Transdermal drug delivery system for levonorgestrel and ethinyl estradiol.

Abstract

A transdermal drug delivery system for transdermally administering levonorgestrel and ethinyl estradiol is provided. [Solution] A transdermal drug delivery system includes a polymer matrix containing levonorgestrel, ethinyl estradiol, an acrylic polymer including a hydroxy-functional acrylic polymer, a humectant, a first enhancer selected from the group consisting of glyceryl monooleate, dipropylene glycol, and methyl laurate, and a second enhancer different from the first enhancer and selected from the group consisting of glyceryl monooleate, dipropylene glycol, methyl laurate, diethylene glycol monoethyl ether, and dimethyl isosorbide, wherein the transdermal drug delivery system continuously delivers levonorgestrel and ethinyl estradiol transdermally for a period of at least 3 days, at least 4 days, or at least 7 days.

Description

[Technical field]

[0001] Related Applications This application claims priority pursuant to 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 188,175, filed June 2, 2015, the entire contents of which are incorporated herein by reference in their entirety. Described herein are compositions and methods for transdermal delivery of levonorgestrel and ethinyl estradiol, which are useful, for example, as contraceptives. [Background technology]

[0002] Transdermal delivery systems (adhesive patches) as a dosage form have been the subject of numerous patent applications over the last 25 years, spawning numerous patents, but few commercial products. For those working in this field, the relatively small number of commercial products is not surprising. Although regulatory, economic, and market barriers limit the number of products on the market, the challenge of developing a transdermal delivery system that achieves the desired physical and pharmacokinetic parameters to satisfy the needs of physicians and patients is even more challenging. Parameters to consider when developing a commercial product include drug solubility, drug stability (e.g., which may result from interactions with other component materials and / or the environment), delivery of therapeutic amounts of drug at the desired delivery rate over the intended period of use, sufficient adhesion at the body site to which it is applied, minimal discomfort, irritation, and sensitization, and integrity (e.g., minimal curling, wrinkling, peeling, and slippage) both during use and during and after removal, and minimal residual adhesive (or other components) after removal. Size may also be important from a manufacturing and patient perspective, as well as appearance from a patient perspective. When more than one drug is formulated, these factors become more complex. The present invention relates generally to a transdermal drug delivery system, and more particularly to a transdermal drug delivery system for delivering levonorgestrel and ethinyl estradiol. Climara Pro® (Bayer) is a three-layer adhesive matrix transdermal patch consisting of a translucent polyethylene backing film, an acrylate adhesive matrix containing estradiol, levonorgestrel, and polyvinylpyrrolidone / vinyl acetate copolymer, and a protective liner of either siliconized or fluorinated polymer-coated polyester film. The active ingredients are estradiol and levonorgestrel. Climara Pro® is used to treat vasomotor symptoms, requiring therapeutic blood levels only about one-eighth of those required for contraception.

[0003] U.S. Patent No. 7,045,145 is directed to a transdermal delivery system comprising a backing layer and an adhesive polymer matrix secured to the backing layer, the adhesive polymer matrix being formulated by combining, on a mass percentage basis, (a) from about 0% to about 10% of a humectant / plasticizer, (b) from about 20% to about 70% of an adhesive copolymer, (c) from about 10% to about 60% of a combination of skin permeation enhancers that are a mixture including dimethylsulfoxide, an aliphatic (C8-C20) alcohol ester of lactic acid, a lower (C1-C4) alkyl ester of lactic acid, and capric acid, present in a ratio ranging from about 2:1:1:0.8 to about 6:1:1:0.8, respectively, (d) a progestin hormone, and an estrogen hormone. U.S. Patent No. 7,384,650 is directed to a transdermal hormone delivery system comprising a backing layer and an adhesive polymer matrix secured to the backing layer, the adhesive polymer matrix comprising (a) an adhesive polymer, (b) a moisturizer, (c) a combination of skin permeation enhancers consisting essentially of about 4% to about 12% dimethyl sulfoxide, about 4.2% to about 12.6% aliphatic (C8-C20) alcohol esters of lactic acid, about 0.7% to about 2.3% lower (C1-C4) alkyl esters of lactic acid, and about 3% to about 9% capric acid, in final weight percentages of the adhesive polymer matrix after fabrication of the system, (d) a progestin, and (e) an estrogen.

[0004] U.S. Patent No. 8,221,785 is directed to a contraceptive delivery system comprising a backing layer and an adhesive polymer matrix secured to the backing layer, the adhesive polymer matrix comprising: (a) an adhesive polymer comprising a polyacrylate copolymer; (b) a humectant comprising polyvinylpyrrolidone; (c) a combination of skin permeation enhancers consisting essentially of, in final weight percentages of the adhesive polymer matrix after fabrication of the system, about 4% to about 12% dimethylsulfoxide, about 4.2% to about 12.6% aliphatic (C8-C20) alcohol esters of lactic acid, about 0.7% to about 2.3% lower (C1-C4) alkyl esters of lactic acid, and about 3% to about 9% capric acid; (d) levonorgestrel; and (e) ethinyl estradiol or 17 beta-estradiol. US Patent No. 5,770,219 is directed to a drug-containing matrix for use in a transdermal drug delivery device, comprising an estrogen dispersed in a pressure-sensitive adhesive body for administering at least one estrogen to skin or mucous membrane area, said pressure-sensitive adhesive comprising acetate acrylate copolymer and polyvinylpyrrolidone, said matrix being essentially free of skin permeation enhancer.In some embodiments, said matrix further comprises levonorgestrel. US Patent Application No. 14 / 141,935 is directed to a transdermal drug delivery system for transdermal delivery of levonorgestrel and ethinyl estradiol in the form of a flexible finite system for topical application comprising a polymer matrix comprising levonorgestrel, ethinyl estradiol, and an acrylic polymer, wherein the acrylic polymer comprises a hydroxy-functional acrylic polymer. In some embodiments, the polymer matrix is ​​substantially free of polyvinylpyrrolidone (PVP) and polyvinylpyrrolidone / vinyl acetate (PVP / VA).

[0005] Nevertheless, transdermal delivery of levonorgestrel and ethinyl estradiol continues to present challenges. Some of the challenges presented by this particular drug combination include the high delivery rate of levonorgestrel and its effect on patch size; undesirable crystallization of levonorgestrel in the polymer matrix; and the difficulty of formulating a composition that can achieve sustained drug delivery (e.g., at therapeutic levels) over a 7-day period. Thus, there remains a need for transdermal drug delivery systems designed to deliver specific drugs and drug combinations, such as levonorgestrel and ethinyl estradiol. Summary of the Invention [Means for solving the problem]

[0006] According to some embodiments, there is provided a transdermal drug delivery system for transdermal delivery of levonorgestrel and ethinyl estradiol in the form of a flexible finite system for topical application, comprising a polymer matrix comprising levonorgestrel, ethinyl estradiol, an acrylic polymer comprising a hydroxy-functional acrylic polymer, a humectant, a first enhancer selected from the group consisting of glyceryl monooleate, dipropylene glycol, and methyl laurate, a second enhancer different from the first enhancer and selected from the group consisting of glyceryl monooleate, dipropylene glycol, methyl laurate, diethylene glycol monoethyl ether, and dimethyl isosorbide, and optionally a third enhancer different from the first and second enhancers and selected from the group consisting of glyceryl monooleate, dipropylene glycol, methyl laurate, diethylene glycol monoethyl ether, and dimethyl isosorbide. In some embodiments, the first and second enhancers are dipropylene glycol and diethylene glycol monoethyl ether.In some embodiments, the first, second and third enhancers are dipropylene glycol, diethylene glycol monoethyl ether and glyceryl monooleate.In some embodiments, the first and second enhancers are dipropylene glycol and diethylene glycol monoethyl ether, and the composition further comprises isopropyl myristate as a third enhancer.

