WO2007011763A2

WO2007011763A2 - Adhesive sheet and methods of use thereof

Info

Publication number: WO2007011763A2
Application number: PCT/US2006/027457
Authority: WO
Inventors: Peter M. Seiler; Ryan D. Gordon
Original assignee: 3M Innovative Properties Company
Priority date: 2005-07-15
Filing date: 2006-07-13
Publication date: 2007-01-25
Also published as: WO2007011763A3

Abstract

An adhesive sheet comprising a backing film and an adhesive layer. The adhesive layer comprises a drug and an oligomeric adjuvant selected from an oligolactic acid, oligolactic acid derivatives, or mixtures thereof.

Description

ADHESIVE SHEET AND METHODS OF USE THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS The present application claims priority to U.S. Provisional Application Serial No. 60/699,697, filed on July 15, 2005, which is incorporated herein in its entirety.

The present invention relates to an adhesive sheet and methods of use thereof. In one embodiment, the present invention relates to a transdermal drug delivery device and methods of transdermal drug delivery.

Background of the Invention

Adhesive sheets have been used for a wide variety of medical applications, such as wound dressings, protective drapes, electrodes, and transdermal drug delivery devices. It is often desirable to include a bioactive compound, such as a drug, in an adhesive sheet article used for medicinal purposes and in some instances, such as in transdermal drug delivery, it is desirable to transport a drug across the skin and into a patient.

Transdermal administration of drugs is known to have many potential advantages, such as avoidance of first-pass metabolism, avoidance of gastro-intestinal irritation, sustained release, and improved patient compliance with treatment regimens.

It is well known, however, that the skin presents a formidable barrier to permeation of most drug molecules and thus makes transdermal delivery difficult in the absence of some sort of mechanism to enhance drug diffusion across the skin. Typical enhancement mechanisms include chemical enhancement (also referred to as "passive"), as well as so-called "active" enhancing mechanisms, such as ultrasound, electroporation, microneedles, and iontophoresis. Although active enhancing mechanisms may be very effective in certain instances at increasing the amount of drug transported across the skin, they bring added complexity to a transdermal dosage form. Thus, it is generally desirable to use chemical enhancement when possible so that the resulting dosage form retains the apparent simplicity of an adhesive bandage.

Currently available chemical permeation enhancers generally have one or more disadvantages. For example, they may have excessive volatility, be irritating to the skin, have chemical incompatibilities with the drug, or cause over-plasticization of an adhesive matrix. Summary of the Invention

In one aspect, the present invention is an adhesive sheet comprising a backing film and an adhesive layer. The adhesive layer comprises a drug and an oligomeric adjuvant selected from an oligolactic acid, oligolactic acid derivatives, or mixtures thereof.

In a second aspect, the present invention is an adhesive sheet comprising a backing film and an adhesive layer. The adhesive layer comprises a drug and an oligomeric adjuvant of the formula:

I wherein Z is hydrogen or -C(O)Ri;

X is selected from the group consisting of hydroxy, -ORj, -SRj, -N(Rj)₂ and divalent or trivalent headgroups terminated in oxygen, nitrogen, or sulfur; y is greater than or equal to 1 and less than or equal to 3; each Ri is independently selected from a linear, branched, or cyclic alkyl, alkoxy, or aryl with 1 to 18 carbon atoms; and n is between about 3 and about 20.

In a third aspect, the present invention is an adhesive sheet comprising a backing film and a pressure-sensitive adhesive matrix releasably adhered to a protective liner. The pressure-sensitive adhesive matrix comprises an adhesive polymer and a compound selected from an oligolactic acid, oligolactic acid derivatives, or mixtures thereof.

In a fourth aspect, the present invention is a method of transdermal delivery comprising the steps of: (a) providing a transdermal drug delivery system comprising a matrix comprising an adhesive, a therapeutically effective amount of a drug, and an oligomer of an alpha-hydroxy acid; (b) placing the delivery system in a delivering relationship to the skin of a mammal; (c) allowing the alpha-hydroxy oligomer to hydrolytically degrade to shorter chain oligomers or monomer; and (d) delivering drug to the mammal.

invention is a method of transdermal delivery comprising the steps of: (a) providing a transdermal drug delivery system comprising a matrix comprising an adhesive, a therapeutically effective amount of a drug, and an oligomer of an alpha-hydroxy acid; (b) placing the delivery system in a delivering relationship to the skin of a mammal; (c) allowing the matrix to absorb moisture; and

(d) delivering drug to the mammal.

In a sixth aspect, the present invention is a method of increasing the solubility of a drug compound in an adhesive matrix comprising the steps of: (a) providing an adhesive; (b) providing a drug; (c) providing an oligomer of an alpha-hydroxy acid; (d) mixing adhesive, drug, and alpha-hydroxy acid to form an adhesive matrix wherein the concentration of dissolved drug is greater than the solubility of the drug in the adhesive in the absence of the alpha-hydroxy acid.

In another aspect, the present invention is an adhesive sheet comprising a backing film and an adhesive layer. The adhesive layer comprises a drug, with the proviso that the drug is not drospirenone, and an oligomeric adjuvant selected from an oligolactic acid, oligolactic acid derivatives, or mixtures thereof.

In another aspect, the present invention is an adhesive sheet comprising a backing film and an adhesive layer. The adhesive layer comprises a drug, with the proviso that the drug is not drospirenone, and an oligomeric adjuvant of the formula:

I wherein Z is hydrogen or -C(O)RJ ;

X is selected from the group consisting of hydroxy, -ORj, -SR], -N(Rj)₂ and divalent or trivalent headgroups terminated in oxygen, nitrogen, or sulfur; y is greater than or equal to 1 and less than or equal to 3; each Rj is independently selected from a linear, branched, or cyclic alkyl, alkoxy, or aryl with 1 to 18 carbon atoms; and n is between about 3 and about 20.

In another aspect, the present invention is a method of transdermal delivery comprising the steps of: (a) providing a transdermal drug delivery system comprising a matrix comprising an adhesive, a therapeutically effective amount of a drug, with the |iroVϊst)!l;th!at !tlie^d3πϊg4i-f^tMtecli-^<Ospirenone, and an oligomer of an alpha-hydroxy acid; (b) placing the delivery system in a delivering relationship to the skin of a mammal; (c) allowing the alpha-hydroxy oligomer to hydrolytically degrade to shorter chain oligomers or monomer; and (d) delivering drug to the mammal. In another aspect, the present invention is a method of transdermal delivery comprising the steps of: (a) providing a transdermal drug delivery system comprising a matrix comprising an adhesive, a therapeutically effective amount of a drug, with the proviso that the drug is not drospirenone, and an oligomer of an alpha-hydroxy acid; (b) placing the delivery system in a delivering relationship to the skin of a mammal; (c) allowing the matrix to absorb moisture; and (d) delivering drug to the mammal.

In another aspect, the present invention is a method of increasing the solubility of a drug compound in an adhesive matrix comprising the steps of: (a) providing an adhesive; (b) providing a drug, with the proviso that the drug is not drospirenone; (c) providing an oligomer of an alpha-hydroxy acid; (d) mixing adhesive, drug, and alpha- hydroxy acid to form an adhesive matrix wherein the concentration of dissolved drug is greater than the solubility of the drug in the adhesive in the absence of the alpha- hydroxy acid.

The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The detailed description that follows more particularly exemplifies illustrative embodiments, but should not be construed to unduly limit this invention.

Detailed Description In one aspect, the present invention is an adhesive sheet comprising a backing film and an adhesive layer. The backing film is a generally flexible film that serves as a carrier for other components of an adhesive sheet, such as adhesives, membranes, and drug reservoirs. The backing film may also serve to protect the other components of an adhesive sheet. In one embodiment, the backing film will serve as both a carrier and a protective layer for an adhesive layer. The backing film may protect other components of the adhesive sheet from physical contact or from exposure to unwanted environmental influences, such as light, moisture, oxygen, and dirt. In one embodiment, the backing film is continuous, but perforated or otherwise non- continuous films may also be suitable for use in the present invention. KliWftl^-llilϊ^€øfϊlexible films employed as conventional tape backings which may be useful as a backing film include those made from polymer films such as polypropylene; polyethylene, particularly low density polyethylene, linear low density polyethylene, metallocene polyethylenes, and high density polyethylene; polyvinyl chloride; polyester (e.g., polyethylene terephthalate); polyvinylidene chloride; ethylene- vinyl acetate (EVA) copolymer; polyurethane; cellulose acetate; and ethyl cellulose. Coextruded multilayer polymeric films are also suitable, such as those described in U. S. Patent No. 5, 783, 269 (Heilmann et al.), the disclosure of which is incorporated herein by reference. Backings that are layered such as polyethylene terephthalate- aluminum-polyethylene composites and polyethylene terephthalate-EVA composites are also suitable. Foam tape backings, such as closed cell polyolefin films used in 3M™ 1777 Foam Tape and 3M™ 1779 Foam Tape are also suitable. Polyethylenes, polyethylene blends, and polypropylenes are preferred polymer films. Polyethylenes and polyethylene blends are most preferred polymer films. In one embodiment, the backing film is translucent or transparent. Additives may also be added to the backing film, such as tackifiers, plasticizers, colorants, and anti-oxidants. It may be desirable to use a flexible backing film, particularly for medical or pharmaceutical applications where the end use product is adhered to skin. In one embodiment, the present method finds particular utility for island placement converting of adhesive laminates having very flexible backings, such as thin polyethylene backings, which are generally difficult to handle in small, individual patch shaped sections.

