of pressure-sensitive adhesive dosage forms in a wide variety of self-supporting sizes, shapes or forms to provide a therapeutic unit which is suitable for comfort and convenience, adhesion and prolonged application for periods of one week or more.

A semi-occlusive backing of the present invention is preferably a polyetherurethane film, about 1.0 mil thick, reinforced with about 3 to about 4 mils of nylon scrim. In a preferred embodiment, the moisture vapor transmission rate of the film is in the range of about 0.3 to about 8.0 g/cm²/24 hr. , as tested by Mocon Analyzer at 38 degrees C. and 90% relative humidity. The nylon scrim provides self-supporting strength to the polyetherurethane backing film and serves as a semi- occlusive backing for a mono- or bi-laminate monolithic pressure-sensitive adhesive matrix.

An occlusive backing is preferably a tri- laminate film of polyethylene/aluminum/polyester such as Scotchpak^® 1009 available commercially from 3M Co. about 2-4 mils thick. In a preferred embodiment, the MVTR of the film is less than about 0.3 g/cm²/24 hr.

When utilized for systemic drug delivery, the backing layer of the dosage form of the present invention has an MVTR less than that of human skin and preferably of about zero to about 100 g/cm²/24 hr. When utilized for local drug delivery (transcutaneous administration) a dosage of the present invention has a backing layer with an MVTR equivalent to or greater than that of human skin and preferably of about 500 to 600 g/cm²/24 hr.

Exemplary pressure-sensitive adhesives which are useful in the adhesive matrix of the present invention are 2-ethylhexylacrylate, acrylate-acrylic acid copolymer, acrylic acid-acrylamide copolymer, dimethylsiloxanes, vinyl acetate-acrylate copolymers, polyisobutylenes and the like. Several of these adhesives are commercially available as solutions in organic solvents or as emulsions in aqueous-based emulsion systems with biocompatible surfactants. The emulsions systems are suitable for short-term adhesive application. The use of emulsion systems is limited for long-term application on the skin. This is due to the loss of adhesion that occurs as a function of time as a result of skin penetration of the surfactants, which in turn modify the skin surface properties. Solvent-based adhesives without surfactants, such as vinyl acetate- acrylate copolymers with a solid content in a range of about 30 to about 50 percent are preferred.

In a preferred embodiment, an absorption promoter such as a hydrophilic excipient is present in a range of about 10 to about 50 weight percent of the adhesive matrix together with a non-aromatic terpene alcohol or ester thereof. Illustrative terpene alcohols include alpha-terpineol, citronellol, geraniol, and linalool. Hydrolyzable esters of the terpene alcohols preferably include the C₂-C₈ monocarboxylic acid esters. Terpene alcohols such as alpha-terpineol have antiseptic properties that reduce the likelihood of bacterial growth and infection during administration. Absorption promoters useful in the present invention are the hydrophilic polyhydroxy alcohols, fatty acid esters of aliphatic alcohols, monoesterified fatty acids, and partially esterified glycols. Preferred absorption promoters include propylene glycol, ethylene glycol monoethyl ether (Transcutol^®) , isopropyl palmitate, 1,2,6-hexanetriol, propylene glycol monolaurate, diisopropyl adipate, polyethylene glycol, and polyethylene glycol 400 acetate.

As used herein, an "absorption promoter" is a compound as described above that facilitates the uptake of a drug from the adhesive matrix through a mammalian body surface such as skin and thus enables a therapeutically effective dosage of the drug to be administered to the mammal.

In a preferred embodiment, an absorption promoter in a dosage form of the present invention is able to increase the permeability of the drug into the body of the mammal to a rate that is at least comparable to the rate of release of the drug from the adhesive matrix.

Absorption promoters are selected for use in a dosage form of the present invention to provide either paracellular drug transport or intracellular drug transport. Paracellular transport maintains drugs in the aqueous extracellular fluid, while intracellular transport dissolves drugs into the lipid containing cellular membranes.

The weight ratio of terpene alcohol to absorption promoter present in the present invention is about 3 to 1 to about 1:3, and preferably 1:1. In a particularly preferred embodiment, alpha-terpineol is combined with propylene glycol at approximately a 1:1 weight ratio. This mixture is combined with a hydratable microparticulate solid material, such as fine-fumed silicon dioxide, and this mix is sheared with a mechanical stirrer to solvate and suspend uniformly the silicon dioxide particles in the admixture. The solvated silicon dioxide serves the purpose of improving the physical holding capacity of the liquid components in the adhesive, as well as improving cohesiveness and tortuosity of the adhesive matrix. Other insoluble hydratable microparticulate material useful in the present invention are microcrystalline cellulose and microcrystalline alginic acid. A portion of this mixture is combined with an active ingredient, i.e., a drug, and added to a predetermined quantity of acrylic resin solution. The final mixture is blended to obtain a viscous composition of the wet adhesive matrix. The wet adhesive matrix composition is then coated, preferably at a thickness of about 0.2 to about 0.7 millimeters, on a silicone-coated paper release liner and air-dried for about fifteen minutes to produce a first layer, followed by application of a second coating layer of the same drug-adhesive composition on top of the first layer, followed by oven drying at 60 degrees C. for about 30 minutes. A backing layer, preferably polyetherurethane

(5 mils thick) with a nylon scrim film or an aluminized or non-aluminized polymer laminate, preferably 3-10 mils thick, is laminated onto the dried adhesive. Appropriate size patches are cut and utilized. A release liner is laminated on the outer or exposed surface of the pressure-sensitive adhesive. Preferred release liners include silicone- or fluoro¬ polymer coated polyester or polyethylene-paper- polyethylene-laminate films of suitable thickness for ease of release in die cutting during processing by a converting process.