[0007] In some embodiments, the first penetration enhancer is selected from glyceryl monooleate, dipropylene glycol, and methyl laurate.In some embodiments, the second penetration enhancer is selected from glyceryl monooleate, dipropylene glycol, methyl laurate, diethylene glycol monoethyl ether, and dimethyl isosorbide.In some embodiments, the first penetration enhancer is selected from glyceryl monooleate, dipropylene glycol, and methyl laurate, the second penetration enhancer is selected from glyceryl monooleate, dipropylene glycol, and methyl laurate, and the polymer matrix may further comprise a third penetration enhancer selected from diethylene glycol monoethyl ether and dimethyl isosorbide. In further specific embodiments, the penetration enhancer comprises glyceryl monooleate and dipropylene glycol; glyceryl monooleate and methyl laurate; glyceryl monooleate, dipropylene glycol and diethylene glycol monoethyl ether; glyceryl monooleate, dipropylene glycol and dimethyl isosorbide; glyceryl monooleate, methyl laurate and diethylene glycol monoethyl ether; or glyceryl monooleate, methyl laurate and dimethyl isosorbide.

[0008] According to any embodiment, the humectant may be one or more of polyvinylpyrrolidone (PVP), cross-linked PVP (crospovidone) and polyvinylpyrrolidone / vinyl acetate (PVP / VA, copovidone). According to any embodiment, the polymer matrix can include, on a dry weight basis, about 0.1-3% levonorgestrel, about 0.1-5% ethinyl estradiol, about 1-30% first, second and optional tertiary penetration enhancers, about 3-10% humectant, and the balance acrylic polymer. According to any embodiment, the transdermal drug delivery system can include an amount of levonorgestrel sufficient to provide sustained delivery of levonorgestrel for a period of at least 3 days, at least 4 days, or at least 7 days. According to any embodiment, the polymer matrix may further include a silicone pressure sensitive adhesive.

[0009] According to any embodiment, the transdermal drug delivery system can include an amount of ethinyl estradiol sufficient to achieve sustained delivery of ethinyl estradiol for a period of at least 3 days, at least 4 days, or at least 7 days. In some embodiments, the transdermal drug delivery system further comprises a surface adhesive layer disposed on the skin-contacting side of the drug-containing polymer matrix. In certain embodiments, the surface adhesive comprises a silicone pressure sensitive adhesive. In further particular embodiments, the polymer matrix comprises isopropyl myristate as an enhancer and comprises a silicone surface adhesive. In any embodiment, the transdermal drug delivery system can further include a backing layer and / or a release liner. Also provided is a method for transdermally delivering levonorgestrel and ethinylestradiol, comprising applying the transdermal drug delivery system described herein to the skin or mucosa of a subject in need thereof.In some embodiments, the subject is a human female subject.In some embodiments, the method is for contraception.In some embodiments, the transdermal drug delivery system is continuously applied for up to 7 days.

[0010] Also provided is the transdermal drug delivery system described herein for use in transdermally delivering levonorgestrel and ethinyl estradiol to a subject and for use in contraception in a subject.Also provided is the use of levonorgestrel and ethinyl estradiol in the preparation of a transdermal drug delivery system medicament described herein for use in transdermally delivering levonorgestrel and ethinyl estradiol to a subject and for use in contraception in a subject.According to any of these embodiments, the subject can be a human female subject.According to any of these embodiments, the transdermal drug delivery system can be continuously applied for up to 7 days.

[0011] Also provided is a method for preparing a transdermal drug delivery system comprising levonorgestrel and ethinyl estradiol as described herein, comprising preparing a polymer matrix as described herein. In some embodiments, the method further comprises applying a surface adhesive layer to the polymer matrix. [Brief description of the drawings]

[0012] [Figure 1A] FIG. 1 illustrates a monolithic transdermal delivery system described herein consisting of a backing, a drug-loaded adhesive matrix layer, and a release liner (if present). [Figure 1B] FIG. 2 illustrates a transdermal delivery system described herein further comprising a surface adhesive layer between the drug-loaded adhesive matrix layer and the release liner (if present). [Diagram 2] FIG. 1 illustrates the mean and cumulative levonorgestrel (LNG) and ethinyl estradiol (EE) flux (μg / cm2 / hr) over time (0-168 hours) from a transdermal delivery system described in the Examples compared to Climara® Pro or OrthoEvra®, respectively. FIG. 2 illustrates results for a system containing glyceryl monooleate (GMO) and methyl laurate (MeLau). [Diagram 3] FIG. 1 illustrates the mean and cumulative levonorgestrel (LNG) and ethinyl estradiol (EE) flux (μg / cm2 / hr) over time (0-168 hours) from a transdermal delivery system described in the Examples compared to Climara® Pro or OrthoEvra®, respectively. FIG. 2 illustrates results for a system containing glyceryl monooleate (GMO) and dipropylene glycol (DPG). [Figure 4] FIG. 1 illustrates the average and cumulative levonorgestrel (LNG) and ethinyl estradiol (EE) flux (μg / cm2 / hr) over time (0-168 hours) from a transdermal delivery system described in the Examples compared to Climara® Pro or OrthoEvra®, respectively. FIG. 2 illustrates results for a system comprising glyceryl monooleate (GMO) and dipropylene glycol (DPG) with a surface adhesive. [Diagram 5] FIG. 1 illustrates the mean and cumulative levonorgestrel (LNG) and ethinyl estradiol (EE) flux (μg / cm2 / hr) over time (0-168 hours) from a transdermal delivery system described in the Examples compared to Climara® Pro or OrthoEvra®, respectively. FIG. 2 illustrates results for a system containing glyceryl monooleate (GMO) and methyl laurate (MeLau) with a surface adhesive. [Figure 6]FIG. 1 illustrates the average and cumulative levonorgestrel (LNG) and ethinyl estradiol (EE) flux (μg / cm2 / hr) over time (0-168 hours) from a transdermal delivery system described in the Examples compared to Climara® Pro or OrthoEvra®, respectively. FIG. 2 directly compares results for systems containing GMO and DPG with and without a surface adhesive. [Figure 7] FIG. 1 illustrates the average and cumulative levonorgestrel (LNG) and ethinyl estradiol (EE) flux (μg / cm2 / hr) over time (0-168 hours) from a transdermal delivery system described in the Examples compared to Climara® Pro or OrthoEvra®, respectively. FIG. 2 directly compares results for systems containing GMO and MeLau with and without a surface adhesive. [Figure 8] FIG. 1 illustrates the average and cumulative levonorgestrel (LNG) and ethinyl estradiol (EE) flux (μg / cm2 / hr) over time (0-168 hours) from the transdermal delivery system described in Example 3 (Formulations 20-22) compared to Climara® Pro or OrthoEvra®, respectively. [Figure 9A] FIG. 9 illustrates the cumulative and mean ethinyl estradiol (EE) (FIGS. 9A, 10A, 11A) and levonorgestrel (LNG) (FIGS. 9B, 10B, 11B) flux (μg / cm2 / hr) over time (0-168 hours) from the transdermal delivery system described in Example 4 (Formulations 23-25). [Figure 9B] FIG. 9 illustrates the cumulative and mean ethinyl estradiol (EE) (FIGS. 9A, 10A, 11A) and levonorgestrel (LNG) (FIGS. 9B, 10B, 11B) flux (μg / cm2 / hr) over time (0-168 hours) from the transdermal delivery system described in Example 4 (Formulations 23-25). [Figure 10A]FIG. 9 illustrates the cumulative and mean ethinyl estradiol (EE) (FIGS. 9A, 10A, 11A) and levonorgestrel (LNG) (FIGS. 9B, 10B, 11B) flux (μg / cm2 / hr) over time (0-168 hours) from the transdermal delivery system described in Example 4 (Formulations 23-25). [Figure 10B] FIG. 9 illustrates the cumulative and mean ethinyl estradiol (EE) (FIGS. 9A, 10A, 11A) and levonorgestrel (LNG) (FIGS. 9B, 10B, 11B) flux (μg / cm2 / hr) over time (0-168 hours) from the transdermal delivery system described in Example 4 (Formulations 23-25). [Figure 11A] FIG. 9 illustrates the cumulative and mean ethinyl estradiol (EE) (FIGS. 9A, 10A, 11A) and levonorgestrel (LNG) (FIGS. 9B, 10B, 11B) flux (μg / cm2 / hr) over time (0-168 hours) from the transdermal delivery system described in Example 4 (Formulations 23-25). [Figure 11B] FIG. 9 illustrates the cumulative and mean ethinyl estradiol (EE) (FIGS. 9A, 10A, 11A) and levonorgestrel (LNG) (FIGS. 9B, 10B, 11B) flux (μg / cm2 / hr) over time (0-168 hours) from the transdermal delivery system described in Example 4 (Formulations 23-25). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] According to some embodiments, the present invention provides a transdermal drug delivery system for transdermally delivering levonorgestrel and ethinylestradiol.In certain embodiments, the system exhibits desired pharmacokinetic properties, such as by allowing formulation for use over a 7-day period, and / or exhibits desired physical characteristics, such as sufficient shear properties, and / or exhibits desired stability characteristics, such as reduced or minimized crystallization of levonorgestrel. The low solubility of levonorgestrel in pressure sensitive adhesives and the low permeability of levonorgestrel make it difficult to design a transdermal drug delivery system capable of delivering a therapeutically effective amount of levonorgestrel over a seven day period in a reasonably sized system. Surprisingly, the inventors have discovered that acrylic polymers containing hydroxyl functional groups (such as hydroxyl functional groups containing vinyl acetate) are particularly suitable for formulating levonorgestrel for sustained delivery over extended periods of time (such as 7 days). In particular, the inventors have identified that such polymers are capable of sufficiently solubilizing levonorgestrel (and ethinyl estradiol) while providing a stable polymer matrix.

