NZ624117B2

NZ624117B2 - Dermal delivery compositions and methods

Info

Publication number: NZ624117B2
Application number: NZ624117A
Authority: NZ
Inventors: Alfred F Altomari; Charles G Arnold; Agis Kydonieus; Thomas M Rossi
Original assignee: Agile Therapeutics Inc; Alfred F Altomari; Charles G Arnold; Agis Kydonieus; Thomas M Rossi
Priority date: 2011-11-04
Filing date: 2012-11-02
Publication date: 2016-05-27

Abstract

Disclosed is a composition for transdermal delivery of a progestin and a transdermal delivery device comprising: (a) a polymeric pressure sensitive adhesive; (b) a progestin such as levonorgestrel; (c) a skin permeation enhancer such as DMSO; (d) an anti-oxidant; and a component that contributes to degradation of the progestin, wherein the component is one or more of an organic solvent, polyvinyl pyrrolidone (PVP), or a PVP copolymer. Also disclosed is a method of improving the stability of a progestin-only transdermal delivery composition comprising an oxidizing agent and an anti-oxidant other than estrogen in the composition. degradation of the progestin, wherein the component is one or more of an organic solvent, polyvinyl pyrrolidone (PVP), or a PVP copolymer. Also disclosed is a method of improving the stability of a progestin-only transdermal delivery composition comprising an oxidizing agent and an anti-oxidant other than estrogen in the composition.

Description

Title Dermal Delivery Compositions and Methods Field of the ion This invention is in the ﬁeld of transdermal delivery of steroid hormones.

Background of the Invention Various adhesive matrix compositions have been developed for transdermal delivery of steroid hormones. For example, US. Patent No. 7,384,650 describes a transdermal hormone delivery system that utilizes an adhesive composition sing a pressure sensitive adhesive (PSA), a humectant, a skin permeation enhancer, an estrogen and a progestin.

US. Patent Publications 2010/0292660 and 2010/0255072 be transdermal ry systems that can be used, among other ways, in conjunction with the PSA matrix described in US 7,384,650.

The above-cited patent and patent applications are incorporated by reference as though fully set forth herein.

Summam ofthe Invention This invention relates to a polymeric matrix useful in a transdermal delivery system for transdermal delivery of a progestin, in the absence of an estrogen.

One aspect of the invention features composition for transdermal delivery of a progestin that ses: (a)a carrier, (b) a progestin, (c) a skin permeation enhancer and (d) an anti- oxidant, wherein the ition comprises a component that contributes to degradation of the progestin, wherein the component is one or more of an organic solvent, polyvinyl pyrrolidone (PVP), or a PVP copolymer. In one embodiment, the carrier is a polymeric pressure sensitive ve. In one ment, the ent that contributes to degradation of the progestin is one or more of PVP, polyvinyl pyrrolidone/vinyl acetate (PVP/VA), or dimethyl sulfoxide (DMSO) and the anti-oxidant is not an estrogen or is onal to an estrogen.

The progestin can be desogestrel, oprogesterone, drospirenone, ethynodiol acetate, ethynodiol diacetate, etogestrel, gestodene, gestogen, l7-hydrogesterone, hydroxyprogesterone caproate, 3-keto-desogestrel, levonorgestrel, medroxyprogesterone acetate, medroxyprogesterone diacetate, megestrol, megestrol acetate, normegesterol, norelgestromin, norethindrone (i.e., norethisterone), norethindrone acetate, norethynodrel, norgestimate, norgestrel, l9-nortestosterone, progesterone, nestorone, yprogesterone, or dl-norgestrel, or any ation of two or more of said tins. In certain embodiments, the progestin is levonorgestrel or norethindrone e.

The anti-oxidant is selected from Vitamins A, C, D, and E, carotenoids, ﬂavanoids, isoﬂavanoids, beta-carotene, butylated hydroxytoluene (“BHT”), ted hydroxyanisole (BHA), glutathione, lycopene, gallic acid and esters thereof, salicylic acid and esters f, sulfites, alcohols, amines, amides, sulfoxides, surfactants, or any combination thereof. In certain embodiments, the anti-oxidant is sodium bisulfite, sodium sulﬁte, isopropyl gallate, Vitamin C and E, Irganox lOlO, Irgafos 168 or BHT or any combination of two or more of those anti-oxidants. In certain embodiments, the anti-oxidant comprises one or more phenolic anti-oxidants. In particular, the anti-oxidant is BHT, pentaerythritol tetrakis(3-(3,5-di-tert- butylhydroxyphenyl)propionate), or tris(2,4-di-tert-butylphenyl) phosphite.

