WO1996008255A1

WO1996008255A1 - Transdermal device for delivery of levonorgestrel

Info

Publication number: WO1996008255A1
Application number: PCT/US1995/012158
Authority: WO
Inventors: Daniel C. Duan; Cheryl L. Moore; Jamieson C. Keister; Steven M. Wick; David J. Wirtanen; John R. Hart
Original assignee: Minnesota Mining And Manufacturing Company
Priority date: 1994-09-14
Filing date: 1995-09-12
Publication date: 1996-03-21
Also published as: AU3723695A

Abstract

A transdermal drug delivery device involving an acrylate or methacrylate based copolymer, a skin penetration enhancing adjuvant, and a therapeutically effective amount of levonorgestrel.

Description

TRANSDERMAL DEVICE FOR DELIVERY OF LEVONORGESTREL

Background of the Invention

Field of the Invention

This invention relates to transdermal drug

delivery devices. In another aspect this invention relates to pharmaceutical formulations containing levonorgestrel.

Description of the Related Art

Transdermal drug delivery devices are designed to deliver a therapeutically effective amount of drug across the skin of a patient. Devices known to the art include reservoir type devices involving membranes that control the rate of drug release to the skin and devices involving a dispersion of the drug in a matrix such as a pressure sensitive adhesive. The skin, however, presents a substantial barrier to ingress of foreign substances into the body. It is therefore often desirable or necessary to incorporate certain materials that enhance the rate at which the drug passes through the skin. However the type of device, the transdermal flux rate that is suitable, and the suitable formulation components are dependent upon the particular drug to be delivered.

Levonorgestrel is a progestational hormone (a progestogen, or progestin) . Such hormones are known to have utility in treating infertility in which the uterus is not receptive to implantation. When

administered cyclically with estrogens they are also used as contraceptives, in treating a variety of conditions such as preeclampsia, toxemia, secondary amenorrhea, dysfunctional uterine bleeding, female sexual infantilism, and in hormone replacement therapy in post-menopausal women.

Summary of the invention

The present invention provides a transdermal delivery device comprising:

(A) a backing;

(B) a matrix layer adhered to one surface of the backing and comprising:

(1) a copolymer comprising

(a) one or more A monomers selected from the group consisting of alkyl acrylates containing 4 to 10 carbon atoms in the alkyl group and alkyl methacrylates containing 4 to 10 carbon atoms in the alkyl group; and

(b) one or more B monomers comprising a functional group selected from the group consisting of carboxylic acid, sulfonamide, urea, carbamate,

carboxamide, hydroxy, amino, oxy, oxo, and cyano;

(2) a therapeutically effective amount of levonorgestrel dissolved in the matrix layer; and

(3) a skin-penetration enhancing amount of an adjuvant dissolved in the matrix layer and selected from the group consisting of C₈-C₂₂ fatty acids, C₈-C₂₂ fatty alcohols, lower alkyl esters of C₈-C₂₂ fatty acids, di(lower)alkyl esters of C₆-C₈ diacids,

monoglycerides of C₈-C₂₂ fatty acids, polyethylene glycol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, N,N-dimethyldodecylamine-N-oxide, tetrahydrofurfuryl alcohol polyethylene glycol ether, and a combination of any one or more of any of the foregoing.

Detailed Description of the Invention The term "lower alkyl" as used herein means straight chain or branched chain alkyl containing 1 to 4 carbon atoms.

The present invention provides transdermal drug delivery devices containing levonorgestrel. The levonorgestrel is present in a transdermal delivery device of the invention in a therapeutically effective amount, i.e., an amount effective to bring about a desired therapeutic result in the treatment of a condition. The amount that constitutes a

therapeutically effective amount varies according to the condition being treated (e.g., osteoporosis, symptoms of menopause), any drugs being coadministered with levonorgestrel, desired duration of treatment, the surface area of the skin over which the device is to be placed, and other components of the transdermal

delivery device. Accordingly it is not practical to enumerate particular preferred amounts but such can be readily determined by those skilled in the art with due consideration of these factors. Generally, however, levonorgestrel is present in a device of the invention in an amount of about 0.05 to about 5 percent,

preferably about 1 to 2.5 percent, by weight based on the total weight of the matrix layer. In a preferred embodiment the matrix is substantially free of solid undissolved levonorgestrel.

The matrix layer contains a copolymer as defined above, levonorgestrel, and any other necessary or desirable adjuvants and excipients. The matrix layer in a device of the invention is generally about 25-600 μm thick. It can be adhered directly to a backing or it can be adhered indirectly to a backing via an intermediate layer.

The copolymer utilized in the practice of the invention should be substantially chemically inert to levonorgestrel. Preferably the inherent viscosity of the copolymer is such as to ultimately provide a suitable pressure sensitive skin adhesive when used in a device of the invention. Preferably the copolymer has an inherent viscosity in the range 0.2 dl/g to about 2 dl/g, more preferably in the range 0.3 dl/g to about 1.4 dl/g.

Suitable copolymers for use in a matrix layer preferably comprise about 40 to 90 percent by weight, more preferably 50 to 70 percent by weight, based on the total weight of all monomers in the copolymer, of one or more A monomers selected from the group

consisting of alkyl acrylates containing 4 to 10 carbon atoms in the alkyl group and alkyl methacrylates containing 4 to 10 carbon atoms in the alkyl group. Examples of suitable alkyl acrylates and methacrylates are n-butyl, n-pentyl, n-hexyl, isoheptyl, n-nonyl, n- decyl, isohexyl, 2-ethyloctyl, isooctyl and 2- ethylhexyl acrylates and methacrylates. Preferred alkyl acrylates include isooctyl acrylate, 2-ethylhexyl acrylate, butyl acrylate, and cyclohexyl acrylate. The most preferred alkyl acrylate is isooctyl acrylate. Preferred alkyl methacrylates include butyl

methacrylate, cyclohexyl methacrylate, isobornyl methacrylate, and methyl methacrylate.

