MXPA99007771A - Transdermal device for the delivery of testosterone - Google Patents

Abstract

A transdermal delivery device including an adhesive layer that contains a therapeutically effective amount of testosterone and a delivery enhancing adjuvant comprising a terpene.

Description

DEVICE FOR THE TRANSDERMAL RELEASE OF TESTOSTERONE The present invention concerns devices for transdermal drug delivery.

Background of the Invention Devices for transdermal drug delivery are designed to deliver a therapeutically effective amount of drugs through the patient's skin. Devices known in the art include reservoir-type devices that involve membranes that control the proportion of drug released to the skin and devices that involve a dispersion of the drug in a matrix such as a pressure-sensitive adhesive. The skin, however, presents a substantial barrier to the entry of foreign substances into the body. It is however often desirable or necessary to incorporate certain materials that improve the rate at which the medicament passes through the skin. However, the type of device, the proportion of the transdermal flow that is adequate, and the components of the appropriate formulation are dependent on the particular medicament to be released. REF. 31049 Testosterone is the main androgenic hormone formed in testes.

Testosterone therapy is currently indicated for the treatment of male hypogonadism. It is also under investigation for the treatment of depleting conditions associated with AIDS and cancer, testosterone replacement in men. that exceed the age of 60, osteoporosis, combined hormone replacement therapy for women and control of male fertility.

In recent years there has been interest in developing a useful method of transdermally releasing testosterone for both men and women. Ebert et al, Patent U.S.A. No. 5,152,997, describes a device for the transdermal release of testosterone containing testosterone in a matrix that additionally includes a penetration enhancer. In U.S. Patent No. 5,460,820 Ebert et al. Discloses a device for providing testosterone in replacement therapy for women that releases 50 to 500 μg / day of testosterone in women. The x820 devices may also include an estrogen compound, thereby providing a combination of hormones for replacement therapy. Pike et al., U.S.A. Patent No. 5,340,586 also describes compositions that can be used to provide estrogens and androgens to women in effective amounts to prevent symptoms of loss of ovarian function.

Brief Description of the Invention The present invention provides a device for the transdermal release of testosterone. This device comprises a reinforcement having an adhesive layer adhered to a surface of the reinforcement, said adhesive layer comprising: (a) an adhesive to the skin sensitive to pressure; (b) a therapeutically effective amount of testosterone and (c) a release enhancing adjuvant comprising a terpene.

The device of the invention is capable of delivering a therapeutically effective amount of testosterone to a subject. Accordingly, the invention also provides a method for treating a condition associated with testosterone deficiency in a mammal comprising a reinforcement having an adhesive layer adhered to a surface of the reinforcement, said adhesive layer comprising: (a) an adhesive to the skin sensitive to pressure; (b) a therapeutically effective amount of testosterone; and (c) a release enhancing adjuvant comprising a terpene, Apply the device to the skin of a mammal; and allowing the device to remain on the skin for a sufficient time to establish or maintain a therapeutically effective blood level of testosterone in the mammal.

Detailed description of the invention The present invention provides a device for the transdermal delivery of a medicament containing testosterone. Testosterone is present in the adhesive layer in a therapeutically effective amount, for example, an effective amount to allow the device to release sufficient testosterone to achieve 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 (for example male hypogonadism, testosterone deficiency in women, depletion in AIDS patients, etc.), some drugs that are coadministered with testosterone, desired duration of treatment, the area of the surface and location of the skin on which the device is placed, and the selection of the adjuvant and other components of the device for transdermal delivery.

It is therefore impractical to list particular preferred amounts but they can be determined by those skilled in the art with due consideration to these and other appropriate factors. Generally, however, testosterone is present in the adhesive layer in an amount of about 2 to 9 percent, preferably about 2.5 to 6.5 percent by weight based on the total weight of the adhesive layer. A device of the invention preferably contains a therapeutically effective amount of testosterone in the adhesive layer. In a more preferred embodiment the adhesive layer is substantially free of undissolved solids of testosterone, and in a preferred embodiment particularly the adhesive layer does not contain undissolved solids of testosterone.

The adhesive layer of the device of the invention also comprises one or more polymers, typically one or more copolymers. The polymers used in the practice of the invention could be substantially chemically inert to testosterone, and is preferably a pressure sensitive skin adhesive. Examples of suitable types of adhesives include acrylates, natural and synthetic gums, polyoxanes, polyurethanes, and other pressure sensitive skin adhesives known in the art, either alone or in combination. Preferably the adhesive copolymer is an acrylate.

The inherent viscosity of the copolymer is such that it eventually provides a suitable pressure sensitive adhesive when used in a device of the invention.

Preferably the copolymer has an inherent viscosity in the range of 0.2 dl / g. to about 2 dl / g., more preferably 0.3 dl / g to about 1.4 dl./g.

Suitable copolymers for use in a dough layer preferably comprise about 45 to 95% by weight, more preferably 55 to 95% by weight, based on the total weight of all monomers in the copolymer, of one or more monomers A selected from the group which consists 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 include n-butyl, n-pentyl, n-hexyl, isoheptyl, n-nonyl, n-decyl, isohexyl, 2-ethylctyl, iso-octyl and 2-ethylhexyl acrylates and methacrylates. Preferred alkyl acrylates include iso-octyl acrylates, 2-ethylarilate, n-butyl acrylate, and cyclohexyl acrylate. The most preferred alkyl acrylate is iso-octyl acrylate.