Preferred lipophilic drugs utilized in the present invention are steroids, particularly estrogens. The present invention utilizes a high boiling non-aromatic terpene alcohol or a hydrolyzable ester thereof, in a range of about 10 to about 50 weight percent of the adhesive matrix, that has acceptable skin tolerance, improved drug solubilization capacity either alone or in combination with another solubilizer that is preferably hydrophilic in nature, functions as a suitable vehicle for pressure-sensitive adhesive matrices and promotes the transdermal/ transcutaneous flux of a drug. A high boiling non- aromatic terpene alcohol, such as alpha-terpineol, also acts as a metabolic inhibitor of beta-hvdroxy dehydrogenases in the skin. The inclusion of such a terpene alcohol in a transdermal/transcutaneous drug delivery system provides antibacterial/antiseptic protection and minimizes potential problems arising from bacterial/mycobacterial growth at the site of application during long-term transdermal/transcutaneous drug therapy, i.e., for a period of over one week or more. Alpha-Terpineol is a preferred terpene alcohol for application as a suitable drug carrier and penetrant aid in the pressure-sensitive adhesive matrix of the present invention. Specifically, alpha-terpineol has a relatively high melting point (18-20 degrees C), boiling point (206-207 degrees C.) and very low vapor pressure. It is relatively stable to oxidation, and has a pleasant piney to floral odor.

In order to improve skin penetration, a mixture of a relatively hydrophobic and a relatively hydrophilic solvent is contemplated. Thus the combination of a non-aromatic terpene alcohol or a hydrolyzable ester thereof, together with a hydrophilic excipient, is utilized in the adhesive compositions of the present invention.

A transdermal patch utilizing the pressure- sensitive adhesive matrix of the present invention is illustrated in FIGURE 4 where hydratable pressure- sensitive adhesive layers 12 and 14 of patch 10 are juxtaposed and contiguous with one another. A backing sheet 16 covers the exposed or outer face 22 of layer 12, while release sheet 18 covers the outer face 24 of layer 14. A cut or a line of severance 20 can be optionally provided in release sheet 18 for facilitating its removal from face 24 when patch 10 is readied for use.

The concentration of the therapeutically active ingredient or drug in adhesive layers 12 and 14 can be the same or different, depending upon the desired transdermal flux of the active ingredient as layers 12 and 14 are hydrated when in place. Similarly, the weight ratio of the active ingredient to the terpene alcohol present can be the same in both adhesive layers or different, again depending upon the desired modulation of the transdermal flux of the active ingredient over the time period when the patch is in place. In a particularly preferred embodiment, the drug dosage form of the present invention contains about 30 to about 50 weight percent of a combination of a non- aromatic terpene alcohol and hydrophilic polyol absorption promoters or esters thereof, about 3 to about 10 weight percent of active ingredient (drug) , about 40 to about 60 weight percent of a medical-grade pressure- sensitive adhesive and up to about 1 weight percent of an insoluble hydratable microcrystalline material such as fumed silica. The weight ratio individually of non- aromatic terpene and hydrophilic polyol is about 7.5 to about 37.5 weight percent each.

The present invention is further illustrated by the following EXAMPLES which are not intended to limit the scope of the invention in any way. EXAMPLE 1

In vitro Skin Penetration Test of 17-beta-Estradiol.

Saturated solutions of 17-beta-estradiol were prepared in citronellol, a 1:1 mixture of citronellol and diisopropyl adipate and a 1:1 mixture of 1,2,6 hexane triol and propylene glycol.

Excized Yucatan pig skin was used in a skin penetration study. The dermal side of the skin was processed with a scalpel to remove excessive fat. Excessive hair on the epidermal side was lightly clipped and circular pieces (4 cm in diameter) were cut and placed over the donor compartment of a Franz cell assembly, as described by Franz J., Invest. Dermatol.

6_ :190-195 (1975), within a constant temperature bath at 32 degrees C. The donor compartment was filled with 40% PEG 400 in normal saline. Care was taken to avoid air bubble accumulation at the exposed dermal surface of the skin, thereby maximizing conditions for drug diffusion from the skin into the receptor solution.

The donor compartment was fitted onto the epidermal side of the skin and a sufficient amount of a saturated solution of 17-beta-estradiol in a given vehicle was added to cover the entire surface of the skin. Care was exercised to assure that the epidermal side of the skin was relatively dry in order to maximize surface contact and skin absorption of the drug in the vehicle combination. Seven hundred microliters (700 mcl) of the receptor solution were sampled intermittently and replaced with a blank vehicle.

The samples were assayed by HPLC. A Waters automated sampler and injection system coupled with a Beckman C-18 ultrasphere (5 micron, 15 cm x 4.6 mm) reverse phase column and a UV detector (Kratos) was set at 210 nm and 0.01 AUF. A mixture of acetonitrile: water and phosphoric acid (50:49.6:0.4 v/v) was used as the mobile phase. Plots of mean cumulative amount of 17-beta- estradiol in the receptor fluid divided by the exposed surface area of the skin as a function of time were prepared and the slope of the linear position of the plot was calculated to estimate the flux of 17-beta- estradiol in micrograms (meg) per centimeter square per hour. The lag time was estimated from best fit line analysis and extrapolated to the time axis. The results of flux studies are illustrated below in TABLE I.

TABLE I

Flux Study Results

Vehicle Lag Time Flux-mcg/cm²/hr. Citronellol 17.9 0.05

Citronellol: iisopropyl

Adipate (1:1) 8.6 0.11

1,2,6-Hexane Triol: propylene glycol (1:1) 19.1 0.16

From this data, it was concluded that a binary combination of propylene glycol with a relatively hydrophobic alcohol such as 1,2,6-hexane triol increases drug flux during steady state skin transport of 17-beta- estradiol.

EXAMPLE 2 Solubility Determination

The solubility of 17-beta-estradiol (estradiol) in a combination of alpha-terpineol with propylene glycol and alpha-terpineol with PEG 400 were measured to determine optimum concentrations of estradiol in these vehicle combinations. Excess amounts of micronized 17-beta-estradiol powder were added in pure propylene glycol, pure PEG 400 and pure alpha- terpineol, as well as in combinations of propylene glycol or PEG 400 with alpha-terpineol. The suspensions were shaken overnight, and, after centrifugation, the supernatant solutions were diluted appropriately and quantitated by spectrophotometry. The results are illustrated in TABLE II below.

TABLE II

Solubility Test Results

Estradiol Solubility, mg/ l

From this data, it was concluded that the best combination of propylene glycol or PEG 400 with alpha- terpineol to produce the maximum amount of estradiol in solution was 25% of alpha-terpineol with propylene glycol or PEG 400. In addition, to determine the maximum loading capacity of the multi-polymer adhesive solution, an experiment was performed with Gelva^® 788 multi-polymer (Monsanto Co., St. Louis, MO) solution and alpha-terpineol combinations.