In one embodiment, the backing film thickness is more than 10 μm, often more than 20 μm, and sometimes more than 40 μm. In another embodiment, the backing film thickness is less than 2 mm, often less than 1 mm, and sometimes less than 150 μm.

Adhesives of the present invention generally comprise a polymer, preferably a polymer selected from the group consisting of acrylates, natural rubbers, synthetic rubbers, such as polyisobutylenes, polyisoprenes, styrenic block copolymers, polyvinylethers, silicone polymers, polyurethanes, polyurethane-ureas, and combinations thereof. The adhesive is preferably suitable for use as a skin-contacting adhesive. In one embodiment, the skin-contacting adhesive may comprise a pressure- sensitive adhesive. Further description of suitable adhesives may be found in U. S. Patent Nos. 5,656,286 (Miranda et al.), 4,693,776 (Krampe et al.), 5,223,261 (Nelson et al.), and 5,380,760 (Wendel et al.) the disclosures of which are incorporated herein by fteffeitgW

adhesive may optionally contain other additives, for example, tackifiers, plasticizers, anti-oxidants, colorants, crystallization inhibitors, and the like.

Acrylate polymers and copolymers are particularly preferred pressure-sensitive adhesives. Examples of suitable monomers for use in acrylate copolymers include alkyl acrylates, such as isooctyl, 2-ethylhexyl, n-butyl, ethyl, methyl, and dimethylhexyl, and alkyl methacrylates, such as lauryl, isodecyl, and tridecyl. Monomers containing functional groups, such as carboxylic acid, hydroxy, amide, and amino may also be incorporated into an acrylate copolymer. Examples of suitable monomers containing functional groups include acrylic acid, hydroxyalkyl acrylates containing 2 to 4 carbon atoms in the hydroxyalkyl group, acrylamide, N-vinyl-2- pyrrolidone, vinyl acetate, and alkoxyethyl acrylates.

Acrylate copolymers may optionally further comprise a substantially linear macromonomer copolymerizable with the other monomers. Suitable macromonomers include polymethylmethacrylate, styrene/acrylonitrile copolymer, polyether, and polystyrene macromonomers. Examples of useful macromonomers and their preparation are described in U.S. Patent No. 4,693,776 (Krampe et al.), the disclosure of which is incorporated herein by reference in its entirety for all purposes.

In one embodiment, the adhesive layer may be a substantially continuous layer having the same general area as the backing film. In another embodiment, the adhesive layer may be ring or donut-shaped, such that it is generally congruent with the perimeter of the backing film and has a central void. The central void may be useful, for example, to house a drug reservoir, an electrode gel, or a water-absorbent hydrocolloid. In another embodiment, the adhesive layer may be perforated or may be formed from a pattern of discontinuous pieces. Such a non-continuous adhesive layer may be particularly beneficial for use in medical or pharmaceutical applications where the end use product is adhered to skin, as the openings in the adhesive layer may allow for increased breathability and may reduce skin trauma due to extensive wear or removal. In one embodiment, the adhesive layer of the present invention comprises a drug. Drugs of the present invention will be present in an amount such that the composition delivers a therapeutically effective amount for the indication being treated. This amount will vary according to the type of drug used, the condition to be treated, the amount of time the composition is allowed to remain in contact with the skin of the ^■"Ili.bjIiltMffi.itJiέiif^tfefψMδwn to those of skill in the art. In one embodiment, the amount of drag present will generally be about 0.01 to 40 wt-%, preferably about 1.0 to 20 wt-%, based on the total weight of the adhesive layer. In one embodiment, the drag is dispersed, preferably homogeneously, and more preferably dissolved in the adhesive layer. In one embodiment, the adhesive layer is substantially free of undissolved drag, and preferably free of undissolved drag. The presence of undissolved drag may be detected, for example, by examination with an optical microscope at 2Ox magnification. It should be understood that where only an occasional crystal or undissolved particle is present or where less than about 1% of the total amount of drag is undissolved, the composition is considered to be substantially free of undissolved drag.

Pharmaceutically active agents (also referred to as "drags") that can be included in the adhesive layer are capable of local or systemic effect when administered to the skin. Some examples include clonidine, estradiol, nicotine, nitroglycerine, scopolamine, and fentanyl, which are commercially available in the form of transdermal devices. Other examples include antiinflammatory drags, both steroidal (e.g., hydrocortisone, prednisolone, triamcinolone) and nonsteroidal (e.g., naproxen, piroxicam); bacteriostatic agents (e.g., chlorhexidine, hexylresorcinol); antibacterials (e.g., penicillins such as penicillin V, cephalosporins such as cephalexin, erythromycin, tetracycline, gentamycin, sulfathiazole, nitrofurantoin, and quinolones such as norfloxacin, flumequine, and ibafloxacin); antiprotazoals (e.g., metronidazole); antifungals (e.g., nystatin); coronary vasodilators; calcium channel blockers (e.g., nifedipine, felodipine, diltiazem); bronchodilators (e.g., theophylline, pirbuterol, salmeterol, isoproterenol); enzyme inhibitors such as collagenase inhibitors, protease inhibitors, elastase inhibitors, lipoxygenase inhibitors (e.g., A64077), and angiotensin converting enzyme inhibitors (e.g., captopril, lisinopril); other antihypertensives (e.g., propranolol); leukotriene antagonists (e.g., ICI204,219); anti-ulceratives such as H2 antagonists; steroidal hormones (e.g., progesterone, testosterone, estradiol; drospirenone); antivirals and/or immunomodulators (e.g., l-isobutyl-lH-imidazo[4,5- c]quinolin-4-amine, l-(2-hydroxy-2-methylpropyl)-lH-imidazo[4,5-c]quinolin-4- amine, and acyclovir); local anesthetics (e.g., benzocaine, propofol); cardiotonics (e.g., digitalis, digoxin); antitussives (e.g., codeine, dextromethorphan); antihistamines (e.g., diphenhydramine, chlorpheniramine, terfenadine); narcotic analgesics (e.g., morphine, buprenorphine); peptide hormones (e.g., human or animal growth hormones, LHRH); cardioactive products such as atriopeptides; proteinaceous products (e.g., insulin);

dextranase); antinauseants; anticonvulsants (e.g., carbamazine); immunosuppressives (e.g., cyclosporine); psychotherapeutics (e.g., diazepam); sedatives (e.g., phenobarbital); anticoagulants (e.g., heparin); analgesics (e.g., acetaminophen); antimigraine agents (e.g., ergotamine, melatonin, sumatripan); antiarrhythmic agents (e.g., flecainide); antiemetics (e.g., metaclopromide, ondansetron); anticancer agents (e.g., methotrexate); neurologic agents such as anxiolytic drugs; hemostatics; anti-obesity agents; and the like, as well as pharmaceutically acceptable salts and esters thereof. In one aspect, any suitable drug may be used with the proviso that the drug is not drospirenone. In one aspect, the drug may be a steroidal hormone drug having a hydroxy functionality, and in particular a steroidal hormone drug having a hydroxy at the C- 17 position, such as testosterone, estradiol, and/or levonorgestrel.

In one aspect, the adhesive layer of the present invention comprises an oligomeric adjuvant selected from oligolactic acid, oligolactic acid derivatives, and mixtures thereof. The oligomeric adjuvant is preferably oligolactic acid.

Oligolactic acid is an oligomer chain derived from a precursor hydroxy-acid that is lactic acid. As the terminology is used herein, a chain "derived from" lactic acid need not be prepared from lactic acid, but rather this terminology is used to designate chains having a structure that could formally be obtained by condensation of lactic acid. The structure of oligolactic acid may be generally represented by formula I:

CH,

Oligolactic acid derivatives are oligomeric chains derived from oligolactic acid. Again, as the terminology is used herein, chains "derived from" oligolactic acid need not be prepared from oligolactic acid, but rather this terminology is used to designate chains having a structure that could formally be obtained by derivatizing one or both terminal groups of an oligolactic acid. That is, an oligolactic acid derivative comprises oligolactic acid where one or both of the end groups (i.e., the terminal hydrogen and/or hydroxy) is replaced by an R group.