In certain embodiments, the polymeric r is a pressure sensitive adhesive (PSA) selected from a polyacrylate adhesive, a polyisobutylene adhesive, or a silicone adhesive. The PSA may be polymerized by free radical polymerization. For instance, the PSA can be a polyacrylate ve. The PSA may comprise a lhexyl acrylate co-monomer. The polyacrylate adhesive can ﬁthher comprise about 50 to 60% w/w vinyl acetate co-monomer.

In certain embodiments, the skin tion er comprises one or more of: ls; alkanones; amides and other nitrogenous compounds; l-substituted azacycloheptanones; bile salts; cholesterol; cyclodextrins and substituted cyclodextrins; ; saturated and unsaturated fatty acids; saturated and unsaturated fatty acid esters; saturated and unsaturated fatty alcohol esters; glycerides and monoglycerides; c acids; methyl nicotinate; pentadecalactone; polyols and esters thereof; phospholipids; sulfoxides; surfactants; terpenes; and combinations thereof. In one embodiment, the skin permeation enhancer comprises an organic solvent. In some instances, the organic solvent is DMSO. In certain embodiments, the skin permeation enhancer comprises one or more of: DMSO, a fatty (Cg-C20) alcohol ester of a hydroxy acid, a lower (C1-C4) alkyl ester of a hydroxy acid, and a C6-C18 fatty acid. In a WO 67346 particular embodiment, the skin permeation enhancer comprises one or more of: DMSO, lauryl lactate, ethyl lactate, and capric acid.

The above-described composition can also include a humectant. In certain embodiments, the humectant is PVP or a PVP ymer, such as PVP/VA.

In various embodiments of the described composition, the tin is present in a concentration based on weight of the composition of 0.1% to 3.0% or 0.2% to 2.0% or 0.5% to 1.5%. The skin permeation enhancer can present in a concentration based on weight of the composition of 1% to 50% or 2% to 40%.

In n ments, the anti-oxidant in the composition includes BHT. The BHT can be present in a concentration based on weight of the hormone of 10% to 500%, 20% to 200%, or 50% to 150%.

In certain embodiments, the composition may be one that does not comprise an estrogen.

In certain embodiments, the anti-oxidant in the composition is pentaerythritol tetrakis (3 -(3,5- di-tert-butylhydroxyphenyl) propionate) or tris (2,4-di-tert-butylphenyl) phosphite.

Another aspect of the invention features a transdermal drug ry device that comprises: (a) a transdermal composition as summarized above, which comprises a PSA and has a skin contacting surface and a non-skin contacting surface; (b) a release liner adjacent the skin contacting surface of the transdermal composition; and (c) a backing layer adjacent the non- skin contacting surface.

Another aspect of the invention features a method of improving the stability of a progestin- only transdermal ry composition that includes an oxidizing agent. The method ses adding an xidant other than an estrogen to the composition. In certain embodiments, the oxidizing agent is one or more of an organic solvent, PVP, or a PVP copolymer. In certain embodiments, the composition comprises a PSA. The tin can be strel, dihydroprogesterone, drospirenone, ethynodiol acetate, ethynodiol diacetate, etogestrel, gestodene, gestogen, 17-hydrogesterone, hydroxyprogesterone caproate, 3-ketodesogestrel , levonorgestrel, medroxyprogesterone acetate, medroxyprogesterone diacetate, megestrol, megestrol acetate, normegesterol, norelgestromin, norethindrone (norethisterone), norethindrone e, norethynodrel, norgestimate, norgestrel, 19-nortestosterone, progesterone, nestorone, methoxyprogesterone, and dl-norgestrel or any combination of two or more of said progestins. In particular, the progestin is levonorgestrel or norethindrone acetate.