The copolymer component of the matrix further comprises one or more ethylenically unsaturated B monomers, preferably in a total amount from about 10 to 60 percent by weight, more preferably greater than 25 to about 50 percent by weight, and most preferably greater than 30 to about 50 percent by weight (based on the total weight of all the monomers in the copolymer). Suitable B monomers include those comprising a

functional group selected from the group consisting of carboxylic acid, sulfonamide, urea, carbamate,

carboxamide, hydroxy, amino, oxy, oxo, and cyano.

Exemplary B monomers include acrylic acid, methacrylic acid, maleic acid, a hydroxyalkyl acrylate containing 2 to 4 carbon atoms in the hydroxyalkyl group, a

hydroxyalkyl methacrylate containing 2 to 4 carbon atoms in the hydroxyalkyl group, acrylamide,

methacrylamide, an alkyl substituted acrylamide

containing 1 to 8 carbon atoms in the alkyl group, diacetone acrylamide, a dialkyl acrylamide having 1 or 2 carbon atoms in the alkyl group, N-vinyl-N-methyl acetamide, N-vinyl valerolactam, N-vinyl caprolactam, N-vinyl-2-pyrrolidone, glycidyl methacrylate,

alkoxyethyl acrylate containing 1 to 4 carbon atoms in the alkoxy group, alkoxyethyl methacrylate containing 1 to 4 carbon atoms in the alkoxy group, 2- ethoxyethoxyethyl acrylate, furfuryl methacrylate, furfuryl acrylate, tetrahydrofurfuryl acrylate,

tetrahydrofurfuryl methacrylate, propylene glycol monomethacrylate, polyethylene oxide methyl ether acrylate, di (lower) alkylamino ethyl acrylate,

di(lower)alkylamino ethyl methacrylate,

di(lower)alkylaminopropyl methacrylamide,

acrylonitrile, and methacrylonitrile.

The preferred B monomers include hydroxyethyl acrylate, hydroxyethyl methacrylate, glyceryl acrylate, N,N-dimethyl acrylamide, 2-ethoxyethoxyethyl acrylate, 2-ethoxyethyl acrylate, tetrahydrofurfuryl acrylate, and acrylic acid. Most preferred B monomers include hydroxyethyl acrylate and N,N-dimethyl acrylamide, and a combination thereof.

The matrix layer further comprises an adjuvant selected from the group consisting of C₈-C₂₂ fatty acids such as isostearic acid, octanoic acid, and oleic acid, C₈-C₂₂ fatty alcohols such as oleyl alcohol and lauryl alcohol, lower alkyl esters of C₈-C₂₂ fatty acids such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate, di (lower) alkyl esters of C₆-C₈ diacids such as diisopropyl adipate, monoglycerides of C₈-C₂₂ fatty acids such as glyceryl monolaurate,

tetrahydrofurfuryl alcohol polyethylene glycol ether, polyethylene glycol, propylene glycol, 2-(2- ethoxyethoxy) ethanol, N,N-dimethyldodecylamine-N-oxide, and a combination of any one or more of any of the foregoing. Preferred adjuvants include glyceryl monolaurate, N, N-dimethyldodecylamine-N-oxide,

tetrahydrofurfuryl alcohol polyethylene glycol ether, propylene glycol, methyl laurate, and diisopropyl adipate.

In a device of the invention the adjuvant is dissolved in the matrix layer and is present in an amount that enhances levonorgestrel penetration through the skin compared to a like device not containing the adjuvant when this phenomenon is measured using the skin penetration model described below.

Certain adjuvants, however, affect aspects of performance of a transdermal device other than and in addition to drug penetration rate. For example, certain adjuvants are useful in softening or increasing the compliance value and/or lowering the glass

transition temperature of otherwise non-compliant (and therefore non-pressure sensitive adhesive) copolymers, rendering them suitable for use as pressure sensitive skin adhesives. However, the adjuvants enumerated above are generally oily substances that function as plasticizers when incorporated in a copolymer. Such materials can affect adversely the performance of a copolymer, for example by softening it to the point of cohesive failure (where substantial residue is left on the skin upon removal of the device from the skin) or by separating from the continuous phase of the layer and forming an oily layer that reduces adhesion. Also, certain adjuvants can crystallize in the copolymer, resulting in unstable drug delivery rates.

Possible adverse effects of adjuvants

notwithstanding, in the practice of this invention adjuvant amounts in excess of 20% and less than about 50% by weight based on the total weight of the matrix layer have been found to be preferred in order to obtain optimal flux rates, and amounts in excess of 30% are more preferred. With proper selection of

adjuvants, monomers and relative amounts thereof, and inherent viscosity of the copolymer, adjuvants can be included in amounts of up to about 60% by weight based on the total weight of the matrix layer without

cohesive failure or crystal formation, and often without loss of suitable skin adhesion.

In order to accommodate high loading with

adjuvant it is sometimes preferred to incorporate in the copolymer a substantially linear macromonomer copolymerizable with the A and B monomers defined above and having a molecular weight in the range 500-500,000, preferably 2,000-100,000, and more preferably 5,000- 30,000, in an amount (e.g., at least about 0.1 percent by weight based on the total weight of comonomers in the copolymer) effective to control the rheological properties of the copolymer such that when borne upon a backing the matrix layer maintains intimate contact with the skin when applied by hand and does not leave substantial residue on the skin when peeled from the skin. The macromonomer, when used, is generally present in an amount of not more than about 30%, more preferably not more than 20%, even more preferably not more than about 15%, and most preferably not more than about 10%, by weight based on the total weight of all monomers in the copolymer.

The macromonomer can be a compound of the formula

wherein X is a moiety comprising an ethylenically unsaturated group (e.g.,

-CH=C(CH₃) (CO₂CH₃),

O

vinyl, or 2-propenyl) copolymerizable with the A and B monomers, R² is a hydrogen atom or a lower alkyl group, R³ is a lower alkyl group, n is an integer from 20 to 500 and each R⁴ is a monovalent radical selected from the group consisting of

-CN, and -CO₂R wherein R⁵ is a hydrogen atom or a lower alkyl group, and R⁶ is a lower alkyl group. Suitable macromonomers include polymethylmethacrylate,

styrene/acrylonitrile, and polystyrene macromonomers. Polymethylmethacrylate macromonomers are preferred.