[0014] The inventors have also surprisingly discovered that each of dipropylene glycol (DPG) and diethylene glycol monoethyl ether (e.g., Transcutol®) is an effective enhancer for levonorgestrel, both alone and in combination with each other and / or with one or more of glyceryl monooleate (GMO) and isopropyl myristate (IMP). The inventors have also surprisingly discovered that each of dipropylene glycol (DPG), glyceryl monooleate (GMO), and methyl laurate (MeLau) is an effective enhancer for levonorgestrel, both alone and in combination with each other and / or with one or more of diethylene glycol monoethyl ether (Transcutol®) and dimethyl isosorbide (DMI). The inventors have also surprisingly found that a combination of dipropylene glycol (DPG) and diethylene glycol monoethyl ether, optionally with one or more of glyceryl monooleate (GMO) and isopropyl myristate (IMP), is an effective enhancer for levonorgestrel, and that a combination of dipropylene glycol (DPG), diethylene glycol monoethyl ether and glyceryl monooleate (GMO), or a combination of dipropylene glycol (DPG), diethylene glycol monoethyl ether and isopropyl myristate (IMP) is a particularly effective enhancer for levonorgestrel.The inventors have also surprisingly found that a combination of two or more of DPG, GMO and MeLau is a particularly effective enhancer for levonorgestrel, and that a combination of two or more of DPG, GMO and MeLau, together with one or more of diethylene glycol monoethyl ether and DMI, is also an effective enhancer for levonorgestrel.

[0015] The inventors have also surprisingly found that it is advantageous to include a humectant (such as PVP, crospovidone and / or PVP / VA) in the polymer matrix containing levonorgestrel. For example, the inventors have surprisingly found that a humectant can inhibit crystallization of levonorgestrel and / or impart desirable physical properties, such as shear and adhesive properties. The inventors have also surprisingly discovered that the physical and adhesive properties of the systems described herein can be improved without substantially affecting drug flux by the use of a surface adhesion layer, such as a silicone surface adhesion layer. Thus, according to some aspects, a transdermal drug delivery system and method for transdermally delivering levonorgestrel and ethinyl estradiol is provided.In certain embodiments, the system exhibits sustained delivery of levonorgestrel and ethinyl estradiol for an extended period of time, such as at least 3 days, 4 days, 7 days or more.

[0016] definition The technical and scientific terms used herein have the meanings that are commonly understood by those skilled in the art to which the present invention pertains, unless otherwise defined. Various methods known to those skilled in the art are referred to herein. Publications and other materials presenting known methods referred to are incorporated herein by reference in their entirety as if fully presented. Any suitable materials and / or methods known to those skilled in the art can be utilized in carrying out the present invention. However, specific materials and methods are described. Materials, reagents, etc. referred to in the following description and examples are available from commercial sources unless otherwise noted. As used herein, the singular forms "a," "an," and "the" refer to both the singular and the plural, unless expressly stated to refer to the singular only. The use of the term "about" and general ranges means that the included numbers, whether or not limited by the term about, are not limited to the numbers themselves provided, but are intended to refer to a range that is substantially within the cited range, without departing from the spirit of the present invention. As used herein, "about" is within the scope of understanding of those of ordinary skill in the art and will vary to some extent in the context in which it is used. When a term is used that is not clear to those of ordinary skill in the art given the context in which it is used, "about" means up to plus or minus 10% of the particular term.

[0017] The phrases "wt % relative to the dry weight of the polymer matrix" and "dry weight %" refer to the weight of the component in the final polymer matrix after drying and evaporation of, for example, volatile processing solvents. The phrases "weight % relative to the wet weight of the polymer matrix" and "wet weight %" refer to the weight of the component in question used to prepare the polymer matrix relative to the weight of the other components in the polymer matrix, not including the weight of any volatile processing solvents used to prepare the polymer matrix. The phrase "substantially free" herein generally means that the described composition (e.g., transdermal drug delivery system, polymer matrix, etc.) contains less than about 5% by weight, less than about 3% by weight, or less than about 1% by weight of the excluded component, based on the total weight of the composition in question. The phrase "free of" herein means that the described composition (e.g., polymer matrix, etc.) is formulated without the addition of the excluded component as an intended component, although trace amounts may be present in other components or as by-products or contaminants, such that the composition contains at most only trace amounts of the excluded component.

[0018] As used herein, "subject" refers to any animal that requires drug therapy, including humans.For example, the subject may suffer from or be at risk of developing a condition that can be treated or prevented with levonorgestrel and ethinylestradiol, or may take levonorgestrel and ethinylestradiol to maintain health.In certain embodiments, the subject is a female subject that takes levonorgestrel and ethinylestradiol for contraception. As used herein, the phrases "therapeutically effective amount" and "therapeutic level" refer to a drug dosage or a plasma concentration in a subject that provides a specific medical response when the drug is administered to a subject in need of such treatment, respectively. It should be emphasized that a therapeutically effective amount or therapeutic level of a drug is not always effective for treating the conditions / diseases described herein, even though such dosages are considered therapeutically effective by those skilled in the art. For convenience only, exemplary dosages, drug delivery amounts, therapeutically effective amounts and therapeutic levels are provided below for adult human subjects. Those skilled in the art can adjust such amounts according to standard practices as necessary to treat a particular subject and / or condition / disease.

[0019] As used herein, "active surface area" refers to the surface area of ​​the drug-containing layer of a transdermal drug delivery system. As used herein, "coating mass" refers to the mass of the drug-containing layer per unit area of ​​the active surface area of ​​the transdermal drug delivery system. As used herein, "flux" (also called "permeation rate") is defined as the absorption of a drug through skin or mucosal tissue, according to Fick's first law of diffusion: J = -D(dCm / dx) It is described by: If J is the flux in g / cm2 / sec, D is the diffusion coefficient of the drug across the skin or mucosa in cm2 / sec, and dCm / dx is the concentration gradient of the drug across the skin or mucosa. As used herein, the term "transdermal" refers to the delivery, administration or application of a drug by direct contact with the skin or mucosa. Such delivery, administration or application is also referred to as transdermal, transcutaneous, transmucosal and buccal. As used herein, "cutaneous" includes the skin and mucosa, including the oral, buccal, nasal, rectal and vaginal mucosa.