In certain embodiments of the , the anti-oxidant is selected from ns A, C, D, and E, carotenoids, ﬂavanoids, isoﬂavanoids, beta-carotene, butylated hydroxytoluene (“BHT”), butylated hydroxyanisole (BHA), glutathione, lycopene, gallic acid and esters thereof, salicylic acid and esters thereof, sulfites, alcohols, amines, amides, sulfoxides, phenolics or surfactants, or any combination of two or more of said anti-oxidants. In particular, the anti-oxidant is sodium bisulfite, sodium sulﬁte, isopropyl gallate, Vitamin C and E, Irganox lOlO, Irgafos 168 or BHT or any combination of two or more of said anti- oxidants.

In certain ments of the method, the polymeric carrier is a PSA selected from a polyacrylate adhesive, a polyisobutylene adhesive, or a silicone adhesive. The PSA may be polymerized by free radical polymerization. For ce, the PSA may be a polyacrylate adhesive. The PSA can comprise a 2-ethylhexyl acrylate monomer. The rylate adhesive can ﬁthher comprises about 3 to 60% w/w vinyl acetate monomer.

In s embodiments of the method, the skin permeation enhancer in the composition comprises one or more of: ls; alkanones; amides and other nitrogenous compounds; 1- substituted azacycloheptanones; bile salts; cholesterol; cyclodextrins and substituted cyclodextrins; ethers; saturated and unsaturated fatty acids; ted and rated fatty acid esters; saturated and unsaturated fatty alcohol esters; glycerides and monoglycerides; organic acids; methyl nicotinate; pentadecalactone; polyols and esters thereof; phospholipids; sulfoxides; tants; terpenes; and ations thereof. In certain embodiments, the enhancer comprises an organic t. In particular, the organic solvent is DMSO. In certain embodiments, the enhancer comprises one or more of: DMSO, a fatty 0) alcohol ester of a y acid, a lower (C1-C4) alkyl ester of a hydroxy acid, and a C6-C18 fatty acid.

In particular, the enhancer comprises DMSO, lauryl lactate, ethyl lactate, and capric acid.

In certain embodiments of the method, the composition ﬁarther comprises a humectant. The humectant may be PVP or a PVP co-polymer, such as PVP/VA.

In various embodiments of the method, the progestin is present in the composition in a concentration based on weight of the composition of 0.1% to 3.0% or 0.2% to 2.0% or 0.5% to 1.5%. The skin permeation enhancer is present in a concentration based on weight of the composition of 1% to 50% or 2% to 40%.

In various embodiments of the , the anti-oxidant in the composition is BHT. The BHT may present in a concentration based on weight of the hormone of 10% to 500%, 20% to 200%, or 50% to 150%.

In various embodiments of the method, the anti-oxidant in the ition is pentaerythritol tetrakis (3-(3,5-di-tert-butylhydroxyphenyl) propionate) or tris (2,4-di-tert-butylphenyl) phosphite.

These and other embodiments, which are more fully described below, are meant to be illustrative and not limiting of the ion.

Detailed Description of the Invention The present invention is useful in delivering a progestin hormone to a patient that can beneﬁt from progestin-only hormone supplementation, z'.e., delivery of a progestin with or without concomitant delivery of an estrogen. In an aspect of the t invention, the progestin, in particular, levonorgestrel, is stabilized, z'.e., ted from degradation, by incorporation of an anti-oxidant. While ethinyl estradiol itself has anti-oxidizing activity, it is contemplated in ance with this invention that if an estrogen is present, then a ﬁarther anti-oxidant that is not an active pharmaceutical ingredient, e.g., that is not ethinyl estradiol or other hormone, is ed in the transdermal composition.

As discussed ﬁarther hereinbelow, n components of a transdermal composition, such as the ermal compositions described in US 7,384,650 and hereinbelow, have been found to contribute to degradation of levonorgestrel. Such components include the polyacrylate pressure sensitive adhesive (“PSA”), the PVP humectant (e. g., PVP/VA), and the dimethyl ide skin permeation enhancer. Incorporation of an excipient that ﬁanctions as an anti- oxidant can t the progestin from degradation, z'.e., it can slow degradation of the progestin, and thereby increase the shelf life of the composition.

Progestin-containing Transdermal Composition: The composition for transdermal delivery, l'.e., systemic delivery through the skin, comprises a progestin, an anti-oxidant, a skin permeation enhancer and a carrier. The composition does not necessarily comprise an estrogen, If it does not, it may be referred to as a “progestin-only transdermal composition”.