The copolymer component of the adhesive layer further comprises about 5 to 55% by weight, more preferably about 5 to 40% by weight, based on the total weight of all monomers in the copolymer, of one or more B monomers. Suitable include those comprising a functional group selected from the group consisting of carboxylic acid, sulfonamide, urea, carbamate, carboxamide, hydroxy, amine, oxy, oxo, and cyano. Exemplary monomers B 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, acrylamide, methacrylamide, an alkyl group substituted acrylamide containing 1 to 8 carbon atoms in the alkyl group, N-vinyl-N-methyl acetamide, N-vinyl valerolactam, N-vinyl caprolactam, N-vinyl-2-pyrrolidone, glycidyl methacrylate, vinyl acetate, 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 acrylate, furfuryl methacrylate, tetrahydrofurfuryl acrylate, tetrahydrofurfuryl methacrylate, propylene glycol monomethacrylate, propylene oxide methyl ether acrylate, di (lower) alkylamino ethyl acrylate, di (lower) alkylamino ethyl methacrylate, di (lower alkyl) aminopropyl methacrylamide, acrylonitrile, and methacrylonitrile. Preferred B-monomers include acrylic acid, methacrylic acid, acrylamide, methacrylamide, and vinyl acetate.

The copolymer can optionally further comprise a linear macromonomer substantially copolymerizable with the monomers A and B and having a molecular weight in the range of 500-500,000, preferably 2,000-1,000,000 and more preferably, 5,000-30,000. The macromonomer, when used, is generally present in an amount of not 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 polymethacrylate, styrene / acrylonitrile, polyether macromonomers and polystyrene. Examples of useful macromonomers and their preparation are described in Kra pe et al., U.S. Pat. No. 4,693,776, which is incorporated herein by reference.

The copolymers described above can be prepared by methods well known to those skilled in the art and described, for example, in U.S. Pat. No. RE 24,906 (Ulrich), U.S. Pat. to. No. 4,732,808 (Krampe), and International Publication Number WO 96/08229 (Garbe), which are incorporated herein by reference.

If desired, the adhesive layer may contain components that modify the properties of the adhesive polymer, such as plasticizers, gumming agents, and the like.

The adhesive layer of the invention additionally comprises an adjuvant that improves the transdermal release of testosterone. Any adjuvant that enhances the transdermal release of testosterone can be used in the device of the invention without regard to the manner in which improvement is achieved. It has been found that terpenes are a particularly suitable class of enhancers, as an aid in solubilizing testosterone in the adhesive as well as improving the release of testosterone. Useful terpenes include pinene, d-limonene, carene, terpineol, terpin-4-ol, carveol, carvone, pulegone, piperitone, menthone, menthol, neomentol, thymol, camphor, borneol, citral, ionone, and cineole, either alone or in any combination. Of these, terpineol, particularly α-terpineol, is preferred.

The adhesive layer may contain adjuvants that improve the release in addition to the terpene. These release enhancing adjuvants include, but are not limited to, alcohols; C3-36 fatty acids, preferably Ce-20, esters, alcohols and amides; and alkyl pyrrolidone carboxylates having alkyl groups containing from 6 to 36 carbon atoms, preferably 8 to 20 carbon atoms.

Preferred enhancement adjuvants include lauryl alcohol, lauramide DEA, lauryl pyrrolidone-5-carboxylate (for example lauridone®); arcorbil palmitate; glycerol; tetraglycol (a- [(tetrahydro-2-furanyl) methyl] -? - hydroxy-poly (oxy-1, 2-ethanediyl), lauryl glycol (for example 1,2-dodecanediol) and mixtures thereof.

If the adjuvants of a device of the invention are dispersed, preferably substantially uniformly, and more preferably dissolved in the adhesive and present in an amount that improves the penetration of testosterone through the skin compared to a similar device that does not contain the adjuvants when this phenomenon is measured using the skin penetration model described below. The total amount of release enhancing adjuvant will generally be about 20 to about 40 weight percent based on the total weight of the adhesive layer.

The adhesive layer optionally further comprises an amount of skin penetration enhancer of lauramine oxide (N, N-dimethyl-dodecamine-N-oxide). When the adhesive layer contains lauramine oxide it will generally be present in an amount of about 1 to about 4 weight percent based on the total weight of the adhesive layer.

Additional conventional components, such as crystallization inhibitors (for example polyvinylpyrrolidone), can be incorporated in the adhesive layer if necessary or desirable.

In certain preferred embodiments of the invention, the amounts of excipients and testosterone are selected such that the testosterone is completely dissolved in the adhesive layer and the device provides a relatively high flow rate through the skin. In a preferred embodiment of the invention, the adjuvant comprises a mixture of terpineol, tetraglycol and lauryl glycollated one present in an amount of about 5 to about 15 percent, preferably about 7 to about 11 percent, by weight based on the total weight of the adhesive layer. Preferably the total amount by weight of adjuvant is about 25 to 35 percent based on the total weight of the adhesive layer, in this embodiment, testosterone is present in the adhesive layer in an amount of about 3 to 6 percent, preferably about 3.5 percent. one hundred to about 4.5 percent, by weight, based on the total weight of the adhesive layer.