[0020] As used herein, a "transdermal drug delivery system" refers to a system (e.g., a device) that includes a composition that releases a drug when applied to the skin (or any other surface as noted above). The transdermal drug delivery system includes a drug-containing layer and may include a backing layer and / or a release liner layer. In some embodiments, the transdermal drug delivery system is a substantially non-aqueous solid form that can conform to the surface it contacts and maintain such contact to facilitate topical application without adverse physiological responses and without significant degradation due to aqueous contact during topical application to a subject. Many such systems are known in the art and are commercially available, such as transdermal drug delivery patches. As described below, in one embodiment, the transdermal drug delivery system includes a drug-containing polymer matrix that includes a pressure-sensitive adhesive or bioadhesive and is adapted for application directly to the skin of a user (e.g., a subject). In other embodiments, the polymer matrix is ​​non-adhesive and can be provided with a separate adhesive means (such as a separate adhesive layer) for application and adhesion to the skin of a user.

[0021] As used herein, a "polymer matrix" refers to a polymer composition that includes one or more drugs. In some embodiments, the matrix includes a pressure-sensitive adhesive polymer or a bioadhesive polymer. In other embodiments, the matrix does not include a pressure-sensitive adhesive or a bioadhesive. As used herein, a polymer is an "adhesive" if it has the properties of an adhesive itself, or if it has the function of an adhesive by adding a tackifier, plasticizer, crosslinker, or other additive. Thus, in some embodiments, the polymer matrix includes a pressure-sensitive adhesive polymer or a bioadhesive polymer with a drug dissolved or dispersed therein. The polymer matrix may also include a tackifier, plasticizer, crosslinker, enhancer, cosolvent, filler, antioxidant, solubilizer, crystallization inhibitor, or other additive as described herein. U.S. Pat. No. 6,024,976 describes polymer blends that are useful according to the transdermal systems described herein. The entire contents of U.S. Pat. No. 6,024,976 are incorporated herein by reference. As used herein, the term "pressure-sensitive adhesive" refers to a viscoelastic material that instantly adheres to most substrates by application of very little pressure and remains permanently tacky. A polymer is a pressure-sensitive adhesive within the meaning of the term as used herein if it has the properties of a pressure-sensitive adhesive itself or if it functions as a pressure-sensitive adhesive by being mixed with tackifiers, plasticizers or other additives.

[0022] The term pressure sensitive adhesive also includes mixtures of various polymers and mixtures of polymers such as polyisobutylene (PIB) of various molecular weights, each resulting mixture being a pressure sensitive adhesive. In the last case, the lower molecular weight polymer in the mixture is not recognized as a "tackifier", although the term is valid for additives that differ from the polymer to which they are added in other ways than by molecular weight. In some embodiments, the polymer matrix is ​​a pressure sensitive adhesive at room temperature and has other desirable characteristics for adhesives used in the field of transdermal drug delivery systems, such as good adhesion to skin, the ability to be peeled off or removed without significant trauma to the skin, retention of adhesion with age, etc. In some embodiments, the polymer matrix has a glass transition temperature (Tg) of about -70°C to 0°C, as measured using a differential scanning calorimeter. As used herein, the term "rubber-based pressure sensitive adhesive" refers to a viscoelastic material having pressure sensitive adhesive properties and comprising at least one natural or synthetic elastomeric polymer.

[0023] In some embodiments, the transdermal drug delivery system includes one or more additional layers, such as one or more additional polymer matrix layers, or one or more adhesive layers that adhere the transdermal drug delivery system to the skin of a user. In certain embodiments, the transdermal drug delivery system includes a surface adhesive layer disposed on the skin-contacting side of the drug-containing polymer matrix. In other embodiments, the transdermal drug delivery system is monolithic, meaning that the system includes a single polymer matrix layer that includes a pressure-sensitive adhesive or bioadhesive having a drug dissolved or dispersed therein, and does not include a rate-controlling membrane or a surface adhesive. The transdermal drug delivery system may also include a drug-impermeable backing layer or film. In some embodiments, the backing layer is adjacent to one surface of the polymeric matrix layer. When present, the backing layer protects the polymeric matrix layer (and any other layers present) from the environment and prevents loss of drug and / or release of other components into the environment during use. Materials suitable for use as backing layers are well known in the art and can include films of polyester, polyethylene, vinyl acetate resin, ethylene / vinyl acetate copolymer, polyvinyl chloride, polyurethane, and the like, metal foils, nonwovens, fabrics, and commercially available laminates. Typical backing materials have thicknesses ranging from 2 to 1000 μm. For example, 3M's ScotchPak™ 1012 or 9732 backing materials (polyester films with a thermal barrier layer of ethylene vinyl acetate copolymer) are useful in the transdermal drug delivery systems described herein.

[0024] Transdermal drug delivery systems can also include a release liner, which is usually located adjacent to the surface opposite to the backing layer of the system.If present, the release liner is removed from the system before use to expose the polymer matrix layer and / or adhesive layer before topical application.Materials suitable for use as release liner are well known in the art, and include the commercially available products of Dow Corning Corporation labeled Bio-Release® liner and Syl-off® 7610 (both silicone-based), and 3M's 1020, 1022, 9744, 9748 and 9749 Scotchpak® (polyester film coated with fluoropolymer). The transdermal drug delivery system can be packaged or provided in a package such as a pouch stock material commonly used in the art for transdermal drug delivery systems, for example, DuPont's Surlyn® can be used in pouch stock materials. As used herein, a "monolithic" transdermal drug delivery system can include a backing layer and / or a release liner and can be provided in a package.

[0025] Polymer Matrix According to some embodiments, the compositions described herein comprise a polymer matrix that comprises, consists essentially of, or consists of levonorgestrel, ethinyl estradiol, at least one acrylic polymer, at least one penetration enhancer, and a moisturizing agent. In this context, the phrase "consists essentially of" means that it is substantially free of other polymeric components (e.g., substantially free of polymers other than one or more acrylic polymers), but the polymer matrix may contain other excipients known to be useful in transdermal compositions (such as viscosity agents, plasticizers, crosslinking agents, or other excipients known in the art). However, these other excipients do not reduce the physical and / or pharmacokinetic properties of the composition to a level that is medicamentally unacceptable. In some embodiments, the polymer matrix comprises (on a dry weight basis) about 0.1-3% levonorgestrel, about 0.1-5% ethinyl estradiol, about 1-30% penetration enhancer, about 3-10% humectant, and the balance acrylic polymer.

[0026] Levonorgestrel Levonorgestrel is a synthetic progestogen. It is an optical isomer of the chiral compound 13-ethyl-17-ethynyl-17-hydroxy-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-one. Ethinyl estradiol Ethinyl estradiol is an estrogen with the chemical name 19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol. The amount of levonorgestrel and ethinyl estradiol incorporated into the polymer matrix varies depending on the desired therapeutic effect and the time interval for which the system provides therapy. For most drugs, drug passage through the skin is the rate-limiting step of delivery. The minimum amount of drug in the system is selected based on the amount of drug that passes through the skin during the time interval for which the system provides therapy. In some embodiments, the system for transdermal delivery of levonorgestrel and ethinyl estradiol is used for a period of about 1 day, about 3 days, about 7 days, or more. Thus, in some embodiments, the system includes an amount of drug (e.g., levonorgestrel and ethinyl estradiol) sufficient to deliver a therapeutically effective amount of drug for a period of 1 to 3 days, 7 days, or more, including 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more.

[0027] Surprisingly, the inventors have discovered that the amount of ethinyl estradiol can be selected and controlled to select and control the transdermal delivery of ethinyl estradiol without substantially affecting the transdermal delivery of levonorgestrel, i.e., the flux of ethinyl estradiol can be increased by increasing the relative amount of ethinyl estradiol without substantially affecting the transdermal delivery of levonorgestrel. In some embodiments, the polymer matrix comprises about 0.1% to about 50% dry weight, including about 1% to about 20%, such as about 1% to about 10% dry weight, of active agent. In some embodiments, the polymer matrix comprises about 0.1% to about 25% dry weight, including about 1% to about 5% dry weight, of levonorgestrel. In some embodiments, the polymer matrix comprises about 0.1% to about 25% dry weight, including about 1% to about 10%, such as about 1% to about 5% dry weight, of ethinyl estradiol. In some embodiments, the polymer matrix comprises about 0.1% to 3% dry weight or 0.1% to 5% dry weight of levonorgestrel. In some embodiments, the polymer matrix comprises about 0.1% to 3% dry weight or 0.1% to 5% dry weight of ethinyl estradiol.