The composition optionally also comprises excipients such as gelling agents, plasticizers, humectants, buffers, and the like. The composition can be formulated and applied to the skin, for instance, as a gel, an ointment, or a spray, or it can be contained within a transdermal delivery device, such as a patch, in which the composition is contained, for example, within a reservoir by a semi-permeable membrane or as a soft polymeric matrix that is in direct contact with the skin, z'.e., that is firm enough that a reservoir membrane is not required.

In an illustrative embodiment of the invention, the composition is a polymeric matrix comprising a polymer such as a pressure-sensitive adhesive (PSA) as a carrier, the progestin, the anti-oxidant and the skin permeation enhancer. The polymer can be a re sensitive adhesive ("PSA") that forms a ically able adhesive polymer matrix capable of forming ve active-containing thin ﬁlms or coatings through which the progestin can pass into the skin. Suitable polymers are biologically and pharmaceutically ible, nonallergenic, insoluble in and compatible with body ﬂuids or tissues with which the device is ted. The use of water soluble polymers is generally less preferred since ution or erosion of the matrix would affect the release rate of the progestin as well as the lity of the dosage unit to remain in place on the skin. So, in certain ments, the polymer is non-water soluble.

Suitable progestin transdermal itions are sed, e.g, in US 7,045,145, US 7,384,650, US 20100255072, US 2660, and US 78323, all ofwhich are orated herein by reference as though fully set forth.

Polymers used to form a polymer matrix in the progestin-containing layer can have glass transition temperatures below room temperature such that they are soft and pliable at room temperature. The polymers are preferably non-crystalline but may have some crystallinity if necessary for the development of other desired properties. Cross-linkable monomeric units or sites can be incorporated into such polymers. For example, cross-linking monomers that can be incorporated into polyacrylate polymers include polymethacrylic esters of polyols such as butylene diacrylate and dimethacrylate, hylol propane trimethacrylate and the like.

Other monomers that provide such sites include allyl te, allyl methacrylate, diallyl maleate and the like.

PSAs that can be used to form the adhesive composition are lly polyacrylate, polyisobutylene, or silicone adhesives. A useful adhesive polymer formulation comprises a polyacrylate adhesive polymer of the l a (I): wherein X represents the number of repeating units sufﬁcient to provide the desired properties in the adhesive polymer and R is H or a lower (Cl-Clo) alkyl, such as ethyl, butyl, 2- ethylhexyl, octyl, decyl and the like. The adhesive polymer matrix can comprise, for instance, a polyacrylate adhesive copolymer having a 2-ethylhexyl acrylate monomer and approximately 50-60% w/w of vinyl acetate as a co-monomer. An example of a suitable polyacrylate adhesive copolymer for use in the present invention includes, but is not limited to, that sold under the tradename of Duro Tak® 87-4098 by Henkel Corporation , Bridgewater, N.J., which comprises Vinyl acetate co-monomer.

Progestins: Progestins useful in the practice of the present invention include desogestrel, dihydroprogesterone, drospirenone, ethynodiol acetate, ethynodiol diacetate, etogestrel, ene, gestogen, rogesterone, hydroxyprogesterone caproate, 3-keto-desogestrel, levonorgestrel, medroxyprogesterone acetate, medroxyprogesterone diacetate, megestrol, megestrol acetate, normegesterol, estromin, norethindrone (i.e., norethisterone), norethindrone e, norethynodrel, norgestimate, norgestrel, l9-nortestosterone, progesterone, nestorone, methoxyprogesterone, and dl-norgestrel or any combination of two or more of said progestins. Of particular interest are levonorgestrel and norethindrone and 2012/063314 norethindrone salts, e.g., norethindrone acetate. Levonorgestrel is a potent tin on a weight-dose basis and may be selected for that or other reasons. The progestin is typically t in a concentration based on weight of the transdermal composition (i.e., wt%) of 0.1 to 3 % or 0.2 to 2.0 % or 05-15 %.

