CZ308199A3 - Transdermal preparation for administering testosterone - Google Patents

Abstract

The present invention provides a transdermal composition comprising an adhesive a layer comprising a therapeutically effective amount of testosterone and a terpene-containing transfer enhancing agent.

Description

Transdermal composition for testosterone administration

Technical field

The present invention relates to transdermal drug delivery devices. In another aspect, the present invention relates to a pharmaceutical composition comprising testosterone.

BACKGROUND OF THE INVENTION

Transdermal drug delivery devices are designed to deliver a therapeutically effective amount of the drug through the skin of a patient. Compositions known in the art include reservoir-type compositions that include a membrane that controls the rate of drug release to the skin and compositions comprising a drug dispersion in a matrix, such as a pressure-sensitive adhesive matrix. However, the skin is a significant barrier to the passage of foreign substances into the body. Therefore, it is often desirable or necessary to use certain materials that increase the rate of drug passage through the skin. However, the type of composition, the appropriate rate of transdermal delivery, and the appropriate components of the composition will depend upon the drug used.

Testosterone is the major androgenic hormone that is produced in the testes. Testosterone therapy is currently indicated for the treatment of male hypogonadism. Its use in the treatment of AIDS and tumor-related cachexia, substitution therapy in men over 60 years of age, osteoporosis and combined hormone replacement therapy for the control of male and female fertility is also being investigated.

In recent years, methods for administering testosterone transdermally to both men and women have been investigated. Ebert et al., 999 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9,999 9,999,999

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9999 9999 99 99 99 99

U.S. Pat. U.S. Patent No. 5,152,997, discloses a composition for transdermal administration of testosterone, which comprises testosterone in a matrix, further comprising a penetration enhancing agent. U.S. Pat. U.S. Patent No. 5,460,820 to Ebert et al. a testosterone replacement therapy for women, which is administered $ 50-500 µ of testosterone per day. The '820 composition may also contain an estrogenic compound to allow for combined hormone replacement therapy. Pike et al. U.S. Patent No. 5,340,586 also discloses compositions that can be used to administer estrogens and androgens to women in an amount effective to prevent symptoms associated with loss of ovarian function.

SUMMARY OF THE INVENTION

The present invention includes a composition for transdermal administration of testosterone. The composition comprises a backing layer having an adhesive layer adhering to one side of the backing layer, said adhesive layer comprising:

(a) a pressure sensitive skin adhesive;

(b) a therapeutically effective amount of testosterone; and (c) a transfer aid which comprises terpene.

By means of the composition of the present invention, a therapeutically effective amount of testosterone can be administered to a subject. Accordingly, the invention also provides a method of treating conditions associated with testosterone deficiency in a mammal, comprising the steps of providing a composition for transdermal administration of testosterone comprising a backing layer having an adhesive layer adhering to one side of the backing layer, said adhesive layer comprising:

(a) a pressure sensitive skin adhesive;

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9999 9999 99 99 99 (b) a therapeutically effective amount of testosterone; and (c) a transfer enhancer comprising terpene; applying the composition to the skin of a mammal; and leaving the composition on the skin for a period of time sufficient to produce or maintain a therapeutically effective concentration of testosterone in the blood of the mammal.

The present invention includes transdermal drug delivery compositions containing testosterone. Testosterone is present in the adhesive layer in a therapeutically effective amount, i.e. in an amount permitting administration of an amount of testosterone that results in the desired therapeutic results in the treatment of a particular condition. The amount constituting the therapeutically effective amount varies according to the condition to be treated (e.g., hypogonadism in men, testosterone deficiency in women, cachexia in AIDS patients, etc.), any drugs administered concomitantly with testosterone, the duration of treatment desired, body surface area, on which the composition is placed and, optionally, auxiliary and other components of the composition for transdermal administration. Therefore, it is not meaningful to calculate particular preferred amounts since these amounts are determined by those skilled in the art according to these and other factors. However, generally, testosterone is present in the adhesive layer in an amount of about 2 to 9%, preferably about 2.5 to 6.5% by weight relative to the total weight of the adhesive layer. The composition of the present invention preferably comprises a therapeutically effective amount of testosterone that is dissolved in the adhesive layer. In a more preferred embodiment, the adhesive layer is substantially free of undissolved testosterone in the solid state, and most preferably, the adhesive layer comprises no undissolved testosterone.

The adhesive layer of the composition of the present invention also

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9999 9999 99 comprises one or more polymers, usually one or more copolymers. The polymer used in the present invention should be substantially chemically inert to testosterone and preferably is a pressure sensitive skin adhesive. Examples of suitable types of adhesives include acrylates, natural and synthetic rubbers, polysiloxanes, polyurethanes, and other pressure sensitive skin adhesives known in the art, either alone or in combination. A preferred adhesive is an acrylate copolymer.

The intrinsic viscosity of the copolymer is such that, when used in the composition of the present invention, a suitable pressure-sensitive adhesive is finally obtained. Preferably, the copolymer has an intrinsic viscosity in the range of from 0.2 dl / g to about 2 dl / g, more preferably from 0.3 dl / g to about 1.4 dl / g.

