HK1096014B - Transdermal hormone delivery system: compositions and methods - Google Patents

Description

Transdermal hormone delivery systems, compositions and methods

This application claims priority to U.S. patent application 10/621,711 filed on 17/7/2003, a continuation-in-part of U.S. patent application 10/130,913 filed on 23/5/2002, a U.S. national phase application of international application PCT/USOO/32043 filed on 22/11/2000, which claims priority to U.S. provisional application 60/167,535 filed on 24/11/1999, the contents of each of which are hereby incorporated by reference.

Technical Field

The present invention relates to hormonal therapy for fertility control and treatment for a variety of diseases and disorders. In particular, the present invention provides formulations and methods of use related to transdermal hormone delivery systems for enhanced delivery of steroid hormones.

Background

Various scientific articles and patent publications are cited herein to describe the state of the art to which this invention pertains. Each of these publications is incorporated by reference in its entirety.

Hormonal treatment with synthetic estrogens and/or progestogens is currently used for controlling fertility and for treating or preventing a variety of hormone-related complaints or deficiencies, including controlling acne, treating endometriosis, inducing or preventing amenorrhea, assisting pregnancy and treating galactorrhea, among others. Traditionally, the combination of synthetic estrogen and synthetic progestin has been administered in the past in oral dosage forms. Although the combination of synthetic progestagens and estrogens is effective in inhibiting ovulation, there are some unwanted side effects associated with such oral contraceptives. For example, in women using oral contraceptives, the incidence of thrombosis and related vascular disorders including stroke and myocardial infarction is high; the relative risk of the user may be 11 times higher than that of the control population. Furthermore, the risk increases dramatically in women over the age of 35 years. Contraceptive use is also associated with an increased incidence of benign liver tumors and with an increased risk of gallbladder disease. In addition, fetal abnormalities may also result if the woman continues to take pills after pregnancy.

Transdermal delivery of hormones offers many advantages and avoids some of the disadvantages associated with oral contraceptives and hormone therapy. Specifically, transdermal rate-controlled administration avoids the variability of absorption and metabolism associated with oral therapy. It also provides for sustained administration, allowing the use of pharmaceutically active factors with short biological half-lives. In addition, there is less likelihood of overdosing or underdosing in a transdermal regimen, and patient acceptance of a multi-day easy to use transdermal regimen exceeds daily oral dosing.

It would therefore be highly desirable to provide formulations and transdermal systems that allow 1) the use of high levels of progestagens, 2) the use of synthetic or natural estrogens, 3) the use of a minimum number of dosage units per menstrual cycle, and the provision of appropriate levels of progestagens and estrogens to fully ensure fertility control or other therapeutic goals with minimal or no production of undesirable metabolic or chemical degradation products.

Various transdermal contraceptive delivery systems for female fertility control have been developed in recent years. U.S. patent 5,296,230 describes a transdermal fertility control polymer matrix dosage unit comprising a backing layer, a polymer layer containing microdispersed doses of estrogen and progestin adhered to the backing layer, and an adhesive layer. Us patent 5,560,922 discloses the delivery of natural estrogen, 17 β -estradiol, or ethinyl estradiol or combinations thereof in the amount of natural progesterone or progestin in a dosage unit comprising a backing layer and an associated polyacrylate adhesive polymer layer containing microreservoirs for release of hormone.

Us patent 5,788,983 discloses transdermal polymer dosage units, a backing layer and a reservoir layer having a plurality of areas which in use contact the skin and optionally containing different drug therapeutic agents providing different rates of absorption. U.S. patent 5,762,956 describes a transdermal contraceptive delivery device and a method of fertility control using the device. The system comprises a backing layer and an adhesive polymer matrix having dispersed therein a hormone effective to control fertility and a combination of three skin permeation enhancers in a specific relative weight ratio.

A drawback of the transdermal delivery systems described above is their insufficient ability to deliver a sufficient amount of a progestin, particularly levonorgestrel, alone or in combination with a selected estrogen, with a suitable balance for one or more purposes. For example, U.S. Pat. Nos. 5,296,230, 5,560,922 and 5,788,983 describe systems comprising dosage units of enormous size, i.e. having a surface area of up to 100cm². U.S.5,762,956 describes dosage units which are said to be smaller, but the delivered progestogen is not sufficiently enhanced.

Accordingly, there is a need for transdermal hormone delivery systems and drug delivery formulations therefor that can readily achieve high serum levels of difficult to deliver progestins, such as levonorgestrel, as well as the profile of progestin required and estrogen selected for contraceptive and other purposes with minimal side effects. It is also desirable that the dosage unit be of a comfortable size, unobtrusive in appearance and adhere firmly.

Brief description of the invention

The present invention relates to skin permeation enhancer compositions for enhancing transdermal absorption of steroid hormones, to hormone delivery formulations, to Transdermal Hormone Delivery Systems (THDS) comprising a backing layer and at least one adhesive polymer matrix dispersed therein effective for fertility control or for other hormone treatments, and to related compositions and methods. A hormone delivery formulation, which may be utilized in a viscous polymer matrix of THDS, comprises one or more skin permeation enhancers, humectants/plasticizers and polymers as detailed herein. The relative and absolute amounts of each skin permeation enhancer in THDS are adjusted to optimize hormone delivery by employing specific starting material amounts and controlling processing parameters such as drying time and temperature to produce THDS.

In accordance with one aspect of the present invention, a skin permeation enhancer composition is provided for use in constructing transdermal hormone deliveryThe system is configured to deliver one or more of a progestin, estrogen or testosterone hormone. The composition comprises a pharmaceutically acceptable organic solvent (such as dimethyl sulfoxide), a fat (C) of a hydroxy acid (such as lactic acid)₈-C₂₀) Alcohol esters, lower (C) of hydroxy acids, e.g. lactic acid₁-C₄) Alkyl esters and C₆-C₁₈Combinations of saturated or unsaturated fatty acids, such as capric acid. In a preferred embodiment using DMSO, the fatty alcohol ester of lactic acid, the lower alkyl ester of lactic acid and the capric acid and the four excipients are combined in a weight ratio of 2: 1: 0.8 to 6: 1: 0.8, respectively, and more specifically 3: 1: 0.8 to 4: 1: 0.8, respectively. In a particular embodiment, the fatty alcohol ester of lactic acid is lauryl lactate and the lower alkyl lactate is ethyl lactate.

Another aspect of the invention features a polymer formulation for use in constructing a transdermal hormone delivery system comprising a backing layer and a polymer matrix, preferably an adhesive polymer matrix, in which is distributed one or more of a progestogen, estrogen or testosterone to be delivered transdermally. The formulation comprises a polymer and from about 0% to about 5% by weight of a humectant/plasticizer and from about 10% to about 30% by weight of a skin permeation enhancer composition comprising a pharmaceutically acceptable organic solvent (e.g., dimethyl sulfoxide), a fat (C) of a hydroxy acid (e.g., lactic acid)₈-C₂₀) Alcohol esters, lower (C) of hydroxy acids, e.g. lactic acid₁-C₄) Alkyl esters and C₆-C₁₈Saturated or unsaturated fatty acids, such as capric acid. In a preferred embodiment using DMSO, the fatty alcohol ester of lactic acid, the lower alkyl ester of lactic acid and the capric acid and the four excipients are combined in a weight ratio of 2: 1: 0.8 to 6: 1: 0.8, respectively, and more specifically 3: 1: 0.8 to 4: 1: 0.8, respectively. Preferably the polymer is an adhesive polymer, and in certain embodiments the adhesive polymer is a polyacrylate adhesive copolymer. More specifically, the polyacrylate adhesive copolymer comprises 2-ethylhexyl acrylate monomer and further comprises from about 3% to about 60% w/w vinyl acetate. In certain embodiments, the humectant/plasticizer is polyvinylpyrrolidone/vinyl acetate. In some implementationsIn the scheme, the fatty alcohol ester of lactic acid is lauryl lactate and the lower alkyl ester of lactic acid is ethyl lactate.