Estrogens: Estrogens useful in the practice of the present invention include, without limitation, ethinyl estradiol, l7-beta-estradiol, estradiol-3,l7-diacetate; estradiolacetate; estradiol l7-acetate; estradiol-3,l7-divalerate; estradiolvalerate; estradiol-l7-valerate; 3- mono-, l7-mono- and 3,17-dipivilate estradiol esters; 3-mono-, l7-mono- and 3,17- dipropionate estradiol esters; 3-mono-, o- and 3,17-dicyclo pentyl-propionate estradiol esters, and estrone. Of ular interest is l estradiol. The estrogen is typically present in a concentration based on weight of the transdermal composition (i.e., wt%) of 0.1 to 3 % or 0.2 to 2.0 % or 0.5 to 1.5 %, e.g., 0.5 to l %.

Skin Permeation Enhancers: A number of skin permeation enhancers have been used to improve passage of progestins h the skin and into the blood stream. These include, e. g., alcohols; alkanones; amides and other nitrogenous compounds; l-substituted azacycloheptanones; bile salts; cholesterol; cyclodextrins and substituted cyclodextrins; ethers; saturated and rated fatty acids; saturated and unsaturated fatty acid esters; saturated and unsaturated fatty l esters; glycerides and monoglycerides; c acids; methyl nicotinate; ecalactone; polyols and esters thereof; phospholipids; sulfoxides; surfactants; es; and combinations thereof As speciﬁc examples, the following can be mentioned: decanol, dodecanol, 2-hexyl decanol, 2-octyl dodecanol, oleyl alcohol, undecylenic acid, lauric acid, myristic acid and oleic acid, fatty alcohol ethoxylates, esters of fatty acids with methanol, ethanol or isopropanol, methyl laurate, ethyl oleate, isopropyl myristate and isopropyl palmitate, esters of fatty alcohols with acetic acid or lactic acid, lauryl lactate, oleyl acetate, l,2-propylene glycol, glycerol, 1,3- butanediol, dipropylene glycol and polyethylene glycols.

Of particular interest are volatile organic solvents, ing, but not limited to, dimethyl sulfoxide (DMSO), C1-C8 branched or unbranched alcohols, such as ethanol, propanol, isopropanol, l, isobutanol, and the like, as well as azone (laurocapram: l- 2012/063314 dodecylhexahydro-2H-azepinone) and methylsulfonylmethane. Also of particular interest are fatty acids and esters thereof.

For example, a skin permeation enhancer useful in the present ion can be a e of (1) a pharmaceutically acceptable organic solvent, such as dimethyl sulfoxide , (2) a fatty (Cg-C20) alcohol ester of a hydroxy acid, such as lauryl lactate, (3) a lower (C1-C4) alkyl ester of a hydroxy acid, e.g., ethyl lactate, and (4) a C6-C18 fatty acid, such as capric acid. In specific embodiments, the fatty l ester of lactic acid is lauryl lactate and the lower alkyl ester of lactic acid is ethyl lactate. A medium- to long-chain fatty acid in the skin permeation enhancer formulation can be employed among the skin tion enhancers. Capric acid is preferred for use but other C6-C18 saturated or unsaturated fatty acids may be used, ing but not limited to caproic acid, caprylic acid, lauric acid and myristic acid, to name a few.

In a particular embodiment, the pharmaceutically acceptable c solvent is DMSO. Other organic solvents suitable for use in the present invention include, but are not limited to, C1-C8 branched or ched alcohols, such as ethanol, propanol, isopropanol, butanol, isobutanol, and the like, as well as azone (laurocapram: 1-dodecylheXahydro-2H-azepinone) and methylsulfonylmethane, to name a few.

The fatty alcohol ester of a hydroxy acid can be a fatty alcohol ester of lactic acid, such as lauryl lactate. However, other hydroxy acids and fatty alcohols may be utilized. Alternative hydroxy acids include, but are not limited to, alpha-hydroxy acids such as glycolic acid, tartaric acid, citric acid, malic acid and mandelic acid, as well as the beta-hydroxy acid, salicylic acid. Alternative fatty alcohols include any C8-C20 saturated or unsaturated fatty alcohols, such as myristyl, palmityl or oleyl alcohols, to name a few.

The lower alkyl ester of hydroxy acid can also utilize lactic acid, and can be, e.g., ethyl e. However, other y acids, such as glycolic acid, tartaric acid, citric acid, malic acid, mandelic acid and salicylic acid, may also be utilized. In addition isopropylmyristic acid (IPM) may be used as a substitute for the lower alkyl ester of hydroxy acid.