In one embodiment, an oligolactic acid or oligolactic acid derivative is a compound of the formula II:

Each oligolactic acid derivative chain is capped on one end by an end group, Z, wherein Z is hydrogen or -C(O)Rj . Each R₁ is independently selected from a linear, branched, or cyclic alkyl, alkoxy, or aryl with 1 to 18 carbon atoms. In one embodiment where y is greater than 1, the R₁ substituent on each chain is equivalent. Suitable examples OfR₁ include methyl or ethyl, and most preferably methyl.

The choice of end group may modify the performance of the oligolactic acid derivatives with respect to that of oligolactic acid. For physical and chemical reasons it may be preferable to modify the end group to affect stability, drug solubility, water affinity, interaction with the drug, etc. Such parameters may influence drug delivery rates. Preferred oligolactic acid derivatives as described herein contain at least one chain capped with an organocarbonyl group, and more preferably, with an acetyl group. Acylation can significantly enhance stability and reduce the hydrophilicity and water solubility of the biocompatible polymers when such properties are desired.

Each chain or chains in the oligolactic acid derivative is capped or bridged on one end by a headgroup, X. Suitable examples of the headgroup X are selected from the group consisting of -OH, -OR₁, -SR₁, -N(R_t)₂, and divalent or trivalent headgroups terminated in -0-, -N-, or -S. A chain may be capped by a monovalent, divalent, or polyvalent organic moiety

(each valence of the capping group being independently bonded to a chain) that does not contain hydrogen atoms capable of hydrogen bonding. The chain may also be capped at one end or both ends by a monovalent, divalent, or polyvalent group, selected from either an ionic group or a group that does contain hydrogen atoms capable of hydrogen bonding. Where y is equal to 1 the chain is typically capped by a monovalent headgroup. Suitable examples of monovalent groups that may cap or terminate the compound include -OH, -OR₁, -SR₁, -N(RO₂. Capping groups need not necessarily terminate the compound; rather, they can bridge chains, which is the case when y is greater than 1. Where y is greater than 1, two or more chains are bridged by a divalent or polyvalent headgroup. For example, ethylenediamine is a suitable divalent

capable- of Iβging two chains. In one embodiment, y is greater than or equal to 1 and less than or equal to 3. In one embodiment, y is 2.

Examples of groups not containing hydrogen atoms capable of hydrogen bonding include organocarbonyl groups such as acetyl and alkoxy groups such as ethoxy. Examples of ionic groups include quaternary ammonium groups, sulfonate salts, carboxylate salts, and the like. Examples of groups capable of hydrogen bonding include hydrogen when bonded to a heteroatom terminus of a chain, as well as acid functional groups, amides, carbamates, and groups such as amino, hydroxyl, thiol, aminoalkyl, alkylamino, hydroxyalkyl, hydroxyalkylamino, sugar residues, and the like. Such end groups are well known and can be readily selected by those skilled in the art, and are disclosed, for example, in U.S. Patent Nos. 5,569,450 and 6,042,811, the disclosures of which are herein incorporated by reference.

In one embodiment, the number of repeat units, n, is greater than or equal to 3. In one embodiment, the number of repeat units, n, is less than or equal to 20, often less than or equal to 10, and sometimes less than or equal to 6. In one embodiment, the number of repeat units, n, is between about 3 and 20, often between about 3 and 10, and sometimes between about 3 and 6.

In one embodiment, the number-average number of repeat units (readily determinable by NMR analysis) is greater than or equal to 3. In one embodiment, the number-average number of repeat units is less than or equal to 20, often less than or equal to 10, and sometimes less than or equal to 6. In one embodiment, the number- average number of repeat units is between about 3 and 20, often between about 3 and 10, and sometimes between about 3 and 6.

In one embodiment, the number-average molecular weight (readily determinable by GPC analysis) is greater than about 150 g/mol, often greater than about

200 g/mol. In one embodiment, the number-average molecular weight (readily determinable by GPC analysis) is less than about 1500 g/mol, often less than about 1000 g/mol, and sometimes less than about 500 g/mol. In one embodiment, the number-average molecular weight is between about 150 and 1500 g/mol, often between about 200 and 1000 g/mol, and sometimes between about 200 and 500 g/mol.

A chain can be formally derived from any combination of L-lactic acid and D- lactic acid units. The chains can possess any sequence of units that can be derived from L-lactic acid and D-lactic acid. The sequence of the units derived from L- and D- isomers can be random or can have a contiguous sequence of a single isomer for a 'PςMty-B>O©iE€l :#$i^e;$g|li. The sequence may also possess a repeating structure comprising units derived from both L- and D- lactic acid units. In the embodiment where y is greater than 1, each sequence of units in the biocompatible compound may have a different isomeric composition. In one embodiment, the precursor hydroxy-acid may be a mixture of L-lactic acid and D-lactic acid. In one embodiment, the precursor hydroxyacid is DL-lactic acid. The chain of units may contain any ratio of units derived from D-lactic acid and L-lactic acid, for example, ranging from 10:1; 1:1, or 1 :10. The preferred ratio of units derived from D-lactic acid and L-lactic acid in the chain of units of formulas I and II is 1:1. The DL form may be advantageous due to its amorphous nature. The L form may also be advantageous as it is endogenous to the human body.

The amount of oligomeric adjuvant is typically greater than about 5 % and sometimes greater than about 10 %, by weight of the total weight of adhesive, drug, and oligomeric adjuvant in the device. The amount of oligomeric adjuvant is typically less than about 30 % and sometimes less than about 20 %, by weight of the total weight of adhesive, drug, and oligomeric adjuvant in the device. In one embodiment, the amount of oligomeric adjuvant is between about 5 and about 30 %, sometimes between about 10 and about 20 %, by weight of the total weight of adhesive, drug, and oligomeric adjuvant in the device. The amount of oligomeric adjuvant is typically greater than about 5 % and sometimes greater than about 10 %, by weight of the total weight of adhesive, drospirenone, and oligomeric adjuvant in the device. The amount of oligomeric adjuvant is typically less than about 30 % and sometimes less than about 20 %, by weight of the total weight of adhesive, drospirenone, and oligomeric adjuvant in the device. In one embodiment, the amount of oligomeric adjuvant is between about 5 and about 30 %, sometimes between about 10 and about 20 %, by weight of the total weight of adhesive, drospirenone, and oligomeric adjuvant in the device.

In one embodiment, the oligomeric adjuvant may provide for a substantial increase in tackiness of the adhesive composition, as measured, for example, by the probe tack method detailed below, while having a surprisingly small effect on the shear creep compliance of the adhesive composition. Low-molecular weight compounds, such as the oligomeric adjuvants of the present invention, will typically have a plasticizing or tackifying effect when added to an adhesive copolymer. This plasticizing or tackifying effect typically manifests itself by a substantial increase in

becomes stickier) and shear creep compliance (i.e., the composition flows more easily under stress) as the amount of high-molecular weight polymer in the composition is diluted. Although not wishing to be bound by theory, it is believed that two or more functional groups on an oligomeric adjuvant of the present invention may interact with two or more adhesive copolymers (through functional groups on the adhesive copolymers) and thus form, at least temporarily, a cross-link between two or more adhesive copolymers. This temporary cross-linking provides increased resistance to flow or creep so that the composition may have a shear creep compliance lower than would be ordinarily expected based on the amount of low- molecular adjuvant present. At the same time, this temporary cross-linking has little effect on tackiness of the composition, so the tackiness may be enhanced as expected by added oligomeric adjuvant.

In one embodiment, the oligomeric adjuvant is a permeation enhancing adjuvant. A permeation enhancing adjuvant is an adjuvant which increases the amount of drug delivered transdermally for some portion of the delivery period of the device when compared to a like device without the adjuvant. For example, the permeation enhancing adjuvant may make the skin more permeable to transport of the drug and thus increase the rate at which the drug can pass through the skin. In another example, the permeation enhancing adjuvant may alter the affinity of the drug for the device, thereby increasing the thermodynamic potential driving the drug from the device into and through the skin.

The oligomeric adjuvant may be prepared according to any conventional synthetic method. Examples of suitable synthetic methods for preparing the oligomeric adjuvant may be found in United States Patent Application Nos. 60/533172 ("Medicinal Compositions and Method for the Preparation Thereof, Capecchi et al.) and 60/613063 ("Medicinal Aerosol Formulations and Methods of Synthesizing Ingredients Therefor", Bechtold et al.), the disclosures of which are herein incorporated by reference.