Exemplary macromonomers include those having a general formula selected from the group consisting of

wherein R⁷ is a hydrogen atom or a lower alkyl group, R⁸ is hydrogen or methyl, and R², R³, and R⁴ are as defined above.

The macromonomers shown in the formulae directly above are functionally terminated polymers having a single functional group and are sometimes identified as "semitelechelic" polymers. (Vol. 27 "Functionally Terminal Polymers via Anionic Methods" D. N. Schultz et al., pages 427-440, Anionic Polymeriza tion, American

Chemical Society (1981)). Such macromonomers are known and may be prepared by the method disclosed in U.S.

Pat. Nos. 3,786,116, 3,842,059 (both to Milkovich et al.), and 4,732,808 (Krampe et al.). Certain

macromonomers are commercially available, for example those polymethylmethacrylate macromonomers sold under the trade designation "ELVACITE" by ICI Acrylics (e.g., ELVACITE 1010, a polymethylmethacrylate macromonomer having an inherent viscosity of 0.070-0.080, a T_g of 105°C, a GPC weight average molecular weight of 7,000- 10,000, a GPC number average molecular weight of 2,500- 4,000, and a polydispersity of 2.5-3.0, and ELVACITE 1020, a polymethylmethacrylate macromonomer having an inherent viscosity of 0.085-0.10, a T_g of 105°C, a GPC weight average molecular weight of 12,000-15,000, a GPC number average molecular weight of 4,600-6,000, and a polydispersity of 2.5-3.0).

The properties desirable in a transdermal device are well known to those skilled in the art. For example, it is desirable for a matrix to have

sufficiently little cold flow such that a device of the invention is stable to flow upon storage. It is also preferred that it adhere to the skin and release cleanly from the skin. In order to achieve skin contact, clean release, and preferred levels of skin adhesion and resistance to cold flow, the amount and structure of the comonomers in the copolymer, the inherent viscosity of the copolymer, and the amount and structure of the adjuvant are selected such that the device has a compliance value (measured according to the test method set forth in detail below) of 1 x 10^-5 to 5 x 10^-4 cm²/dyne. Compliance values outside this range sometimes are obtained from materials that are suitable. However, those matrices having substantially lower compliance values will generally be relatively stiff and have less than optimal adhesion to skin.

Those having substantially higher compliance values will generally have less than optimal cold flow and might leave substantial residual matrix when removed from the skin. Also, a matrix that is intended to function as a pressure sensitive skin adhesive

preferably has a glass transition temperature of -10°C or lower .

Particularly suitable compositions can be readily selected for a given set of desired properties

considering the effects of comonomers, inherent

viscosity, and adjuvants on the properties of the resulting composition. Certain of such effects are well known to those skilled in the art, and others are described below:

Strongly hydrogen bonding B monomers have been found to increase the amount of levonorgestrel and decrease the amount of oily adjuvant that can be dissolved in a matrix layer. Further, a strongly hydrogen bonding copolymer will be a relatively less compliant material. Therefore if B monomers such as acrylic acid or acrylamide are used a lesser amount of macromonomer (or none at all) will be required in order to lower compliance sufficiently to avoid cohesive failure.

Macromonomers also decrease compliance. Therefore a given target compliance value can often be achieved using a lower inherent viscosity A/B copolymer

combination and a greater amount of macromonomer, or a higher inherent viscosity A/B combination and less macromonomer .

A relatively high compliance pressure sensitive skin adhesive layer involving a macromonomer will generally have better adhesive properties than an A/B copolymer having the same compliance value. Increasing macromonomer content generally increases the amount of adjuvant that can be loaded into a pressure sensitive skin adhesive without cohesive failure. Increasing inherent viscosity will also tend to allow higher adjuvant loading without cohesive failure.

A change that would increase inherent viscosity of a copolymer (such as increased molecular weight through selection of polymerization conditions and/or solvent ratios) will generally decrease compliance.

Further conventional components, such as

stabilizers and reinforcers (e.g., colloidal silicon dioxide), can be incorporated into the matrix if necessary or desirable.

A transdermal delivery device of the invention also comprises a backing. The backing is flexible such that the device conforms to the skin. Suitable backing materials include conventional flexible backing

materials used for pressure sensitive tapes, such as polyethylene, particularly low density polyethylene, linear low density polyethylene, high density

polyethylene, polyester polyethylene terephthalate, randomly oriented nylon fibers, polypropylene,

ethylene-vinyl acetate copolymer, polyurethane, rayon and the like. Backings that are layered, such as polyethylene-aluminum-polyethylene composites, are also suitable. The backing should be substantially inert to the ingredients of the matrix layer.

The adhesive copolymers described above for use in a device of the invention can be prepared by methods well known to those skilled in the art and described, for example, in U.S. Patent RE 24,906 (Ulrich) and U.S. Pat. No. 4,732,808 (Krampe at al.).

Transdermal delivery devices of the invention are preferably prepared by combining the copolymer, any desired adjuvants, and the levonorgestrel with an organic solvent (e.g., ethyl acetate, methanol, acetone, 2-butanone, ethanol, isopropyl alcohol, toluene, alkanes, and mixtures thereof) to afford a coating formulation. The total solids content of the coating formulation is preferably in a range of about 15 to 40 percent by weight, and more preferably in the range of about 20 to 35 percent by weight, based on the total weight of the coating formulation. The

components of the coating formulation are combined and shaken at high speed until a homogeneous formulation is obtained, then allowed to stand to dissipate air bubbles. The resulting coating formulation is knife coated onto a suitable release liner to provide a predetermined uniform thickness of the coating

formulation. Suitable release liners include

conventional release liners comprising a known sheet material such as a polyester web, a polyethylene web, or a polystyrene web, or a polyethylene-coated paper, coated with a suitable fluoropolymer or silicone based coating. The coated release liner is dried and then laminated onto a backing material using conventional methods. Devices of the invention involving a matrix that is not a skin adhesive can be adhered to the skin using conventional means such as a peripheral ring of adhesive surrounding the matrix.