Suitable copolymers for use in the adhesive layer preferably comprise from about 45% to about 95% by weight, more preferably from 55% to 9% by weight, of the total weight of all monomers in the copolymer of which one or more A monomers are selected from the group consisting of 4 to 6 alkyl acrylates. 10 alkyl atoms of the alkyl group and alkyl methacrylates containing from 4 to 10 carbon atoms in the alkyl group. Examples of suitable alkyl acrylates and methacrylates include n-butyl, n-pentyl, isoheptyl, n-nonyl, n-decyl, isohexyl, 2-ethyloctyl, isooctyl and 2-ethylhexyl acrylates and methacrylates. Preferred alkyl acrylates include isooctylacrylate, 2-ethylhexylacrylate, n-butyl acrylate and cyclohexyl acrylate.

The most preferred alkyl acrylate is isooctyl acrylate.

The copolymer component of the adhesive layer further comprises about 5% to 55% by weight, preferably about 5% to about 40% by weight of the total weight of all copolymer monomers, one or more B monomers. Suitable B monomers include those

·· · * · •

contain a functional group selected from the group consisting of carboxyolic acid, sulfonamide, urea, carbamate, carboxamide, hydroxyl, amino, oxy, oxo-, and cyano. Examples of B monomers include acrylic acid, methacrylic acid, maleic acid, C 2 -C 4 hydroxyalkyl hydroxyalkyl, C 2 -C 4 hydroxyalkyl methacrylate, acrylamide, methacrylamide, C 1 -C 8 alkyl substituted acrylamide N-vinyl, -N-methylacetamide, N-vinylvalerolactam, N-vinylcaprolactam, N-vinyl-2-pyrrolidone, glycidyl methacrylate, vinyl acetate, C 1 -C 4 alkoxyethyl acrylate, C 1 -C 4 alkoxyethyl methacrylate alkoxy, 2-ethoxyethoxyethyl acrylate, furfuryl acrylate, furfuryl methacrylate, tetrahydrofurfuryl methacrylate, propylene glycol monomethacrylate, propylene oxide methyl ether acrylate, di (lower) alkylaminoethyl acrylate, di (lower alkyl) aminopropyl methacrylamide and acrylonitrile. Preferred B monomers are acrylic acid, methacrylic acid, acrylamide, methacrylamide and vinyl acetate.

The copolymer may optionally further comprise a linear macromonomer copolymerizable with A and B monomers and having a molecular weight in the range of 500-500000, preferably 2000-1000000, and most preferably 5000-30000. The macromonomer, when used, is typically present in an amount of no more than 20%, preferably not more than about 10% by weight based on the total weight of all monomers in the copolymer. Suitable macromonomers include polymethyl methacrylate, styrene / acrylonitrile, polyether and polystyrene macromonomers. Examples of suitable macromonomers and their preparation are described in Krampe et al., U.S. Pat. No. 4,693,776, the disclosures of which are incorporated herein by reference.

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The copolymers described above can be prepared by methods well known to those skilled in the art, such as described in U.S. Pat. U. S. Patent No. RE 24906 (Ulrich); No. 4,732,808, and International Application No. WO 96/08229 (Garbe), the disclosures of which are incorporated herein by reference.

If desired, the adhesive layer may comprise components that modify the properties of the adhesive polymer, such as softening agents, tackifier and the like.

The adhesive layer of the present invention further comprises adjuvants improving the transdermal administration of testosterone. Any adjuvant that enhances the transdermal delivery of testosterone can be used in the composition of the present invention, regardless of the manner in which this improvement is achieved. Terpenes have been found to be a particularly suitable class of such agents since they aid in solubilizing testosterone in the adhesive as well as enhancing testosterone transfer. Useful terpenes include pinene, d-limonene, carene, terpineol, terpine-4-ol, carveol, carvone, pulegon, piperitone, menthon, menthol, neomenthol, thymol, camphor, borneol, citral, ionone and cineol, alone or in any combination. Of these terpenes, terpineol, in particular α-terpineol, is preferably used.

The adhesive layer may contain, in addition to terpene, another adjuvant to improve administration. Such auxiliary agents for improving administration include, without limitation, alcohols, _C., preferably C fatty acids, esters, alcohols and amides, and alkyl pyrrolidone carboxylates having alkyl groups containing from 6 to 36 carbon atoms, preferably 8 to 20 carbon atoms.

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Preferred transfer enhancers are lauryl alcohol, lauramide DEA, laurylpyrrolidone-5-carboxylate (e.g. Laurydon ^R ), ascorbyl palmitate, glycerol, tetraglycol (α- [(tetrahydro-2-furanyl) methyl] -omega-hydroxy-poly (oxy- 1,2-ethanediyl), lauryl glycol (ie 1,2-dodecanediol) and mixtures thereof.

In the composition of the present invention, the adjuvant is dispersed, preferably substantially evenly and preferably dissolved in the adhesive, and is present in an amount that enhances testosterone penetration through the skin compared to a similar formulation that does not contain an adjuvant when measured using the skin penetration model described below. The total amount of transfer aid is generally 20 to 40% by weight based on the total weight of the adhesive layer.