In certain embodiments of the invention, the polymeric formulation comprises a progestin, which in a preferred embodiment is levonorgestrel. The polymer formulation may also include a progestin and an estrogen, in particular levonorgestrel and ethinyl estradiol or 17 β -estradiol. An exemplary embodiment of this type of formulation includes, on a weight percent basis, about 79.65% polyacrylate adhesive copolymer, about 1.25% polyvinylpyrrolidone/vinyl acetate, about 9.51% dimethyl sulfoxide, about 3.10% lauryl lactate, about 3.10% ethyl lactate, about 2.39% capric acid, about 0.58% levonorgestrel, and about 0.28% ethinyl estradiol. In additional embodiments, the polymeric formulation includes a progestin and an estrogen and a testosterone. In another embodiment, the formulation includes only testosterone.

Another aspect of the invention features THDS comprising a backing layer that is substantially impermeable to skin permeation enhancers and progestins and estrogens to be delivered transdermally. The hormone is dispersed in an adhesive polymer matrix that is affixed to the backing layer. The adhesive polymer matrix is made from the adhesive polymer formulation described above. Upon completion of the construction of the THDS, the adhesive polymer matrix comprises the final weight percentages based on the adhesive polymer matrix of: from about 0% to about 5% of a humectant/plasticizer; from about 12% to about 36% of a skin permeation enhancer, the combination being a mixture comprising from about 4% to about 12% of a pharmaceutically acceptable organic solvent, such as dimethyl sulfoxide, from about 4.2% to about 12.6% of a fat (C) of a hydroxy acid, such as lactic acid₈-C₂₀) Alcohol ester, from about 0.7% to about 2.3% of a lower (C) hydroxy acid such as lactic acid₁-C₄) Alkyl ester and from about 3% to about 9% of C₆-C₁₈Fatty acids, such as capric acid; and one or more hormones effective to provide a predetermined daily dosage of each hormone for about one to about nine days. In certain embodiments, the progestin is levonorgestrel and the estrogen isThe hormone is ethinyl estradiol or 17 β -estradiol. Alternative embodiments include THDS modulation for delivery of (1) progestin alone, (2) testosterone with progestin and estrogen, or (3) testosterone alone.

In a particular embodiment of the invention, the humectant/plasticizer is polyvinylpyrrolidone/vinyl acetate. The adhesive copolymer comprises a polyacrylate copolymer, preferably a copolymer comprising 2-ethylhexyl acrylate monomers further comprising about 3 to 60% w/w vinyl acetate.

In addition to the foregoing specific amounts of skin permeation enhancers placed on the constructed THDS, certain embodiments require the presence of about 4-8 parts DMSO, about 4-8 parts fatty alcohol lactate, about 1 part lower alkyl ester of lactic acid and about 3-6 parts capric acid in the enhancer in weight ratios. Preferably, DMSO and the fatty alcohol lactate are present in a weight ratio of about 1.5: 1 to about 1: 1.5.

In a specific embodiment, the THDS is formulated for delivery of ethinyl estradiol and levonorgestrel, wherein ethinyl estradiol is delivered transdermally at a rate of about 10 μ g and 50 μ g per day for a period of about one day to about nine days, and levonorgestrel is delivered transdermally at a rate of at least 20 μ g per day, more particularly at least 30 μ g per day, for about one day to about nine days. In use, THDS delivers sufficient levonorgestrel transdermally to produce a steady state serum concentration of at least 1,000 pg/ml.

The THDS of the present invention enables enhanced delivery of progestin, estrogen and testosterone, even from a relatively small surface area. Accordingly, another aspect of the invention features a THDS comprising a backing layer and an adhesive polymer matrix, wherein the adhesive polymer matrix has a maximum surface dimension of about 20cm²And has a maximum cross-sectional dimension of about 300 μm and which is capable of delivering levonorgestrel at least 20 μ g/day, more preferably at least 30 μ g/day, for about one to about nine days. In a preferred embodiment, the adhesive polymer matrix has a maximum surface dimension of 17.5cm²Or 15cm². In particular embodiments, the THDS is formulated for delivery of levonorgestrelAnd delivering an amount of levonorgestrel sufficient to produce a serum concentration of levonorgestrel of at least 1,000 pg/ml.

In further embodiments, the THDS is formulated for delivery of levonorgestrel and an estrogen, such as ethinyl estradiol or 17 β -estradiol. More specifically, the estrogen is ethinyl estradiol and is delivered at 10 μ g to 50 μ g per day for about 1 to about 9 days.

The THDS of the present invention is made by combining suitable amounts of adhesive polymer, humectant/plasticizer, skin penetration enhancer and hormone, then applying the mixture to the backing layer and drying the mixture at a predetermined temperature for a predetermined period of time. In another embodiment, the adhesive polymer formulation is coated onto a strip of releasable liner. The initial amounts of ingredients and processing parameters (e.g., coating thickness and drying time and temperature) are adjusted to achieve the final weight ratio and weight percentage of each skin permeation enhancer. Specifically, the method comprises the following steps: (1) a viscous polymer formulation was prepared by combining a viscous copolymer solution based on weight percent of the viscous polymer formulation with: from about 0% to about 5% of a humectant/plasticizer; from about 10% to about 30% of a skin permeation enhancer combination that is a mixture comprising a pharmaceutically acceptable organic solvent, such as DMSO, a fat (C) of a hydroxy acid, such as lactic acid₈-C₂₀) Alcohol esters, lower (C) of hydroxy acids, e.g. lactic acid₁-C₄) Alkyl esters and C₆-C₁₈Fatty acids, such as capric acid; and an amount of one or more selected hormones effective to provide a predetermined daily dosage of each hormone for about one day to greater than nine days, thereby forming a viscous polymer matrix starting solution; (2) applying an adhesive polymer starting solution to the cushion layer; and (3) drying the coated backing layer for a time and at a temperature sufficient to produce the transdermal hormone delivery system described above. In a specific embodiment, the adhesive polymer starting formulation is coated onto the cushion layer at a thickness of about 300 μm to about 800 μm, and the coated material is dried at a temperature of about 40 ℃ to about 80 ℃ for about 5 minutes to about 25 minutes.

In certain embodiments, the THDS dosage unit is provided with a cover layer. The cover layer may be secured to the backing layer or it may be provided separately, applied at the discretion of the user. The cover layer is coated with an adhesive and extends beyond some or all of the gasket layer and the edge of the adhesive polymer matrix. In further embodiments, a non-tacky polymer replaces the tacky polymer, and skin adhesion is performed by an adhesive on the cover layer.

According to another aspect of the invention there is provided a method of controlling fertility comprising applying THDS as described above to the skin of a subject in need of such treatment. THDS is changed once a week for three to four weeks of a menstrual cycle, and is desirable as fertility control for longer than continuous menstrual cycles. In a particular embodiment, the THDS delivers levonorgestrel and an estrogen, preferably ethinyl estradiol or 17 β -estradiol. In further embodiments, the THDS is suitable for the delivery of a progestin alone, preferably levonorgestrel.

In a preferred embodiment, the method comprises transdermal delivery of ethinyl estradiol and levonorgestrel, wherein ethinyl estradiol is delivered at a rate of about 10 μ g to 50 μ g per day for about one day to about nine days, and levonorgestrel is delivered at a rate of at least 20 μ g per day, preferably at least 30 μ g per day for about one day to about nine days. In these embodiments of the method, levonorgestrel is delivered at a serum concentration sufficient to produce at least 1,000pg/ml, which exceeds the serum levels required for fertility control.

The above method is suitable for subjects who wish to eliminate menses completely. In this case, as birth control, THDS is changed once a week for continuous number of weeks, and elimination of menstruation is achieved.

In a further modification, the THDS of the invention is formulated to deliver testosterone alone. THDS is used to treat circulating testosterone levels deficient in libido decline (both in men and women), and the treatment involves administering THDS once a week for the number of consecutive weeks required for the treatment.

Further features and advantages of the invention will be understood from the following detailed description and examples.