In this experiment different proportions of alpha-terpineol and Gelva^® 788 were mixed and the mixtures were observed visually for any physical incompatibility, such as cloudiness, coagulation or other forms of precipitation in the mixtures. The adhesive combination was then coated on a- #1361 (3M Company, St. Paul, MN) paper release liner, air-dried for 15 minutes in a forced-air exhaust hood and then subsequently in a convective air-drying oven for half an hour at 60 degrees C. Visual observations for phase separation and syneresis were made. Based on physical data, it was concluded that alpha-terpineol is compatible with Gelva^® 788 at 5 - 23% of solid, dry total content of the adhesive combination.

EXAMPLE 3

Patch Compositions

Semi-occlusive transdermal and transcutaneous patch compositions for estradiol, ketoprofen and piroxicam were prepared. The process of fabrication of these patches was as follows. For each composition, required amounts of materials were weighed according to the proportions listed in TABLE III. The drug was dissolved in the penetrant aid vehicle before the addition of the adhesive in a suitable size glass bottle with an airtight cap. The adhesive composition was blended for approximately two hours. It was then coated on a #1361 paper release liner (3M Company, St. Paul, MN) using an SV-l Coater (Werner-Mathis Company, Concord, NC) and a Doctor Knife with 0.6 mm slit for wet coating. The coated adhesive was air-dried in a forced- air exhaust hood for 15 minutes followed by convective air-drying for two hours in an oven at 60 degrees C. The dried adhesive was laminated on a 1 mil polyetherurethane film reinforced with a 4 mil Nylon^® scrim (supplied by Gila River Products, Inc., Chandler, AZ) . Circular patches (6.4 cm² and 9.5 cm²) of the sheet were die cut to obtain the semi-occlusive transdermal/transcutaneous drug delivery systems of each drug. TABLE III

Transdermal/Transcutaneous Drug Delivery Compositions of 17-beta-Estradiol. Ketoprofen and Piroxicam

Composition #

ED-4

ED-5

KF-23

KF-24

PX-1

PX-2

PX-3

PX-4

Composition # f g h 1 KF PGML DIPA PX

KF-23

KF-24

PX-1

PX-2

PX-3

PX-4

a-G737 Gelva^® Multi-polymer 737 solution, a commercially available acrylate medical adhesive from Monsanto Company, St. Louis. MO.

b-G-7SS Gelva^® Multi-polymer 788 solution, a commercially available acrylate medical adhesive from Monsanto Company, St. Louis, MO.

c-CTNL Citronellol, commercially available terpene alcohol from Berje, Inc., Bloomfield, NJ.

d-TCT Transcutol^®, a commercially available diethylene glycol monomethyl ether from Gateffose Co., Elmsford, NY.

e-ED 17-beta-estradiol in micronized form, available commercially from Biosyth, Inc., Chicago, IL.

f-KF Ketoprofen, commercially available from Sims, France

g-PGML Propylene Glycol Monolaurate, commercially available from Stefan Company, Maywood, NJ

07607.

h-DIPA Diisopropyl Adipate, commercially available from Scher Chemicals, Inc., Clifton, NJ, under the trade name Schercemol DIA.

i-PX Piroxicam batch # 35-36, commercially available from Profarmaco, S.p.a. Italy. EXAMPLE 4

Composition for Transcutaneous Drug Delivery

The following composition of ketoprofen for transcutaneous delivery was prepared and tested in vitro for drug release and skin penetration using excized Yucatan pig skin.

Composition Ingredient Amt/Batch.g % (on dry wt)

KF-14 Gelva^®377 14.9 35.34

Gelva^®788 6.7 21.19

Transcutol^® 4.0 31.62 Ketoprofen 1.5 11.86

The procedure, other equipment, and components used for preparation of the patches were similar to that described in EXAMPLE 2. The mono-laminate dosage form was used in these studies.

For drug release studies and quantitation of ketoprofen, circular patches (6.413 cm ) were die cut and used as follows. For skin penetration studies, circular patches (17.81 cm²) were die cut to suit the size of the skin samples used for in vitro penetration studies.

The assay of samples was performed using HPLC. The C-18 reverse phase Bond-a-Pak^® (Beckman) column (as described in EXAMPLE 1) was used for ketoprofen separation. The mobile phase used was acetonitrile: water: phosphoric acid (50:49.6:0.4) and the detector was set at an AUF of 0.01. The flow rate was set at 1.0 ml/min and detection was done at 254 nm.

The.dosage form had a ketoprofen content of 2.0 mg/cm². Drug release studies were conducted using USP apparatus I (paddle method) . In this method an assembly composed of a covered vessel made of glass or other transparent material, a motor, a paddle formed from a blade and metallic drive shaft, and a cylindrical basket is utilized. The vessel is partially immersed in a suitable water bath that permits holding the temperature inside the vessel at 37+0.5 degrees C. during the procedure and keeping the bath fluid in constant, smooth motion. There is no significant motion, agitation or vibration of the assembly beyond that due to the smoothly rotating stirring element. The vessel is cylindrical, with a hemispherical bottom; it is 160 mm to 175 mm high, has an inside diameter of 98 mm to 106 mm and a nominal capacity of about 1000 ml. The sides of the vessel are flanged at the top and a fitted cover, with openings for thermometer insertion and sample withdrawal, is preferably used.

The shaft is positioned so that its axis is not more than 2 mm at any point from the vertical axis of the vessel, and rotates smoothly without significant wobble. The blade passes through the diameter of the shaft so that the bottom of the paddle blade is flush with the bottom of the shaft. The distance between the blade and the inside bottom of the vessel is maintained at 25+2mm. The blade and shaft comprise a single entity that can be coated with a suitable inert coating. The dosage form (patch) is allowed to sink to the bottom of the vessel before rotation of the blade is started. If the patch would otherwise float, it is attached to a metal/glass plate with an adhesive tape to prevent flotation.