Optionally, the adhesive layer further comprises an amount of lauramine oxide (N, N-dimethyl-dodecanamine-N-oxide) that enhances penetration through the skin. When the adhesive layer comprises lauramine oxide, the lauramine oxide is typically present in an amount of about 1% to 4% by weight of the total weight of the adhesive layer.

Other conventional components such as crystallization inhibitors (e.g., polyvinylpyrrolidone) can be incorporated into the adhesive layer, if necessary or desired.

In some preferred embodiments of the present invention, the amounts of additives and testosterone are selected such that testosterone is completely dissolved in the adhesive layer and the composition allows relatively rapid transmission through the skin. In one preferred embodiment of the invention, the co-agent is a mixture of terpinol, tetraglycol and lauryl glycol, each present in an amount of from about

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5% to about 15%, preferably from about 7% to about 11% by weight, based on the total weight of the adhesive layer. Preferably, the total amount of auxiliary agent is 25 to 35% by weight based on the total weight of the adhesive layer. In this embodiment, testosterone is present in the adhesive layer in an amount of from about 3% to about 6%, preferably from about 3.5 'to about 4.5% by weight, based on the total weight of the adhesive layer.

In another preferred embodiment of the invention, the adhesive layer comprises terpineol in an amount of from about 20% to about 30% by weight based on the total weight of the adhesive layer, and lauramine oxide in an amount of from about 1% to about 4% weight based on the total weight of the adhesive layer.

In this embodiment, testosterone is present in the adhesive layer in an amount of from about 5% to about 9%, preferably from about 5.5% to about 6.5% by weight, based on the total weight of the adhesive layer.

In yet another preferred embodiment of the invention, the adhesive layer comprises from about 15% to about 25% by weight of terpineol; from about 3% to about 10% by weight of lauryl alcohol; from about 1% to about 6% by weight of glycerol; and from about 1% to about 6% by weight of laurylpyrrolidone-5-carboxylate, based on the total weight of the adhesive layer.

Properties suitable for the transdermal formulation are known to those skilled in the art. For example, it is desirable to have a sufficiently low cold release to be stable in storage. It is also desirable that it adheres well to the skin and releases clean skin. To achieve low temperature release resistance and to achieve the desired level of skin adhesion and ease of release, the amount and structure of comonomers in the copolymer are intrinsic viscosity % of the copolymer and the amount and type of auxiliary agents selected such that the adhesive layer preferably has a compliance value of 2 x 10 ^-5 to 4 x 10 ^-5 cm ² / dyn. Compliance values can be determined using the Creep Complience Procedure described in U.S. Patent No. 4,737,559 (Kellen), the disclosure of which is incorporated herein by reference. Adhesive layers having compliance values outside this range are also suitable. However, adhesive layers having significantly lower compliance values will usually be relatively stiff and will have suboptimal skin adhesion. Adhesive layers having significantly higher compliance values will generally have suboptimal cold release and residual adhesive may remain on the skin upon removal from the skin.

The transdermal delivery device of the present invention also comprises a backing layer. The backsheet is flexible so that the device conforms to the shape of the skin. Suitable backsheet materials include conventional flexible backsheet materials used for adhesive tapes such as polyethylene, especially low density polyethylene, linear low density polyethylene, metallocene polyethylenes, high density polyethylene, polypropylene, polyesters such as polyethylene terephthalate, nylon random orientation fibers, polypropylene, ethylene-vinyl acetate copolymer, polyurethane, natural fibers such as rayon and the like. Backsheets composed of layers such as polyethylene-aluminum-polyethylene are also suitable. The backing layer should be substantially inert with respect to the components of the adhesive layer.

The transdermal compositions of the present invention are preferably prepared by combining a copolymer, adjuvant, lauramine oxide (if present) and testosterone with an organic solvent (e.g., ethyl acetate, methanol, acetone, 2-butanone). , ethanol, isopropanol, toluene, alkanes and mixtures thereof) to form a coating composition. The components of the coating composition are mixed and mixed at high speed to obtain a homogeneous composition which is allowed to settle to remove air bubbles. The resulting coating means is applied by means of a knife coating machine to a suitable removable substrate in a predetermined uniform thickness. Suitable release liners include conventional release liners such as sheet materials such as polyester mesh, polystyrene mesh or paper that are coated with a suitable coating such as a fluoropolymer or other coating containing perfluorinated groups, a silicone-based coating or a hydrocarbon-based coating such as is polyethylene. The coated release liner is then dried to remove the organic solvent and then bonded to the back using conventional techniques. Depending on the selected drying parameters (e.g., temperature, oven time, and air flow through the oven), some auxiliary agents may also be removed from the adhesive layer during drying. This loss can be compensated by the inclusion of an additional auxiliary agent in the coating composition. The amount of additional auxiliary needed may be readily determined by one of ordinary skill in the art using conventional drying experiments (ie, coating a composition comprising a known amount of auxiliary agent on a release pad, drying the coated release pad under controlled conditions, determining the amount of auxiliary agent in the resulting coating) and calculating the amount. a co-agent which was removed during drying).

The following examples illustrate the present invention.

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DETAILED DESCRIPTION OF THE INVENTION

Method for testing skin penetration in vitro

The skin penetration data given in the examples below was obtained as follows. The diffusion cuvette was used either with skin of nude mice or with skin from human corpses.