Detailed description of illustrative embodiments

Described below are various embodiments of the invention, including formulations for preparing the viscous polymer matrices of THDS described herein, and processing parameters for constructing THDS such that it can reliably achieve high serum levels of difficult-to-deliver progestins, such as levonorgestrel, as well as a desired profile of progestins and selected estrogens and/or other hormones for contraceptive and other purposes. These formulations and the THDS produced using these formulations differ from currently disclosed or available formulations and constitute a significant advance in the field of transdermal hormone delivery. In one aspect, the THDS of the invention comprises a progestogen, most suitably levonorgestrel, and an estrogen, most suitably ethinyl estradiol or 17- β estradiol, dispersed in an adhesive polymer matrix that is fixed to a backing layer. In another aspect, THDS comprises a progestin only. In another aspect, THDS comprises a progestin, an estrogen and a testosterone, or testosterone alone.

Dosage units of THDS of the invention, sometimes referred to as "patches", comprise in their simplest form a backing layer having immobilised thereon an adhesive polymer matrix containing the hormones to be delivered and other excipients which facilitate transdermal delivery of these hormones at a suitable rate. Briefly, the dosage unit is prepared by combining an adhesive polymer, hormone and excipient into a starting formulation, coating the formulation onto a backing layer (or in another embodiment onto a release liner), and drying the coated backing layer for a period of time and at a temperature designed to produce a dosage unit in which the hormone and excipient are present in specific amounts that are optimized for delivery of the hormone. For the reasons detailed herein, the amounts of each component in the starting formulation are different from the amounts of each component present in the final THDS after completion of the build process. For purposes of differentiation, the terms "adhesive polymer formulation," "adhesive polymer solution," or "starting solution" as used herein refer to the starting formulation prior to being applied to a backing layer and dried. The term "adhesive polymer matrix" as used herein refers to an adhesive polymer solution after it has been coated onto a backing layer and dried (i.e., "post-construction").

Components of the adhesive polymer formulation:

skin permeation enhancer: drug molecules released from transdermal delivery systems must be able to penetrate the layers of skin. To increase the permeability of the drug molecules, the transdermal drug delivery system must be capable of specifically increasing the permeability of the outermost skin, the stratum corneum, which provides the greatest barrier to molecular permeation. In this regard, the present invention provides a transdermal hormone delivery system utilizing an amount of one or more skin permeation enhancers. It is the control of the absolute and relative amounts of the skin permeation enhancer that provides sufficient flux of the permeating hormone. Skin penetration enhancers also provide the desired permeation rate of these hormones to achieve the desired amount of release from the transdermal contraceptive delivery system and delivery into the body to produce the desired effect.

Combinations of skin permeation enhancers are preferred for use in the practice of the present invention. The combination comprises a mixture of: (1) pharmaceutically acceptable organic solvents, e.g. dimethyl sulfoxide (DMSO), fats (C) of (2) hydroxy acids₈-C₂₀) Alcohol esters, e.g. lauryl lactate, (3) lower (C) hydroxy acids₁-C₄) Alkyl esters, e.g. ethyl lactate and (4) C₆-C₁₈Fatty acids, such as capric acid. These skin penetration enhancers are present in the adhesive polymer matrix described in detail above in an amount to optimize hormone delivery. In certain embodiments, one or more skin permeation enhancers may be removed from the polymer matrix. However, the specific amounts of the remaining enhancers and their relative ratios in weight percent (in the starting solution as well as in the final dosage unit) should be kept within the ranges described herein.

In a preferred embodiment, the pharmaceutically acceptable organic solvent is DMSO. It is composed ofOrganic solvents suitable for use in the present invention include, but are not limited to, C₁-C₈Branched or unbranched alcohols such as ethanol, propanol, isopropanol, butanol, isobutanol and the like, and azone (laurocapram: 1-dodecylhexahydro-2H-azepin-2-one) and methylsulfonylmethane and the like.

The fatty alcohol ester of a hydroxy acid is preferably a fatty alcohol ester of lactic acid, such as lauryl lactate. However, other hydroxy acids and fatty alcohols may also be used. Additional hydroxy acids include, but are not limited to, alpha-hydroxy acids such as glycolic acid, tartaric acid, citric acid, malic acid and mandelic acid and beta-hydroxy acids, sialic acid. Additional fatty alcohols include any C₈-C₂₀Saturated or unsaturated fatty alcohols such as myristyl alcohol, palmityl alcohol and oleyl alcohol, etc.

The hydroxy acid lower alkyl ester is also preferably lactic acid, most preferably ethyl lactate. However, other hydroxy acids, such as glycolic acid, tartaric acid, citric acid, malic acid, mandelic acid and sialic acid may also be used. Additionally isopropyl myristate (IPM) can be used as an alternative to lower alkyl esters of hydroxy acids.

The inventors have found that the inclusion of medium to long chain fatty acids in skin permeation enhancer formulations improves the transdermal delivery profile of the hormones employed in the present invention. Capric acid is preferably used. However, other C's may be used₆-C₁₈Saturated or unsaturated fatty acids, including but not limited to caproic acid, caprylic acid (caprytic acid), lauric acid, myristic acid, and the like.

Combinations of the above skin permeation enhancers may be used to enhance transdermal delivery of steroid hormones from any type of transdermal delivery device. Preferably, the adhesive polymer matrix-type systems described in detail herein are used; however, the enhancer combination may also be used in non-adhesive polymers, as well as in multi-layer or depot transdermal delivery systems and the like.

Hormones: THDS utilizing the skin permeation enhancers described above can be used to deliver any type of hormone that can be delivered transdermally. More particularly, the THDS of the present invention is formulated to deliver animal steroid hormones. In one embodiment, a combination of a progestin and an estrogen is used for one or more of the following purposes: (1) controlling the breeding; (2) acne control, (3) treatment of endometriosis and (4) induction of amenorrhea. In further embodiments, only the progestogen is used for one or more of the following purposes: (1) fertility control, (2) assisted pregnancy, (3) hormone therapy as a replacement for subjects contraindicated to the use of estrogens (e.g., females in lactation); and (4) prevention of galactorrhea. In another embodiment, a combination of a progestin, an estrogen and a testosterone is used as a hormone replacement therapy for the treatment of females lacking these hormones. Another embodiment relates to THDS formulated for delivery of testosterone alone, testosterone being preferably used to treat decreased libido due to male and female testosterone deficiency.

The THDS containing levonorgestrel in the present invention is preferably used for delivery of a combination of hormones as well as for delivery of a progestin only. Levonorgestrel is known to be difficult to deliver transdermally; however, the hormone can be effectively delivered by the THDS of the present invention. With the controlled release of the hormone at a relatively steady rate over an extended period of time, typically several days, and preferably one week to nine days, the subject is provided the advantage of stabilizing the hormone, for example, over a prolonged period of time.

Levonorgestrel is a potential progestin on a weight-dose basis, which is an important factor because progestins often exhibit a lower degree of transdermal absorption than estrogens. Other progestogens that can be used partially or completely are norgestrel, norgestimate, desogestrel, gestodene, norethindrone, hydrogenated progesterone, norethindrone diacetate, hydroxyprogesterone caproate, medroxy progesterone acetate, norethindrone acetate, progesterone, megestrol acetate, gestagen and certain other biocompatible and percutaneously absorbable progestogens. These include biocompatible progestagen derivatives, which may be transdermally absorbed, and some of which may advantageously be biologically converted to the original progestagen after transdermal absorption. The progestogen and the selected other hormone should have a high compatibility with each other.

For the progestogen and estrogen groupIn particular, the synthetic hormone ethinyl estradiol is suitable. The hormone may be delivered transdermally with a particularly suitable progestogen, levonorgestrel, at the desired daily rate of both hormones by the TDHS of the present invention. Ethinyl estradiol and levonorgestrel are compatible and may be dispersed in viscous polymer formulations. Generally, a transdermal dosage unit designed for one-week treatment should deliver at least about 20 μ g/day of levonorgestrel (or an equivalent amount of another progestin) and 10-50 μ g/day of ethinyl estradiol (or an equivalent amount of another estrogen). These respective amounts of progestin and estrogen are believed to be necessary to inhibit ovulation and to maintain normal female physiological function and characteristics. In the present invention, the amount of levonorgestrel delivered transdermally is preferably 30 μ g per day at 15cm²The transdermal delivery device delivers for more than one day to about one week.