A speed-regulating device is used that allows the shaft rotation speed to be selected and maintained at a specified rate within 4%. The shaft and basket components of the stirring element are fabricated from stainless steel, and the basket can have a gold coating 2.5 urn thick. A stock solution of 40% PEG 400 was used as the dissolution (drug release) medium.

A patch (6.413 cm²) was affixed onto a glass plate and it was exposed to 9004 ml of dissolution medium maintained at 37 degrees C. Samples were collected at 1.3, 2.0, 3.0, 6.0, 9.0, 12.0, 17.0, 22.0, 25.0, 26.0, 27.0, 30.0, 33.0 and 46.0 hours. The mean triplicate runs were 27.89%, 40.53%, 51.45%, 69.97%, and 87.52% drug released at 2 hours, 6 hours, 12 hours, 25 hours, and 30 hours, respectively. This is indicative of the controlled release of the drug from the monolithic matrix under sink conditions.

In vitro skin penetration studies were conducted on a compartment surface area using a Franz cell assembly with 4.918/cm² donor. The hair present on a portion of excized Yucatan pig skin was lightly clipped and the skin was processed to remove excessive fat on the dermal side. The release liner of the patch was removed and the adhesive matrix with non-occlusive backing was affixed on a relatively dry skin surface with gentle hand pressure. The skin preparation with the dosage form was mounted between the donor and receptor compartments using a spring activated holder and a ring between the skin and the receptor compartment. The receptor fluid (40% PEG 400 in normal saline) in direct contact with the skin was maintained bubble-free throughout the study. Approximately 700 microliters (mcls) of receptor fluid was removed at predetermined intervals ranging from 0 to 72 hours after initiation of the study. The samples were replaced with blank receptor fluid after each sampling time. Samples were assayed by the above-described HPLC procedure.

Plots of mean cumulative amount of ketoprofen in the receptor solution per cm² versus sampling time were constructed and the slope of the linear (steady state) portion of the regression line was calculated as the flux in mcg/cm²/hr. For this test composition, the flux was 2.1 mcg/cm²/hr. with an estimated lag time of about 6 hours to achieve steady state.

EXAMPLE 5

Semi-Occlusive Dosage Forms

The following semi-occlusive dosage forms of 17-beta-estradiol were prepared and tested for in vitro skin penetration using Estraderm^® 0.05 (CIBA-Geigy) as a reference standard for flux determination:

Composition Ingredient Amount/Batch

ED-14 Gelva^® 788 16.3g

Alpha-Terpineol 4.Og 17-beta-Estradiol 0.12g

ED-15 Gelva^® 788 16.8g

Alpha-Terpineol 3.2g

PEG 400 l.Og 17-beta-Estradiol 0.3g

ED-16 Gelva^® 788 16.5g

Alpha-Terpineol 2.2g

Propylene glycol 2.Og 17-beta-Estradiol 0.3g

The compositions were processed for coating by the procedure described in EXAMPLE 2. A mono-laminate dosage form was prepared. In vitro skin penetration studies in triplicate were conducted for each composition, and the flux was estimated by the procedure described in EXAMPLE 2. The results are illustrated below in TABLE IV.

TABLE IV

Flux Test Results

Composition • In Vitro Flux-mg/cm/hr. ED-14 0.03 ED-15 0.06

ED-16 0.21

Estraderm^® 0.05 0.23

The results illustrated that approximately 1:1 combination of alpha-terpineol and propylene glycol in the Gelva^® 788 adhesive matrix showed a transdermal flux of 17-beta-estradiol similar to that of the Estraderm^® 0.05 system.

EXAMPLE 6

Transdermal Compositions

The following compositions were prepared:

Amount/Batch/g. Ingredient #ED-25 Placebo

Gelva^®

788 Adhesive 17.0 17.0

Alpha-Terpineol 2.20 2.20

Fumed silicon dioxide 0.50 0.50

Propylene glycol 2.0 2.0

17-beta-Estradiol 0.5 The procedure used for preparing the patches was as follows:

Alpha-Terpineol (2.2 g) and propylene glycol (2.0 g) were weighed and mixed in a sealed container. Then, to this mixture was added micronized 17-beta- estradiol (0.5g) and fumed silicon dioxide (0.5g). The mixture was allowed to mix well for about three hours. To this mixture was added Gelva^® 788 adhesive (17.Og) and this wet adhesive composition was mixed for an additional two hours. A suitable size (approximately

12" x 14") of #1361 paper release liner (3M Company, St. Paul, MN) was mounted on a SV-1 film coating apparatus and the adhesive was coated as a wet film of 0.6 mm thickness using a Doctor Knife as a coating knife. The adhesive film was air-dried for 15 minutes in a forced-air hood and then for 30 minutes at 60 degrees C. in a forced-air drying oven. A polyetherurethane film reinforced with a nylon scrim (Type II polyurethane film, Gila River Products, Inc. Chandler, AZ) was laminated on the top of the dried adhesive using a lamination roller. Placebo compositions without 17-beta-estradiol were prepared in a similar manner as described above. Placebo and active circular patches of 4.91 cm² and 6.413 cm² were die cut for determination of content and skin irritation testing. The potency of active patches was determined by HPLC.

A standard of 2.246 g/liter of 17-beta- estradiol in methanol:water (1:100 solution) was used for HPLC analysis. The release liner was removed and each patch was extracted in 50 ml of methanol under constant shaking in a water bath for 4 hours at room temperature. An aliquot of this solution was diluted with water and assayed by HPLC as described in EXAMPLE 1. The 6.413 cm² active patches contained 2.05 mg of 17-beta-estradiol. The coefficient of variation of 1% was suggestive of a very good coating weight control.

EXAMPLE 7

Acceptance Testing

Irritation and product acceptance testing of placebo patches prepared in EXAMPLE 6 were tested on three female subjects. Test studies were performed as follows. Each subject was provided with an adhesive patch and an Adhesive Patch Evaluation Form. The subjects were instructed to apply the patch on the abdomen for a period of one week. The patch was evaluated for visual irritation, comfort, duration of adhesion to skin and edge curling problems.

The results are illustrated in TABLE V.

The above results demonstrate that irritation, as measured by visual inspection of site of application for erythema, skin eruptions or itching, was not evidenced, despite application of the patch without active ingredients. The patch can provide the necessary platform for long-term transdermal or transcutaneous delivery of drugs for systemic and topical therapy.