[0028] Acrylic Polymer The term "acrylic polymer" is used herein interchangeably with "polyacrylate," "polyacrylic polymer," and "acrylic adhesive," as in the art. The acrylic polymer may be any homopolymer, copolymer, terpolymer, etc., of various acrylic acids or esters. In some embodiments, the acrylic polymer is an adhesive polymer. In other embodiments, the acrylic polymer functions as an adhesive by adding tackifiers, plasticizers, crosslinkers, or other additives. The acrylic polymer can include copolymers, terpolymers, and multipolymers. For example, the acrylic polymer can be any homopolymer, copolymer, terpolymer, etc. of various acrylic acids. In some embodiments, the amount and type of acrylic polymer depends on the amount of levonorgestrel and ethinyl estradiol used.

[0029] Acrylic polymers useful in the practice of the invention include polymers of one or more monomers of acrylic acid and other copolymerizable monomers. Acrylic polymers also include copolymers of alkyl acrylates and / or methacrylates and / or copolymerizable secondary monomers or monomers with functional groups. Combinations of acrylic polymers based on their functional groups are also contemplated. Acrylic polymers with functional groups include copolymers and terpolymers that further include monomer units with free functional groups in addition to non-functional monomer units. The monomers may be monofunctional or polyfunctional. The adhesive properties of the resulting acrylic polymer can be varied by varying the amount of each type of monomer added, as is known in the art. In some embodiments, the acrylic polymer consists of at least 50% by weight of acrylate or alkyl acrylate monomers, 0-20% of functional monomers copolymerizable with acrylates, and 0-40% of other monomers.

[0030] Acrylate monomers that can be used include acrylic and methacrylic acid and alkyl acrylates or methacrylates such as methyl acrylate, ethyl acrylate, propyl acrylate, amyl acrylate, butyl acrylate, butyl methacrylate, hexyl acrylate, methyl methacrylate, hexyl methacrylate, heptyl acrylate, octyl acrylate, nonyl acrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate, glycidyl acrylate, and the corresponding methacrylates. A non-functional acrylic polymer can include any acrylic polymer that is free or substantially free of free functional groups. Functional monomers which are copolymerizable with the above alkyl acrylates and methacrylates which can be used include acrylic acid, methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate, methoxyethyl acrylate and methoxyethyl methacrylate.

[0031] As used herein, a "functional monomer or group" is a monomer unit typically present in an acrylic polymer that has a reactive chemical group that directly modifies the acrylic polymer or provides a site for further reaction. Examples of functional groups include carboxyl, epoxy, hydroxyl, sulfoxyl, and amino groups. Acrylic polymers with functional groups further include monomer units with free functional groups in addition to the non-functional monomer units listed above. The monomers may be monofunctional or polyfunctional. These functional groups include carboxyl, hydroxyl, amino, amide, epoxy, and the like. Typical carboxyl-functional monomers include acrylic acid, methacrylic acid, itaconic acid, maleic acid, and crotonic acid. Exemplary hydroxy-functional monomers include 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, hydroxymethyl acrylate, hydroxymethyl methacrylate, hydroxyethyl acrylate, hydroxyethyl methacrylate, hydroxypropyl acrylate, hydroxypropyl methacrylate, hydroxybutyl acrylate, hydroxybutyl methacrylate, hydroxyamyl acrylate, hydroxyamyl methacrylate, hydroxyhexyl acrylate, and hydroxyhexyl methacrylate. As noted above, in some embodiments, the acrylic polymer does not contain such functional groups.

[0032] In some embodiments, the acrylic polymer comprises a hydroxy-functional monomer, including an acrylic polymer having a vinyl acetate group. Such polymers generally exhibit good solubility for levonorgestrel, such that sufficient levonorgestrel can be loaded into the polymer to prepare a system that provides transdermal delivery of a therapeutically effective amount of the active agent for an extended period of time, such as at least 3 days, at least 4 days, at least 7 days, or more. Further details and examples of acrylic adhesives suitable for the practice of the present invention are described in Satas, "Acrylic Adhesives," Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., p. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989); "Acrylic and Methacrylic Ester Polymers," Polymer Science and Engineering, Vol. 1, 2nd ed., p. 234-268, John Wiley & Sons, (1984); U.S. Pat. No. 4,390,520; and U.S. Pat. No. 4,994,267, all of which are expressly incorporated by reference in their entireties.

[0033] Suitable acrylic polymers also include commercially available pressure sensitive adhesives, such as acrylic adhesives sold under the trademarks DURO-TAK® (such as DURO-TAK® 87-900A, 87-2516, 87-2287, -4098, -4287, -2852, -2196, -2296, -2194, -2516, -2070, -2353, -2154, -2510, -9085, -9088, and 73-9301) and GELVA® Multipolymer Solution (such as GELVA® 2480, 788, 737, 263, 1430, 1753, 1151, 2450, 2495, 3067, 3071, 3087, and 3235), both from Henkel Corporation, Bridgewater, N.J. Other suitable acrylic adhesives include those sold under the trademark EUDRAGIT® by Evonik Industries AG Pharma Polymers, Darmstadt, Germany. For example, hydroxy-functional adhesives having reactive functional OH groups in the polymer chain can be used. Commercially available examples of this type of adhesive include, but are not limited to, both GELVA® 737, 788, and 1151 and DURO-TAK® 87-2287, -4287, -2510, -2516 387-2510, and 387-2287. In some embodiments, the acrylic polymer comprises up to, and including, 100% by weight of the polymer content of the polymer matrix.

[0034] Silicone Polymer The term "silicone polymer" is used herein interchangeably with the terms siloxane, polysiloxane and silicone as known in the art. Suitable silicone polymers may also be pressure sensitive adhesives. Thus, in some embodiments, the silicone-based polymer is an adhesive polymer. In other embodiments, the silicone-based polymer functions as an adhesive by adding a tackifier, a plasticizer, a crosslinker, or other additives. Suitable silicone polymers include silicone pressure sensitive adhesives based on two main components (i) a polymer or gum and (ii) a tackifying resin. Silicone pressure sensitive adhesives can be prepared by crosslinking the gum, which is typically a high molecular weight polydiorganosiloxane, with the resin to produce a three-dimensional silicate structure via a condensation reaction in a suitable organic volatile solvent such as ethyl acetate or heptane. The physical properties of silicone pressure sensitive adhesives can be modified by adjusting the ratio of resin to polymer. See Sobieski et al., “Silicone Pressure Sensitive Adhesives,” Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., pp.508-517 (D.Satas,ed.), Van Nostrand Reinhold,New York (1989).

[0035] Exemplary silicone pressure-sensitive polymers are adhesives (e.g., can stick to the site of topical application), including pressure-sensitive adhesives.Exemplary examples of silicone polymers with reduced silanol concentration include those described in U.S. Patent Re. 35,474 and U.S. Patent No. 6,337,086, the entirety of which is incorporated herein by reference, and silicone-based adhesives (and capped polysiloxane adhesives), such as those commercially available from Dow Corning Corporation (Dow Corning Corporation, Medical Products, Midland, Michigan) as BIO-PSA® 7-4100, -4200 and -4300 product series, and non-pressure-sensitive adhesives that are produced with compatible organic volatile solvents (such as ethyl acetate or heptane) and commercially available as BIO-PSA® 7-4400 series, -4500 series and 4600 series. Further details and examples of silicone pressure sensitive adhesives useful in the polymer matrices, compositions and methods described herein are described in the following U.S. Patents: 4,591,622, 4,584,355, 4,585,836, and 4,655,767, all of which are expressly incorporated herein by reference in their entirety. It should also be understood that silicone fluids are contemplated for use in the polymer matrices and methods described herein.