Derivatives of 17 β -estradiol that are biocompatible and can be absorbed transdermally and preferably be bioconverted to 17 β -estradiol may also be used if the absorbed amount meets the requirements of the daily dosage of the estrogenic component and if the hormonal component is compatible. Such estradiol derivatives include esters, mono-esters or diesters. The monoester may be a 3-or 17-ester. The estradiol esters may be, for example, estradiol-3, 17-diacetate; estradiol-3-acetate; estradiol 17-acetate; estradiol-3, 17-dipentanoate; estradiol-3-valerate; estradiol-17-valerate; 3-mono-, 17-mono-and 3, 17-dipivilateters; 3-mono-, 17-mono-and 3, 17-dipropionate; 3-mono-, 17-mono-and 3, 17-dicyclopentyl-propionate; the corresponding cypionate, heptanoate, benzoate and similar esters; thinyl estradiol; estrone; and other transdermally absorbed estrogenic steroids and derivatives thereof.

Combinations of the above with estradiol itself (e.g., a combination of estradiol and estradiol-17-valerate or additionally a combination of estradiol-17-valerate and estradiol-3, 17-dipentanate) may be used to obtain advantageous results. For example, 15-80% of each component based on the total weight of the estrogenic component can be used to achieve the desired result. Other combinations may also be used to achieve the desired absorption and to treat the level of 17 β -estradiol in the subject.

Formulations containing testosterone may utilize natural testosterone or synthetic testosterone that can be transdermally absorbed. For example, methyltestosterone is suitable for use in the present invention. In premenopausal women, the testosterone yield is about 300 μ g/day. Thus, THDS for testosterone delivery should be formulated to deliver a partial or complete lack of supplemental testosterone, i.e. an amount of up to about 300 μ g per day. Similarly, to treat testosterone deficiency in men, THDS should be formulated to deliver up to about 3-6mg per day.

It will be appreciated that the hormones may be used not only in the form of pure chemical compounds but also in admixture with other transdermally applicable drugs or other components compatible with the substances mentioned above. Thus, simple pharmaceutically acceptable derivatives of the hormone, such as ethers, esters, amides, acetals, salts and the like, may be used if appropriate. In some cases, such derivatives may be preferred. The progestogenic compound and estrogenic steroid are typically dispersed or dissolved simultaneously to create a viscous polymer matrix containing the hormone or they may be dispersed or dissolved separately.

Adhesive polymer: in general, the polymers used to form the biocompatible adhesive polymer matrix are those capable of forming a film or coating through which the hormone can pass at a controlled rate. Suitable polymers are biologically and pharmaceutically compatible, non-allergenic, insoluble in and compatible with body fluids, compatible with the tissue with which the device is in contact. Soluble polymers are avoided because decomposition or erosion of the matrix can affect the release rate of the hormone and the ability of the dosage unit to remain in place for removal.

Suitable materials for use as the adhesive polymer formulation include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone elastomers, especially medical grade polydimethylsiloxane, neoprene, polyisobutylene, polyacrylates, chlorinated polyethylene, polyvinyl chloride, vinyl chloride-vinyl acetate copolymers, crosslinked polymethacrylate polymers (hydrogels), polyvinylidene chloride, poly (ethylene terephthalate), butyl rubber, epichlorohydrin, ethylene vinyl alcohol copolymers, ethylene ethyleneoxyethanol copolymers; silicone copolymers, for example, polysiloxane polycarbonate copolymers, polysiloxane polyethyleneoxide copolymers, polysiloxane-polymethacrylate copolymers, polysiloxane-alkylene copolymers (e.g., polysiloxane-vinylsilane copolymers), and the like; cellulose polymers such as methyl or ethyl cellulose, hydroxypropylmethyl cellulose and cellulose esters; a polycarbonate; polytetrafluoroethylene; and so on.

Preferably, the adhesive polymer should be selected from polymers having a glass transition temperature below room temperature. These polymers may, but need not, have some degree of crystallinity at room temperature. Cross-linked monomer units or sites may be incorporated into such polymers. For example, crosslinking monomers that can be incorporated into polyacrylate polymers include polymethacrylates of polyols, such as butenyl diacrylate and dimethacrylate, trimethylolpropane trimethacrylate, and the like. Other monomers providing such sites include allyl acrylate, allyl methacrylate, diallyl maleate, and the like.

Preferably, the adhesive polymer formulation comprises a polyacrylate adhesive polymer of formula (I):

wherein x represents a number of repeating units sufficient to provide the desired properties in the adhesive polymer, and R is H or lower (C)₁-C₁₀) Alkyl groups such as ethyl, butyl, 2-ethylhexyl, octyl, decyl, and the like. More specifically, it is preferred that the adhesive polymer matrix comprises a polyacrylate adhesive copolymer having 2-ethylhexyl acrylate monomer and about 50-60% w/w of vinyl acetate as a comonomer. Examples of polyacrylate adhesive copolymers suitable for use in the present invention include, but are not limited toA copolymer sold under the trade name Duro Tak 87-4098 by National Starch and Chemical co., Bridgewater, n.j., which includes a percentage of vinyl acetate comonomer.

Wetting agent/plasticizer: preferably, the humectant/plasticizer is dispersed in the viscous polymer formulation. Incorporation of a humectant in the formulation allows the dosage unit to absorb moisture from the skin surface which can help reduce skin irritation and prevent failure of the adhesive polymer matrix of the delivery system. The plasticizer/humectant may be a conventional plasticizer used in the pharmaceutical industry, such as polyvinylpyrrolidone (PVP). In particular, PVP/vinyl acetate copolymers, such as those having a molecular weight of from about 50,000, are suitable for use in the present invention. PVP/vinyl acetate acts as a plasticizer to control the hardness of the polymer matrix and also as a humectant to regulate the moisture content of the matrix. Preferably, the PVP/vinyl acetate is PVP/VA S-630 provided by Wayne, New Jersey of International Specialty Products, Inc.

Backing layer: the backing layer may be made of any suitable material that is impermeable to the hormones and other excipients of the adhesive polymer matrix. The backing layer serves as a protective cover for the matrix layer and provides a support function. The backing layer may also be formed so that it is substantially the same size as the hormone-containing adhesive polymer matrix or it may be of a larger size so that it may extend outside of the adhesive polymer matrix so that the extended surface of the backing layer may serve as the basis for an adhesive cover layer, as will be described in more detail below. The backing layer may be of any suitable thickness that provides the desired protective and supportive function. Suitable thicknesses range from about 10 to about 300 microns. More specifically, the thickness is less than about 150 microns, more specifically, it is less than about 100 microns and most specifically, the thickness is less than about 50 microns.

Examples of materials suitable for preparing the backing layer are films of high and low density: polyethylene, polypropylene, polyurethane, polyvinyl chloride, polyesters such as poly (vinyl phthalate), metal foils, such asMetal foils of suitable polymer films, and the like. Polyester films, e.g. Scotchpak9732(3M company), are particularly suitable for use in the present invention.

Preparation of adhesive polymer formulations: according to the present invention, THDS dosage units are prepared taking into account the concentration of the components within the patch after the construction process is completed. Thus, the parameters may be varied to obtain the appropriate final amounts and proportions of the components comprising the starting formulation, as well as the processing parameters for constructing the patch, as described below.

In the preparation of viscous hormone-containing polymer preparations, it is preferred to use polyacrylate viscous polymers of the above formula. The hormone is added in an amount determined by the dose of hormone and the desired treatment time in each dosage unit.

In general, it is preferred that the starting formulation include about 10 to about 30 chalk-holding skin permeation enhancer combinations based on the weight of the adhesive polymer starting solution. More preferably, about 13 to 27%, more preferably about 16-24% or even more preferably about 19-21% of the skin permeation enhancer combination is used, based on the weight of the viscous polymer starting solution. In a preferred embodiment, the skin permeation enhancer is formulated in a viscous polymer starting solution in a weight ratio of DMSO, fatty alcohol lactate, lower alkyl lactate, and capric acid (weight percent of viscous polymer matrix) of 2: 1: 0.8 to 6: 1: 0.8, respectively. More specifically, the ratio is 3: 1: 0.8 to 4: 1: 0.8. These weight ratios are particularly suitable for use with THDS constructed using processing parameters including: the viscous solution was applied to the backing layer at a thickness between 500 μm and 700 μm and dried at about 60 ℃ for 15 minutes.