In another preferred embodiment of the invention the adhesive layer comprises terpineol present in an amount of about 20 to 30 weight percent based on the total weight of the adhesive layer and laurylamine oxide present in an amount of about 1 to 4 percent by weight. weight based on the total weight of the adhesive layer, in this embodiment, testosterone is present in the adhesive layer in an amount of about 5 to 9 percent, preferably about 5.5 to about 6.5 percent, by weight based on the total weight of the adhesive layer.

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

The desirable properties in a transdermal device are well known to those skilled in the art. For example, it is desirable to have sufficiently little cold flow for a device of the invention to be stable to flow in storage. It is also preferred that it adhere well to the skin and release it cleanly on the skin. In order to achieve cold flow resistance, preferred skin adhesion and clean release nievels, the amount and structure of the comonomers in the copolymer, the inherent viscosity of the copolymer, and the amount and type of adjuvant are selected such that the adhesive layer preferably has an elasticity value of 2 X 10-? up to 4 X 10-5 cm2 / dyne. Elasticity values can be determined using the Slip Elasticity Procedure described in U.S.A. No. 4,737,559 (Kellen), the disclosure of which is incorporated herein by reference. Adhesive coatings that have elastic values outside this range are also appropriate. However, adhesive layers having substantially lower elastic values will generally be rigid and will have less than optimal adhesion to the skin. Those that have substantially higher elastic values will generally have less than the optimum cold flow and are likely to leave substantial residual adhesive when removed from the skin. A transdermal delivery device of the invention also comprises a reinforcement. The reinforcement is flexible in such a way that the device conforms to the skin. Suitable reinforcing materials include conventional flexible reinforcing materials used for pressure-sensitive patches, such as polyethylene, particularly low density polyethylene, linear low density polyethylene, metallocene polyethylenes, high density polyethylene, polypropylene, polyesters such as polyethylene terephthalate, nylon azaharosamente oriented fibers, polypropylene, ethylene vinyl acetate copolymer, polyurethane, natural fibers such as rayon and the like. Reinforcements that are weathered such as polyethylene-aluminum-polyethylene compounds are also appropriate. The reinforcement would be substantially inert to the components of the adhesive layer.

Transdermal devices of the invention are preferably prepared by combining the polymer, the adjuvant, the laurylamine oxide ((if any) and the testosterone with an organic solvent (for example ethyl acetate, methanol, acetone, 2-butanone, ethanol, isopropanol, toluene, alkanes, and mixtures thereof) to provide a coating formulation The components of the coating formulation are combined and stirred at high speed until a homogeneous formulation is obtained, then maintained at rest until the air bubbles dissipate The resulting coating formulation is finely weathered onto a release liner to provide a predetermined uniform thickness of coating formulation Suitable release liners include conventional release liners comprising a sheet of known material such as a polyester mesh, a mesh polyethylene, a mesh of polies tireno, or a paper, coated with a suitable coating such as fluoropolymer or other coating containing perfluorinated groups, silicone-based coatings or a hydrocarbon-based coating such as polyethylene. The coated release coating is then dried until the organic solvent is removed and then laminated in a reinforcement using conventional methods. Depending on the drying parameters (eg oven temperature, residence time in the oven, air flow through the oven) that are selected, some of the adjuvant can also be removed from the adhesive layer during drying. This loss can be compensated by the inclusion of additional adjuvant in the coating formulation. The amount of additional adjuvant required can be readily determined by one skilled in the art by using conventional drying experiments (eg coating a formulation containing a known amount of adjuvant on a release coating, drying the coated release coating under controlled, determine the amount of adjuvant in the resulting coating, and calculate the amount of adjuvant that was lost during drying).

The examples set forth below are an attempt to illustrate the invention.

In Vitro Skin Penetration Test Methods The skin penetration data given in the examples that follow were obtained using the following test method. A diffusion cell is used with either mouse scalp skin or human corpse skin.

When a transdermal delivery device is evaluated, 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 resulting laminated skin / patch is placed on the upper side of the patch through the hole in the lower portion of the diffusion cell. The diffusion cell is assembled and the lower portion is filled with 10 ml. of hot receiving fluid (32 ° C) so that the receiving fluid is in contact with the skin. The receiver fluid is agitated using a magnetic stirrer. The sampling port is covered except when in use.

The cell is then placed in a chamber at a constant temperature (32 ± 2 ° C) and humidity (50 ± 10% relative humidity). The receptor fluid is agitated by means of a magnetic stirrer throughout the experiment to ensure a uniform sample and a reduced diffusion barrier on the dermal side of the skin. The entire volume of the receiving fluid is discharged at specific time intervals and immediately replaced with fresh fluid. The discharged fluid is filtered through an o-filter. 5 μM, then analyzed for testosterone using high performance liquid chromatography (Column: Supelcosil LC-18, 150 X 4.6 mm ID; Mobile phase: 60% desareated water, 40% HPLC grade acetonitrile, flow rate: 2 ml. / min; Detector: UV, 241 nm to 0.2 AUFS; Run time: 5 minutes; Injection volume: 20 μL). The cumulative amount of testosterone that penetrates the skin and the flow rate are calculated. The solubility of testosterone in various adjuvants was determined by a sequence of quantitative additions of testosterone to the respective adjuvant. The results of this evaluation are shown below.