[0036] In some embodiments, the silicone polymer comprises about 1% to about 25% of the polymer matrix, including about 1%, about 5%, about 10%, about 15%, or about 25% by weight of the polymer matrix, based on the dry weight of the polymer matrix. In some embodiments, the amount and type of silicone polymer depends on the amount and type of acrylic polymer (if any) used in the polymer matrix and / or the amount of levonorgestrel and ethinyl estradiol formulated. For example, in some embodiments, the amount of acrylic polymer and silicone polymer affects the delivery rate of the drug from the system and through the skin by adjusting to modify the saturation concentration of the drug in the polymer matrix. Penetration Enhancer In some embodiments, the polymer matrix comprises a permeation enhancer. A "permeation enhancer" is an agent that is known to accelerate drug delivery in the skin. These agents are also called accelerators, adjuvants and sorption enhancers, and are collectively referred to herein as "enhancers". This class of agent includes agents with a wide range of mechanisms of action, including agents that function to improve percutaneous absorption, for example, by changing the water-retaining ability of the stratum corneum, softening the skin, improving the permeability of the skin, acting as a permeation aid or hair follicle opener, or by changing the skin condition, including the boundary layer.

[0037] Exemplary penetration enhancers include, but are not limited to, polyhydric alcohols such as dipropylene glycol, propylene glycol, and polyethylene glycol; oils such as olive oil, squalene, and lanolin; aliphatic ethers such as cetyl ether and oleyl ether; fatty acid esters such as isopropyl myristate; urea and urea derivatives such as allantoin, which affect the ability of keratin to retain moisture; polar solvents such as dimethydecyl phosphoxide, methyl octyl sulfoxide, dimethyl lauryl amide, dodecyl pyrrolidone, isosorbitol, dimethyl acetonide, dimethyl sulfoxide, decyl methyl sulfoxide, and dimethyl formamide, which affect keratin permeability; salicylic acid, which softens keratin; amino acids, which are penetration aids; benzyl nicotinate, which is a hair follicle opener; and high molecular weight aliphatic surfactants such as lauryl sulfate salts, which alter the surface condition of the skin and the administered drug. Other agents include oleic and linoleic acid, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate, and isopropyl palmitate.

[0038] As mentioned above, one problem addressed by the present invention is the low skin permeability of levonorgestrel.Surprisingly, the inventors have found that each dipropylene glycol (DPG) and diethylene glycol monoethyl ether are effective enhancers for levonorgestrel, both alone and in combination with each other and / or in combination with one or more of glyceryl monooleate (GMO) and isopropyl myristate (IMP).Also surprisingly, the inventors have found that the combination of dipropylene glycol (DPG) and diethylene glycol monoethyl ether, which may be together with one or more of glyceryl monooleate (GMO) and isopropyl myristate (IMP), is an effective enhancer for levonorgestrel, and the combination of dipropylene glycol (DPG), diethylene glycol monoethyl ether, and glyceryl monooleate (GMO), or the combination of dipropylene glycol (DPG), diethylene glycol monoethyl ether, and isopropyl myristate is a particularly effective enhancer for levonorgestrel. Thus, in some embodiments, the penetration enhancer includes DPG and diethylene glycol monoethyl ether (Transcutol®), and may include one or more of a GMO and an IPM together, including combinations of DPG, diethylene glycol monoethyl ether and GMO, and combinations of DPG, diethylene glycol monoethyl ether and IPM.

[0039] Also surprisingly, the inventors have found that each of DPG, GMO and MeLau is an effective enhancer for levonorgestrel, both alone and in combination with each other and / or with one or more of diethylene glycol monoethyl ether and / or DMI, and that the combination of two or more of DPG, GMO and MeLau is particularly effective, either alone or in further combination with one or more of diethylene glycol monoethyl ether and / or DMI.Thus, in some embodiments, the penetration enhancer comprises any two or more of DPG, GMO and MeLau, or all three.In other embodiments, the penetration enhancer comprises a mixture of one or more of GMO, DPG and MeLau with one or more of diethylene glycol monoethyl ether and DMI. In certain embodiments, the penetration enhancer comprises glyceryl monooleate and dipropylene glycol; glyceryl monooleate and methyl laurate; glyceryl monooleate, dipropylene glycol and diethylene glycol monoethyl ether; or glyceryl monooleate, dipropylene glycol and dimethyl isosorbide. Surprisingly, it has been found that the use of these enhancers increases the contraceptively effective levonorgestrel flux over a sustained delivery period, such as 7 days. These effects are discussed in more detail in the examples below. (Because ethinyl estradiol has relatively high solubility in hydroxyl-functional acrylic polymers, its flux can be adjusted by modifying its concentration in the polymer matrix.) In some embodiments, the total amount of permeation enhancer is up to about 30%, including up to 30%, up to about 20%, including 20%, up to about 10%, including 10%, or up to about 5%, including 5%, by dry weight of the polymer matrix. In some embodiments, the total amount of permeation enhancer is from about 1% to about 25%, including about 1%, 2%, 3%, 4%, 5%, 6%, 10%, 15%, 20%, 25%, 28%, or 30% by weight.

[0040] When a combination of enhancers is used, the individual enhancers may be present in an amount of about 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 11.0%, 12.0%, 13.0%, 14.0%, 15.0%, 16.0%, 17.0%, 18.0%, 19.0%, 20.0%, 21.0%, 22.0%, 23.0%, 24.0%, 25.0%, 26 Various amounts can be used, such as 0.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 11.0%, 12.0%, 13.0%, 14.0%, 15.0%, 16.0%, 17.05%, 18.0%, 19.0% and 20.0% by weight. For example, DPG can increase the flux of levonorgestrel when used in an amount of about 5% or less by dry weight or about 2.75% or less by dry weight. GMO can increase the flux of levonorgestrel when used in an amount of about 6.5% or less by dry weight or about 3% or less by dry weight. Diethylene glycol monoethyl ether can increase the flux of levonorgestrel when used in an amount of about 0.5% by dry weight or less, or about 0.4% by dry weight or less, or about 0.3% by dry weight or less. DMI can increase the flux of levonorgestrel when used in an amount of about 1.5% by dry weight or less. IPM can increase the flux of levonorgestrel when used in an amount of about 5% by dry weight or less. Given this guidance, one skilled in the art can determine the flux-increasing amount of each individual enhancer described herein used in combination with one or more other enhancers described herein by routine screening, such as by evaluating the flux of levonorgestrel when the amount of enhancer is varied.

[0041] In some embodiments, the polymer matrix comprises about 2.75% by weight dipropylene glycol, about 0.3% to about 0.4% by weight diethylene glycol monoethyl ether (including about 0.3% or about 0.4% by weight diethylene glycol monoethyl ether), and about 3% to about 6.5% by weight glyceryl monooleate (including about 3% or about 6.5% by weight glyceryl monooleate). In other embodiments, the polymer matrix comprises about 5% by weight dipropylene glycol, about 0.3% to about 0.4% by weight diethylene glycol monoethyl ether (including about 0.3% or about 0.4% by weight diethylene glycol monoethyl ether), and about 5% by weight isopropyl myristate, all based on the dry weight (dry weight %) of the polymer matrix.

[0042] In some embodiments, the polymer matrix comprises about 10% by weight glyceryl monooleate and about 10% by weight dipropylene glycol; or about 10% by weight glyceryl monooleate and about 5% by weight methyl laurate; or about 10% by weight glyceryl monooleate, about 10% by weight dipropylene glycol, and about 8% by weight diethylene glycol monoethyl ether; or about 10% by weight glyceryl monooleate, about 10% by weight dipropylene glycol, and about 8% by weight dimethyl isosorbide, all based on the wet weight (wet weight %) of the polymer matrix. In other embodiments, the polymer matrix comprises about 3% by weight glyceryl monooleate, about 6.5% by weight dipropylene glycol, and about 2.1% by weight diethylene glycol monoethyl ether; or about 3% by weight glyceryl monooleate, about 4.2% by weight dipropylene glycol, and about 2.75% by weight diethylene glycol monoethyl ether; or about 3% by weight glyceryl monooleate, about 4.2% by weight dipropylene glycol, and about 4.2% by weight dimethyl isosorbide, all based on the wet weight (wet weight %) of the polymer matrix.