The transdermal delivery devices of the invention can be made in the form of an article such as a tape, a patch, a sheet, a dressing or any other form known to those skilled in the art. Generally the device will be in the form of a patch of a size suitable to deliver a preselected amount of levonorgestrel through the skin. Generally the device will have a surface area of about 1 cm² to about 40 cm².

A device of the invention can be used to treat any condition capable of treatment with levonorgestrel. The device can be placed on the skin and allowed to remain for a time sufficient to achieve or maintain the intended therapeutic effect. The time that constitutes a sufficient time can be selected by those skilled in the art with consideration of the flux rate of the device of the invention and upon the condition being treated.

The examples set forth below are intended to illustrate the invention.

In Vitro Skin Penetration Test Method The skin penetration data given in the examples below was obtained using the following test method. A Diffusion cell is used. Human cadaver skin (Dermatomed skin about 500μM thick obtained from a skin bank) is mounted epidermal side up between the upper portion and the lower portion of the cell, which are held together by means of ball joint clamp.

The portion of the cell below the mounted skin is completely filled with receptor fluid (30% N-methyl-2- pyrrolidone in water) such that the receptor fluid is in contact with the skin. The receptor fluid is stirred using a magnetic stirrer (not illustrated). The sampling port is covered except when in use. When a transdermal delivery device is evaluated, the skin is placed across the orifice of the lower portion of the diffusion cell, the release liner is removed from a 2.0 cm² patch and the patch is applied to the skin and pressed to cause uniform contact with the skin. The diffusion cell is assembled and the lower portion is filled with 10 mL of warm (32°C) receptor fluid.

The cell is then placed in a constant temperature (32 ± 2°C) and humidity (50 ± 10% relative humidity) chamber. The receptor fluid is 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 is withdrawn at specified time intervals (6, 12, 24, 48 and 72 hours) and immediately replaced with fresh fluid. The withdrawn fluid is filtered through a 0.45 μM filter. A 1 mL portion of filtrate is then analyzed for levonorgestrel using high performance liquid chromatography (Column: 15 cm X 4.6 mm I.D.

ZORBAX™ RX-C18 from duPont, 5 μM particle size; Mobile Phase: 60/40 v/v water/acetonitrile; Flow Rate: 1.5 mL/min; Run Time: 11.0 min; Detection: uv at 230 nm). The cumulative amount of levonorgestrel penetrating the skin is calculated. The greatest slope of the plot of the cumulative penetration versus time is taken as the steady state levonorgestrel flux rate measured in μg/cm²/hour. 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 adhesive surface is folded back on itself in the lengthwise direction to produce a "sandwich"

configuration, i.e., backing/adhesive/backing. The "sandwiched" sample is passed through a laminator then two test samples of equal area are cut using a

rectangular die. One test sample is centered on the stationary plate of a shear-creep rheometer with the long axis of the test sample centered on the short axis of the plate. 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 matching the axial orientation of the first test sample. The large, non-stationary plate is placed over the second test sample and the entire assembly is clamped into place. The end of the small, non-stationary plate that is opposite the end with the hook is connected to a chart recorder. 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. The chart recorder is started and at the same time the weight is quickly released so that it hangs free. The weight is removed after exactly 3 minutes has elapsed. The displacement is read from the chart recorder. The compliance is then calculated using the equation:

where A is the area of one face of the test sample, h is the thickness of the adhesive mass (i.e., two times the thickness of the matrix on the tested sample), X is the displacement and f is the force due to the mass attached to the string. Where A is expressed in cm², h in cm, X in cm and f in dynes, the compliance value is given in cm²/dyne.

Preparation of Adhesive Copolymers The adhesive copolymers used in the examples that follow were prepared generally according to the methods described below. The inherent viscosity values which are reported were measured by conventional means using a Cannon-Fenske #50 viscometer in a water bath

controlled at 27°C to measure the flow time of 10 milliliters of a polymer solution (0.15-0.25 g per deciliter of polymer in ethyl acetate). The test procedure followed and the apparatus used are described in detail in "Textbook of Polymer Science", F.W.

Billmeyer, Wiley-Interscience, Second Edition, 1971, p. 84-85. Preparation of Isooctyl Acrylate: Dimethylacrylamide: Hydroxyethyl Acrylate: Polymethylmethacrylate

Macromonomer

(60/15/15/10) Copolymer

Isooctyl acrylate (141.0 g), N,N- dimethylacrylamide (35.25 g), hydroxyethyl acrylate (35.25 g) , ELVACITE™ 1010 polymethylmethacrylate macromonomer (23.50 g, ICI), ethyl acetate (251.75 g), isopropanol (13.25 g) and 2,2'-azobis(2,4- dimethylpentanenitrile) (0.47 g, VAZO™ 52, duPont) were charged into a one liter bottle. The mixture was deoxygenated by purging with nitrogen (lL/min) for 2 minutes. The bottle was sealed and placed in a

rotating water bath at 45°C for 24 hours. The bottle was removed, opened, charged with an additional 0.47 g of VAZO 52, repurged with nitrogen as before, sealed and placed in the launderometer for an additional 24 hours. The percent solids of the resulting solution of copolymer was 45.51%. The inherent viscosity was 0.469 deciliter/gram in ethyl acetate at 0.25 g/ deciliter.