When testing the transdermal device, the removable pad is removed from the 2.0 cm ² patch and the patch is applied to the skin and pressed to achieve uniform skin contact. The resulting patch / skin joint is placed upside down the mouth of the diffusion cuvette. The diffusion cuvette is assembled and the bottom is filled with 10 ml of warm (32 ° C) receptor fluid so that the receptor fluid is in contact with the skin. The receptor fluid is mixed using a magnetic rod. The sample inlet is closed except for use.

The cuvette is then placed in a chamber of constant temperature (32 ± 2 ° C) and humidity. The receptor fluid is then mixed with a magnetic bar throughout the experiment to ensure sample homogeneity and to reduce the diffusion barrier on the dermal side of the skin.

The entire volume of receptor fluid is withdrawn at specified time intervals and replaced immediately with fresh liquid. The collected liquid is filtered through a 0.45 μΜ filter and then analyzed for testosterone content by high performance liquid chromatography (column: Supelcosil LC-18, 150 x 4.6 mm ID, mobile phase: 60% de-aerated water, 40% acetonitrile grade for HPLC, flow rate: 2 ml / min, detector: UV, 241 nm at 0.2 AUFS, processing time: 5 minutes, injection volume: 20 μΐ). The cumulative amount of testosterone penetrating through the skin and the rate of penetration is calculated.

The solubility of testosterone in the various adjuvants is determined by a set of quantitative additions of testosterone to the respective adjuvant. The results of this testing are shown below.

Auxiliary agent

Solubility mg / ml

Terpineol 139.9 Tetraglycol 67.4 Laurylglycol 40.0

Penetration of testosterone through the skin of nude mice from a saturated solution of testosterone in various adjuvants is determined using the skin penetration test described above, using 2 ml solutions instead of the trandermal formulation. The results of this test are shown in the following table.

Auxiliary agent

Cumulative penetration amount (gg / ml) 24 hours 48 hours

Terpineol 1255 Tetraglycol 34 Laurylglycol 752

2842

1771

Method for testing compliance

The compliance values shown in the following examples were obtained using the modified version of the Creep Complience Procedure described in U.S. Pat. No. 4,737,559 (Kellen).

The removable washer is removed from the sample of the test material. The exposed surface is folded longitudinally to form a sandwich configuration, i.e. a backsheet / adhesive layer / backsheet. The sandwich sample is placed in a laminator and then two test samples of the same area are cut with a rectangular blade. One test sample is placed on a stationary shear-creep rheometer plate where the long axis of the test sample is oriented in the short axis of the plate. The small, non-stationary shear-creep rheometer plate is centered on the first sample on the stationary plate so that the hook is at the front and in front of the rheometer face. The second test sample is placed on the top surface of a small, non-stationary plate in the same axial orientation as the first test sample. A large non-stationary plate is placed on the second test sample and the entire assembly is attached. The end of the small non-stationary plate, opposite to the hook side, is connected to the recorder. A string is attached to the hook of a small, non-stationary plate and stretched over the rheometer pulley. Weights (for example, 500 g) are attached to the free end of the string. The recorder starts at the same time as the weight is quickly released, so it hangs freely. The weight is removed exactly after 3 minutes. The offset is read from the recorder. The compliance is then calculated using the equation:

AX j = 2hf where A is the area of one side of the test sample, h is the thickness of the adhesive mass (ie twice the thickness of the adhesive layer on the test sample), X is the displacement af is the force exerted by the weight attached to the string. If A is expressed in cm ² , h is in cm, X is in cm and f is in dynes, then the compliance value is expressed in cm ² / dyne.

Preparation of copolymer

The copolymers used in the following examples are prepared by the techniques described below. The intrinsic viscosity values described are measured by conventional means using a Canon-Fenske # 50 viscometer in a 27 ° C controlled water bath to measure the 10 mm polymer solution flow time (0.15 g polymer per deciliter ethyl acetate). The procedure and apparatus used are described in detail in the Textbook of polymer science, F.W. Billmeyer, Wiley-Interscience, Second Edition, 1971, pp. 84-85).

Preparation of copolymers isooctylacrylate / acrylamide / vinyl acetate 73/7/20

The masterbatch was prepared by mixing isooctyl acrylate (1233.75 g), acrylamide (118.125 g), vinyl acetate (337.500 g) and 2.2 ¹ -azobis (2-methylbutanenitrile) (1.6875 g). A portion of the premix (225.475 g), ethyl acetate (257.7) and methanol (28.6 g) were placed in a 1 L amber tube. The mixture was degassed by flushing with nitrogen (1 L / min) for 2 minutes. Seal the tube and place in a rotating water bath at 57 ° C for 24 hours.

The tube was removed, opened, and then charged with ethyl acetate (214.8 g) and methanol (23.8 g). Mix the contents of the tube until homogeneous (usually overnight). The percentage of solids of the resulting copolymer solution is 26.4. The intrinsic viscosity is 1.47 dl / g in ethyl acetate at 0.15 g / dl.