EXAMPLE 8

Preparation of Bi-laminate Compositions

The following bi-laminate composition (DHEA-1) was prepared and tested for skin irritation and duration of adhesion for one week:

Amount Batch

In a suitable sized container with a screw cap labeled as DHEA-1-Part A, were weighed 2.4 g of alpha- terpineol and 2.2 g of propylene glycol. These components were mixed for approximately 15 minutes. To this mixture was added 0.3 g of dehydroepiandrosterone and this mixture was shaken for 1 hour on a rotating mixer. To this mixture was added 0.3 g of fumed silicon dioxide, and the mix was again blended for 2 hours. Finally, 17.0 g of Gelva^® 788 multi-polymer solution was added and the final blend was mixed for two hours to obtain a lightly translucent composition for coating.

Similarly, the Part B portion of the composition was prepared with higher drug loading. Part A composition was then coated on a Scotchpak^® product 1361 release liner fitted on a SV-1 Coater, using a Doctor Knife with a 0.6 mm setting for wet coating thickness. It was air-dried in a forced-air exhaust hood for one hour, followed by coating of Part B, with the same knife setting, on top of it. The bi-laminate composition was air-dried for 15 minutes followed by oven drying for 30 minutes in a convective air-drying oven at 60 degrees C. The dried bi-laminate adhesive was laminated under pressure onto a Type II reinforced 1 mil polyetherurethane backing. The tetra-laminate sheet prepared, as above, was composed of the semi-occlusive reinforced polyetherurethane backing, an adhesive laminate with a low drug loading onto which was affixed a second adhesive laminate with a higher drug loading and a release liner. The release liner of Part B dried composition is held in position as the final laminate of the semi-occlusive dosage system for long-term therapy. Circular patches (6.418 cm²) were die cut to obtain dosage units.

The dosage systems were tested for product acceptance and skin tolerance on two healthy male subjects. After removing the release liner, one system was applied on the upper chest area devoid of excessive hair. Both subjects were supplied with a product evaluation form to fill out as illustrated in EXAMPLE 7. After one week, the patches were removed. Despite routine showers and normal daily activities, the patches remained in place without any edge curling, lack of adhesion or redness, itching or burning. This was suggestive of excellent tolerance of the semi-occlusive dosage system.

DHEA was chosen as an acceptable substitute for 17-beta-estradiol in a semi-occlusive dosage form for long-term steroidal replacement therapy. DHEA is produced abundantly by the adrenal glands as a sulfate conjugate as well as in its free form. It has been demonstrated that elevated serum DHEA (free and sulfate form) levels tend to prolong longevity through reduction of cardiovascular risk factors in male adults in the proximity of 50 years of age (Barrett-Conners, et al. New Engl. J. Med.. 315. 1519 (1986)). The transdermal administration of DHEA can be therapeutically beneficial for such a purpose.

EXAMPLE 9

Dosage Form for 17-beta-Estradiol

The following composition (ED-1) of 17-beta- estradiol was prepared and tested for in vitro skin flux using excized Yucatan pig skin:

Amount/Patch(g) Part B 17.0 2.4

0.3 2.2

0.6

The procedure for preparation of the bilaminate composition was similar to that described above for a DHEA dosage form for long-term therapy. Circular patches (6.413 cm² and 17.81 cm²) were die cut from the tetra-laminate sheets. The larger patches were tested for in vitro skin penetration by the procedure, described in EXAMPLE 4.

The dose per 6.413 cm² patch was determined to be 0.64 meg/cm². The skin flux data for 10 cm² Estraderm 0.05 patch (CIBA Geigy) and the above- described 17.5 cm² patch containing 0.6 meg/cm² dose is illustrated in FIGURE 1.

It should be noted that the lag time for Estraderm 0.05 and the ED-1 patch are quite similar and approximate at about 15 hours post application. The Estraderm patch shows two linear phases of steady state flux of estradiol. The first phase lasts about 65 hours with a mean flux of 0.06 mcg/cm²/hr. The second phase has a flux of about 0.2 mcg/cm²/hr. The semi-occluded pharmaceutical dosage form of 17-beta-estradiol (ED-1) shows a steady single phase of skin flux of 0.05 meg/cm /hr.

It is unclear whether or not ethanol contributed to the secondary phase of transdermal flux beginning at approximately 65 hours post application of the Estraderm^® 0.05 therapeutic system. In all experiments conducted, a single phase steady state flux was noted of 17-beta-estradiol from the semi-occlusive dosage systems containing a combination of a high boiling, non-aromatic terpene alcohol and a hydrophilic topical vehicle such as propylene glycol.

Composition ED-1, was tested in a comparative bioavailability study with the Estraderm^® 0.05 therapeutic system. The test animals were nine ovariectomized pigs weighing 90-120 pounds each. The animals were maintained under standard veterinary care. Three groups of three animals per group were used in the study. One group was used to apply Estraderm^® 0.05 patch per pig for 3 days on a lightly shaved area of the animal's back. The second group was used to apply one ED-1 (4 mg) patch per pig for 6 days. The third group received two ED-1 patches per pig for 6 days. Twenty- two hours prior to patch application, blood samples were withdrawn and serum estradiol and estrone levels in each pig were determined to establish a baseline. Subsequently blood samples were withdrawn at 4 hours, 8 hours, 24 hours, 48 hours, 72 hours, 95 hours, 120 hours and 144 hours after patch application. Specific radio- immunoassay methods were used to measure the serum levels of estradiol (Cox et al., Biol. Reprod. 27, 1126 (1982)) and estrone (Mason et al., Endo. Res. Cgmm, 2., 357 (1975)) whose disclosures are incorporated herein by reference. FIGURES 2 and 3 are bar plots for serum estradiol and estrone levels before and after application of one and two semi-occlusive transdermal estradiol dosage forms (Composition ED-1) .