Preparation of Isooctyl Acrylate:

Dimethylacrylamide: Polymethylmethacrylate Macromonomer

(50/40/10) Copolymer

Isooctyl acrylate (117.5 g), N,N- dimethylacrylamide (94.0 g), ELVACITE™ 1010

polymethylmethacrylate macromonomer (23.5 g), ethyl acetate (251.75 g), isopropanol (13.25 g) and VAZO 52 (0.47 g) were charged into a one liter bottle. The mixture was deoxygenated by purging with nitrogen

(lL/min) for 2 minutes. The bottle was sealed and placed in a rotating water bath at 45°C for 24 hours. The bottle was removed, opened, charged with an

additional 0.47 g of VAZO 52, repurged with nitrogen as before, sealed and placed in the launderometer for an additional 24 hours. The percent solids of the

resulting solution of copolymer was 46.19%. The inherent viscosity was 0.532 deciliter/g in ethyl acetate at 0.25 g/deciliter.

Preparation of Isooctyl Acrylate:

Dimethylacrylamide: Polymethylmethacrylate Macromonomer

(63/27/10) Copolymer

Isooctyl acrylate (157.5 g), N,N- dimethylacrylamide (67.5 g), ELVACITE™ 1010

polymethylmethacrylate macromonomer (25.0 g), ethyl acetate (261.25 g), isopropanol (13.75 g) and VAZO 52 (0.5 g) were charged into a one liter bottle. The mixture was deoxygenated by purging with nitrogen

(lL/min) for 3 minutes. The bottle was sealed and placed in a rotating water bath at 45°C for 24 hours. The bottle was removed, opened, charged with an

additional 0.5 g of VAZO 52, repurged with nitrogen as before, sealed and placed in the launderometer for an additional 24 hours. The percent solids of the

resulting solution of copolymer was 47.8%. The

inherent viscosity was 0.394 deciliter/gram in ethyl acetate at 0.15 g/deciliter. Preparation of Isooctyl Acrylate:

Hydroxyethyl Acrylate: Polymethylmethacrylate

Macromonomer

(55/40/5) Copolymer

Molecular sieves (50 g of 8-12 mesh, 4A, 1.6 mm beads) were added to each of 4 quart (0.95 L) wide mouth jars. The jars were filled with isooctyl

acrylate, hydroxyethyl acrylate, ethyl acetate, and isopropanol respectively. The jars were tightly capped and allowed to stand for at least 24 hours. The molecular sieves were then removed by filtration through Whatman filter paper No. 4. The "dry" monomers and solvents were then stored in tightly capped bottles until used to prepare copolymer. Isooctyl acrylate

(137.5 g), hydroxyethyl acrylate (100.0 g), ELVACITE™ 1010 polymethylmethacrylate macromonomer (12.5 g), ethyl acetate (318.75 g), isopropanol (56.25 g) and VAZO 52 (0.5 g) were charged into a one liter bottle. The mixture was deoxygenated by purging with nitrogen (1L/min) for 3 minutes. The bottle was sealed and placed in a rotating water bath at 45°C for 24 hours. The bottle was removed, opened, charged with an

resulting solution of copolymer was 39.30%. The inherent viscosity was 0.335 deciliter/gram in ethyl acetate at 0.15 g/dl. Preparation of "Dried" Adhesive

Dried adhesive is prepared by knife coating a 25 to 50 percent solids solution of the adhesive copolymer at a thickness of 15 to 25 mil (380 to 635 μM) onto a release liner. The adhesive coated release liner is oven dried (e.g. 4 min at 110°F (43°C), 2 minutes at 185°F (85°C), and 10 minutes at 300°F

(149°C)) to remove solvent and reduce the amount of residual monomers. The dried adhesive copolymer is stripped off the release liner and stored in a glass container.

In the examples that follow all percentages are weight/weight unless otherwise indicated. The weight percentages of the formulations after drying are calculated values and assume that only solvent was evaporated during the drying process. The

abbreviations DDAO, DGME, DIPA, GML, IPM, LG, ML, PG and TG are used for N,N-dimethyldodecylamine-N-oxide, diethylene glycol monoethyl ether, diisopropyl adipate, glyceryl monolaurate, isopropyl myristate, lauryl glycol, methyl laurate, propylene glycol and

tetraglycol respectively. The abbreviations IOA, HEA, DMACM and PMMAMac are used for isooctyl acrylate, hydroxyethyl acrylate, dimethylacrylamide and

polymethylmethacrylate macromonomer respectively.

Except as noted, the polymethylmethacrylate

macromonomer was ELVACITE 1010. The abbreviation LN is used for levonorgestrel. Each of the steady state flux values represents the average of three independent determinations.

Example 1

Adhesive (7.5348 g of 55/40/5 isooctyl

acrylate/hydroxyethylacrylate/polymethylmethacrylate macromonomer copolymer, 39.3% solids in 85/15 w/w ethyl acetate/isopropanol, iv = 0.335 dl/g), levonorgestrel (0.0509 g) and diethylene glycol monoethyl ether, i.e., 2- (2-ethoxy ethoxy) ethanol (2.0088 g) were combined in an 11 dram (40.7 mL) glass vial. The vial was capped then shaken overnight on a platform shaker. The resulting formulation was knife coated at a thickness of 20 mil (508 μm) onto a release liner (Daubert 164Z 5 mil (127 μM) PESTER). The coated release liner was oven dried for 4 minutes at 110°F (43°C), for 2 minutes at 185°F (85°C) and for 2 minutes at 225°F (107°C).

The resulting adhesive coating contained 59.0 percent 55/40/5 isooctyl acrylate/hydroxyethyl

acrylate/polymethylmethacrylate macromonomer adhesive copolymer, 1.0 percent levonorgestrel and 40.0 percent diethylene glycol monoethyl ether. The coated liner was then laminated onto the corona treated surface of a 3 mil (76.2 μm) polyethylene backing. The laminate was die cut into 2 cm patches . Penetration through human cadaver skin was determined using the test method described above. The steady state flux was 0.11 μg/cm²/hour. Examples 2 - 16

Using the general method of Example 1, a series of transdermal delivery devices in which the amount and type of skin penetration enhancer were varied was prepared. In all instances the adhesive used was

55/40/5 IOA/HEA/PMMAMac copolymer (iv = 0.335 dl/g) and levonorgestrel was present at 1.0 percent. The weight percent and identity of the skin penetration

enhancer (s) and the steady state flux are shown in Table 1 below.