Preparation of dried copolymers

The dried copolymer is prepared by coating the copolymers with a knife coater at a thickness of approximately 9 mil (229 μΜ) on a removable backing. The coated removable pad is dried at about 275 ° F (135 ° C) to remove the solvent and reduce the amount of residual monomers. The dried copolymer is 9 9 9 9 9 · 9 9 9 9 9 9 9 9

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Example 1

Terpineol (442.31 g), lauramine oxide (25.00 g), testosterone, USP (75.00 g), copolymer (862.50 g dried 73/7/20 isooctylacrylate / acrylamide / vinyl acetate copolymer, iv = 1.36 dl / g before drying), ethyl acetate (3202.00 g) and methanol (356.00 g) were mixed in a 2 gallon (7.57 L) flask. The vessel was sealed and then shaken for 14.5 hours on a plate shaker. The resulting material was allowed to stand until all air bubbles had disappeared and then applied to a silicone removable pad in a thickness of 31 mil (787 μ nož) with a knife coater. The coated mat is dried in an oven for 4 minutes at 112 ° F (44 ° C), for 2 minutes at 185 ° F (85 ° C) and for 2 minutes at 225 ° F (107 ° C). It is assumed that 35% of the initial weight of terpineol evaporates on drying, so that the resulting adhesive coating contains 23.0% terpineol, 2.0% lauramine oxide, 6.0% testosterone and 69.0% 73/7/20 isooctyl acrylate / acrylamide copolymer / vinyl acetate. The coated mat was then bonded to the back (1109 Scotchpak ™ tan, polyester film layer, available from 3M Company, St. Paul, MN, USA). The laminate is cut with a blade on a patch. The compliance is measured using the test described above and is 2.322 x 10 ⁵ cm ² / dyn. Penetration through the skin of human corpses and hairless mice is determined using the assay described above. The results are shown in Table 1, below, in which each value is the average of six independent measurements.

Example 2

Terpineol (160.71 g), tetraglycol (133.93 g), lauryl glycol (130.81 g), testosterone, USP (48.75 g), copolymer (863.75 g of dried 73/7/20 isooctyl acrylate / acrylamide copolymer / T · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Vinyl acetate, iv = 1.36 dl / g before drying), ethyl acetate (3202.00 g) and methanol (356.00 g) were mixed in a 2 gallon (7.57 L) flask. The vessel was sealed and then shaken for 14.5 hours on a plate shaker. The resulting material was allowed to stand until all air bubbles had disappeared and then applied to a silicone removable mat in a 30 mil (762 μΜ) thickness using a knife coater. The coated mat is dried in an oven for 4 minutes at 111 ° F (44 ° C), for 2 minutes at 184 ° F (84 ° C) and for 2 minutes at 225 ° F (107 ° C). It is assumed that 30% of the initial weight of terpineol, 16% of the initial weight of tetraglycol and 14% of the initial weight of lauryl glycol evaporate on drying so that the resulting adhesive coating contains 9.0% terpineol, 9.0% tetraglycol, 9.0% lauryl glycol, 3 9% testosterone and 69.1% 73/7/20 isooctylacrylate / acrylamide / vinyl acetate copolymer. The coated mat was then bonded to the back (1109 Scotchpak ™ tan, polyester film layer, available from 3M Company, St. Paul, MN, USA). The laminate is cut with a blade on a patch. The compliance is measured using the test described above and is 2.477 x 10 -5 ^s cm ² / dyn. Penetration through the skin of human corpses and hairless mice is determined using the assay described above. The results are shown in Table 1, below, in which each value is the average of six independent measurements.

Example 3

Tetraglycol (238.10 g), lauryl glycol (116.28 g), testosterone, USP (36.25 g), copolymer (913.75 g of dried 73/7/20 isooctylacrylate / acrylamide / vinyl acetate copolymer, iv = 1.36 dl / g before drying), ethyl acetate (3202.00 g) and methanol (356.00 g) were mixed in a 2 gallon (7.57 L) flask. The vessel was sealed and then shaken for 14.5 hours on a plate shaker. The resulting material is allowed to stand until all air bubbles have disappeared and then applied to a silicone 30 mil (762 μΜ) knife knife with a knife coater. removable washer. The coated mat is dried in an oven for 4 minutes at 111 ° F (44 ° C), for 2 minutes at 185 ° F (85 ° C) and for 2 minutes at 226 ° F (108 ° C). It is assumed that 16% of the initial weight of tetraglycol and 14% of the initial weight of lauryl glycol evaporate on drying, so that the resulting adhesive coating comprises 16.0% tetraglycol, 8.0% lauryl glycol, 2.9% testosterone and 73.1% copolymer 73 / 7/20 isooctylacrylate / acrylamide / vinyl acetate. The coated mat was then bonded to the back (1109 Scotchpak ™ tan, polyester film layer, available from 3M Company, St. Paul, MN, USA). The laminate is cut with a blade on a patch. Compliance is measured using the assay described above and is 3.795 x 10 ^-5 cm ² / dyn. Penetration through the skin of human corpses and hairless mice is determined using the assay described above. The results are shown in Table 1 below, in which each value is the average of six independent measurements.