Adjuvant Solubility (mg./ml.) Terpineol 139.9 Tetraglycol 67.4 Lauryl glycol 40.0 The penetration of testosterone through the skin of the mouse scalp of a saturated solution of testosterone into various adjuvants was determined using the skin penetration test method described above with a 2 L portion of solution which is used in place of the transdermal delivery device. The results of this evaluation are shown in the table below Adjuvant Cumulative Quantity Penetrating (μg / mL) 24 Hours 48 Hours Terpineol 1255 2842 Tetraglycol 34 95 Lauryl glycol 752 1771 Elasticity Test Method The elasticity values given in the following examples were obtained using a modified version of the Slip Elasticity Procedure described in US Patent No. 4,737,559 (Relien). The release coating is removed from a sample of the material to be tested. The exposed surface is bent back on itself in the longitudinal direction to produce a "sandwich" configuration, for example, reinforcement / adhesive / reinforcement. The sample "ensadwichada" is passed through a laminator then two test samples of equal area are cut using a rectangular die. A test sample is centered on the stationary plate of a rheometer for sliding effort with the long axis of the test sample centered on the short axis of the plate. The small, non-stationary plate of the rheometer for sliding effort is centered on the first sample on the stationary plate as the hook is coated on the top and towards the front of the rheometer. The second test plate is centered on the upper surface of the small, non-stationary plate that matches the axial orientation of the first test sample. The large non-stationary plate is placed on the second test sample and the complete assembly is attached to the site. The end of the small, non-stationary plate which is opposite the end with the hook, is connected to the registration card. A rope is connected to the hook of the small plate, not stationary and extended on the front of the rheometer pulley. A weight (for example 500 g.) Is tied to the free end of the rope. The registration letter is initiated and at the same time the weight is quickly released so that the hook is released. The weight is removed after exactly 3 minutes. The displacement is read from the registration letter. The elasticity is then calculated using the equation: J = 2 (AX / hf) where A is the area of a face of the test sample, h, is the thickness of the adhesive mass (for example, twice the thickness of the adhesive layer on the sample examined), X is the displacement and f is the force due to the mass tied to the rope. Where A is expressed in cm2, h in cm, X in cm and f in dynes, the value of the elasticity is given in cm2 / dyne.

Preparation of Copolymer The copolymer used in the following examples was generally prepared according to the methods described below. The values of the inherent viscosity that are reported were measured by conventional means using a Canon-Fenske No. 50 viscometer in a water bath controlled at 27 ° C to measure the flow time of 10 milliliters of a polymer solution (0.15). g of polymer per deciller of ethyl acetate). The test procedure followed and the stop used are described in detail in "Textbook of Polymer Science," F. W. Billmeyer, Wiley-Interscience, Second Edition, 1971, pp. 84-85.

Preparation of Isooctyl Acrylate / Acrylamide / Vinyl Acetate Copolymer 73/7/20 A master bath is prepared by mixing isooctyl acrylate (1233.75 g.), Acrylamide (118.125 g.), Vinyl acetate (337,500 g.) And 2 , 2'-azobis (2- methylbutanonitrile) (1.688 g.). A portion (225,475 g.) Of the maetsro bath, ethyl acetate (257.7) and methanol (28.6 g.) Were placed in a one liter amber bottle. The mixture was deoxygenated by purging with nitrogen (1 L./min.) For two minutes. The bottle was sealed and placed in a rotating water bath at 57 ° C for 24 hours. The bottle was removed, opened, and then charged with ethyl acetate (214.8 g.) and methanol (23.8 g.). The content was mixed until uniform (usually all night). The percent solids of the resulting copolymer solution was 26.4. The inherent viscosity was 1.47 dl / g in ethyl acetate at 0.15 g / dl.

Preparation of "Dry" Copolymer Dry copolymer is prepared by thinning a solution of the copolymer to a thickness of about 9 mil (229 8M) on a release coating. The coated release coating is oven dried at approximately 275 ° F (135 ° C) to remove the solvent and reduce the level of residual monomers. The dried copolymer is peeled off from the release coating and stored until use.