Examples 17 - 32

Using the general method of Example 1, a series of transdermal delivery devices that were similar, except for the adhesive copolymer, to those of Examples 1-16 was prepared. In all instances the adhesive used was 63/27/10 IOA/DMACM/PMMAMac copolymer (iv = 0.39 dl/g), levonorgestrel was present at 1.0 percent, and the coated release liners were oven dried for 4 minutes at 125°F (52°C), for 2 minutes at 185°F (85°C) and for 2 minutes at 225°F (107°C). The weight percent and identity of the skin penetration enhancer(s) and the steady state flux are shown in Table 2 below.

Examples 33 - 38

55/40/5 IOA/HEA/PMMAMac copolymer (iv = 0.325 dl/g), the formulations were coated at 16 mil (406 μM) wet thickness, and the coated release liners were oven dried for 4 minutes at 125°F (52°C), for 2 minutes at 185°F (85°C) and for 2 minutes at 225°F (107°C).

Levonorgestrel was present at 1.0 percent, except in Example 36, where it was present at 1.1 percent. The weight percent and identity of the skin penetration enhancer (s), the steady state flux, and the compliance values are shown in Table 3 below.

Examples 39 - 44

63/27/10 IOA/DMACM/PMMAMac copolymer (iv = 0.39 dl/g), levonorgestrel was present at 1.0 percent, the

formulations were coated at 16 mil (406 μM) and the coated release liners were oven dried for 4 minutes at 125°F (52°C), for 2 minutes at 185°F (85°C) and for 2 minutes at 225°F (107°C). The weight percent and identity of the skin penetration enhancer (s), the steady state flux, and the compliance values are shown in Table 4 below.

Examples 45 - 60

60/15/15/10 IOA/HEA/DMACM/PMMAMac copolymer (iv = 0.47 dl/g), the formulations were coated at 16 mil (406 μM), and the coated release liners were oven dried for 4 minutes at 125°F (52°C), for 2 minutes at 185°F (85°C) and for 2 minutes at 200°F (93°C). Levonorgestrel was present at 1.0 percent, except for Example 60, where it was present at 0.9 percent. The weight percent and identity of the skin penetration enhancer(s) and the steady state flux are shown in Table 5 below.

Examples 61 - 64

55/40/5 IOA/HEA/PMMAMac copolymer (i.v. = 0.51 dl/g), levonorgestrel was present at 1.4 percent, the

formulations were coated at 16 mil (406 μM) and the coated release liners were oven dried for 4 minutes at 125°F (52°C), for 2 minutes at 185°F (85°C) and for 2 minutes at 200°F (93°C). The weight percent and identity of the skin penetration enhancer(s) and the steady state flux are shown in Table 6 below.

Examples 65 - 68

55/40/5 IOA/HEA/PMMAMac copolymer (i.v. = 0.51 dl/g), the coated (16 mil (406 μM) wet thickness) release liners were oven dried for 4 minutes at 125°F (52°C), for 2 minutes at 185°F (85°C) and for 2 minutes at 200°F (93°C), and the backing was a 0.5 mil (12.7 μM) polyester film. Levonorgestrel was present at 1.4 percent in the compositions of Examples 65, 67 and 68; and at 1.5 percent in Example 66. The weight percent and identity of the skin penetration enhancer (s) and the steady state flux are shown in Table 7 below.

Examples 69 - 72

63/27/10 IOA/DMACM/PMMAMac copolymer (i.v. = 0.48 dl/g), levonorgestrel was present at 1.1 percent, the coated (16 mil (406 μM) wet thickness) release liners were oven dried for 4 minutes at 125°F (52°C), for 2 minutes at 185°F (85°C) and for 2 minutes at 200°F (93°C), and the backing was a 0.5 mil (12.7 μM) polyester film. The weight percent and identity of the skin penetration enhancer(s) and the steady state flux are shown in Table 8 below.

Examples 73 - 76

50/40/10 IOA/DMACM/PMMAMac copolymer (i.v. = 0.53 dl/g), the coated (16 mil (406 μM) wet thickness) release liners were oven dried for 4 minutes at 125°F (52°C), for 2 minutes at 185°F (85°C) and for 2 minutes at 200°F (93°C), and the backing was a 0.5 mil (12.7 μM) polyester film. Levonorgestrel was present at 1.5 percent in the compositions of Examples 73, 74 and 76; and at 1.4 percent in Example 75. The weight percent and identity of the skin penetration enhancer(s) and the steady state flux are shown in Table 9 below.

Examples 77 - 80

60/15/15/10 IOA/DMACM/HEA/PMMAMac copolymer (i.v. = 0.47 dl/g), levonorgestrel was present at 1.2 percent, the coated (16 mil (406 μM) wet thickness) release liners were oven dried for 4 minutes at 125°F (52°C), for 2 minutes at 185°F (85°C) and for 2 minutes at 200°F (93°C), and the backing was a 0.5 mil (12.7 μM) polyester film. The weight percent and identity of the skin penetration enhancer(s) and the steady state flux are shown in Table 10 below.