Table 1

Example C. Cumulative amount penetrating in 24 hours (^ g / cm ² ) Skin of hairless mice Skin human corpses 1 523 174 2 198 113 3 148 87

Examples 14-17

Following the procedure of Example 1, a series of transdermal compositions are prepared in which the amount of testosterone and the amount and choice of adjuvant vary. In all cases it is • 9 • 9

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The copolymer used is 73/7/20 isooctylacrylate / acrylamide / vinyl acetate. The weight percent testosterone, the weight percent and identity of the adjuvant, the weight percent lauramine oxide (if used) and the cumulative skin penetration of nude mice are shown in Table 2, below. For each composition, the copolymer was added to 100% by weight. The abbreviations T, TP, TG, LG and LAO are used for testosterone, terpineol, tetraglycol, lauryl glycol and lauramine oxide, respectively.

Table 2

Example C. % T Auxiliary agent Cumulative penetration amount (jtzg / cm ² ) 24 hours 48 hours 4 5.9 3 0% TP 286 473 5 6.3 35% TP; 3% LAO 575 686 6 3.6 30% TP; 3% LAO 484 not performed 7 4.3 10% TP; 10% TG; 10% LG 320 447 8 5.2 20% TP; 10% TG 320 501 9 5.1 20% TP; 10% LG 252 436 10 3.8 30% TG 120 238 11 4.0 30% TG 179 309 12 3.3 3 0% LG 151 272 13 3.5 30% LG 185 293 14 3.4 30% LG; 3% LAO 362 not performed 15 Dec 3.9 30% TG; 3% LAO 285 not performed 16 4.4 10% TP; 10% TG; 10% LG; 420 not performed 3% LAO 17 3.7 15% TG; 15% LG 262 367

· «* * * * * * * * * * * * * * * * * * * · · · 99 «· Φ ·········· 99 99 99

Examples 18-23

Following the procedure of Example 1, a series of transdermal compositions are prepared in which the amount of testosterone and the amount and choice of adjuvant vary. In all cases, the 73/7/20 copolymer used is isooctylacrylate / acrylamide / vinyl acetate. The weight percent testosterone, the weight percent and identity of the adjuvant and the cumulative skin penetration from human corpses are shown in Table 3, below. For each composition, the copolymer was added to 100% by weight. The abbreviations T, TP, TG and LG are used for testosterone, terpineol, tetraglycol and lauryl glycol, respectively.

Table 3

Example C. % T Auxiliary agent Cumulative penetration amount ^ g / cm ² ) 24 hours 48 hours 18 6.1 30% TP 153 252 19 Dec 4.0 30% TG 255 336 20 May 3.4 3 0% LG 281 346 21 5.1 15% TP; 15% TG 243 347 22nd 4.8 15% TP; 15% LG 116 192 23 3.8 15% TG; 15% LG 223 284

Examples 24 - 28

Following the procedure of Example 1, a series of transdermal compositions are prepared in which the amount of testosterone and the amount and choice of adjuvant vary. In all cases, it is a tall tall tall tall tall tall tall tall tall. 9999 99 99 used copolymer 73/7/20 isooctylacrylate / acrylamide / vinyl acetate. The weight percent testosterone, the weight percent and the identity of the adjuvant mean skin flow of human corpses are shown in Table 4, below. For each composition, the copolymer was added to 100% by weight. The abbreviations T, TP, TG and LG are used for testosterone, terpineol, tetraglycol and lauryl glycol, respectively. Each flow value is the average of 3 independent measurements.

Table 4

Example C. % T Auxiliary agent Average flow ^ g / cm ² / hour) 24 8.0 30% TP 3.37 25 4.75 15% TP; 7.5% TG; 7.5% LG 3.82 26 4.33 10% TP; 10% TG; 10% LG 5.31 27 Mar: 3.34 30% LG 4.15 28 3.68 20% TG; 10% LG 5.21

Example 29

Terpineol (3.5294 g), N, N-cocodiethanolamide (3.0011), testosterone (0.9801 g), copolymer (13.020 g of dried 73/7/20 isooctylacrylate / acrylamide / vinyl acetate copolymer, iv = 1.36 dl (g before drying), ethyl acetate (47.747 g) and methanol (9.259 g) were mixed in a 4 ounce (118 mL) glass vessel. The vessel was sealed tightly and then shaken for 12 hours in a rotary mixer. The resulting material was sonicated to remove bubbles. Apply 30 mil (762 μΜ) of thickness to the silicone removable mat with a knife coater. The coated washer has been coated with a waterproofing pad. Air-dried at ambient temperature for 1.5 minutes and then oven dried at 110 ° F for 10 minutes (43 ° C). ° C).

It is assumed that 15% of the initial weight of terpineol evaporates on drying, so that the resulting adhesive coating comprises 15.0% terpineol, 15.0% cocamide DEA, 4.9% testosterone and 65.1% 73/7/20 isooctyl acrylate copolymer / acrylamide / vinyl acetate. The coated washer was then joined to the back (1109 Scotchpak ™). The laminate is cut with a blade on a patch. Penetration through the skin of human corpses and hairless mice is determined using the assay described above. The results are shown in Table 5, below, in which each value is the average of four independent measurements

Examples 30-31

Following the procedure of Example 29, a series of transdermal compositions are prepared in which the amount of testosterone and the amount and choice of adjuvant vary. In all cases, the 73/7/20 copolymer used is isooctylacrylate / acrylamide / vinyl acetate. The weight percent testosterone, the weight percent and identity of the adjuvant and the cumulative skin penetration from human corpses and hairless mice are shown in Table 5, below. For each composition, the copolymer was added to 100% by weight. The abbreviations T, TP, CDEA, GLY and LPCA are used for testosterone, terpineol, N, N-cocodiethanolamide, glycerol and laurylpyrrolidone-5-carboxylate, respectively.