The aforementioned combination of skin permeation ers may be used to enhance transdermal delivery of steroid hormones from any type of transdermal delivery composition, as discussed above. An adhesive polymer matrix-type system as described in detail herein and in US 145, US 7,384,650, US 20100255072, US 2010292660, and US 20100178323 are illustrative; however, the enhancer combination may also be utilized in non- adhesive polymers, as well as in multi-layer or reservoir-type transdermal delivery systems, gels, ointments, sprays, and lotions, to name a few.

The skin permeation enhancer is typically present in a concentration of at least 1% or at least 2% by weight of the composition. It may be present in a concentration of up to 50% or up to 40% by weight of the composition. In certain embodiments, the skin permeation er is present in a concentration based on weight of the composition (i. 6., wt%) of l to 50 % or 10 to 40 % or 20 to 30 % of the composition.

Optional Additional Excipients.‘ A number of excipients are employed in transdermal delivery compositions for various purposes. Of particular interest are polymers that ﬁanction as ants and/or as plasticizers. oration of a humectant in the formulation allows the dosage unit to absorb moisture from the e of skin, which in turn helps to reduce skin irritation and to prevent the adhesive polymer matrix of the delivery system from failing to adhere for a sufficient duration. The plasticizer/humectant may be a conventional plasticizer used in the pharmaceutical industry, for example, polyvinyl pyrrolidone (PVP). In ular, PVP/vinyl e (PVP/VA) co-polymers, such as those having a molecular weight of from about 50,000, are le for use in the present invention. The PVP/VA acts as both a plasticizer, acting to control the rigidity of the polymer matrix, as well as a humectant, acting to regulate moisture content of the matrix. The PVP/VA can be, for example, Plasdone® S- 630 Copovidone (International Specialty Products, Inc. (ISP), Wayne, New Jersey), which is a 60:40 PVP:VA co-polymer that has a lar weight of 24,000 to 30,000 and a glass transition temperature of 106°C. The amount of ant/plasticizer is directly related to the on of adhesion of the overlay.

Anti-oxidants: Anti-oxidants ﬁlnction to prevent or inhibit oxidation of other molecules by themselves ng oxidized. In a polymeric matrix comprising both a progestin and an estrogen such as ethinyl estradiol, the ethinyl estradiol ons as an anti-oxidant and thereby helps to reduce oxidative degradation of the progestin. Employment of an additional anti-oxidant further reduces oxidative degradation. In a tin-only composition, employment of an anti-oxidant can be even more important.

For example, certain polymers, in particular, polymers formed by free radical polymerization, have been found to act as ing agents in a polymeric matrix comprising a progestin, whereby the ity of the progestin is compromised. For example, it has been discovered in accordance with the present invention that polyacrylate ves cause ion of a tin, e. g., levonorgestrel.

It has also been discovered in accordance with the present invention that PVP, which is commonly used in transdermal ric compositions, also contributes to oxidation of a progestin. Therefore, in transdermal compositions comprising PVP, or PVP/VA, and a progestin, addition of an anti-oxidant improves the stability of the progestin.

It has also been discovered in accordance with the present invention that certain permeation enhancers, e.g., DMSO, can also cause oxidation of a progestin, e.g., levonorgestrel.

Thus, one aspect of the invention features a polymeric matrix comprising the tin, the anti-oxidant, the skin permeation enhancer and a pressure sensitive adhesive ("PSA"), wherein the PSA is a polyacrylate adhesive, e.g., a rylate/vinyl acetate copolymer such as Duro Tak® 87-4098, and/or wherein the polymeric matrix ses PVP or PVP/VA, and/or wherein the permeation enhancer comprises DMSO.

A number of nds can act as anti-oxidants in the transdermal composition of the present invention. Among compounds known to act as anti-oxidants are: Vitamins A, C, D, and E, carotenoids, ﬂavanoids, isoﬂavanoids, beta-carotene, butylated hydroxytoluene (“BHT”), butylated hydroxyanisole (BHA), glutathione, ne, gallic acid and esters thereof, lic acid and esters thereof, sulfites, alcohols, amines, amides, sulfoxides, surfactants, etc. Of ular interest are phenolic anti-oxidants, e.g., BHT, pentaerythritol tetrakis(3-(3,5-di-tert-butylhydroxyphenyl)propionate), e.g. and tris(2,4-di- , x 1010, tert-butylphenyl) phosphite, e.g., Irgafos 168, as well as sodium bisulflte, sodium sulﬁte, isopropyl gallate, Vitamin C and n E.