Example 1 Terpineol (442.31 g.), Lauramine oxide (25.00 g), testosterone, USP (75.00 g.), Copolymer (862.50 g. Of copolymer isooctyl acrylate / acrylamide / vinyl acetate 73/7/20 dry, iv = 1.36 g. / g prior to drying), ethyl acetate (3202.00 g) and methanol (356.00 g.) were combined in a 2 gallon (7.57 L) jug. The container was hermetically covered then stirred for 14.5 hours on a shaking platform. The resulting formulation was kept at rest until all the air bubbles were dissipated then coated in a thin layer of 31 mil (787 μM) on a silicone release liner. The coated coating was baked in the oven for 4 minutes at 112 ° F (44 ° C), for 2 minutes at 185 ° F (85 ° C) and 2 minutes at 225 ° F (107 ° C). Assuming that 35% of the initial weight of evaporated terpineol was dried, the resulting adhesive coating contained 23.0 percent of terpineol, 2.0 percent of lauramine oxide, 6.0 percent of testosterone and 69 percent of isooctyl acrylate / acrylamide / acetate copolymer of vinyl 73/7/20. The coated coating was then laminated in a reinforcement (1109 Scotchpak ™ tan, laminated polyester film, available from 3M Company, St. Paul, MN, USA). The laminate was cut into cubes in the patches. The elasticity was measured using the test method described above and it was found to be 2,342 X 10-cm cm 2 / dynes. Penetration through a human corpse and mouse scalp was determined using the test method described above. The results are shown in Table 1 below, where each value is the average of six independent determinations.

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 isooctyl acetate / acrylamide / dry vinyl acetate / 73/7/20 copolymer, iv = 1.36 dl / g prior to drying) ethyl acetate (3202.00 g.) And methanol (356.00 g) were combined in a 2 gallon jug (7.57 L.). the container was hermetically covered then stirred for 14.5 hours on a shaking platform. The resulting formulation was kept at rest until all the air bubbles were then dissipated from the thinned coating of a thickness of 30 mil (762 μM) onto a silicone release liner. The coated coating was baked in the oven for 4 minutes at 111 ° F (44 ° C), for 2 minutes at 184 ° F (84 ° C) and 2 minutes at 225 ° F (107 ° C). Assuming that 30% of the initial weight of terpineol, 16 ¥ • of the initial weight of tetraglycol, and 14% of the initial weight of evaporated lauryl glycol were dried, the resulting adhesive coating contained 9.0% of terpineol, 9.0 percent of tetraglycol, 9.0 percent percent lauryl glycol, 3.9 percent testosterone, and 69.1 percent isooctyl acrylate / acrylamide / vinyl acetate copolymer 73/7/20. The coated reinforcement was then laminated to a liner (1109 Scotchpak ™ tan color, laminated polyester film, available from 3M Company, St. Paul, MN, USA). The laminate was cut into cubes in the patches. The elasticity was measured using the test method described above and found to be 2,477 X 10-5 cm2 / dynes. Penetration through human corpse and mouse scalp was determined using the test methods described above. The results are shown in Table 1 below, where each value is the average of six independent determinations.

Example 3 Tetraglycol (238.10 g.), Lauryl glycol (116.28 g.), Testosterone, USP (36.25 g.), Copolymer (913.75 g of isooctyl acrylate / acrylate ida / vinyl acetate 73/7/20 dry, iv = 1.36 dl / g before drying), ethyl acetate (3202.00 g.) and methanol (356.00 g.) were combined in a 2-gallon jug (7.57 L). The garrafon was hermetically covered then agitated for 14.5 hours on a platform agitator. The resulting formulation was kept at rest until the air bubbles had dissipated and was coated in a thin layer of 30 mil (762 μM) on a silicone release liner.

The coated coating was baked in the oven for 4 minutes at 111 ° F (44 ° C), for 2 minutes at 185 ° F (85 ° C) and 2 minutes at 226 ° F (108 ° C). Assuming that 16% of the initial weight of tetraglycol and 14% of the initial weight of evaporated lauryl glycol was dried, the resulting adhesive coating contained 16.0% tetraglycol, 8% lauryl glycol, 2.9% testosterone, and 73.1% iso-octyl acrylate copolymer / acrylamide / vinyl acetate 73/7/20. The coating was then laminated to a coating (1109 Scotchpak ™ tan color, a laminated polyester film, available from 3M Company, St. Paul, MN, USA). The laminate is cut into cubes in the patches. The elasticity was measured using the test method described above and found to be 3.795 X 10-s cm2 / dyne. Penetration through human cadaver skin and mouse scalp was determined using the test methods described above. The results are shown in Table 1 below, where each value is the average of six independent determinations.

Table 1 Example Cumulative quantity that penetrates in 24 hours (μg / cm-) Number Mouse scalp Human corpse skin 1 523 174 2 198 113 3 148 87 Example 4-17 Using the general method of Example 1, a series of transdermal delivery devices in which the amount of testosterone and the amount and selection of adjuvant were varied was prepared. In all examples the copolymer used was isooctyl acrylate / acrylamide / vinyl acetate 73/7/20. Weight percent of testosterone, percent by weight and identity of adjuvant, percent by weight of lauryl amide oxide (if used), and cumulative penetration into the skin through the mouse scalp are given in Table 2 below.

The balance of each formulation up to 100 weight percent was copolymer. The abbreviations T, TP, TG, LG and LAO are used for testosterone, terpineol, tetraglycol, lauryl glycol and laurylamine oxide respectively.