From these data, it is concluded that the rate and extent (area-under-the-curve, AUC) of estradiol and estrone bioavailability over a period of 3 days for Estraderm^® 0.05 and over 6 days for the compositions of the present invention (one and two patches) is much higher than that observed for a Estraderm^® 0.05 which contains an equivalent total dose of 4 mg. It is also concluded that the rate of decline in estradiol plasma levels, 24 hours post-application period, is similar for both Estraderm^® 0.05 and ED-1 compositions, which is suggestive of sustained drug delivery from both dosage forms.

The sharp rise in serum estradiol levels seen for both Estraderm^® 0.05 and Composition 1 indicates efficient transdermal delivery of the estrogen from the delivery systems; one occluded, the other semi-occluded. The present composition showed much higher serum estradiol levels, thus demonstrating an improved in vivo transdermal flux of estradiol from the present bi-laminate adhesive composition with alpha-terpineol and propylene glycol, notwithstanding the fact that this is a semi-occlusive system. An assay of the residual estradiol content of the patches removed after 6 days of application confirmed that the dose delivered to the animals ranged from approximately 10.4% to 14.8% per Composition ED-1 patch with a smaller surface area (6.413 cm²) relative to Estraderm^® with 10 cm² surface area. The estrone levels in the serum are comparatively similar after an initial high level corresponding to high estradiol levels for the Composition ED-1 patch. The pig skin at the application site in the animals with Estraderm^® 0.05 patches showed a slightly brownish tinge. The animals with Composition-ED-1 patches showed no discoloration; this indicated excellent skin tolerance of the patch even after 6 days of application.

EXAMPLE 10

17-beta-Estradiol Dosage Form

The following composition of 17-beta-estradiol was prepared and tested for both in vitro skin penetration and in vivo tolerance on menopausal women:

Amount/Batch, g Ingredient Part A Part-B

The procedure for preparation of the compositions in tetra-laminate sheet form was similar to that described in EXAMPLE 9 except that Part A and Part B were coated separately on a #1361 release liner (3M Company) and dried. Then Part B was. dry laminated on Part A adhesive layer which was laminated onto a polyurethane backing. Circular 6.413 cm²patches were prepared. Tolerance and in vitro flux studies were carried out with excized Yucatan pig skin. For in vitro skin penetration studies, the

17.8 cm² size patches of this composition and 10 cm² size patches of Estraderm^® 0.05 (CIBA Geigy) were used. The penetration study was conducted as described in EXAMPLE 4. The Estraderm^® 0.05 Patch was run as a control each time to determine the relative performance of the system of the present invention. The skin flux of Estraderm^® 0.05 was estimated to be 0.23 mcg/cm²/hr. as against 0.14 mcg/cm²/hr. estimated for this composition. For skin tolerance testing, three female subjects with estradiol levels (in the range of 5-20 pg/ml) indicative of postmenopausal state were provided one patch and a product evaluation form. The subjects were asked to wear the patch on the abdomen for a period of one week and perform daily routines after which the patch was removed. The results of the skin tolerance study are illustrated in TABLE VI, below.

TABLE VI

Results of Skin Tolerance Study

Subject #

One Two Three

Test Parameter

Irritation (visual)

Comfort

¹The scale for the test parameter was measured as High = H (8-10), Medium = M (5-7), Low = L (1-4) and None = N (0) .

These results demonstrate that tolerance as well as acceptance by postmenopausal women were excellent for this semi-occlusive pharmaceutical dosage- form for long- term therapy. EXAMPLE 11

Stability Tests

Circular patch samples (6.413 cm²), prepared as described in EXAMPLES 7 and 8, of the bi-laminate composition of EXAMPLE 10 were packaged in aluminum laminated foil pouches and monitored at 60 degrees C. for 2 weeks, 40 degrees C. and 70% relative humidity, room temperature and 4 degrees-7 degrees C. for a period of four weeks. The samples were assayed for drug content and an initial drug release profile was determined using the USP dissolution method I. The patch sample was affixed on a 3" x 3" steel plate paddle with Scotch^® tape. The sample was placed in 1000 ml of 40% PEG 400 in normal saline, as the drug release medium, maintained at 37 degrees C. The paddle was rotated at 75 RPM. The results are compiled in TABLE VII, below.

The results of this abbreviated stability testing show that the semi-occlusive 17-beta-estradiol pharmaceutical dosage form retains its potency and drug release characteristics after storage under adverse test conditions.

EXAMPLE 12

Piroxicam Compositions

The following compositions of piroxicam in solvent-based acidic acrylate adhesive MSP 93188 (3M Company) in combination with adhesive compatible vehicles were prepared and tested for potency, and drug flux across excized Yucatan pig skin:

Amount Per Batch, g

Ingredient Part A Part B

Composition: PIR- PIR- -1 -3 -5 -1 -3 -5

3M Acrylate Adhesive

MSP-93188 85.0 85.0 85.0 85.0 85.0 85.0

Transcutol^® 12.1 12.1 12.1 12.1 12.1 12.1

Propylene Glycol 10.0 10.0 10.0 10.0 10.0 10.0

Fumed

Silicon

Dioxide 1.5 1.5 1.5 1.5 1.5 1.5

Piroxicam 1.0 1.0 1.0 1.0 1.0 1.0

Ethyl Acetate 10.0ml 10.0ml 10.0ml

For preparation of these compositions, a pre- mix of 100 g of propylene glycol and 15 g of fumed silicon dioxide was homogenized using a laboratory high speed stirrer. A required amount of this suspension was weighed in a suitable container and a required amount of piroxicam (for each part) was added along with a required amount of ethyl acetate and 12.1 g of Transcutol^®. The mixture was blended on a rotating mixer for 30 minutes. Acrylate adhesive (85.0 g) was then added and the mixture was blended overnight to obtain the final composition of Part A and Part B for coating. Each composition was coated on a #1361 release liner fitted on a SV-1 coating apparatus with a Doctor Knife setting at 0.6 mm. Each coated adhesive part was air-dried for 15 minutes and oven-dried for 30 minutes. Part A composition was laminated under pressure onto a reinforced Type II polyetherurethane non-occlusive backing. The release liner was removed and Part B adhesive was laminated onto the Part A to obtain tetra- laminate sheets of each composition. Large (17.8 cm ) and small (6.413 cm²) circular patches were die cut from the sheets for penetration and drug content.