Example 81

Dried adhesive (4.5228 g of 50/40/10

IOA/DMACM/PMMAMac copolymer; iv = 0.50 dl/g prior to drying; iv = 0.64 dl/g after drying), levonorgestrel (0.1130 g), methyl laurate (1.7168 g), glyceryl

monolaurate (0.1991 g), N,N-dimethyldodecylamine-N- oxide (0.1148 g), tetraglycol (1.593 g) and

approximately 6.5 g of 95/5 w/w ethyl

acetate/isopropanol were combined in a glass vial. The vial was capped then shaken overnight on a platform shaker. The resulting formulation was allowed to stand to dissipate bubbles and then coated at a thickness of 16 mil (406 μm) onto a release liner (5 mil (127 μM) Daubert silicone release liner). The coated release liner was oven dried for 4 minutes at 110°F (43 °C), for 2 minutes at 185°F (85°C) and for 2 minutes at 200°F

(93°C). The resulting adhesive coating contained 54.8 percent 50/40/10 IOA/DMACM/PMMAMac copolymer, 1.4 percent levonorgestrel, 20.8 percent methyl laurate, 2.4 percent glyceryl monolaurate, 1.4 percent dimethyl- dodecylamine-N-oxide and 19.3 percent tetraglycol. The coated liner was then laminated onto a 2 mil (50.8 μm) polypropylene backing. The laminate was die cut into 2 cm² patches. Penetration through human cadaver skin was determined using the test method described above. The steady state flux was 0 μg/cm²/hour. The compliance was 13.23 x 10^-5 cm²/dynes.

Example 82

Using the method of Example 81, transdermal delivery devices coated with a composition containing

55.3 percent 50/40/10 IOA/DMACM/PMMAMac copolymer (iv = 0.50 dl/g prior to drying; iv = 0.64 dl/g after

drying), 1.4 percent levonorgestrel, 19.8 percent propylene glycol, 2.4 percent glyceryl monolaurate, 1.5 percent N,N-dimethyldodecylamine-N-oxide and 19.7 percent tetraglycol were prepared. The steady state flux was 0 μg/cm²/hour. The compliance was 8.4 x 10^-5 cm²/dynes. Examples 83 - 87

Using the general method of Example 81, a series of transdermal delivery devices in which the amount and type of skin penetration enhancer were varied was prepared. In all instances the adhesive used was

55/40/5 IOA/HEA/PMMAMac copolymer (iv = 1.06 dl/g before drying; iv = 1.29 dl/g after drying) and

levonorgestrel was present at 1.5 percent. The weight percent and identity of the skin penetration

enhancer(s) and the steady state flux are shown in Table 11 below.

Examples 88 - 91

50/40/10 IOA/DMACM/PMMAMac copolymer (iv = 0.50 dl/g prior to drying; iv = 0.64 dl/g after drying and levonorgestrel was present at 1.4 percent. The weight percent and identity of the skin penetration

enhancer(s) and the steady state flux are shown in Table 12 below.

The tetraglycol was saturated with levonorgestrel prior to its inclusion in the formulation so the total amount of levonorgestrel in this formulation was greater than 1.4%.

Example 92

Levonorgestrel (19.85 g), methyl laurate (330.8 g), propylene glycol (198.5 g), glyceryl monolaurate (33.08 g), N,N-dimethyldodecylamine-N-oxide (19.85 g) and adhesive (1803 g of 55/40/5 IOA/HEA/PMMAMac

copolymer, 40% solids in 95/5 w/w ethyl

acetate/isopropanol, which had been dried then

resolvated, iv = 0.59 dl/g after drying) were placed in a 1 gallon (3.8 L) high density polyethylene carboy. The carboy was tightly capped then placed on a

roller/shaker for 19 hours. The carboy was allowed to stand until all entrapped air bubbles had dissipated. The resulting formulation was knife coated at a wet thickness of 16 mil (406 μM) onto a silicone coated polyester (5 mil, 127 μM) film. The coated release liner was oven dried at 127°F (53 °C) for 30 minutes. The resulting adhesive coating contained 1.5 percent levonorgestrel, 15.0 percent propylene glycol, 25.0 percent methyl laurate, 2.5 percent glyceryl

monolaurate, 1.5 percent N, N-dimethyldodecylamine-N- oxide, and 54.5 percent 55/40/5 IOA/HEA/PMMAMac

copolymer. The coated liner was allowed to cool for 10 minutes then it was laminated to the corona treated side of a 2 mil (51 μM) polypropylene film. The compliance was measured using the test method described above and found to be 6.57 x 10^-5 cm²/dynes. Skin penetration through human cadaver skin was measured using the test method described above; the steady state flux was found to be 0.40 μg/cm²/hr.

Example 93

Levonorgestrel (18.29 g), methyl laurate (457.2 g), glyceryl monolaurate (65.31 g), N,N- dimethyldodecylamine-N-oxide (13.06 g) and adhesive (1401 g or 50/40/10 IOA/DMACM/PMMAMac copolymer, 53.7% solids in 95/5 w/w ethyl acetate/isopropanol, which had been dried then resolvated, iv = 0.55 dl/g before drying; iv = 0.52 dl/g after drying) were placed in a 1 gallon (3.8 L) high density polyethylene carboy. The carboy was tightly capped then placed on a

roller/shaker for 19 hours. The carboy was allowed to stand until all entrapped air bubbles had dissipated. The resulting formulation was knife coated at a wet thickness of 12 mil (305 μM) onto a silicone coated polyester (5 mil, 127 μM) film. The coated, release liner was oven dried at 127°F (53°C) for 80 minutes. The resulting adhesive coating contained 1.4 percent levonorgestrel, 35.0 percent methyl laurate, 5.0 percent glyceryl monolaurate, 1.0 percent N,N- dimethyldodecylamine-N-oxide, and 57.6 percent 50/40/10 IOA/DMACM/PMMAMac copolymer. The coated liner was allowed to cool for 10 minutes then it was laminated to the corona treated side of a 2 mil (51 μM)

polypropylene film. The compliance was measured using the test method described above and found to be 5.74 x 10^-5 cm²/dynes. Skin penetration through human cadaver skin was measured using the test method described above; the steady state flux was found to be 0.30 μg/cm²/hr.