Table 2 Example% Adjuvant Cumulative amount that penetrates (μg / cm2) 24 hours 48 hours . 9 30% TP 286 473 6.3 35% TP, 3 LAO 575 686 6 3.6 30% TP, 3% LAO 484 Did not run 4. 3 10% TP, 10% TG, 10% LG 320 447 . 2 20% TP, 10% TG 320 501 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 30% LG 151 272 13 3.5 30% LG 185 293 14 3.4 30% LG, 3% LAO 362 did not run 3.9 30% TG, 3% LAO 285 did not run 16 4.4 10% TP, 10% TG, 10% LG, 3% LAO 420 did not run 17 3.7 15% TG, 15% LG 262 367 Examples 18-23 Using the general method of Example 1, a series of transdermal delivery devices in which the amount of testosterone and the amount and selection of adjuvant were varied and prepared. In each case the copolymer used was isooctyl acrylate / acrylamide / vinyl acetate 73/7/20. The weight percent of testosterone, percent by weight and identity of the adjuvant, and the accumulated penetration into the skin through the human cadaver skin are given in Table 3 below. The balance of each formulation up to 100% by weight was copolymer. The abbreviations T, TP, TG, and LG are used for testosterone, terpineol, tetraglycol and lauryl glycol respectively.

Table 3 Example% Adjuvant Quantity Cumulative Number that penetrates (μg / cm2) 24 hours 48 hours 18 6.1 30% TP 153 252 19 4.0 30% TG 255 336 3.4 30% LG 281 346 21 5.1 15% TP, 15% TG 243 347 22 4.8 15% TP, 15% LG 116 192 23 3.8 15% TG, 15% LG 223 284 Examples 24-28 Using the general method of Example 1, a series of transdermal delivery devices in which the amount of testosterone and the amount and selection of adjuvant were varied and prepared. In all examples the copolymer used was isooctyl acrylate / acrylamide / vinyl acetate 73/7/20. The weight percent of testosterone, weight percent and identity of adjuvant, and average flow through human cadaver skin are given in Table 4 below. The balance of each formulation at 100% was copolymer. The abbreviations T, TP, TG, and LG are used for testosterone, terpineol, tetraglycol and lauryl glycol respectively. Each flow rate is the average of 3 independent determinations.

Table 4 Example% Adjuvant Average Flow Number (μg / cm2 / hr) 24 8 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 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 isooctyl acrylate / acrylamide / vinyl acetate 73/7/20 copolymer dry, i «= 1.36 dl / g before drying), ethyl acetate (47,747 g.) And methanol (9,259 g.) Were combined in a 4 oz glass jar (118 ml.). The jar was hermetically covered then agitated on a roller mixer for 12 hours. The resulting formulation was sonicated until the bubbles were removed. The formulation was covered with a delayed 30 mils (762 μM) layer on a silicone coating. The coated coating was kept in dry air at room temperature for 1.5 minutes then oven baked at 110 ° F (43 ° C) for 10 minutes. assuming that 15% of the initial weight of evaporated terpineol was dried, the resulting adhesive coating contained 15.0% of terpineol, 15.0% of cocamide DEA, 4.9 percent of testosterone, and 65.1 percent of iso-octyl acrylate / acrylamide / vinyl acetate copolymer 73 / 7 / 20. The coated coating was laminated in a reinforcement (1014 Scotchpak ™). The laminate was cut into cubes in the patches. Penetration through the skin of human cadaver and mouse scalp was determined using the test method described above. The results are shown in Table 5 below, where each value is the average of four independent determinations.

Example 30-31 Using the general method of Example 29, a series of transdermal devices in which the amount of testosterone and the amount and selection of the adjuvant were varied and prepared. In all cases the copolymer used was isooctyl acrylate / acrylamide / vinyl acetate 73/7/20. the weight percent of testosterone, weight percent and identity of the adjuvant, and the accumulated skin penetration through the human cadaver and mouse scalp skin are given in Table 5 below, the balance of the formulation up to 100 weight percent was copolymer. The abbreviations T, TP, CDEA, GLY and LPCA are used for testosterone, terpineol, N, N-cocodiethanolamide, glycerol and lauryl pyrrolidone-5-carboxylate respectively Table 5 Example% Adjuvant Cumulative quantity that Number penetrates in 24 hours (μg / cm2) Human cadaver Leatherette of mouse 29 4.9 15% TP; 15% CDEA 346 463 3.0 10% TP; 10% GLY; 10% LPCA 120 156 ! 0% TP; 5% GLY 281 370 LPCA Example 32 Terpineol (1.9392 g.), Lauryl pyrrolidone-5-carboxylate (0.279 g.), Glycerol (0.270 g.), Testosterone (0.3001 g.), Copolymer (3.900 g., Dry isooctyl acrylate / acrylamide / vinyl acetate copolymer, iv = 1.47 of / g. before drying), ethyl acetate (23.0219 g.) and methanol (2,569 g.) Were combined in a glass jar of 11 drams (41 ml.). The bottle was hermetically covered then stirred, on a shaking platform for 12 hours. The formulation was thin-film coated to a thickness of 44 μls (1118 μM) on a silicone release coating. The coated reinforcement was kept in dry air at room temperature for 2 minutes then oven dried at 110 ° F (43 ° C) for 4 minutes, at 185 ° F (85 ° C) for 2 minutes, and at 225 ° F ( 107 ° C) for 2 minutes. Assuming that 35 percent of the initial weight of evaporated terpineol was dried, the resulting adhesive coating contained 21 percent terpineol, 4.5 percent lauryl pyrrolidone-5-carboxylate, 4.5% glycerol, 5.0% testosterone, and 65.0 percent of isooctyl acrylate / acrylamide / vinyl acetate copolymer 72/8/20. The coated coating was laminated in a reinforcement (1012 Scotchpak ™ transparent, heat-sealable, laminated polyester film). The laminate cut into cubes in patches. Penetration through the mouse scalp was determined using the test methods described above. The results are shown in Table 6 in which each value is the average of four independent determinations.