As can be seen from the data of examples 1-3, various skin permeation enhancers produced different increases/losses in the construction of THDS. For example, the percentage by weight of DMSO in the constructed adhesive polymer matrix is about 65 to 90% of the amount added to the starting formulation under the processing parameters set forth in examples 1-3. Similarly, ethyl lactate is reduced to about 50-75% of its initial amount. In contrast, the final level of lauryl lactate is about 2.6 to 4 times greater than the starting percentage, while capric acid similarly increases to about 2.5-3.9-times its starting percentage. These different changes may result from an overall decrease in matrix volume after construction, as well as different volatility of each skin permeation enhancer. Whatever the reason for the observed change, the amount of each enhancer in the starting formulation should be taken into account for different increases or losses during processing. Those skilled in the art will be able to utilize the information provided herein, as well as information well known in the pharmaceutical and medicinal chemistry arts, and make appropriate adjustments to the starting materials.

Preferably, the viscous hormone-containing polymer matrix contains dispersed hormone in excess of the desired delivered dose. To achieve this effect, the starting formulation may contain from about 5.0 to about 50 times more hormone than the desired dose. More preferably, from about 10 to about 25 times more than the desired dosage to be transdermally absorbed.

In THDS formulated for delivery of an estrogen and a progestin, it is preferred that the starting formulation include the progestin and estrogen in a ratio of at least about 1.8: 1, more preferably about 2: 1. Without being bound by any particular substrate of action, it is believed that the lower amount of estrogen present increases the amount of free progestogen in the blood because estrogen is known to induce the production of the hormone-bound globulin, which binds the progestogen. Thus, it is believed that not only is the proportion of progestin and estrogen significant, but the total amount of estrogen in the formulation is preferably kept to a minimum, e.g., less than about 0.3% based on the weight of the starting viscous polymer described herein.

Depending on the hormone utilized and the desired drug delivery, suitable amounts of plasticizer may vary from 0 to about 10% based on the weight of the adhesive polymer matrix. Preferably, the amount of humectant/plasticizer present in the final dosage unit is less than 5%. When PVP/vinyl acetate is used, it can be added as an aqueous solution, with the PVP/vinyl acetate content varying from 0.5% to about 5% based on the weight of the dry matrix of the final patch, noting that the weight percentage of humectant/plasticizer in the final product is greater than that in the starting formulation.

Example 1 sets forth an exemplary starting formulation of the present invention. The formulation is suitable for use with the preferred construction process parameters described below.

Preferably, the hormone used is dissolved and dispersed in a solution containing a combination of a plasticizer and a skin penetration enhancer prior to mixing with the adhesive polymer. More preferably, the enhancer composition and plasticizer solution are combined, the hormone added thereto and mixed.

Typically, the viscous polymer solution is added to a hormone solution dispersed in an enhancer composition/plasticizer solution. The mixture of viscous polymer and plasticizer/enhancer/hormone solution is then thoroughly mixed using a high torque mixer to form a uniform dispersion or solution of the hormone in the viscous polymer. The mixed solution is then left without agitation until degassed, for example for a period of at least 1 hour up to 24 hours.

Construction of THDS dosage units: after degassing, the viscous polymer solution is applied to the backing layer material and then dried at a set temperature for a set time. In further embodiments, the adhesive polymer matrix may be applied to a release liner in place of the liner layer. Accordingly, references herein to applying an adhesive polymer matrix to a backing layer will be understood to include this alternative embodiment. Application of the degassed adhesive polymer matrix to the backing layer can be accomplished using commercially available laboratory coating/drying equipment conventionally used for this purpose. For example, the Werner Mathis Model LTSV/LTH equipment, as well as other laboratory coating devices from Werner Mathis AG (Zurich, Switzerland) may be used. Other suitable devices include, but are not limited to, instruments manufactured by chemistems, Inc.

The thickness of the adhesive polymer applied to the backing layer, as well as the temperature and time of drying, are processing parameters that can be varied to obtain the final concentrations and ratios of hormone and permeation enhancer within the patch. For example, as detailed in example 3, it has been found that the thickness of the adhesive polymer matrix applied to the backing layer (e.g., from 300 to 800 μm) results in an overall stronger retention of the skin penetration enhancer when the other two processing parameters, drying time and drying temperature, are held constant. In contrast, varying the drying time, e.g., from 5 to 25 minutes, or varying the drying temperature, e.g., from 40-100 ℃, produces an overall reduction in the retention of skin permeation enhancers, the magnitude of which depends on the enhancer.

Thus, one skilled in the art will appreciate that in addition to selecting the appropriate amounts of starting materials in the adhesive polymer starting formulation, the appropriate combination of (1) the initial thickness of the degassed adhesive polymer solution coated on the backing layer, (2) the drying time, and (3) the drying temperature may be selected to obtain the final composition of skin permeation enhancer and hormone in THDS, as described below. Suitable initial thicknesses of the degassed viscous polymer matrix may range from 300 to 800 μm, more particularly from 400 or 500 to 700 μm, with an average thickness of about 600-700 μm. Suitable drying times should be at least 5 minutes, but may extend to 10, 15, 20, 25 or more minutes, depending on the other processing parameters chosen. Similarly, suitable drying temperatures extend from room temperature to 40, 50, 60, 70 or 80 ℃, again depending on the other processing parameters selected. In a preferred embodiment, the initial thickness of the coated solution is about 500-700 μm, more preferably 600-700 μm; drying at a temperature of about 50-80 deg.C, more preferably 55-65 deg.C, more preferably about 60 deg.C; and the drying time is about 10 to 20 minutes, more preferably about 15 minutes. An exemplary embodiment of the present invention employs an initial coating thickness of 600-700 μm, a drying temperature of 60 deg.C and a drying time of 15 minutes.

After completion of the build, the total amount of reinforcing agent in the dry adhesive polymer matrix is about 12-36% w/w, more specifically about 15 to 33%, more specifically about 18 to 30%, more specifically about 21 to 27%, and most specifically about 23-25% w/w of the polymer matrix, especially when acrylate copolymers are used.

After construction, the THDS of the present invention also includes a specific amount of a separate skin permeation enhancer based on the weight of the adhesive polymer matrix, which is different from the amount before drying for the reasons described above. Thus, in the dried adhesive polymer layer, the DMSO comprises about 4% to 12%, more specifically about 5% to 11%, more specifically about 6-10%, more specifically about 7-9% and most specifically about 8% of the adhesive polymer matrix based on the polymer matrix. The fatty alcohol lactate comprises from about 4.2% to about 12.6% of the viscous polymer matrix, more specifically from about 5.2% to about 11.6%, more specifically from about 6.2% to about 10.6%, more specifically from about 7.2% to about 9.6%, and most specifically about 8.4% by weight of the polymer matrix. The lower alkyl ester of lactic acid comprises about 0.7% to 2.3% of the viscous polymer matrix, more specifically about 1.0% to 2.0%, more specifically about 1.2-1.8%, and most specifically about 1.5%, by weight of the polymer matrix. The capric acid comprises about 3% to 9% of the viscous polymer matrix, more specifically about 4% to 8%, more specifically about 5-7%, and most specifically about 6% by weight of the polymer matrix.

After construction, it is also preferred that the skin permeation enhancer is present in the adhesive polymer matrix in the following weight proportions: about 4-8 parts DMSO, about 4-8 parts fatty alcohol lactate, and about 3-6 parts capric acid per part lower alkyl lactate. In other words, the ratio of DMSO, fatty alcohol lactate, lower alkyl lactate, and decanoic acid is usually (4-8) to (1 to 3-6). In a preferred embodiment using lauryl lactate as the fatty alcohol lactate and ethyl lactate as the lower alkyl lactate, the weight ratio of DMSO to lauryl lactate is between about 1: 1.5 and 1.5: 1, advantageously about 1: 1.