· # ··

99 99 99 99

9 9 99 9

9999 99 ··

99 9 9999 ··· 99 «•

9900 99 99 ·· 99

Table 5

Example C. % T Auxiliary agent Cumulative penetration amount per 24 h ^ g / cm ² ) Human corpses Hairless mice 29 4.9 15% TP; 15% CDEA 346 463 30 3.0 10% TP; 10% GLY; 10% LPCA 120 156 31 5.5 20% TP; 5% LPCA 5% GLY; 281 370

Example 32

Terpineol (1.9392 g), laurylpyrrolidone-5-carboxylate (0.270 g), glycerol (0.270 g), testosterone (0.3001 g), copolymer (3.900 g of dried 72/8/20 isooctylacrylate / acrylamide / vinyl acetate copolymer, i v = 1.47 dl / g before drying), ethyl acetate (23.0219 g) and methanol (2.569 g) were mixed in an 11 dram (41 mL) glass vessel. The vessel was sealed and then shaken for 12 hours on a plate shaker. Apply the product at a thickness of 44 mil (1118 μΜ) to a silicone removable pad using a knife coater. The coated mat is air dried at ambient temperature for 2.0 minutes and then dried in an oven for 4 minutes at 110 ° F (43 ° C), 2 minutes at 185 ° F (85 ° C) and for 2 minutes. 2 minutes at 225 ° F (107 ° C). It is assumed that 35% of the initial weight of terpineol evaporates on drying, so that the resulting adhesive coating contains 21.0% terpineol, 4.5% laurylpyrrolidone-5-carboxylate, 4.5% glycerol, 5.0% testosterone and 65.0 % of copolymer 72/8/20 isooctylacrylate / acrylamide / vinyl acetate.

9 · · ·· ♦ · 9 9 9 9 * ··· 9 9 9 9 99 9 • 9 9 »··· · ···

9,999 9,999,999,999

9 9 9 9 9

9999 9999 99 99 99 99

The coated washer is then joined to the back (1012

Scotchpak ™, transparent, heat-sealable polyester film layer). The laminate is cut with a blade on a patch. Penetration through the skin of nude mice is determined using the assay described above. The results are shown in Table 6, below, in which each value is the average of four independent measurements.

Examples 33-37

Following the procedure of Example 32, a series of transdermal compositions are prepared in which the amount of testosterone and the amount and choice of adjuvant vary. In all cases, the 72/8/20 copolymer used is isooctylacrylate / acrylamide / vinyl acetate. The weight percent testosterone, the weight percent and identity of the adjuvant and the cumulative skin penetration of nude mice are shown in Table 6, below. For each composition, the copolymer was added to 100% by weight. Abbreviations T,

TP, GLY and LPCA are used for testosterone, terpineol, glycerol and laurylpyrrolidone-5-carboxylate, respectively.

this to it ··· · ··· · · to • this to ···

Table 6

Example C. % T Auxiliary agent Cumulative penetration amount per 24 h ^ g / cm ² ) 32 5.0 21% TP; 4.5% GLY; 4.5% LPCA 332 33 4,5 21% TP; 4.5% GLY; 4.5% LPCA 293 34 4.0 21% TP; 4.5% GLY; 4.5% LPCA 230 35 4,5 23.25% TP; 4.0% GLY; 2.25% LPCA 231 36 5.0 23.25% TP; 4.5% GLY; 2.25% LPCA 243 37 5.5 23.25% TP; 4.5% GLY; 2.25% LPCA 315

Example 38

Terpineol (1.1071 g), lauryl alcohol (0.2020), laurylpyrrolidone-5-carboxylate (0.120 g), glycerol (0.180 g), testosterone (0.1923 g), copolymer (2.800 g of dried 73/7/20 copolymer) isooctylacrylate / acrylamide / vinyl acetate, iv = 1.36 dl / g before drying), ethyl acetate (10.2462 g) and methanol (1.1447 g) were mixed in a 6 dram (22 mL) glass vessel. The vessel was sealed and then shaken for 12 hours on a plate shaker. Apply 30 mil (762 μΜ) of thickness to the silicone removable mat with a knife coater. The coated substrate is air dried at ambient temperature for at least 3 to 4 minutes and then dried in an oven for 4 minutes at 110 ° F (43 ° C), 2 minutes at 185 ° F (85 ° C) and after for 2 minutes at 225 ° F

r ·

I (107 ° C). It is assumed that 35% of the starting weight of terpineol and 5% of the starting weight of lauryl alcohol evaporate on drying, so that the resulting adhesive coating contains 17.1% terpineol, 4.6% lauryl alcohol, 2.8% laurylpyrrolidone-5-carboxylate, 4.3 % glycerol, 4.6% testosterone and 65.6% 73/7/20 isooctylacrylate / acrylamide / vinyl acetate copolymer. The coated substrate is then joined to the back (1012 Scotchpak ™, transparent, heat-sealable polyester film layer). The laminate is cut with a blade on a patch. Penetration through the skin of nude mice is determined using the assay described above. The results are shown in Table 7, below, in which each value is the average of four independent measurements