Phenolic anti-oxidants, like BHT, which are sometimes referred to as primary anti-oxidants, are particularly suitable. Larger phenolic anti-oxidants, e.g. molecular weight greater than 500 (e.g., tris(2,4-di-tert-butylphenyl) phosphite) or greater than 1000 (e.g., pentaerythritol tetrakis(3-(3,5-di-tert-butylhydroxyphenyl)propionate) may be utilized to advantage.

The pH of the transdermal composition can be maintained at about pH 6 to about pH 8, e.g. at about pH 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2., 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 or 8.0. In one embodiment, the composition is ined at about pH 6.5 to pH7.5.

In another ment, the composition is maintained at about pH 7. Anti-oxidants that would increase pH, e.g., sodium metabisulflte, are ably avoided. BHT can be present, e.g., in a concentration based on the weight of the hormone of at least 10 wt% or at least 20 wt% or at least 30 wt% of the hormone. BHT can be present, e.g., in a concentration of up to 150 wt% or 200 wt% or 500 wt% of the hormone. In n embodiments, BHT is present in a concentration based on weight of the hormone of 10 to 500 %, 20 to 200 %, or 50 to 150 % of the e. Suitable concentrations of other anti-oxidants are readily ascertainable. For example, suitable concentrations of tris(2,4-di-tert-butylphenyl) phosphite, e.g., Irgafos 168, include concentrations that are similar to those of BHT, although lower or higher concentrations may also be employed; suitable trations of pentaerythritol tetrakis (3- (3,5-di-tert—butylhydroxyphenyl) nate), e.g., Irganox 1010, include similar concentrations although lower or higher concentrations may be employed, e.g., concentrations that are up to about 10%, 20% or 30% higher.

The following examples are set forth to describe the invention in greater detail. They are intended to illustrate, not limit, the invention.

Examples Example 1 A master blend, utilizing the formula listed in Table 1, below, was produced. The master blend was divided and spiked with ethinyl estradiol or known anti-oxidants as shown in Table 3. Each blend was then coated on a release liner at a target coat weight of 133 g/m2 and dried at 60°C. The sheets were laminated, cut into 15 cm2 samples, placed between two release liners, pouched, and then stored at 80°C. Samples were evaluated at five time points as shown in Table 2.

WO 67346 Table 1. Master Blend Formula 038% Penetration Enhancers, 3 9'0 A)0 PVP/VA, Ethyl Acetate 605% * PSA = polyacrylate adhesive copolymer having a 2-ethylhexyl acrylate monomer and approximately 50-60% w/w of vinyl acetate as a co-monomer Table 2. Sampling Plan Table 3. Test Blends Batch #1 Vlaster Blend Batch #2 r Blend -- l estradiol, 1.53 mg/15 cm r Blend -- BHT, 1.14 mg/15 cm Vlaster Blend -- BHT, 1.71 mg/15 cm Vlaster Blend -- Irganox 1010, 1.11 mg/15 cm -- Irgafos 168, 0.57 mg/15 cm Vlaster Blend -- Irganox 1010, 1.66 mg/15 cm -- Irgafos 168, 0.85 mg/15 cm Vlaster Blend -- ethinyl estradiol, 0.97 mg/15 cm The amounts of levonorgestrel in each composition at each time point are shown in Table 4 as an average of 3 samples of each batch as a percentage of the target amount of levonorgestrel (“%TL”), which is 0.868 % based on the weight of the polymeric matrix.

Table 4. Levonorgestrel Stability as % Target Levonorgestrel These results demonstrate that ethinyl estradiol functions as an xidant in the composition and that levonorgestrel stability is markedly ed by addition of an anti- oxidant to the composition.

Example 2 To six batches of a master blend of levonorgestrel, ation enhancers, polyvinylpyrrolidone/vinyl acetate copolymer, and pressure sensitive ve, substantially as described in Example 1, BHT was added at different amounts ranging from 0.02 mgs per patch (each patch contains 300 mgs of master blend) to 1.7 mgs per patch (the value of 1.7 mgs represents the molar equivalent of the amount of rgestrel in each patch).