A dry adhesive polymer matrix is combined with a release liner (e.g., Scotchpak)1022 or 9744, 3M co., st. paul Minn.) (or a backing layer, if an alternative embodiment is employed) are placed adjacent the laminae, preferably of the same size to form a layer of the transdermal hormone delivery system. The resulting layer may be cut with a steel rule die and a hydraulic press to form a disc or square, etc., having a desired shape and size. The disk or squareThe general area of the shape is not more than 60cm²Preferably, the disc or square is about 5 to 50cm²And more preferably from about 8 to about 40cm². Most preferably, the disk is about 10 to about 20cm². Preferably 15cm²Because of its relatively small size, still allows for the dispersion of high concentrations of hormones. Particular embodiments of the invention are characterized by a patch surface area of 10, 12.5, 15, 17.5 or 20cm². However, other sizes may be employed. The THDS of the present invention is advantageous in that it can be constructed of thin, transparent materials, such as Scotchpakt as exemplified herein9732A cushion layer. The patch appearance is small and inconspicuous and aesthetically appealing to the user.

In a preferred embodiment of the invention, the THDS patch has a cover film, which may also be selected from a variety of thin, preferably transparent films available in the art. In one embodiment, the cover layer is designed to extend beyond the perimeter of the patch in all directions, typically about 0.1 to 1.0cm, more particularly about 0.3 to 0.7cm, and even more particularly about 0.5cm beyond the edge of the perimeter of the patch. In further embodiments, the cover layer is referred to as being partially beyond the edges of the patch, i.e. forming a "label" of cover layer material extending beyond the edges of the patch. The cover layer may be built with other elements of the THDS, i.e. it may be fixed to the spacer layer when building the THDS. Alternatively, the cover layer may be constructed separately, e.g., in a separate pouch, with its own peelable liner, so that the cover layer can be applied at the discretion of the user. Cover layer systems are commonly used for patches and other dermal devices and may be prepared according to any standard method.

Although patches without a cover layer are also suitable for use in the present invention, patches comprising a cover layer offer the advantage that THDS adheres more reliably during its use (typically one week). Furthermore, in THDS without a cover layer, the perimeter of the patch may be glued to an adhesive polymer matrix extending to the edges of the patch. The glued perimeter can accumulate dirt, clothing lint, etc. from the external environment, creating an aesthetically unsightly "dark ring" at the edge of the patch. In patches in the form of a cover layer, the perimeter of the THDS is shielded from the environment by the cover layer and the perimeter of the cover layer is exposed to the environment at a much narrower edge (e.g., the thickness of the cover layer and adhesive combination is about 75-100 μm in the preferred embodiment). This minimizes the accumulation of foreign matter on the patch, while substantially avoiding "dark circles", constituting another aesthetic advantage of the cover system.

The resulting THDS dosage units, prepared with or without a cover layer, are then placed in suitable packaging for storage, such as paper and/or foil pouches, until they are used for transdermal therapy.

Because of the importance of the ultimate absolute and relative amounts of skin penetration enhancers in THDS patches, if one or more of the foregoing formulation or processing parameters are changed, an important final step in the construction process is to quantify these components after the process has been completed. This can be done according to standard analytical techniques known in the art, such as solvent extraction of the components followed by liquid or other chromatography. An example of a suitable method is shown in example 2.

The using method comprises the following steps: the THDS of the present invention employs the usual method of applying a predetermined amount of patch to the skin of a subject for a predetermined time commensurate with the particular discomfort requiring treatment. The subject is typically a mammal and more typically a human, although the invention may be practiced on animals for a variety of veterinary purposes. Typically, although not necessarily, the patch is formulated to deliver an effective amount of one or more hormones for a period of time of 1 to 7-9 to achieve the desired effect. For sustained delivery of hormones, the patch is replaced with a fresh patch before the hormone loss is below an effective amount at this point. During the course of a typical treatment, the patch is changed once a week.

Biological control in women is a preferred application of the THDS of the invention. For contraceptive systems employing a progestin and an estrogen, the THDS of the invention provides an increased rate of hormone release, thereby providing a high rate of stimulationAnd (4) delivering the element. The levels of levonorgestrel that can be delivered by the THDS of the invention exceed the level of about 1,000pg/ml required for contraception. In fact, levels in excess of 1500-2000pg/ml were achieved using the system of the present invention (see example 4). In addition, serum levels of ethinyl estradiol are about 20-80pg/ml, providing effective support for the endometrium. Suitable serum levels of hormone may be achieved by using the relatively small patches described above, preferably having an area of 10 to 20cm²In particular 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 (or an increment of an intermediate value, for example 12.5 or 17.5) cm²Which increases the convenience for the user.

Under certain conditions (e.g., other health conditions that require the avoidance of estrogen), fertility control may be provided by the use of progestin alone. It is generally preferred to use levonorgestrel, but transdermal delivery of sufficient amounts of transdermal levonorgestrel is a pre-existing problem. The THDS of the present invention is particularly advantageous in this respect, producing levonorgestrel which can achieve high serum levels through its use. For fertility control with different estrogens, serum levels lasting 300pg/ml were found to be effective in subcutaneous levonorgestrel implants. This serum level can be readily achieved using the THDS of the present invention.

Protocols for transdermal administration of hormones for controlling fertility are well known. The patch is typically formulated to deliver a fertility controlling effective amount of the hormone for 1 to 7-9 days. In a typical regimen, which includes a 28 day cycle, the patches are changed once a week for three weeks. At week four, no patch or a placebo patch was used.

In the alternative, the patch may be worn around the fourth week to provide a continuous transdermal supply of hormone. This regimen may be employed by women who wish to avoid menses altogether. Menses can continue indefinitely or terminate after several months (e.g., 3, 4, or 6 months).

The THDS of the present invention may be used for other symptoms than fertility control. For example, a fertility controlling amount of an estrogen/progestin combination can also be used to control acne, control endometriosis, and induce amenorrhea. THDSs formulated with a fertility controlling amount of a progestin alone (e.g., levonorgestrel) can also be used to aid pregnancy and in subjects with estrogen contraindication (e.g., women at risk for breast cancer), as well as to inhibit galactorrhea, which is the secretion of milk in male or non-lactating women.

The THDS of the present invention provides many advantages over the transdermal hormones and contraceptive systems currently in use. As discussed in detail above, the primary advantages include delivery of high amounts of birth control hormone, particularly levonorgestrel, from a relatively small surface area, which patches may be made with transparent backing and cover materials, thereby improving their aesthetics. Additionally to increasing the usefulness and absorption of the THDS of the present invention for the various purposes described herein, the tenderness and congestion of the chest typically associated with such treatment has been found to be significantly reduced in patients using the THDS of the present invention as compared to other systems, which are now nausea and/or vomiting.

The following examples serve to describe the invention in detail. They are used for illustrative purposes and are not intended to limit the present invention.

Example 1

Construction of THDS dosage units for contraception

Material	mg	wt％
			Wetting agent PVP/VA-S630	9.66	1.25
Skin penetration enhancer (ceramiy)31)

DMSO	73.77	9.51
			Lactic acid lauryl ester	24.59	3.10
Lactic acid ethyl ester	24.59	3.10
			Capric acid	18.54	2.39
Adhesive polymer: duro Tak 87-4098	617.59	79.65
			Hormones
Levonorgestrel	4.48	0.58
			Ethinyl estradiol	2.20	0.28
Backing layer-Scotchpak9732(3M Co.)	16 pieces
			Tear-off liner-Scotchpak1022(3M Co.)	16 pieces
Total of	775.41mg	100.00％

The method comprises the following steps:

the hormone is dissolved and dispersed in a solution containing a combination of PVP/vinyl acetate and a skin penetration enhancer. A viscous polymer solution of Duro-Tak 87-4098 (33% solids) was added and the container was sealed. The solution was stirred at about 200rpm for 3 hours at room temperature using a magnetic stir bar to form a homogeneous solution. The stirred solution is degassed by allowing the stirred solution to stand without stirring for one hour or until all air bubbles have disappeared. The degassed solution was coated using a laboratory coater/dryer (model LTSV/LTH, Werner Mathis, Switzerland)Onto a backing layer of 700 μm thickness and then dried at 60 ℃ for 15 minutes. The dried adhesive polymer matrix was laminated with a release liner of the same size as the liner layer to form a sheet of THDS. These pieces were cut to 15cm using a steel rule die and 4000psi water pressure²The dosage unit of (a). Each dosage unit is individually packaged in paper or foil bags and stored at 4 ℃.