[0043] In other embodiments, the polymer matrix comprises 3% by weight glyceryl monooleate, about 4.25% by weight dipropylene glycol, and about 0.3% by weight diethylene glycol monoethyl ether; or about 3% by weight glyceryl monooleate, about 2.75% by weight dipropylene glycol, and about 0.4% by weight diethylene glycol monoethyl ether; or about 3% by weight glyceryl monooleate, about 2.75% by weight dipropylene glycol, and about 2.5% by weight dimethyl isosorbide, all based on the dry weight (dry weight %) of the polymer matrix.

[0044] Moisturizer In some embodiments, the polymer matrix comprises a humectant. Suitable humectants for use in transdermal drug delivery systems are known and include polyvinylpyrrolidone (PVP), cross-linked PVP (crospovidone) and polyvinylpyrrolidone / vinyl acetate (PVP / VA, copovidone), as well as combinations of any two or more thereof. The amount of humectant can be selected based on the desired properties, such as an amount effective to inhibit crystallization of levonorgestrel and / or an amount effective to impart desired physical properties, such as adhesive properties, such as shear, of the polymer matrix. In some embodiments, the humectant is used in an amount of up to about 3% to about 10% by dry weight of the polymer matrix, including about 3%, about 5%, or about 10% by dry weight. Other Ingredients The polymer matrix can further include a variety of thickeners, fillers and other additives or components known for use in transdermal drug delivery systems. As noted above, in embodiments in which the polymer matrix comprises a pressure-sensitive adhesive or bioadhesive, the polymer matrix can serve as the adhesive portion of a system (e.g., a reservoir device) or can serve as one or more layers of a multi-layer system. Alternatively, a polymer matrix comprising a pressure-sensitive adhesive or bioadhesive with a drug dissolved or dispersed therein can constitute a monolithic device. In embodiments in which the polymer matrix does not comprise an adhesive, but instead comprises, for example, a polymerizable drug reservoir, the polymer matrix can be used in combination with one or more adhesive layers or with a surrounding adhesive portion, as known to those skilled in the art.

[0045] Transdermal Drug Delivery Systems In some embodiments, the transdermal drug delivery system consists essentially of a polymer matrix layer. By "consist essentially of a polymer matrix layer" it is meant that the system does not contain any other layers that affect drug delivery, such as additional surface adhesive layers, rate-controlling polymer layers, rate-controlling membranes, or drug reservoirs. However, it is understood that the system consisting essentially of a polymer matrix layer may also include a backing layer and / or a release liner. In some embodiments, the transdermal drug delivery system includes a surface adhesive layer disposed on the skin-contacting side of the drug-containing polymer layer as illustrated in FIG. 1B. In certain embodiments, the surface adhesive is a silicone surface adhesive that includes a silicone adhesive, such as a silicone pressure sensitive adhesive, and may include one or more permeation enhancers, such as those discussed above. In certain embodiments, the surface adhesive includes, on a dry weight / weight basis, about 90 to about 100% silicone adhesive polymer and about 0 to about 10% of one or more permeation enhancers. Suitable pressure sensitive adhesives for use in the surface adhesive layer include silicone pressure sensitive adhesives manufactured by Dow Corning, such as those in the BIO-PSA 4100, 4200, 4300, 4500, 4600 series. The surface adhesive may consist of a single silicone pressure sensitive adhesive or a blend of two or more silicone pressure sensitive adhesives. In certain embodiments, the surface adhesive consists of Bio PSA4502 or a blend of BIO-PSA5402 and 4602, such as a blend in which the ratio of BIO-PSA4502:Bio-PSA4602 is 1:1 or 1:3. As noted above and illustrated in the examples below, it has surprisingly been discovered that the presence of a surface adhesive layer in the systems described herein does not substantially affect drug flux.

[0046] The system may be of any shape or size suitable for transdermal application. The polymer matrix described herein can be prepared by methods known in the art. The polymer matrix can be formed into a system by methods known in the art. For example, the polymer matrix material can be applied to a backing layer and a release liner by methods known in the art and formed into a size and shape suitable for use. For example, after the polymer matrix is ​​formed, it can be contacted with a support layer, such as a release liner layer or a backing layer, by any manner known to those skilled in the art. Such techniques include calendar coating, hot melt coating, solution coating, and the like. When a surface adhesive layer is present, the system can be made by forming the polymer matrix on a backing material, forming a surface adhesive layer on a release liner, and then applying the surface adhesive layer to the polymer matrix layer.

[0047] For example, the polymer matrix can be prepared by blending the components of the polymer matrix, applying the matrix material to a support layer such as a backing layer or release liner, and removing any residual solvent, such as by drying. The levonorgestrel and ethinyl estradiol can be added at any stage. In one embodiment, all of the polymer matrix components, including levonorgestrel and ethinyl estradiol, are blended together. In another embodiment, the polymer matrix components other than levonorgestrel and ethinyl estradiol are blended together, and then the levonorgestrel and ethinyl estradiol are dissolved or dispersed therein. The order of the stages, the amount of components, and the amount and time of stirring or mixing can be determined and optimized by a specialist. An exemplary general method is as follows: Appropriate amounts of polymer, levonorgestrel, ethinyl estradiol, enhancer, and organic solvent (eg, toluene, or ethyl acetate and / or isopropyl alcohol) are combined in a container and mixed together thoroughly.

[0048] The formulation is then transferred to a coating operation where it is coated at a specific, controlled thickness onto a protective release liner. The coated product is then passed through an oven to remove all volatile process solvents. The dried product on the release liner is then bonded to a backing material and wound into a roll for storage. If a surface adhesive is used, a surface adhesive solution containing the surface adhesive in a suitable solvent can be coated onto a release liner and dried in a convection oven. The dried surface adhesive on the release liner can be laminated with a prepared drug-loaded adhesive polymer matrix (after removing the release liner) to form a laminate with the surface adhesive. "Systems" of appropriate size and shape are die cut from roll material and then placed into pouches. Other manufacturing methods suitable for producing the systems described herein are known in the art.

[0049] In some embodiments, a method is provided for carrying out effective transdermal drug delivery of levonorgestrel and ethinylestradiol by applying the system described herein to the skin or mucosa of a subject in need thereof.In some embodiments, the system is applied for a period of at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, or at least about 7 days, such as 1, 2, 3, 4, 5, 6 or 7 days.In some embodiments, the method is effective for achieving therapeutic levels of levonorgestrel and ethinylestradiol in the subject during the application period. In some embodiments, the systems described herein are designed for use by female patients, such as for contraception. The following specific examples are included as illustrations of the transdermal drug delivery systems and polymer matrices described herein. These examples are not intended to limit the scope of the invention in any way. Other aspects of the invention will be apparent to those of skill in the art to which the invention pertains. EXAMPLES

[0050] (Example 1) A polymer matrix containing 0.5% ethinyl estradiol and 1.2% levonorgestrel in a hydroxyl functional acrylic polymer may be prepared using the following ingredients and applied to a backing material and dried to provide a surface adhesive layer containing a blend of silicone pressure sensitive adhesive. Shear properties and drug flux in human cadaver skin were evaluated. Shear results are displayed in the table below and flux results are displayed in Figures 2-5 compared to Climara® Pro (levonorgestrel) or Ortho Evra (ethinyl estradiol). Figures 6 and 7 directly compare drug flux using systems with and without a surface adhesive.

[0051] TIFF0007625623000001.tif175168

[0052] As can be seen from the shear data, the matrices formulated without humectants exhibited very little shear (and low adhesive strength), while the matrices formulated with humectants exhibited satisfactory shear values ​​(and satisfactory adhesive strength). As can also be seen from the figure, the matrices formulated with humectants also exhibited good drug flux. Surprisingly, the results show that the systems described herein, including various combinations of GMO, DPG and MeLau enhancers, can achieve good drug flux with good Jmax values, sustained drug flux over extended delivery periods, and increased cumulative delivery with relatively little degradation. See, e.g., Figures 2-5. Also surprisingly, the results show that the use of a surface adhesive did not substantially affect drug flux, see Figures 6 and 7. Furthermore, the shear values ​​of the systems with a surface adhesive were comparable to the shear values ​​of the corresponding systems without a surface adhesive.