Adhesive sheets of the present invention may further comprise a protective release liner that covers and protects the skin-contacting surface prior to use by a patient. Suitable release liners include conventional release liners comprising a known sheet material such as a polyester web, a polyethylene web, a polypropylene web, or a polyethylene-coated paper coated with a suitable fluoropolymer or silicone based coating. In one embodiment the release liner is the same shape and size as the area of 'Ihp'HihilβiMlQΛlIΦbJfl® ^'device. It may be desirable to have one or more cuts or splits in the release liner to assist in removal of the adhesive portion from the liner. In one embodiment the release liner has a larger area than the adhesive portion of the device, thereby providing an extended liner. The distance that the release liner extends beyond the margins of the adhesive portion of the device can be any suitable distance, and may depend upon a number of factors including, for example, the size of the adhesive portion of the patch, the types of adhesive, backing, and liner employed, and the patient population using the patch. The distance that the liner extends may be uniform around the circumference of the patch or it may vary, for example, by providing a smaller circular patch on a square-shaped extended liner.

In one embodiment the adhesive sheets prepared may be transdermal drug delivery devices. Suitable transdermal drug delivery devices include gelled or liquid reservoirs, such as in U. S. Patent No. 4,834,979 (Gale), so-called "reservoir" patches; devices containing matrix reservoirs attached to the skin by an adjacent adhesive layer, such as in U. S. Patent No. 6,004,578 (Lee, et al.), so-called "matrix" patches; and devices containing pressure-sensitive adhesive reservoirs, such as in U. S. Patent Nos. 6,365,178 (Venkateshwaran et al.), 6,024,976 (Miranda et al.), and 6,149,935 (Chiang et al.), so-called "drug-in-adhesive" patches, the disclosures of which are incorporated herein by reference. The term reservoir is used herein to describe a portion of the patch which houses a drug and as described above may be liquid, solid, adhesive, or any other suitable form.

The length of time that the device remains in a delivering relationship is typically an extended time, for example, from about 12 hours to about 14 days. In certain embodiments, the length of time that the reservoir remains in a delivering relationship is about 1 day (i.e., daily dosing), about 3 to 4 days (bi-weekly dosing), or about 7 days (weekly dosing).

In one embodiment, the reservoir may contain other additives or excipients in addition to the pharmaceutically active agent. Such additives include pharmaceutically acceptable materials that may be used as skin permeation enhancers (i.e., substances that increase the permeation rate of a drug across or into the skin) or solubilizers (i.e., substances that effectively solubilize a drug) in transdermal drug delivery systems. Suitable materials used as skin permeation enhancers include C₈-C₂₀ fatty acids such as isostearic acid, octanoic acid, and oleic acid; C₈-C₂₀ fatty alcohols such as oleyl alcohol and lauryl alcohol; lower alkyl esters of C₈-C₂₀ fatty acids such as ethyl oleate, Isppi^slφiiisiae_/bi^K-siSέarate, and methyl laurate; di(lower) alkyl esters OfC₆-C₈ diacids such as diisopropyl adipate; monoglycerides of C₈-C₂₀ fatty acids such as glyceryl monolaurate; tetraglycol (tetrahydrofurfuryl alcohol polyethylene glycol ether); tetraethylene glycol (ethanol,2,2'-(oxybis(ethylenoxy))diglycol); C₆-C₂₀ alkyl pyrrolidone carboxylates; polyethylene glycol; propylene glycol; 2-(2- ethoxyethoxy)ethanol; diethylene glycol monomethyl ether; N₅N- dimethyldodecylamine-N-oxide and combinations of the foregoing. Alkylaryl ethers of polyethylene oxide, polyethylene oxide monomethyl ethers, polyethylene oxide dimethyl ethers, glycerol, and N-methyl pyrrolidone are also suitable. The terpenes are another useful class of pharmaceutical excipients, including pinene, <i-limonene, carene, terpineol, terpinen-4-ol, carveol, carvone, pulegone, piperitone, menthone, menthol, neomenthol, thymol, camphor, borneol, citral, ionone, and cineole, alone or in any combination. Examples of other additives include tackifiers, plasticizers, and antioxidants. Generally, the device will have a surface area greater than about 1 cm , and sometimes greater than about 5 cm². Generally, the device will have a surface area of less than about 100 cm , and sometimes less than about 40 cm . In one embodiment, devices may be packaged individually in a foil-lined pouch for storage. In one embodiment, devices may alternatively be provided in a rolled or stacked form suitable for use with a dispensing apparatus.

In one embodiment, transdermal drug delivery devices of the invention are prepared by combining the copolymer, drug, and oligomeric adjuvant with an organic solvent (e.g., ethyl acetate, isopropanol, methanol, acetone, 2-butanone, ethanol, toluene, alkanes, and mixtures thereof) to provide a coating composition. The mixture is shaken or stirred until a homogeneous coating composition is obtained. The resulting composition is then applied to a release liner using conventional coating methods (e.g., knife coating or extrusion die coating) to provide a predetermined uniform thickness of coating composition. The release liner that has been coated with the composition is then dried and laminated onto a backing using conventional methods. In one embodiment, the present invention comprises a method of transdermal delivery wherein the transdermal drug delivery device comprises an adhesive matrix comprising an oligomer of an alpha-hydroxy acid which undergoes hydrolytic degradation to form shorter chain oligomers or monomers during use. These shorter chain oligomers or monomers may act as permeation enhancers to increase the amount pf'dtjIgrøfeecSidJia ψMfM. For example, an oligolactic acid may hydrolytically degrade to shorter chain oligomers or lactic acid when exposed to moisture. Formation of shorter chain oligomers or monomers in situ may be beneficial, since it may be desired to avoid the presence of large amounts of shorter chain oligomers or monomers in the device during shelf storage, as these components may, for example, cause physical or chemical instability during long term storage. It may also be desirable to form shorter chain oligomers or monomers in situ so as to control or adjust the rate at which drug is delivered to a patient. For example, it may be desirable to have the amount of permeation enhancing shorter chain oligomers or monomers increase during the wear period of the device to counterbalance the decreasing amount of drug left in the device.

Examples of suitable oligomers of alpha-hydroxy acids include oligomers derived from lactic acid, glycolic acid, and mixtures thereof. Examples of other suitable oligomers of alpha-hydroxy acids are disclosed, for example, in U.S. Patent No. 5,569,450, the disclosure of which is herein incorporated by reference.

In one embodiment, the present invention comprises a method of transdermal delivery wherein the transdermal drug delivery device comprises an adhesive matrix comprising an oligomer of an alpha-hydroxy acid which absorbs moisture into the device after the device has been applied to a mammal. The absorbed moisture may serve to hydrolytically degrade the oligomer as described above. In one embodiment, the absorbed moisture may serve to alter the thermodynamic potential of the adhesive matrix and thereby alter the driving force of the drug across the skin. For example, absorbed moisture may lower the solubility of a largely hydrophobic drug dissolved in the adhesive matrix and thereby increase the thermodynamic driving force of the drug across the skin, thus increasing the transdermal flux. Such an increase in thermodynamic driving force with increasing length of wear period may counterbalance the decreasing amount of drug left in the device. The moisture may be absorbed directly from the mammal or the moisture may be absorbed from the external environment after the device has been applied to the mammal. In one embodiment, the present invention comprises a method increasing the solubility of a drug compound in an adhesive matrix by using an oligomer of an alpha- hydroxy acid as a solubilizing agent. A solubilizing agent is a generally low molecular weight compound (i.e., typically with a molecular weight of 2000 g/mol or less) that may be added to an adhesive in order to increase the solubility of a drug within the

will be greater in the solubilizing agent than it is in the adhesive, and thus a mixture of adhesive and solubilizing agent will be able to dissolve a higher concentration of drug than the adhesive can alone.

Examples

In Vitro Skin Permeation Test Method

The skin permeation data given in the examples below was obtained using the following test method. A 1.0 cm² transdermal patch was die-cut from a larger sheet for use as the test sample. The release liner was removed, and the patch was applied to the stratum corneum surface of human cadaver skin and pressed to cause uniform contact with the skin. The resulting patch/skin laminate was placed patch side up across the orifice of the lower portion of a vertical diffusion cell. The diffusion cell was assembled and the lower portion filled with 5 mL of warm (32°C) receptor fluid (30 % (v/v) N-methyl-2-pyrrolidone in water) so that the receptor fluid contacted the skin. The sampling port was covered except when in use.

The cells were maintained at 32 ± 1°C throughout the course of the experiment. The receptor fluid was stirred by means of a magnetic stirrer throughout the experiment to assure a uniform sample and a reduced diffusion barrier on the dermal side of the skin. The entire volume of receptor fluid was withdrawn at specified time intervals and immediately replaced with fresh fluid. The withdrawn fluid was analyzed for drug using conventional high performance liquid chromatography methods. The cumulative (or total) flux of drug penetrating through the skin was calculated and reported as μg/cm². Unless noted, the results are reported as the average of 4 to 6 replicates. Unless noted, the total flux was determined after a time period of 7 days.