In vitro skin penetration was performed by a procedure similar to that described in EXAMPLE 3. Drug content in the patches and receptor solutions were determined by HPLC. Piroxicam was extracted from patches in 50 ml of methanol, and a 5 ml aliquot of the extract was diluted with 100 ml of water. An aliquot of this sample was processed using HPLC on a filled C-18 reverse phase column. Piroxicam was eluted using acetonitrile: water: phosphoric acid. The detection was done with a UV detector set at 300 nm.

TABLE VIII illustrates the results of these studies.

These results illustrate that piroxicam dispensed with a suitable solvent provides a better means for maximizing thermodynamic activity in the bi- laminate matrix, thus improving piroxicam flux across the pig skin in vitro.

EXAMPLE 13

The following composition of 17-beta-estradiol in solvent-based aerylate-vinyl acetate copolymer adhesive (Gelva^® 788, Monsanto Company, St. Louis, MO) was prepared and tested using backings with varying degrees of occlusivity and moisture vapor transmission rates (MVTR) . Ingredient Amount Per Batch, g.

Part A Part B

Gelva^® 788 34.0 34.0

Alpha-Terpineol 7.5 7.5

Propylene Glycol 6.0 6.0 Sylloid^® 244FP 0.6 0.6

(Fumed Silicon Dioxide)

17-beta-Estradiol 0.9 0.9

A premix of alpha-terpineol, propylene glycol and fumed silicon dioxide was homogenized using a high¬ speed stirrer. To 14.1 g of the pre-mix was added 0.9 g of micromized estradiol and the mix was agitated for about 1.5 hours to disperse and solubilize the drug. Finally, 34.0 g of the Gelva^® 788 adhesive was added and the mixture was agitated gently for about 2 hours to obtain the coating solution as Part A and Part B.

A #1361 Scotchpak^® release liner (3M Company, St. Paul, MN) was stretched on a frame of an SV-1 Coater (Werner-Mathis) (U.S.A.) Inc., Concord, NC) for coating. The setting of the slit was set at 0.2 mm with a Doctor Knife for the first coat with Part A. After initial air-drying for 15 minutes in an air exhaust hood, the Part B coat was applied with a knife setting at 0.3 mm. After an initial air-drying in the hood for 15 minutes, the adhesive matrix composition was oven-dried at 60 degrees C. for 30 minutes. Three different backing materials were laminated respectively onto the adhesive to form three groups of patches, each of which had a different backing material, and die cut 17.81 cm² patches were prepared for skin penetration testing. The three backing materials used were Type II reinforced polyether urethane film (Gila River Corporation, Chandler, AZ) , Polyester-polyethylene laminate film (Scotchpak^® 1220, 3M Health Care, 3M Company, St. Paul, MN) and an occlusive tetra-laminate film (Scotchpak^® 1009) .

The skin penetration testing of 17.81 cm² patches was performed along with Estraderm^® 0.05 patch as described in EXAMPLE 4. The results are illustrated in TABLE IX and FIGURE 5.

TABLE IX

Skin Flux Results

MVTR Skin Flux,

Backing Film g/cm²/24 hr. mcg/cm²/hr.

1. Reinforced PEU Type II (Gila River) 550-670 0.02

2. Polyester/Polyethylene

Laminate (Scotchpak^® 1220) 0.3-8.0 0.23 3. Tetra-laminate

Film (Scotchpak^® 1009) about 0-0.3 0.17

(max.)

4. Control (Estraderm^®) — 0.15 These results illustrate that as the moisture vapor transmission rate of the film decreases substantially, the estradiol flux across the skin increases substantially. It is also demonstrated that total occlusivity of the backing film is not essential to establish steady state estradiol flux in vitro across the skin that is comparable to a commercial product.

EXAMPLE 14

Semi-occlusive patches were prepared with a tetra-laminate film (Scotchpak^® 1009, 3M Health Care, 3M Company, St. Paul, MN) backing layer and were assayed by extraction in 30 ml of ethanol to determine its content by an HPLC procedure similar to that described in EXAMPLE 1. The dose per 17.81 cm² size circular patch was determined to be 9.0 mg. Skin tolerance and estradiol bioavailability studies were performed with four postmenopausal subjects. This was established by predetermination of estradiol levels which ranged between 10-25 pg/ml for the test subjects. After a pre- study sampling of plasma estradiol and estrone levels for at least one day, one patch per subject was applied securely on the abdomen. Blood samples were withdrawn on a predetermined schedule during the entire period of patch application for one week.

A similar procedure was followed by the determination of estradiol bioavailability from a twice- a-week Estraderm^® 0.1 patch applied for 3 days on the abdomen of four postmenopausal subjects. The results of these studies are illustrated in FIGURE 6. These data illustrate that the patch of the present invention, applied for one week, showed sustained bioavailability of estradiol at about 50 pg/ml or above. The plasma estrone levels remained essentially similar for both products for up to a period of 5 days during or after (for Estraderm^®) removal of the patch. All subjects wearing the patch of the present invention for one week were asked to evaluate the performance of the patch on the skin with respect to tolerance and product acceptance.

TABLE X illustrates results of this evaluation.

TABLE X

Estradiol Patch Evaluation Results

Two out of four subjects experienced edge lifts after 4 days of patch application. An external adhesive tape was applied on the top of patches on these subjects to retain the patches in place and complete the bioavailability study. Overall, none of the subjects reported any skin irritation problems due to occlusion or components of the matrix composition suggestive of a very good tolerance of the product during prolonged application for a one-week period. TABLE XI and TABLE XII illustrate pharmacokinetic parameters derived based on the bioavailability results of these two products. TABLE XI

Phar acokinetic Parameters for Estradiol After Application of Estraderm^® Patch for Three Days on Four Postmenopausal Subjects.