[0053] (Example 2) A polymer matrix containing 0.5% ethinylestradiol and 1.2% levonorgestrel in a hydroxy-functional acrylic polymer may be prepared using the following ingredients, applied to a backing material, and dried to provide a surface adhesive layer containing a silicone pressure sensitive adhesive. Drug flux in human cadaver skin was evaluated and compared with Climara® Pro and another reference system with DMSO as an enhancer. The results are shown in the table below.

[0054] TIFF0007625623000002.tif211168

[0055] TIFF0007625623000003.tif137168

[0056] TIFF0007625623000004.tif102168

[0057] Surprisingly, the results show that the systems described herein that include GMO and DPG enhancers can achieve drug fluxes comparable to those of a reference DMSO-based composition that has been reported to be effective for contraception (as shown by the "ratio" data reported above). Also surprising, the results show that the systems described herein that include GMO, DPG, and diethylene glycol monoethyl ether or DMI as enhancers can achieve greater flux levels than the reference DMSO-based composition. Similar to Example 1, these results also show that the surface adhesive does not negatively impact drug flux, which was surprising.

[0058] (Example 3) A polymer matrix containing 0.3% ethinylestradiol and 1.0% levonorgestrel in a hydroxy-functional acrylic polymer was prepared using the following components, applied to a backing layer, and dried. Drug flux in human cadaver skin was evaluated and compared with Climara® Pro and another reference system with DMSO as an enhancer. The results are displayed in the table below and in Figure 8. Formulation 20 (dry mass%): EEE=0.3% LNG=1.0% PVP K-30=5.0% GMOs = 3.0% DPG=4.25% Transcutol® = 0.3% DuroTak® 87-2516 = QS (approximately 86.15%) Formulation 21 (dry mass%): EEE=0.3% LNG=1.0% PVP K-30=5.0% GMOs = 3.0% DPG=2.75% Transcutol® = 0.4% DuroTak® 87-2516 = QS (approximately 87.55%) Formulation 22 (dry mass%): EEE=0.3% LNG=1.0% PVP K-30=5.0% GMOs = 3.0% DPG=2.75% DMI=2.5% DuroTak® 87-2516 = QS (approximately 85.45%)

[0059] TIFF0007625623000005.tif94168

[0060] TIFF0007625623000006.tif84168

[0061] (Example 4) Polymer matrices were prepared to maximize the levonorgestrel content based on solubility and drug flux, and the ethinyl estradiol content was varied to obtain a suitable ratio of ethinyl estradiol to levonorgestrel for use in contraception. The matrices were applied to backing layers and release liners and their properties were evaluated and summarized below. Formulation 23 (dry mass%) E = 0.25% LNG=1.0% IPM=5% DPG=5% Transcutol® = 0.3% K-30=10% DuroTak 87-2516=QS=78.45% Coating mass 12.5mg / cm 2 Apply in Silicone pressure sensitive adhesive surface adhesive (5mg / cm 2 ) Formulation 24 (dry mass%) EEE=0.3% LNG=1.0% GMOs = 6.5% DPG=2.75% Transcutol® = 0.4% K-30=5% DuroTak 87-2516=QS=84.05% Coating mass: 12.5mg / cm 2 Formulation 25 (dry mass%) EEE=0.3% LNG=1.0% GMO=3% DPG=2.75% Transcutol® = 0.4% K-30=5% Bio PSA 4502=15% DuroTak 87-2516=QS=72.55% Coating mass: 12.5mg / cm 2

[0062] 9-11 show the mean and cumulative ethinyl estradiol (EE) (FIGS. 9A, 10A, 11A) and levonorgestrel (LNG) (FIGS. 9B, 10B, 11B) flux (μg / cm) over time (0-168 hours) from the transdermal delivery systems described in Example 4 (Formulations 23-25). 2 The results show that the systems described herein, including the enhancers dipropylene glycol, diethylene glycol monoethyl ether, and either glyceryl monooleate or isopropyl myristate, provide good drug delivery and can provide sustained drug flux over an extended delivery period.

[0063] The placebo versions of formulations 23-25 ​​(containing neither EE nor LNG) proved to be particularly good formulations to use in 7-day applications, as they showed good results in wear and animal irritation tests (data not shown). The results of these studies also show that the systems described herein comprising a polymer matrix containing isopropyl myristate as an enhancer and a silicone pressure sensitive adhesive surface adhesive exhibited both good fluxing properties and particularly good 7-day wear properties, with excellent adhesion in the 7-day wear study.

Claims

1. A transdermal drug delivery system for transdermal delivery of levonorgestrel and ethinyl estradiol in the form of a flexible, finite system for topical application, comprising a polymer matrix comprising levonorgestrel, ethinyl estradiol, an acrylic polymer comprising a hydroxy-functional acrylic polymer, a humectant, a first enhancer comprising glyceryl monooleate, and a second enhancer comprising methyl laurate, wherein the transdermal drug delivery system provides sustained transdermal delivery of the levonorgestrel and ethinyl estradiol for a period of at least 3 days, at least 4 days, or at least 7 days.

2. 2. The transdermal drug delivery system of claim 1, wherein the polymer matrix comprises, on a dry weight basis, about 0.1-3% levonorgestrel, about 0.1-5% ethinyl estradiol, about 1-30% first and second enhancers, about 3-10% humectant, and the remainder acrylic polymer.

3. 2. The transdermal drug delivery system of claim 1, wherein the humectant is selected from the group consisting of polyvinylpyrrolidone (PVP), cross-linked PVP (crospovidone) and polyvinylpyrrolidone / vinyl acetate (copovidone).

4. The transdermal drug delivery system of claim 1 , wherein the polymer matrix further comprises a silicone pressure sensitive adhesive.

5. The transdermal drug delivery system of claim 1 further comprising a backing layer.

6. The transdermal drug delivery system of claim 1 further comprising a release liner.

7. 7. The transdermal drug delivery system of claim 1, further comprising a surface adhesive layer disposed on the skin-contacting side of the polymer matrix.

8. The transdermal drug delivery system of claim 7 , wherein the surface adhesive layer comprises a silicone pressure sensitive adhesive.

9. A transdermal drug delivery system for use in transdermally delivering levonorgestrel and ethinyl estradiol to a subject in need thereof, which may include a surface adhesive layer disposed on the skin-contacting side of the polymer matrix and is applied to the skin or mucosa of the subject, as described in any one of claims 1 to 5.

10. A transdermal drug delivery system for use in providing contraception to a female subject in need thereof, which may include a surface adhesive layer disposed on the skin-contacting side of the polymer matrix and is applied to the skin or mucosa of the subject, as described in any one of claims 1 to 5.

11. 11. The transdermal drug delivery system of claim 9 or 10, wherein the transdermal drug delivery system is applied continuously for up to 7 days.

12. Use of levonorgestrel and ethinyl estradiol for preparing a medicament for contraception in a female subject in need thereof, wherein the medicament is in the form of a transdermal drug delivery system as described in any one of claims 1 to 5, and the transdermal drug delivery system may comprise a surface adhesive layer disposed on the skin-contacting side of the polymer matrix.

13. 1. A method for preparing a transdermal drug delivery system comprising levonorgestrel and ethinyl estradiol in the form of a flexible, finite system for topical application, comprising: preparing a polymer matrix comprising, on a dry weight percent basis, about 0.1-3% levonorgestrel, about 0.1-5% ethinyl estradiol, a hydroxyl-functional acrylic polymer, about 3-10% humectant selected from the group consisting of polyvinylpyrrolidone (PVP), cross-linked PVP (crospovidone) and polyvinylpyrrolidone / vinyl acetate (copovidone), and about 1-30% first and second enhancers; the first enhancer comprises glyceryl monooleate and the second enhancer comprises methyl laurate; The method, wherein the transdermal drug delivery system provides sustained transdermal delivery of levonorgestrel and ethinyl estradiol for a period of at least 3 days, at least 4 days, or at least 7 days.

14. The method of claim 13 further comprising applying a surface adhesion layer to the polymer matrix.

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