Probe Tack Test Method

The tack data given in the examples below was obtained using a Digital Polyken Probe Tack Tester, Model 80-02-01 (Testing Machines, Inc., Amityville, NY). The machine settings were as follows: separation rate: 0.5 cm/second, contact time: 2 seconds; contact pressure: 100 g/cm². A stainless steel probe was used. The result of the test is the force required to break the bond between the probe and the surface of the test sample. The force is measured in "grams of tack". i$HI^rar Creep Compliance Test Method

The compliance values given in the examples below were obtained using a modified version of the Creep Compliance Procedure described in U.S. Pat. No. 4,737,559 (Kellen). The release liner is removed from a sample of the material to be tested. The exposed surface is folded back on itself in the lengthwise direction to produce a "sandwich" configuration (i.e., backing/pressure sensitive adhesive/backing). The sandwich sample is passed through a laminator. Two test samples of equal area are cut from the laminated sandwich using a die. One test sample is centered on the stationary plate of a shear-creep rheometer. The small, non-stationary plate of the shear-creep rheometer is centered over the first sample on the stationary plate such that the hook is facing up and toward the front of the rheometer. The second test sample is centered on the upper surface of the small, non-stationary plate. The large non- stationary plate is placed over the second test sample and the entire assembly is clamped into place. A string is connected to the hook of the small, non-stationary plate and extended over the front pulley of the rheometer. A weight (e.g., 500 g) is attached to the free end of the string and supported so as not to place a load on the non- stationary plate. The support for the weight is removed to allow it to hang freely. The weight exerts a load on the non-stationary plate and the displacement of the non- stationary plate is recorded as a function of time. The weight is removed after exactly 3 minutes have elapsed. The shear creep compliance is then calculated using the equation:

J = 2^ hf where A is the area of one face of the test sample, h is the thickness of the pressure sensitive adhesive mass (i.e., two times the thickness of the pressure sensitive adhesive layer on each sandwich), X is the displacement and /is the force due to the mass attached to the string. Where A is expressed in cm², h in cm, X in cm and/in dynes, the compliance value is given in cmVdyne. In some instances the sample displacement was monitored for an additional time period of 3 minutes following removal of the weight to measure the distance that the sample elastically recovers following shear creep. The distance recovered, or recovery, is reported as a percentage of the original displacement during the shear creep phase of the experiment (e.g., a recovery of 100% indicates a complete elastic recovery of the displacement during the shear creep phase). Preparation of "Dried" Copolymer

Dried copolymer was prepared by knife coating a solution of the copolymer onto a release liner. The coated release liner was oven dried to remove the solvent and reduce the level of residual monomers. The dried copolymer was then stripped off of the release liner and stored in a container until used.

Copolymer Dl. Preparation of Isooctyl Acrylate/Acrylamide/Vinyl Acetate (75/5/20)

Copolymer

A solution of isooctyl acrylate, acrylamide, and vinyl acetate (75:5:20) copolymer was prepared according to the general method described in Part D of U.S.

Patent No. 5,223,261, the disclosure of which is hereby incorporated by reference. The resulting copolymer solution was approximately 32 % solids in a 90:10 blend of ethyl acetate and methanol. The inherent viscosity (IV) of the copolymer solution was approximately 1.35 dL/g.

Copolymer D2. Preparation of Isooctyl Acrylate/Acrylamide/Vinyl Acetate (71/9/20)

Copolymer

A solution of isooctyl acrylate, acrylamide, and vinyl acetate (71:9:20) copolymer was prepared according to the general method described in Example 1 of U.S. Patent Application Publication No. 2003 -054025 , the disclosure of which is hereby incorporated by reference. The resulting copolymer solution was 16.4% solids in an 80:20 blend of ethyl acetate and methanol. The inherent viscosity (IV) of the copolymer solution was 1.53 dL/g.

Copolymer D3. Preparation of Isooctyl Acrylate/Acrylamide/Vinyl Acetate (70/10/20)

Copolymer

A solution was prepared by combining isooctyl acrylate (140 g), acrylamide (20 g), vinyl acetate (4 g), 2,2'-azobis(2-methylbutyronitrile) (0.3 g), ethyl acetate (203.6 g) and methanol (58.9 g) in a 1 quart (0.95 L) amber glass bottle. The bottle was purged for 2 minutes with nitrogen at a flow rate of 1 L per minute. The bottle was sealed and placed in a rotating water bath at 57⁰C for 24 hours. The resulting copolymer was diluted with ethyl acetate (169.7 g) and methanol (49.4 g) to 30 % solids. The inherent viscosity was 1.17 dL/g.

of Isooctyl Acrylate/Acrylamide/Vinyl Acetate (71/9/20)

Copolymer

Isooctyl Acrylate/Acrylamide/Vinyl Acetate (71/9/20) copolymer was prepared according to the following procedure. Isooctyl acrylate (88.75 g), acrylamide (11.25 g), vinyl acetate (25.00 g), 2,2'-azobis(2,4-dimethylρentanenitrile) (0.25 g), ethyl acetate (132.06 g) and methanol (14.67 g) were combined in a 1 quart (0.95 L) amber glass bottle. The bottle was purged for 2 minutes with nitrogen at a flow rate of 1 L per minute. The bottle was sealed and placed in a rotating water bath at 55⁰C for 24 hours. The resulting copolymer was diluted with ethyl acetate (331.92 g) and methanol (110.64 g). The percent solids of the resultant copolymer was 15.2%. The inherent viscosity was 1.45 dL/g.

Example 1

Drospirenone (0.3933 g), methyl laurate (0.3655 g), and glyceryl monooleate (.6083 g) were added to a solvent mixture of ethyl acetate (5.9515 g) and acetone

(1.8472 g) and mixed until the drospirenone was dissolved. To this solution, copolymer (2.0746 g of dried Isooctyl acrylate/ Acrylamide/Vinyl Acetate (75/5/20) from Copolymer Dl above) and oligolactic acid of formula I with an average value of n of 3.7 (0.5851 g) were added and mixed for at least 12 hours and until a uniform coating formulation was obtained. The coating formulation was knife coated at a wet thickness of 25 mil (635 μm) onto a silicone coated release liner. The coated liner was oven dried for 10 minutes at HO⁰F (43⁰C). The dried formulation was then laminated onto a backing (SCOTCHP AK™ 9732 polyester film laminate; available from 3M Company). The resulting formulation had a nominal composition of 9.1 % methyl laurate, 15.1 % glyceryl monooleate, 9.8 % drospirenone, and 14.5 % oligolactic acid with n=3.7. The remainder of the formulation was copolymer Dl . The dry coating weight was approximately 16.9 mg/cm². The permeation through human cadaver skin was determined using the test method described above. The total drospirenone flux was 500 ± 30 μg/cm².

Example 2

Drospirenone (0.4085 g) and methyl laurate (0.9845 g) were added to a solvent mixture of ethyl acetate (6.2665 g) and acetone (1.8660 g) and mixed until the drospirenone was dissolved. To this solution, copolymer (2.0859 g of dried Isooctyl IcxyM€j€itfilaihaeWiliflScetate (75/5/20) from Copolymer Dl above) and oligolactic acid of formula I with an average value of n of 3.7 (0.5608 g) were added and mixed for at least 12 hours and until a uniform coating formulation was obtained. The coating formulation was knife coated at a wet thickness of 25 mil (635 μm) onto a silicone coated release liner. The coated liner was oven dried for 10 minutes at HO⁰F

(43⁰C). The dried formulation was then laminated onto a backing (SCOTCHP AK™ 9732 polyester film laminate; available from 3M Company). The resulting formulation had a nominal composition of 24.4 % methyl laurate, 10.1 % drospirenone, and 13.9 % oligolactic acid with n=3.7. The remainder of the formulation was copolymer Dl . The dry coating weight was 17.6 mg/cm². The permeation through human cadaver skin was determined using the test method described above. The total drospirenone flux was 470 ± 130 μg/cm².