Example 2

Quantitative analysis of dried viscous polymer matrices

The THDS dosage units constructed in example 1 were subjected to quantitative analysis to determine the content of each component after construction. The amounts of Levonorgestrel (LNG) and Ethinyl Estradiol (EE) were determined as follows. The dosage units are removed from the foil pouch and the tear-off liner is removed. The dosage units are folded together on the viscous side and placed in an extraction container, to which 100ml of methanol is added. The container was shaken vigorously by hand and then placed on an orbital shaker for 12 hours until all of the adhesive on the dosage unit was dissolved. 21ml of the extracted solution was placed in a centrifuge tube and 9ml of HPLC-grade water was added to produce an aqueous methanol solution comprising 70% methanol. The sample was centrifuged and the supernatant filtered through 0.45 μm (nylon or Teflon) filter paper into HPLC vials. The filtrate was injected into a high pressure liquid chromatograph with a UV monitor.

The amounts of the other excipients were determined as follows. The dosage units are removed from the foil pouch and the tear-off liner is removed. The dosage units are folded together on the sticky side and placed in an extraction container, to which 2ml Tetrahydrofuran (THF) is added to dissolve the binder. After four hours, 38ml of hexane containing 0.01% (v/v) hexyl acetate (as internal reference) was added to the THF solution (5% by volume of THF). The vessel was shaken until all the units were dissolved. The samples were centrifuged and transferred to HPLC vials. The filtrate was injected into a gas chromatograph with FID detector. The results are shown below.

Average thickness of adhesive polymer matrix: 100 μm

Average composition of the adhesive polymer matrix:

components	mg per 15cm2Patch	wt％
			PVP/VA-S630	10.0	3.34
Duro Tak 87-4098	211.3	70.43
			Skin penetration enhancer
DMSO	24.0	8.00
			Lactic acid lauryl ester	25.2	8.40
Lactic acid ethyl ester	4.5	1.50
			Capric acid	18.0	6.00
Hormones
			Levonorgestrel	4.7	1.57
Ethinyl estradiol	2.3	0.77
			Total of	300.0	100.00

Example 3

Effect of processing parameters on the Final composition of skin penetration enhancers in adhesive Polymer matrices

The effect of the THDS construction parameters on the final composition of the skin penetration enhancer in the adhesive polymer matrix was examined. Four processing parameters were varied: drying temperature, drying time, initial coating thickness and weight percent of total reinforcing agents in the initial formulation. The results are shown in the following table. Each value represents the average of four patches. The values are given in mg/g of adhesive polymer matrix.

TABLE 1 enhancer composition in Patches receiving different processing parameters

Group #

Drying temperature (. degree.C.)

Drying time (min)

Coating thickness (mm)

Initial enhancer (Wt%)

Lactic acid ethyl ester

DMSO

Capric acid

Lactic acid lauryl ester

1

40

15

600

20.77

35.28±1.17

224.84±6.54

76.24±1.12

99.78±6.48

2

50

15

600

20.77

25.10±0.74

158.04±6.33

84.27±2.56

115.57±3.84

3	60	15	600	20.77	17.74±0.92	111.12±3.19	90.07±1.52	124.79±1.60
									4	70	15	600	20.77	11.31±0.78	53.32±4.47	91.88±4.17	130.17±4.27
5	80	15	600	20.77	7.55±0.41	27.17±4.23	92.87±4.88	138.30±4.27
									6	100	15	600	20.77	2.23±0.21	2.00±0.21	58.48±1.72	126.70±2.97
									7	60	5	600	20.77	37.52±2.45	234.32±7.67	74.14±2.38	108.28±2.79
8	60	10	600	20.77	21.00±0.46	154.11±4.52	83.33±2.23	115.07±3.55
									3	60	15	600	20.77	17.74±0.92	111.12±3.19	90.07±1.52	124.79±1.60
9	60	20	600	20.77	10.73±0.55	74.64±4.05	91.98±1.76	136.25±2.68
									10	60	25	600	20.77	ND	17.21±1.16	107.94±5.61	203.79±8.46
									11	60	15	300	20.77	5.38±0.61	47.51±3.29	91.85±1.73	135.87±4.09
12	60	15	400	20.77	5.07±0.35	42.34±4.51	92.77±2.18	166.10±2.17
									13	60	15	500	20.77	6.54±0.27	76.17±2.86	94.04±5.31	154.79±9.54
3	60	15	600	20.77	17.74±0.92	111.12±3.19	90.07±1.52	124.79±1.60
									14	60	15	700	20.77	18.92±1.06	137.58±5.47	82.72±3.64	120.69±5.44
15	60	15	800	20.77	21.63±0.42	142.27±3.28	78.42±1.19	110.09±1.12
16	60	15	600	7.15	ND	ND	50.24±10.64	ND
									17	60	15	600	11.98	7.64±0.21	56.58±1.37	60.23±0.52	59.65±1.36
18	60	15	600	16.81	10.35±1.37	76.71±10.58	69.35±12.03	94.64±12.73
									3	60	15	600	20.77	17.74±0.92	111.12±3.19	90.07±1.52	124.79±1.60
19	60	15	600	26.47	21.63±0.42	142.27±3.28	78.42±1.19	110.09±1.12
20	80	5	600	20.77	13.35±1.13	92.23±7.15	68.15±1.34	113.23±4.28
									21	80	10	600	20.77	4.95±0.41	40.69±4.48	78.77±1.98	110.59±1.73
5	80	15	600	20.77	7.55±0.41	27.17±4.23	92.87±4.88	138.30±4.27
									22	80	20	600	20.77	0.29±0.58	7.89±1.35	67.02±6.25	108.45±6.55

Example 4

Clinical research

Open-label, dose-response, 4-cycle, multi-center studies were performed to determine the levels of LNG, EE, progesterone, LH and estradiol following treatment with THDS prepared according to the protocol of example 1. The aim of the clinical study was: (1) determining the safety of LNG/EE THD for 7 days in healthy ovulatory women; (2) determining the serum levels of LNG and EE following treatment with LNG/EE THDS; (3) determining the serum level of progesterone as an indicator of ovulation after treatment with LNG/EE THDS; and (4) determining the levels of LH and estradiol following treatment with LNG/EE THDS.

Serum levels of LNG and EE were measured three times per week in this study. Serum levels of LH, estradiol and progesterone were also measured three times per week in this study. Levels of progesterone equal to or greater than 3ng/ml are assumed to give rise to ovulation. Cycle control was assessed by determining the occurrence of drip bleeding, breakthrough bleeding, regression bleeding and amenorrhea from a diary card. Drip bleeding is defined as a small amount of bleeding that requires up to two pantiliners. Breakthrough bleeding is defined as a large amount of bleeding that requires the use of two or three or more pantiliners. Drip bleeding and/or breakthrough bleeding is defined as bleeding that occurs between days 5-21, in addition to bleeding that begins before day 21 and continues until that day has elapsed. Amenorrhea is defined as the absence of any bleeding throughout the 28 day cycle. Regressive bleeding is defined as any drip bleeding or bleeding more than one day on or after day 22 (within 7 days without THDS administration).

Safety was assessed by not prompting the patient for the described side effects. Physical examination, virus detection, vital signs and changes in laboratory function are also measured.

LNG serum samples were analyzed by RIA and EE serum samples were analyzed by gas chromatography/mass spectrometry to periodically determine the serum levels of these hormones in the subjects under study. 15, 17.5 and 20cm respectively²The preliminary results of the formula for the patch of (a) are shown in the table below.

Table 2 serum levels of levogestrel and ethinyl estradiol in subjects tested in clinical trials over four cycles of THDS administration.