TABLE XII

Pharmacokinetic Parameters for Estradiol After Application of a Watson 9 mg Patch for Seven Days on Four Postmenopausal Subjects

AREA UNDER THE TIME-PLASMA TIME TO REACH PEAK PLASMA PEAK PLASMA CONCENTRATION CURVES CONCENTRATIONS, Tmax CONCENTRATIONS (0-168 hrs.) AUC (picogram-hours/ml) max (hours) ^c _max (picograms/ml)

Subject ESTRADIOL ESTRONE ESTRADIOL ESTRONE ESTRADIOL ESTRONE

Mean 24007.15 39591.25

SD (+) 7111.23 6883.69

C.V. (%) 29.62 17.39

Range (min.) 17091.00 31688.00 36 . 00 36. 00

(max.) 30753.00 47588.00 60 . 00 60. 00

N.C. - Not Calculated

As mentioned earlier, the present estradiol batch composition was applied for a one-week period; whereas the Estraderm^® 0.1 patch was applied for a period of 3 days in order to complement the recommended twice-a-week schedule for administration of the product. The mean AUC (area under the plasma concentration - time curve) for estradiol, a measure of relative bioavailability of the patch of the present invention with reference to Estraderm^® 0.1 was about twofold. Since the patch was applied for 7 days compared to 3 days¹ application of the Estraderm^® patch, it is reasonable to expect these results. The T_maχ (time to achieve maximum plasma concentration in hours) for estradiol was substantially different for the patch of the present invention as compared to the Estraderm^® 0.1 patch. However, the C_π)ax (maximum plasma concentrations) achieved during the test periods of 3 to 7 days of patch application were observed to be quite similar (FIGURE 6) for both estradiol and estrone. The results of this study thus illustrate the point that a suitable matrix composition as described herein with a suitable semi-occlusive backing with a defined MVTR can provide sustained systemic drug therapy over a period of one week with a high level of product tolerance and acceptance by the test subjects.

The foregoing description and the EXAMPLES are intended as illustrative and are not to be taken as limiting. Still other variations within the spirit and scope of this invention are possible and will readily present themselves to those skilled in the art.

Claims

We Claim:

1. An anhydrous but hydratable pressure- sensitive adhesive matrix suitable for the transdermal delivery of a therapeutically active ingredient and containing a non-aromatic terpene alcohol or an ester thereof in an amount sufficient to enhance the release of said active ingredient from said matrix upon hydration of the matrix.

2. The pressure-sensitive adhesive matrix in accordance with claim 1 wherein said terpene alcohol is alpha-terpineol.

3. The pressure-sensitive adhesive matrix in accordance with claim 1 and additionally containing an absorption promoter for said therapeutically active ingredient.

4. The pressure-sensitive adhesive matrix in accordance with claim 3 wherein said promoter is propylene glycol.

5. A drug delivery system suitable for transdermal administration of a drug and comprising: an anhydrous, hydratable pressure-sensitive adhesive matrix comprising a pressure-sensitive adhesive and distributed within said adhesive a non-aromatic terpene alcohol or an ester thereof, an absorption promoter and a drug; and a backing layer coextensive with said adhesive matrix.

6. The drug delivery system in accordance with claim 5, wherein said pressure-sensitive adhesive is selected from the group consisting of a polydimethyl siloxane, polyisobutylene, acrylic acid-acrylamide copolymers, acrylate-acrylic acid copolymers, 2-ethylhexyl acrylate, and vinylacetate-acrylate copolymers.

7. The drug delivery system in accordance with claim 6, wherein said pressure-sensitive adhesive is an acrylic acid-acrylamide copolymer.

8. The drug delivery system in accordance with claim 5, wherein said absorption promoter is selected from the group consisting of propylene glycol, propylene glycol monolaurate, isopropyl palmitate, 1,2,6-hexanetriol, polyethylene glycol, diisopropyl adipate, polyethylene glycol 400 acetate, and ethylene glycol monoether.

9. The drug delivery system in accordance with claim 8, wherein said absorption promoter is propylene glycol.

10. The drug delivery system in accordance with claim 5, wherein said non-aromatic terpene alcohol is alpha-terpineol.

11. The drug delivery system in accordance with claim 5, wherein said drug is a lipophilic drug.

12. The drug delivery system in accordance with claim 11, wherein said lipophilic drug is a steroid.

13. The drug delivery system in accordance with claim 12, wherein said steroid is an estrogen.

14. The drug delivery system in accordance with claim 13, wherein said estrogen is 17-beta- estradiol.

15. The drug delivery system in accordance with claim 12, wherein said steroid is dehydroepiandrosterone.

16. The drug delivery system in accordance with claim 5, wherein said matrix is monolithic.

17. The drug delivery system in accordance with claim 5, wherein said backing layer is a moisture vapor permeable polyetherurethane film.

18. The drug delivery system in accordance with claim 5, wherein said pressure-sensitive adhesive has a solids content of about 30 to about 50 percent by weight.

19. The drug delivery system in accordance with claim 5, wherein said pressure-sensitive adhesive matrix further includes finely fumed silicon dioxide particles.

20. The drug delivery system in accordance with claim 5, wherein said backing layer further includes a nylon scrim film attached to the outer surface thereof.

21. The drug delivery system in accordance with claim 5 wherein said system is a transdermal patch.

22. A dosage form for the administration of drugs to a mammal constituted by an adhesive matrix capable of attachment to the skin of said mammal by means of said adhesive and a backing layer; said adhesive matrix comprising a pressure-sensitive adhesive, a non-aromatic terpene alcohol or an ester thereof, an absorption promoter, and a lipophilic drug.

23. The dosage form in accordance with claim 22, wherein said dosage form is a transdermal patch.

24. The dosage form in accordance with claim 22, wherein said backing layer is a moisture vapor permeable polyetherurethane film.

25. The dosage form in accordance with claim 22, wherein said adhesive matrix is a monolithic multi- laminated pressure-sensitive adhesive matrix.

26. The dosage form in accordance with claim

22, wherein said adhesive matrix comprises an ethylhexyl acetate adhesive, alpha-terpineol, propylene glycol in addition to said lipophilic drug.

27. The dosage form in accordance with claim 26, wherein said lipophilic drug is an estrogen.

28. A method for extended administration of a lipophilic drug to a mammal comprising: attaching a pressure-sensitive adhesive drug dosage form to the skin of said mammal wherein said drug dosage form comprises:

(a) an anhydrous, hydratable pressure- sensitive adhesive matrix comprising a pressure- sensitive adhesive, a non-aromatic terpene alcohol or an ester thereof, an absorption promoter and a drug; and (b) a backing layer coextensive with a surface of said adhesive matrix.