Example 3 Drospirenone (0.284 g), methyl laurate (0.337 g), and benzyl alcohol (0.417 g) were added to a 70/30 (w/w) ethyl acetate/methanol solvent mixture (7.2 g) and mixed until the drospirenone was dissolved. To this solution, copolymer (1.648 g of dried Isooctyl acrylate/Acrylamide/Vinyl Acetate (70/10/20) from Copolymer D3 above), oligolactic acid of formula I with an average value of n of 3.7 (0.512 g), and oligolactic acid of formula I with an average value of n of 5.2 (0.213 g), were added and mixed for at least 12 hours and until a uniform coating formulation was obtained. The coating formulation was knife coated at a wet thickness of 25 mil (635 μm) onto a silicone coated release liner. The coated liner was oven dried for 10 minutes at HO⁰F (43⁰C). The dried formulation was then laminated onto a backing (SCOTCHP AK™ 9732 polyester film laminate; available from 3M Company). The resulting formulation had a nominal composition of 9.9 % methyl laurate, 12.2 % benzyl alcohol, 8.3 % drospirenone, 15.0 % oligolactic acid with n=3.7, and 6.2 % oligolactic acid with n=5.2. The remainder of the formulation was copolymer D3. The dry coating weight was approximately 15 to 20 mg/cm². The permeation through human cadaver skin was determined using the test method described above. The total drospirenone flux was 670

± 250 μg/cm². Drospirenone (0.282 g), methyl lactate (0.343 g), and benzyl alcohol (0.454 g) were added to a 70/30 (w/w) ethyl acetate/methanol solvent mixture (5.66 g) and mixed until the drospirenone was dissolved. To this solution, copolymer (1.588 g of dried Isooctyl acrylate/Acrylamide/Vinyl Acetate (70/10/20) from Copolymer D3 above), oligolactic acid of formula I with an average value of n of 3.7 (0.384 g), and oligolactic acid of formula I with an average value of n of 5.2 (0.354 g), were added and mixed for at least 12 hours and until a uniform coating formulation was obtained. The coating formulation was knife coated at a wet thickness of 25 mil (635 μm) onto a silicone coated release liner. The coated liner was oven dried for 10 minutes at 11O⁰F (43⁰C).

The dried formulation was then laminated onto a backing (SCOTCHP AK™ 9732 polyester film laminate; available from 3M Company). The resulting formulation had a nominal composition of 10.1 % methyl lactate, 13.3 % benzyl alcohol, 8.3 % drospirenone, 11.3 % oligolactic acid with n=3.7, and 10.4 % oligolactic acid with n=5.2. The remainder of the formulation was copolymer D3. The dry coating weight was approximately 15 to 20 mg/cm². The total drospirenone flux was 360 ± 130 μg/cm².

Example 5 Drospirenone {0.291 A g), ethinyl estradiol (0.0178 g), and glyceryl monooleate

(0.8088 g) were added to a 70/30 (w/w) ethyl acetate/methanol solvent mixture (4.81 g) and mixed until the drospirenone and ethinyl estradiol was dissolved. To this solution, copolymer (1.34 g of dried Isooctyl aery late/ Acrylamide/Vinyl Acetate (71/9/20) from Copolymer D2 above), oligolactic acid of formula I with an average value of n of 3.7 (0.37 g), oligolactic acid of formula I with an average value of n of 5.2 (0.11 g), and oligolactic acid of formula I with an average value of n of 10.6 (0.13 g) were added and mixed until a uniform coating formulation was obtained. The coating formulation was knife coated at a wet thickness of 25 mil (635 μm) onto a silicone coated release liner. The coated liner was oven dried for 10 minutes at HO⁰F (43⁰C). The dried formulation was then laminated onto a backing (SCOTCHP AK™ 9732 polyester film laminate; available from 3M Company). The resulting formulation had a nominal composition of 25.3 % glyceryl monooleate, 12.0 % oligolactic acid with n=3.7, 3.6 % oligolactic acid with n=5.2, and 4.2 % oligolactic acid with n=10.6. The concentration of drospirenone and ethinyl estradiol were analytically determined by HPLC to be 7.0 ψϋ. ά&4 &χ3%

weight of the total composition. The remainder of the formulation was copolymer D3. The dry coating weight was approximately 20 mg/cm². The permeation through human cadaver skin was determined using the test method described above. The total drospirenone flux and ethinyl estradiol flux is reported in Table 1.

Examples 6 - 35

Samples were prepared according to the procedure of Example 5 with the exception that the composition of the liquid excipient was varied. The amount of drospirenone and ethinyl estradiol were adjusted to account for their relative solubility in the liquid excipient mixtures. The formulation compositions are shown in Table 1. All formulations had a nominal composition of 12.0 % oligolactic acid with n=3.7, 3.6 % oligolactic acid with n=5.2, and 4.2 % oligolactic acid with n=10.6. Except where noted, the amounts of drospirenone and ethinyl estradiol were analytically determined by high performance liquid chromatography and the amounts of liquid excipient were analytically determined by gas chromatography. The permeation through human cadaver skin was determined using the test method described above. The total drospirenone flux and ethinyl estradiol flux is reported in Table 1. Cumulative drospirenone flux as a function of time is reported in Table 2. Probe tack and shear creep compliance were measured on selected samples and the results are reported in

Table 3.

to

its

*Nominal amount based on input amounts to formulation.

Example 36

Drospirenone (0.2938 g) and ethinyl estradiol (0.0160 g) were added to a 70/30 (w/w) ethyl acetate/methanol solvent mixture (9.271 g) and mixed until the drospirenone and ethinyl estradiol was dissolved. To this solution, copolymer (1.981 g of dried Isooctyl acrylate/Acrylamide/Vinyl Acetate (71/9/20) from Copolymer D2 above) and oligolactic acid of formula I with an average value of n of 3.7 (0.636 g) were added and mixed for at least 12 hours and until a uniform coating formulation was obtained. The coating formulation was knife coated at a wet thickness of 25 mil (635 μm) onto a silicone coated release liner. The coated liner was oven dried for 10 minutes at 11O⁰F (43⁰C). The dried formulation was then laminated onto a backing (SCOTCHP AK™ 9732 polyester film laminate; available from 3M Company). The resulting formulation had a nominal composition of 0.55 % ethinyl estradiol, 10.0 % drospirenone, and 21.7 % oligolactic acid with n = 3.7. The remainder of the formulation was copolymer D2. The dry coating weight was 20 mg/cm². The probe tack force was determined to be 1025 g according to the procedure described above. The permeation through human cadaver skin was determined using the test method described above. The total drospirenone flux was 420 ± 250 μg/cm² and the total ethinyl estradiol flux was 23 ± 7 μg/cm².

Example 37

A sample was prepared as in example 36 with the exception that the oligolactic acid was acetylated. The resulting formulation had a nominal composition of 0.52 % ethinyl estradiol, 9.8 % drospirenone, and 21.1 % acetylated oligolactic acid. The remainder of the formulation was copolymer D2. The permeation through human cadaver skin was determined using the test method described above. The total drospirenone flux was 350 ± 80 μg/cm² and the total ethinyl estradiol flux was 27 ± 4 μg/cm².

Example 38

A sample was prepared as in example 36 with the exception that the terminal carboxyl group of the oligolactic acid was functionalized with a benzyl group and the average value of n was about 3. The resulting formulation had a nominal composition of 0.54 % ethinyl estradiol, 10.0 % drospirenone, and 22.9 % functionalized oligolactic acid. The remainder of the formulation was copolymer D2. The permeation through human cadaver skin was determined using the test method described above. The total drospirenone flux was 190 ± 70 μg/cm² and the total ethinyl estradiol flux was 17 ± 4 μg/cm².

Example 39

Drospirenone (0.3003 g), methyl laurate (0.479 g), and benzyl alcohol (0.400 g) were added to a 70/30 (w/w) ethyl acetate/methanol solvent mixture (6.546 g) and mixed until the drospirenone was dissolved. To this solution, copolymer (1.63 g of dried Isooctyl acrylate/Acrylamide/Vinyl Acetate (75/5/20) from Copolymer Dl above) and oligolactic acid of formula I with an average value of n of 3.7 (0.363 g) were added and mixed for at least 12 hours and until a uniform coating formulation was obtained. The coating formulation was knife coated at a wet thickness of 25 mil (635 μm) onto a silicone coated release liner. The coated liner was oven dried for 10 minutes at 11O⁰F (43⁰C). The dried formulation was then laminated onto a backing (SCOTCHP AK™ 9732 polyester film laminate; available from 3M Company). The resulting formulation had a nominal composition of 15.1 % methyl laurate, 12.6 % benzyl alcohol, 9.5 % drospirenone, and 11.4 % oligolactic acid with n=3.7. The remainder of the formulation was copolymer Dl . The dry coating weight was approximately 15 to 20 mg/cm². The permeation through human cadaver skin was determined using the test method described above. The total drospirenone flux was 560 ± 50 μg/cm².

Example 40

Testosterone (0.3037 g) was added to a 60/40 (v/v) ethyl acetate/methanol solvent mixture (9.39 g) and mixed until the testosterone was dissolved. To this solution, copolymer (2.1O g of dried Isooctyl acrylate/Acrylamide/Vinyl Acetate (75/5/20) from Copolymer Dl above) and oligolactic acid of formula I with an average value of n of 3.3 (0.58 g) were added and mixed for at least 12 hours and until a uniform coating formulation was obtained. The coating formulation was knife coated at a wet thickness of 20 mil (508 μm) onto a silicone coated release liner. The coated liner was oven dried for 10 minutes at HO⁰F (43⁰C). The dry coating weight was 7.2 mg/cm². The dried formulation was then laminated onto a backing (SCOTCHP AK™ 9732 polyester film laminate; available from 3M Company). The permeation through human cadaver skin was determined using the test method described above. The total testosterone flux after a time period of 24 hours was 300 ± 80 μg/cm².