Examples 39-40

Following the procedure of Example 38, a series of transdermal delivery formulations are prepared in which the amount of testosterone and the amount and choice of adjuvant vary. In all cases, the 73/7/20 copolymer used is isooctylacrylate / acrylamide / vinyl acetate. The weight percent testosterone, the weight percent and identity of the adjuvant and the cumulative skin penetration of nude mice are shown in Table 7, below. For each composition, the copolymer was added to 100% by weight. The abbreviations T, TP, GLY, LALC and LPCA are used for testosterone, terpineol, glycerol, lauryl alcohol and laurylpyrrolidone-5-carboxylate, respectively.

»9 9 9 9 9 9 9

9 9 9 9 9

9 99 99999 999 999

9 9 9 9 9

9999 9999 99 99 99 99

Table 7

Example C. % T Auxiliary agent Cumulative penet quantity per 24 h rujujici (/ zg / cm ² ) 38 4.6 17.1% TP; 4.3% GLY; 4.6% LALC; 2.8% LPCA 341 39 4.3 15.8% TP; 4.5% GLY; 8.6% LALC 306 40 5.2 18.8% TP; 9.4% LALC 320

Example 41

Following the procedure of Example 38, a transdermal formulation is prepared wherein the adhesive comprises 18% terpineol, 4.5% lauryl alcohol, 4.5% glycerol, 3.0% laurylpyrrolidone-5-carboxylate, 4.8% testosterone, and 65% 73 (7) 20 isooctyl acrylate / acrylamide / vinyl acetate. Penetration through the skin of hairless mice and through various skin parts from human corpses is determined using the assay described above. The results are shown in Table 8, below, in which each value is the average of four independent measurements.

Example 42

Following the procedure of Example 38, a transdermal formulation is prepared wherein the adhesive comprises 19.8% terpineol, 9.9% lauryl alcohol, 5.5% testosterone and 64.8%

73/7/20 isooctyl acrylate / acrylamide / vinyl acetate. Penetration through the skin of hairless mice and through various skin parts from human corpses is determined using the assay described above. The results are shown in Table 8, below, in which each value is an average of four ·· «· · ··

Φ • ·

Φ Φ · · · • • • • • • • Φ Φ Φ Φ ΦΦ

Φ Φ ·

ΦΦ * ·

ΦΦ ΦΦ

Φ Φ Φ Φ Φ Φ Φ Φ

Φ ΦΦΦ Φ ·

* Independent measurement.

Table 8

Cumulative amount penetrating in 24 hours (^ g / cm ² )

Type of leather Example 41 Example 42 The Human Corpse (Episode 1) 280 256 Human corpse (part 2) 330 270 The Human Corpse (Episode 3) 136 116 Hairless mouse 411 337

The present invention has been described in several of its embodiments, the detailed description and examples given are merely illustrative and not limiting of the scope of the present invention. It will be apparent to those skilled in the art that changes may be made to these embodiments without departing from the scope of the invention. Accordingly, the present invention is not limited to the details and means disclosed, but is limited to the structures and compositions described in the claims and equivalents thereof.

Claims (6)

A transdermal composition for administering testosterone comprising a backing layer provided with an adhesive layer adhering to one surface of the backing layer, said adhesive layer comprising: (a) a pressure sensitive skin adhesive; (b) a therapeutically effective amount of testosterone; and (c) a transfer aid which comprises terpene. A composition according to claim 1 wherein the terpene is α-terpineol. 3. A testosterone transdermal composition comprising a backing layer provided with an adhesive layer adhering to one surface of the backing layer, said adhesive layer comprising: (a) a pressure sensitive skin adhesive comprising a copolymer of (i) one or more A monomers selected from the group consisting of C 4 -C 10 alkyl (meth) acrylates and (ii) one or more ethylenically unsaturated B monomers containing a functional group selected from carboxylic acid, sulfonamide, urea, carbamate, carboxamide, hydroxyl, amino, oxo-, oxy and cyano; (b) a therapeutically effective amount of testosterone; and (c) a transfer aid which comprises terpene. 4. A composition according to claim 3 wherein the A monomer is isooctylacrylate. • · 9 9 ·· 9 9 9 9 9 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 999 999 OQ 99999 98 Z 27 9999 9999 99 99 99 99 The composition of claim 3, further comprising one or more substantially linear macromonomers that are copolymerizable with A and B monomers. 6. A method of treating conditions associated with testosterone deficiency in a mammal comprising the steps of: (a) providing the composition of claim 1; (b) applying the composition to the skin of a mammal; and (c) leaving the composition on the skin for a period of time sufficient to produce or maintain a therapeutically effective testosterone concentration in the blood of said mammal.