Examples 33-37 Using the general method of Example 32, a series of transdermal devices in which the amount of testosterone and the amount and selection of adjuvant were varied were prepared, in all cases the copolymer used was isooctyl acrylate / acrylamide / vinyl acetate 72 / 8/20. The weight percent of testosterone, weight percent and identity of adjuvant, and cumulative penetration through the skin of mouse scalp are given in Table 6 below. The balance of each formulation up to 100 weight percent was copolymer. The abbreviations T, TP, GLY and LPCA are used for testosterone, terpineol, glycerol and lauryl pyrrolidone-5-carboxylate respectively.

Table 6 Example% Adjuvant Cumulative quantity Number that penetrates in 24 hours (μg / cm2) . 0 21% TP, 4.5% GLY 332 4.5% LPCA 33 4.5 21% TP, 4.5% GLY 293 4.5% LPCA 34 4.0 21% TP, 4.5% GLY 230 4.5% LPCA 4.5 23.25% TP, 4.% GLY 231 2.25% LPCA 36 5.0 23.25% TP, 4.5% GLY 243 2.25% LPCA 37 5.5 23.25% TP, 4.5% GLY 315 2.25% LPCA Example 38 Terpineol (1.1071 g.), Lauryl alcohol (0.2020), lauryl pyrrolidone-5-carboxylate (0.120 g.), Glycerol (0.180 g.), Testosterone (0.1923 g.), Copolymer (2.800 g., Dry isooctyl acrylate copolymer / Acrylamide / ethyl acetate 73/7/20, iv = 1.36 g / g before drying), ethyl acetate (10.2461 g) and methanol (1.1447 g.) were combined in a glass jar of 6 drams 822 ml. ). The bottle was hermetically covered then agitated on a platform agitator for 12 hours. The formulation was thin-film coated to a thickness of 30 mils (762 μM) on a silicone release liner. The coated coating was kept in dry air at room temperature for a minimum of 3 to 4 minutes then baked in the oven at 110 ° F (43 ° C) for 4 minutes, at 118 ° F (85 TC) for 2 minutes, 225 ° F (107 ° C) for 2 minutes. Assuming that 35% of the initial weight of terpineol and 5% of initial weight of evaporated lauryl alcohol were removed from the drying, the resulting adhesive coating contained 17.% of terpineoi, 4.6% of iaurii alcohol, 2.8% of iaurii pyrroiidone- 5- carboxyiate, 4. 3% glyceroi, 4.6% testosterone and 65.6 percent isooctyl acrylate / acrylamide / vinyl acetate copolymer 73/7/20. The coated coating was laminated in a reinforcement (1012 Scotchpak ™ transparent, thermoset, laminated polyester film). The laminate was cut into cubes in two patches. Penetration through the mouse scalp was determined using the test method described above. The results are shown in Table 7 below, where each value is the average of four independent determinations.

Examples 39-40 Using the general method of Example 38, a series of transdermal devices in which the amount of testosterone and the amount and selection of adjuvant were varied were prepared. In all cases the copolymer used was isooctyl acrylate / acrylamide / vinyl acetate. The weight percent of testosterone, weight percent and identity of adjuvant, and cumulative penetration into the skin through the mouse scalp are given in Table 7 below. The balance of each formulation up to 100% by weight was copolymer. The abbreviations T, TP, GLY, LALC and LPCA are used for testosterone, terpineol, glycerol, lauryl alcohol and lauryl pyrrolidone-5-carboxylate respectively.

Table 7 Example% Adjuvant Cumulative quantity number that penetrates in 24 hours (μg / cm2) 38 4.6 17.1% TP, 4.3% GLY 341 4.6% LALC, 2.8% LPCA 39 4.3 15.8% TP, 4.5% GLY 306 8.6% LALC 40 5.2 18.8% TP, 9.4% LALC 320 Example 41 Using the general method of Example 38, transdermal delivery devices were prepared in which the adhesive coating contained 18.0 percent terpineol, 4.5 percent lauryl alcohol, 4.5 percent glycerol, 3.0 percent lauryl pyrrolidone-5-carboxylate , 4.8 percent testosterone and 65.2 percent isooctyl acrylate / acrylamide / vinyl acetate 73/7/20. Penetration through the mouse scalp and through three different batches of human cadaver skin was determined using the method test described above. The results are shown in Table 8 below, where each income is the average of four independent determinations.