Example 41

Levonorgestrel (0.0307 g) was added to a 70/30 (v/v) ethyl acetate/methanol solvent mixture (10.9648 g) and mixed until the levonorgestrel was dissolved. To this solution, copolymer (2.34 g of dried Isooctyl acrylate/Acrylamide/Vinyl Acetate (75/5/20) from Copolymer Dl above) and oligolactic acid of formula I with an average value of n of 3.3 (0.63 g) were added and mixed for at least 12 hours and until a uniform coating formulation was obtained. The coating formulation was knife coated onto a silicone coated release liner. The coated liner was oven dried for 10 minutes at 11O⁰F (43⁰C). The dry coating weight was 6.9 mg/cm². The dried formulation was then laminated onto a backing (SCOTCHPAK™ 9732 polyester film laminate; available from 3M Company). The permeation through human cadaver skin was determined using the test method described above. The total levonorgestrel flux after a time period of 168 hours was 57.5 ± 12.1 μg/cm².

Example 42

Estradiol (0.1502 g) was added to a 70/30 (v/v) ethyl acetate/methanol solvent mixture (10.233 g) and mixed until the estradiol was dissolved. To this solution, copolymer (2.25 g of dried Isooctyl acrylate/Acrylamide/Vinyl Acetate (75/5/20) from Copolymer Dl above) and oligolactic acid of formula I with an average value of n of 3.3 (0.59 g) were added and mixed for at least 12 hours and until a uniform coating formulation was obtained. The coating formulation was knife coated onto a silicone coated release liner. The coated liner was oven dried for 10 minutes at HO⁰F (43⁰C). The dry coating weight was 7.4 mg/cm². The dried formulation was then laminated onto a backing (SCOTCHP AK™ 9732 polyester film laminate; available from 3M Company). The permeation through human cadaver skin was determined using the test method described above. The total estradiol flux after a time period of 168 hours was 278 ± 36 μg/cm².

Example 43

Felodipine (0.4537 g) was added to a 70/30 (v/v) ethyl acetate/methanol solvent mixture (8.476 g) and mixed until the felodipine was dissolved. To this solution, copolymer (1.95 g of dried Isooctyl acrylate/Acrylamide/Vinyl Acetate (75/5/20) from Copolymer Dl above) and oligolactic acid of formula I with an average value of n of 3.3 (0.61 g) were added and mixed for at least 12 hours and until a uniform coating formulation was obtained. The coating formulation was knife coated onto a silicone coated release liner. The coated liner was oven dried for 10 minutes at HO⁰F (43⁰C). The dry coating weight was 9.3 mg/cm². The dried formulation was then laminated onto a backing (SCOTCHPAK™ 9732 polyester film laminate; available from 3M Company). The permeation through human cadaver skin was determined using the test method described above. The total felodipine flux after a time period of 168 hours was 460 ± 350 μg/cm². Example 44

A series of testosterone containing formulations were prepared according to the general procedure described in Example 41 with the exception that the amount of testosterone was varied from 1% to 20% by weight of the total formulation. Formulations were prepared at the following testosterone concentrations: 1.0, 2.5, 5.0,7.5, 10.0, 12.5, 15.0, and 20.0% by weight of the total formulation. The coated and dried formulations on release liner were laminated to a polyester film, packaged in heat sealed foil pouches containing a desiccant material, and stored under conditions of 40 ⁰C and 75% relative humidity. The samples were observed after storage for 1 week and 2 weeks to determine if any testosterone crystals were present. Samples were observed for the presence of microcrystals using an optical microscope (at 4X to 4OX magnification) unless there were crystals large enough to view with the unaided eye (i.e., macrocrystals). Samples were rated on a scale of 1 to 5 for amount of crystals observed (1 = no crystals, 2 = a few visible microcrystals, 3 = microcrystals throughout, 4 = some macrocrystals, 5 = fully crystallized). After both 1 and 2 weeks storage, the samples having testosterone concentrations of 10% and below had a rating of 1 (i.e., no crystals). Samples with testosterone concentration of 12.5% and 15% had a rating of 4 after both 1 and 2 weeks. The sample with testosterone concentration of 20.0% had a rating of 5 after both 1 and 2 weeks. A comparable formulation with a testosterone concentration of 10%, but lacking oligolactic acid, had a rating of 4 after 1 week and 5 after 2 weeks.

Example 45

A series of formulations having varying concentrations of oligolactic acid were prepared as follows. Oligolactic acid of formula I with an average value of n of 4.8 was added to Copolymer solution D4 and mixed for at least 12 hours and until a uniform coating formulation was obtained. The coating formulation was knife coated at a thickness of 25 mil (635 μm) onto a silicone coated release liner. The coated liner was allowed to dry for 10 minutes under ambient conditions and then oven dried for 10 minutes at 110⁰F (43⁰C). The dried formulation was then laminated onto a backing (SCOTCHP AK™ 9732 polyester film laminate; available from 3M Company). Samples were prepared having 5, 10, 15, 20, and 30% by weight oligolactic acid. In addition, a comparative example was prepared having no oligolactic acid. Probe tack (n = 5) and shear creep compliance (n = 3) were measured on all of the samples and the results are reported in Table 4.

The present invention has been described with reference to several embodiments thereof. The foregoing detailed description and examples have been provided for clarity of understanding only, and no unnecessary limitations are to be understood therefrom. It will be apparent to those skilled in the art that many changes can be made to the described embodiments without departing from the spirit and scope of the invention. Thus, the scope of the invention should not be limited to the exact details of the compositions and structures described herein, but rather by the language of the claims that follow. Where a numerical parameter is described as having a range between two values it should be understood that the range is inclusive of the two values that define the range.

Claims

We claim:

1. An adhesive sheet comprising: a backing film; and an adhesive layer comprising a drug and an oligomeric adjuvant selected from an oligolactic acid, oligolactic acid derivatives, or mixtures thereof.

2. An adhesive sheet according to claim 1 wherein the oligomeric adjuvant comprises oligolactic acid.

3. An adhesive sheet according to claim 1 wherein the oligomeric adjuvant comprises an acetylated oligolactic acid.

4. An adhesive sheet according to any one of claims 1 to 3 wherein the number-average molecular weight of the oligomeric adjuvant is between about 200 and 1000 g/mol.

5. An adhesive sheet according to claim 4 wherein the number-average molecular weight of the oligomeric adjuvant is between about 300 and 600 g/mol.

6. An adhesive sheet according to any one of the preceding claims wherein the adhesive layer is substantially free of undissolved drug.

7. An adhesive sheet according to any one of the preceding claims wherein the oligomeric adjuvant is a skin permeation enhancer.

8. An adhesive sheet according to any one of the preceding claims wherein the adhesive layer further comprises a second adjuvant, wherein the second adjuvant is a permeation enhancing adjuvant.

9. An adhesive sheet according to any one of the preceding claims wherein the adhesive layer comprises an acrylate polymer.

10. An adhesive sheet according to any one of the preceding claims wherein the oligomeric adjuvant is homogeneously dispersed throughout the adhesive layer.

11. An adhesive sheet according to any one of the preceding claims wherein the amount of oligomeric adjuvant in the adhesive layer is between about 5 % and 30 % by weight of a total weight of the adhesive layer.

12. A transdermal drug delivery device comprising an adhesive sheet according to any one of the preceding claims.

13. A transdermal drug delivery device according to claim 12 and further comprising a protective release liner.

14. An adhesive sheet comprising: a backing film; and an adhesive layer comprising a drug and an oligomeric adjuvant of the formula:

II wherein Z is hydrogen or -C(O)Ri;

X is selected from the group consisting of hydroxy, -ORj, -SRj, -N(Ri)₂ and divalent or trivalent headgroups terminated in oxygen, nitrogen, or sulfur; y is greater than or equal to 1 and less than or equal to 3; each Rj is independently selected from a linear, branched, or cyclic alkyl, alkoxy, or aryl with 1 to 18 carbon atoms; and n is between about 3 and about 20.

15. An adhesive sheet according to claim 14 wherein y is 1, Z is hydrogen, and X is hydroxy.

16. An adhesive sheet according to claim 14 wherein Z is -C(O)Rj .

17. An adhesive sheet according to any one of claims 14 to 16 wherein the number- average molecular weight of the oligomeric adjuvant is between about 300 and 1000 g/mol.