Levonorgestrel (pg/ml) ethinyl estradiol (pg/ml)

Period of time

Sky

15cm2

17.5cm2

20cm2

15cm2

17.5cm2

20cm2

1

1

2.00(N＝11)

2.00(N＝11)

2.00(N＝17)

1.08±0.21(N＝10)

1.03±0.16(N＝11)

1.19±0.41(N＝17)

3

844.71±724.50(N＝13)

1001.01±634.24(N＝11)

920.73±525.40(N＝16)

30.48±9.56(N＝13)

41.77±21.88(N＝11)

42.73±32.94(N＝16)

8

1054.45±642.21(N＝11)

1249.42±626.77(N＝12)

1019.48±521.57(N＝18)

21.06±6.50(N＝11)

32.78±21.45(N＝12)

27.65±24.10(N＝19)

10

1589.84±565.74(N＝12)

2052.75±1100.75(N＝13)

2112.87±693.04(N＝12)

30.88±10.71(N＝12)

46.46±23.52(N＝13)

39.79±9.62(N＝12)

15

1222.61±399.92(N＝13)

1664.76±462.71(N＝11)

1392.26±711.44(N＝17)

24.35±10.21(N＝11)

38.50±18.62(N＝10)

23.19±10.45(N＝16)

17

2574.70±1461.29(N＝12)

2644.92±1506.96(N＝9)

2460.92±1185.72(N＝14)

41.05±13.17(N＝11)

60.78±34.20(N＝10)

46.35±23.74(N＝16)

22

1460.10±574.76(N＝12)

1898.69±843.73(N＝12)

1616.14±1033.81(N＝17)

22.27±9.82(N＝12)

41.54±18.81(N＝13)

29.73±23.84(N＝19)

2

1

923.77±1184.97(N＝7)

408.51±683.41(N＝8)

254.44±418.96(N＝8)

18.46±18.42(N＝7)

9.25±8.19(N＝8)

11.89±17.09(N＝8)

3

1223.70±277.64(N＝5)

1820.44±1084.88(N＝9)

1513.82±601.49(N＝7)

35.51±14.05(N＝6)

64.65±25.22(N＝8)

39.70±15.82(N＝7)

8

929.07±126.26(N＝6)

1442.98±689.62(N＝9)

1397.46±815.37(N＝7)

28.44±16.11(N＝7)

40.24±19.43(N＝9)

36.19±23.06(N＝7)

10

1904.12±583.88(N＝6)

2433.64±1092.91(N＝9)

3016.86±1871.56(N＝7)

36.49±13.86(N＝6)

58.67±33.72(N＝9)

49.12±22.02(N＝7)

15

1454.02±597.78(N＝7)

1545.99±639.46(N＝9)

1940.63±1118.38(N＝6)

26.90±9.54(N＝7)

39.57±22.80(N＝9)

25.15±8.81(N＝6)

17

2674.99±1335.90(N＝7)

3177.80±1379.79(N＝7)

2863.36±1556.44(N＝7)

40.23±14.93(N＝7)

65.79±33.65(N＝7)

41.82±17.90(N＝7)

22

1403.37±413.89(N＝7)

1811.11±856.59(N＝9)

2071.22±1161.46(N＝7)

27.32±18.59(N＝7)

36.49±21.38(N＝9)

26.11±13.85(N＝6)

3

1

62.00

2.00

97.38±66.64(N＝4)

5.63

0.98

5.92±3.52(N＝4)

3

467.00

2124.11

1878.00±506.67(N＝4)

19.38

80.24

43.15±15.74(N＝4)

8

362.41±164.88(N＝2)

1424.82

2026.13±943.19(N＝4)

18.89±20.14(N＝2)

31.98

33.37±13.09(N＝4)

10

1084.63±266.77(N＝2)

3274.46

3780.44±1783.33(N＝4)

41.77±15.76(N＝2)

101.75

52.07±12.37(N＝4)

15

937.32±176.32(N＝2)

1775.66

2500.13±752.94(N＝4)

34.20±17.42(N＝2)

43.61

27.72±6.83(N＝4)

	17	947.81±978.37(N＝2)	7175.00	2911.94±953.73(N＝4)	31.06±34.20(N＝2)	87.21	25.34±10.93(N＝4)
									22	919.69±116.95(N＝2)	2274.46	2175.81±1273.49(N＝4)	22.17±4.83(N＝2)	34.89	29.20±12.24(N＝4)
4	1	49.00	ND	44.13±59.57(N＝2)	4.38	ND	3.30±3.29(N＝2)
									8	576.00	ND	1559.75±392.09(N＝2)	16.88	ND	34.51
	15	940.00	ND	2634.88±1458.23(N＝2)	10.63	ND	27.16±4.91(N＝2)
									22	1283.00		2588.50±1093.89(N＝2)	17.50	ND	23.01±3.70(N＝2)

The invention is not limited to the embodiments described and exemplified above, but may be varied and modified within the scope of the claims.

Claims (14)

1. A transdermal hormone delivery system comprising a backing layer impermeable to skin permeation enhancers and steroid hormones to be delivered transdermally and an adhesive polymer matrix affixed to the backing layer, wherein the adhesive polymer matrix comprises an adhesive polymer, and further comprising, based on the final weight percent of the adhesive polymer matrix:

a) from 0% to 5% of a humectant/plasticizer;

b) from 12% to 36% of a combination of skin permeation enhancers comprising from 4% to 12% of a pharmaceutically acceptable organic solvent, from 4.2% to 12.6%Hydroxy acid fats (C)₈-C₂₀) Alcohol ester, from 0.7% to 2.3% of hydroxy acid lower (C)₁-C₄) Alkyl ester and from 3% to 9% of C₆-C₁₈A mixture of fatty acids, wherein the organic solvent is dimethyl sulfoxide, hydroxy acid fat (C)₈-C₂₀) The alcohol ester is fatty alcohol lactate and hydroxy acid lower (C)₁-C₄) Alkyl esters are lower alkyl lactates, C₆-C₁₈The fatty acid is capric acid, and wherein dimethyl sulfoxide and fatty alcohol lactate are present in a weight ratio of 1.5: 1 to 1: 1.5; and

c) an amount of a steroid hormone to be transdermally delivered effective to provide a predetermined daily dosage of the hormone for one to nine days, wherein the steroid hormone is levonorgestrel and ethinyl estradiol and the weight ratio of levonorgestrel to ethinyl estradiol is at least 1.8: 1.

2. The transdermal hormone delivery system of claim 1, wherein the weight ratio of levonorgestrel to ethinyl estradiol is at least 2: 1.

3. The transdermal hormone delivery system of claim 1 or 2, wherein the ethinyl estradiol is less than 0.3% by weight of the initial adhesive polymer formulation.

4. The transdermal hormone delivery system of claim 1, wherein the humectant/plasticizer is polyvinylpyrrolidone.

5. The transdermal hormone delivery system of claim 1, wherein the humectant/plasticizer is polyvinylpyrrolidone/vinyl acetate.

6. The transdermal hormone delivery system of claim 1, wherein the adhesive polymer comprises a polyacrylate copolymer.

7. The transdermal hormone delivery system of claim 6, wherein the polyacrylate copolymer comprises a 2-ethylhexyl acrylate monomer.

8. The transdermal hormone delivery system of claim 7, wherein the polyacrylate copolymer further comprises 3 to 60% w/w vinyl acetate.

9. The transdermal hormone delivery system of claim 1, wherein the fatty alcohol ester of lactic acid is lauryl lactate and the lower alkyl ester of lactic acid is ethyl lactate.

10. The transdermal hormone delivery system of claim 1, wherein the skin permeation enhancer is present in a weight ratio of 4 to 8 parts dimethyl sulfoxide, 4 to 8 parts fatty alcohol lactate, 1 part lower alkyl lactate and 3 to 6 parts capric acid.

11. The transdermal hormone delivery system of claim 1, formulated for delivery of ethinyl estradiol and levonorgestrel, wherein ethinyl estradiol is transdermally delivered at a rate of 10 μ g to 50 μ g per day for one to nine days, and levonorgestrel is transdermally delivered at a rate of at least 20g per day for one to nine days.

12. The transdermal hormone delivery system of claim 11, wherein the levonorgestrel is delivered transdermally in an amount sufficient to produce a steady state serum concentration of at least 1,000 pg/ml.

13. The transdermal hormone delivery system of claim 1, further comprising an overlay layer, wherein the overlay layer is coated with an adhesive and extends beyond part or all of the perimeter of the backing layer and the adhesive polymer matrix.

14. The transdermal hormone delivery system of claim 13, wherein a non-adhesive polymer replaces the adhesive polymer, and wherein skin adhesion is achieved by coating an adhesive overlay.