Example 42 Using the method of Example 38, transdermal delivery devices in which the adhesive coating contained 19.8 percent of terpineol, 9.9 percent of lauryl alcohol, 5.5 percent of testosterone and 64.8 percent of isooctyl acrylate / acrylamide / vinyl acetate 73 / 7/20 were prepared. Penetration through the mouse scalp and through three different batches of human cadaver skin was determined using the method described above. The results are shown in Table 8 below, where each income is the average of four independent determinations.

Table 8 Cumulative amount that penetrates in 24 hours (μg. / Cm2) Skin type Example 41 Example 42 Human carcass (Lot 1) 280 256 Human carcass (Lot 2) 330 270 Human carcass (Lot 3) 136 116 Mouse scalps 411 337 The present invention has now been described with reference to various embodiments thereof. The above detailed description and examples have been given for clarity of understanding only. Unnecessary limitations have not been understood from this. It will be obvious to those skilled in the art that many changes can be made in the described embodiments without departing from the scope of the invention. Thus, the scope of the present invention would not be limited in the exact details of the composition and structures described herein, but preferably by the structures and compositions described by the language of the claims and their equivalents.

It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as above, it is claimed as property in the following,

Claims (20)

1. A device for the transdermal release of testosterone comprising a reinforcement having an adhesive layer adhered to a surface of the reinforcement, said adhesive layer being characterized in that it comprises: (a) an adhesive to the skin sensitive to pressure; (b) a therapeutically effective amount of testosterone; Y (c) a release enhancing adjuvant comprising a terpene.

2. The device of claim 1 which is characterized in that the release enhancing adjuvant comprises a terpene and a fatty acid derivative.

3. The device of claim 1 which is characterized in that the terpene comprises pinene, d-limonene, carene, terpineol, terpinen-4-ol, carveol, carvone, pulegone, piperitone, menthone, menthol, neomentol, thymol, camphor, borneol, citral , ionone, and cineola, or a combination of these.

4. The device of claim 1 which is characterized in that the terpene comprises α-terpineol.

5. The device of claim 2 which is characterized in that the fatty acid derivative comprises a derivative of a C0-20 fatty acid.

6. The device of claim 2 which is characterized in that the fatty acid derivative is a lauric acid derivative.

7. The device of claim 2 which is characterized in that the fatty acid derivative comprises lauroglycol, lauramide DEA, lauryl alcohol, lauryl pyrrolidone-5-carboxylate, lauramine oxide, or a combination thereof.

8. The device of claim 1 which is characterized in that the release enhancing adjuvant additionally comprises glycerol.

9. The device of claim 1 which is characterized in that the release enhancing aid comprises a terpene, a fatty acid derivative and glycerol.

10. The device of claim 1 which is characterized in that the release enhancing adjuvant comprises terpineol and lauryl alcohol.

11. The device of claim 10 which is characterized in that the release enhancing adjuvant additionally comprises lauryl pyrrolidone-5-carboxylate and glycerol.

12. The device of claim 1 which is characterized in that the testosterone is dissolved in the adhesive layer.

13. A device for the transdermal release of testersterone which is characterized in that it comprises a reinforcement having an adhesive layer adhered to a surface of the reinforcement, said adhesive layer, is characterized in that it comprises; (a) a pressure sensitive skin adhesive comprising a copolymer of (i) one or more monomers A selected from the group consisting of alkyl (meth) acrylates containing 4 to 10 carbons in the alkyl group and (ii) one or more ethylenically unsaturated B monomers containing a functional group selected from the group consisting of carboxylic acid, sulfonamide, urea, carbamate, carboxamide, hydroxy, amino, oxy, oxo and cyano; (b) a therapeutically effective amount of testosterone; Y (c) a release enhancing adjuvant comprising a terpene.

14. The device of claim 13 which is characterized in that the one or more monomers A are selected from the group consisting of isooctyl acrylate, 2-ethylexyl acrylate, butyl acrylate, and cyclohexyl acrylate.

15. The device of claim 13 which is characterized in that monomer A is isooctyl acrylate.

16. The device of claim 13 which is characterized in that the one or more monomers B are selected from the group consisting of acrylic acid, methacrylic acid, acrylamide, vinyl acetate and methacrylamide.

17. The device of claim 13 which is characterized in that the copolymer further comprises one or more substantially linear macromonomers copolymerizable with monomers A and B.

18. The device of claim 13 which is characterized in that the copolymer is a copolymer of isooctyl acrylate, acrylamide, and vinyl acetate.

19. A device for the transdermal release of testosterone comprising a reinforcement having an adhesive layer adhered to a surface of the reinforcement, said adhesive layer being characterized in that it comprises; (a) a pressure sensitive skin adhesive comprising a copolymer of isooctyl acrylate, acrylamide, and vinyl acetate; (b) a therapeutically effective amount of testosterone; (c) α-terpineol; (d) lauryl alcohol; (e) lauryl pyrrolidone-5-carboxylate; Y (f) glycerol.

20. A method of treatment for a condition associated with testosterone deficiency in a mammal that is characterized in that it comprises the steps of (a) providing a device according to claim 1; (b) applying the device to the skin of a mammal; Y (c) allowing the device to remain on the skin for a sufficient time to establish or maintain a therapeutically effective blood level of testosterone in the mammal.