Example 94

Levonorgestrel (18.04 g), methyl laurate (264.6 g), tetrahydrofurfuryl alcohol polyethylene glycol ether (tetraglycol, 96.23 g), glyceryl monolaurate

(60.14 g), N,N-dimethyldodecylamine-N-oxide (12.03 g) and adhesive (1400 g of 50/40/10 IOA/DMACM/PMMAMac copolymer, 53.7% solids in 95/5 w/w ethyl

acetate/isopropanol, which had been dried then

resolvated, iv = 0.55 dl/g before drying; iv = 0.52 dl/g after drying) were placed in a 1 gallon (3.8 L) high density polyethylene carboy. The carboy was tightly capped then placed on a roller/shaker for 19 hours. The carboy was allowed to stand until all entrapped air bubbles had dissipated. The resulting formulation was knife coated at a wet thickness of 13 mil (330 μM) onto a silicone coated polyester (5 mil, 127 μM) film. The coated release liner was oven dried at 127°F (53°C) for 75 minutes. The resulting adhesive coating contained 1.5 percent levonorgestrel, 22.0 percent methyl laurate, 8.0 percent tetraglycol, 5.0 percent glyceryl monolaurate, 1.0 percent N,N- dimethyldodecylamine-N-oxide, and 62.5 percent 50/40/10 IOA/DMACM/PMMAMac copolymer. The coated liner was allowed to cool for 10 minutes then it was laminated to the corona treated side of a 2 mil (51 μM)

polypropylene film. The compliance was measured using the test method described above and found to be 8.72 x 10^-5 cm²/dynes. Skin penetration through human cadaver skin was measured using the test method described above; the steady state flux was found to be 0.30 μg/cm²/hr. Examples 95 - 143

Using the general method of Example 1, except that the wet coating thickness was 16 mil (406 μM), a number of coated sheet materials were prepared in order to assess the effect of increasing the amount of skin penetration enhancer(s) on the compliance of certain formulations. The compliance was measured using the test method described above. The formulations and the J-values are shown in Table 13, where amounts are percent by weight. PMMAMac* indicates that the

polymethylmethacrylate macromonomer was ELVACITE™ 1020. The inherent viscosities (iv) are expressed in units of deciliter/gram.

Examples 144 - 178

Using the general method of Example 1, except that the formulations were coated at 16 mil (406 μM) wet thickness, a series of coated sheet materials were prepared in order to assess the amount of

levonorgestrel that could be included in a particular formulation without causing crystal formation. The coated sheet materials were stored at 4°C then examined with a microscope after 1 week and 2 weeks of storage. The formulations and the results of the microscopic examinations are shown in Table 14.

r

Claims

WHAT IS CLAIMED IS:

1. A transdermal delivery device comprising: (A) a backing;

(B) a matrix layer adhered to one surface of the backing and comprising:

(1) a copolymer comprising

carboxamide, hydroxy, amino, oxy, oxo, and cyano;

(2) a therapeutically effective amount of levonorgestrel dissolved in the matrix layer; and (3) a skin-penetration enhancing amount of an adjuvant dissolved in the matrix layer and selected from the group consisting of C₈-C₂₂ fatty acids, C₈-C₂₂ fatty alcohols, lower alkyl esters of C₈-C₂₂ fatty acids, di (lower) alkyl esters of C₆-C₈ diacids,

monoglycerides of C₈-C₂₂ fatty acids, polyethylene glycol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, tetrahydrofurfuryl alcohol polyethylene glycol ether, and a combination of any one or more of any of the foregoing. 2. A device according to Claim 1, wherein the one or more A monomers are selected from the group consisting of isooctyl acrylate,

2-ethylhexyl acrylate, butyl acrylate, and cyclohexyl acrylate.

3. A device according to Claim 1, wherein the one or more B monomers are selected from the group consisting of acrylic acid, methacrylic acid, maleic acid, a hydroxyalkyl acrylate containing 2 to 4 carbon atoms in the hydroxyalkyl group, a hydroxyalkyl

methacrylate containing 2 to 4 carbon atoms in the hydroxyalkyl group, acrylamide, methacrylamide, an alkyl substituted acrylamide containing 1 to 8 carbon atoms in the alkyl group, diacetone acrylamide, a dialkyl acrylamide having 1 or 2 carbon atoms in the alkyl group, N-vinyl-N-methyl acetamide, N-vinyl valerolactam, N-vinyl caprolactam, N-vinyl-2- pyrrolidone, glycidyl methacrylate, alkoxyethyl

acrylate containing 1 to 4 carbon atoms in the alkoxy group, alkoxyethyl methacrylate containing 1 to 4 carbon atoms in the alkoxy group, 2-ethoxyethoxyethyl acrylate, furfuryl methacrylate, furfuryl acrylate, tetrahydrofurfuryl acrylate, tetrahydrofurfuryl

methacrylate, propylene glycol monomethacrylate, polyethylene oxide methyl ether acrylate,

di(lower)alkylamino ethyl acrylate, di(lower)alkylamino ethyl methacrylate, di(lower)alkylaminopropyl

methacrylamide, acrylonitrile, and methacrylonitrile.

4. A device according to Claim 1, wherein the one or more A monomers are present in a total amount of 40 to 90 percent by weight, based on the total weight of all monomers in the copolymer.

5. A device according to Claim 1, wherein the adjuvant is selected from the group consisting of glyceryl monolaurate, N,N-dimethyldodecylamine-N-oxide, tetrahydrofurfuryl alcohol polyethylene glycol ether, propylene glycol, diisopropyl adipate, and methyl laurate.

6. A device according to Claim 1, wherein the copolymer further comprises a substantially linear macromonomer copolymerizable with the A and B monomers and having a molecular weight in the range 5,000-30,000 in an amount of not more than about 30% by weight based on the total weight of the comonomers in the copolymer.

7. A device according to Claim 6, wherein the macromonomer is selected from the group consisting of polymethylmethacrylate macromonomers,

styrene/acrylonitrile macromonomers, and polystyrene macromonomers.

8. A method of treating in an animal a condition capable of treatment by levonorgestrel, comprising the steps of:

(i) providing a transdermal drug delivery device according to Claim 1;

(ii) applying the device to the skin of the animal; and

(iii) allowing the device to remain on the skin for a time sufficient to establish or maintain a therapeutically effective blood level of levonorgestrel.