18. An adhesive sheet according to claim 17 wherein the number-average molecular weight of the oligomeric adjuvant is between about 300 and 600 g/mol.

19. An adhesive sheet according to any one of claims 14 to 18 wherein the adhesive layer is substantially free of undissolved drug.

20. An adhesive sheet according to any one of claims 14 to 19 wherein the oligomeric adjuvant is a skin permeation enhancer.

21. An adhesive sheet according to any one of claims 14 to 20 wherein the adhesive layer further comprises a second adjuvant, wherein the second adjuvant is a permeation enhancing adjuvant.

22. An adhesive sheet according to any one of claims 14 to 21 wherein the adhesive layer comprises an acrylate polymer.

23. An adhesive sheet according to any one of claims 14 to 22 wherein the oligomeric adjuvant is homogeneously dispersed throughout the adhesive layer.

24. An adhesive sheet according to any one of claims 14 to 23 wherein the amount of oligomeric adjuvant in the adhesive layer is between about 5 % and 30 % by weight of the total weight of the adhesive layer.

25. An adhesive sheet comprising: a backing film; and a pressure sensitive adhesive matrix comprising an adhesive polymer and a compound selected from an oligolactic acid, oligolactic acid derivatives, or mixtures thereof; wherein the pressure sensitive adhesive matrix is releasably adhered to a protective liner.

26. An adhesive sheet according to claim 25 wherein the oligomeric adjuvant comprises oligolactic acid.

27. An adhesive sheet according to claim 25 wherein the oligomeric adjuvant comprises an acetylated oligolactic acid.

28. An adhesive sheet according to any one of claims 25 to 27 wherein the number- average molecular weight of the oligomeric adjuvant is between about 300 and 1000 g/mol.

29. An adhesive sheet according to claim 28 wherein the number-average molecular weight of the oligomeric adjuvant is between about 300 and 600 g/mol.

30. An adhesive sheet according to any one of claims 25 to 29 wherein the adhesive layer comprises an acrylate polymer.

31. An adhesive sheet according to any one of claims 25 to 30 wherein the oligomeric adjuvant is homogeneously dispersed throughout the adhesive layer.

32. A method of transdermal delivery comprising the steps of:

(a) providing a transdermal drug delivery system according to any one of claims 12 or 13;

(b) placing the delivery system in a delivering relationship to the skin of a mammal; and

(c) delivering drug to the mammal.

33. A method of transdermal delivery comprising the steps of:

(a) providing a transdermal drug delivery system comprising a matrix comprising an adhesive, a therapeutically effective amount of a drug, and an oligomer of an alpha- hydroxy acid;

(b) placing the delivery system in a delivering relationship to the skin of a mammal;

(c) allowing the alpha-hydroxy oligomer to hydrolytically degrade to shorter chain oligomers or monomer; and

(d) delivering drug to the mammal.

34. A method of transdermal delivery comprising the steps of:

(c) allowing the matrix to absorb moisture; and

(d) delivering drug to the mammal.

35. A method of transdermal delivery according to any one of claims 33 or 34 wherein the alpha-hydroxy acid is lactic acid.

36. A method of increasing the solubility of a drag compound in an adhesive matrix comprising the steps of:

(a) providing an adhesive;

(b) providing a drug;

(c) providing an oligomer of an alpha-hydroxy acid;

(d) mixing the adhesive, the drug, and the alpha-hydroxy acid to form an adhesive matrix wherein the concentration of dissolved drug is greater than the solubility of the drag in the adhesive in the absence of the alpha-hydroxy acid.

37. A method of increasing the solubility of a drag compound in an adhesive matrix according to claim 36 wherein the alpha-hydroxy acid is lactic acid.

38. An adhesive sheet comprising: a backing film; and an adhesive layer comprising a drug and an oligomeric adjuvant selected from an oligolactic acid, oligolactic acid derivatives, or mixtures thereof, with the proviso that the drug is not drospirenone.

39. An adhesive sheet according to claim 38 wherein the oligomeric adjuvant comprises oligolactic acid.

40. An adhesive sheet according to claim 38 wherein the oligomeric adjuvant comprises an acetylated oligolactic acid.

41. An adhesive sheet according to any one of claims 38 to 40 wherein the number- average molecular weight of the oligomeric adjuvant is between about 200 and 1000 g/mol.

42. An adhesive sheet according to claim 41 wherein the number-average molecular weight of the oligomeric adjuvant is between about 300 and 600 g/mol.

43. An adhesive sheet according to any one of claims 38 to 42 wherein the adhesive layer is substantially free of undissolved drug.

44. An adhesive sheet according to any one of claims 38 to 43 wherein the oligomeric adjuvant is a skin permeation enhancer.

45. An adhesive sheet according to any one of claims 38 to 44 wherein the adhesive layer further comprises a second adjuvant, wherein the second adjuvant is a permeation enhancing adjuvant.

46. An adhesive sheet according to any one of claims 38 to 45 wherein the adhesive layer comprises an acrylate polymer.

47. An adhesive sheet according to any one of claims 38 to 46 wherein the oligomeric adjuvant is homogeneously dispersed throughout the adhesive layer.

48. An adhesive sheet according to any one of claims 38 to 47 wherein the amount of oligomeric adjuvant in the adhesive layer is between about 5 % and 30 % by weight of a total weight of the adhesive layer.

49. A transdermal drug delivery device comprising an adhesive sheet according to any one of claims 38 to 48.

50. A transdermal drug delivery device according to claim 49 and further comprising a protective release liner.

51. An adhesive sheet comprising: a backing film; and an adhesive layer comprising a drug and an oligomeric adjuvant of the formula:

II wherein Z is hydrogen or -C(O)Rj ;

X is selected from the group consisting of hydroxy, -ORj , -SRj, -N(Rj)₂ and divalent or trivalent headgroups terminated in oxygen, nitrogen, or sulfur; y is greater than or equal to 1 and less than or equal to 3; each R\ is independently selected from a linear, branched, or cyclic alkyl, alkoxy, or aryl with 1 to 18 carbon atoms; and n is between about 3 and about 20, with the proviso that the drug is not drospirenone.

52. An adhesive sheet according to claim 51 wherein y is 1, Z is hydrogen, and X is hydroxy.

53. An adhesive sheet according to claim 51 wherein Z is -C(O)Rj .

54. An adhesive sheet according to any one of claims 51 to 53 wherein the number- average molecular weight of the oligomeric adjuvant is between about 300 and 1000 g/mol.

55. An adhesive sheet according to claim 54 wherein the number-average molecular weight of the oligomeric adjuvant is between about 300 and 600 g/mol.

56. An adhesive sheet according to any one of claims 51 to 55 wherein the adhesive layer is substantially free of undissolved drug.

57. An adhesive sheet according to any one of claims 51 to 56 wherein the oligomeric adjuvant is a skin permeation enhancer.

58. An adhesive sheet according to any one of claims 51 to 57 wherein the adhesive layer further comprises a second adjuvant, wherein the second adjuvant is a permeation enhancing adjuvant.

59. An adhesive sheet according to any one of claims 51 to 58 wherein the adhesive layer comprises an acrylate polymer.

60. An adhesive sheet according to any one of claims 51 to 59 wherein the oligomeric adjuvant is homogeneously dispersed throughout the adhesive layer.

61. An adhesive sheet according to any one of claims 51 to 60 wherein the amount of oligomeric adjuvant in the adhesive layer is between about 5 % and 30 % by weight of the total weight of the adhesive layer.

62. A method of transdermal delivery comprising the steps of:

(a) providing a transdermal drug delivery system according to any one of claims 39 or 40;

(c) delivering drug to the mammal.

63. A method of transdermal delivery comprising the steps of:

(a) providing a transdermal drug delivery system comprising a matrix comprising an adhesive, a therapeutically effective amount of a drug, with the proviso that the drug is not drospirenone, and an oligomer of an alpha-hydroxy acid;

(d) delivering drug to the mammal.

64. A method of transdermal delivery comprising the steps of:

(c) allowing the matrix to absorb moisture; and

(d) delivering drug to the mammal.

65. A method of transdermal delivery according to any one of claims 63 or 64 wherein the alpha-hydroxy acid is lactic acid.

66. A method of increasing the solubility of a drug compound in an adhesive matrix comprising the steps of:

(a) providing an adhesive;

(b) providing a drug, with the proviso that the drug is not drospirenone;

(c) providing an oligomer of an alpha-hydroxy acid; (d) mixing the adhesive, the drug, and the alpha-hydroxy acid to form an adhesive matrix wherein the concentration of dissolved drug is greater than the solubility of the drug in the adhesive in the absence of the alpha-hydroxy acid.

67. A method of increasing the solubility of a drug compound in an adhesive matrix according to claim 66 wherein the alpha-hydroxy acid is lactic acid.