Each batch was heated to 80°C and analyzed at the time points of 0, 4 and 8 days. All BHT loading values had a positive effect on the stability of levonorgestrel. The amounts of LNG remaining at T = Day 0, T = Day 4, and T = Day 8 are shown in Table 5.

Table 5. Effect of BHT concentration on the degradation of levonorgestrel (mg/pm) Example 3 The following test batches were ed and tested as described. a) Levonorgestrel (2.6 mg) was ved in 412 mg Duro Tak 87-4098 (hereinbelow, er”). Drawdowns were made and heated at 80°C for 4 and 8 days. The amounts of levonorgestrel remaining and the percent of degradants for the samples heated at 4 and 8 days were determined. b) Levonorgestrel (2.6 mg) and 60 mg of PVP/VA were dissolved in 412 mg of Carrier.

Drawdowns were made and heated at 80°C for 4 and 8 days. The amounts of rgestrel remaining and the percent of degradants for the samples heated at 4 and 8 days were determined. c) Levonorgestrel (2.6 mg), 1.71 mg BHT and 60 mg PVP/VA were dissolved in 412 mg Carrier. Drawdowns were made and heated at 80°C for 4 and 8 days. The amounts of levonorgestrel remaining and the percent of degradants for the samples heated at 4 and 8 days were determined. d) The same ure as described in c) was performed, except 1.14 mg BHT was added.

The batch formulations are summarized in Table 6.

Table 6. Summary of Batch Formulations -—levonorgestrel(mg) n———— u——m_— -——m__1-71 n——m__1-14 HPLC is was conducted to identify degradants of levonorgestrel. An aliquot of approximately 200 mg and 100 mg of the sample (exact weight recorded) for 4 and 8 day ity was used. The sample was dissolved in 5 mL of l :l tetrahydroﬁlran:methanol (THF/MeOH). lO uL was ed for HPLC analysis.

Levonorgestrel degradants appeared after incubation in the 80°C oven for 4 days and 8 days for samples a and b. No degradant was found for samples c and d. The results are shown in Table 7 Table 7. Peak Area Percentage of Total Degradants —Tota|degradants (%) Samp 9| ID 4 day 8 day The peak area percentages of remaining levonorgestrel after incubation in 80°C oven are shown in Table 8.

Table 8. Peak Area Percentage of Remaining Substances Sam“MD —99-52 99-25 —_98.74 98.72 ooooo ooooo -—ooooo ooooo Note for Table 8: Remaining levonorgestrel tages were directly obtained from peak area percentages.

The force degradation study described above indicated that addition of BHT reduced degradation of levonorgestrel, while addition of Povidone (PVP) slightly sed the degradation.

Example 4 Transdermal ry patches were prepared comprising penetration enhancers, polyvinylpyrrolidone/vinyl acetate copolymer, re sensitive adhesive, and varying amounts of levonorgestrel (LNG) and BHT, as follows: Lot 1: LNG (2.17 mg, 0.87 wt%) - 12.5 cm2 patch; Lot 2: LNG (2.6 mg, 0.87 wt%) plus BHT (1.712 mg, 0.57 wt%) - 15 cm2 patch; Skin ﬂux across human r skin (3 donor skin samples, 3 replicates per skin donor) was compared. Data are reported in Table 9.

Table 9. Cumulative amounts ofLNG permeated as a ﬁanction of time.

Cumulative amounts of LNG permeated (ug/cm ) -——————— I401475 2.456 3.256 3.895 4.569 5.230 --/ 5.770 --11.336--/- 17.092--/- 22.650--/— 27.795--/- 32.689--/— 37.355 1.900 2.755 3.578 4.286 4.969 5.551 --/— 6.110 The mean steady-state ﬂux of levonorgestrel (ug/cmZ/h) in each batch is shown in the following table.

Table 10. Mean steady-state ﬂux of levonorgestrel (ug/cm2/h) 0-2442 --/- 0-0312 0-/0312 These data show that permeation of rgestrel was not impeded by the on of BHT.

Example 5 As shown in Table 11, seven transdermal compositions, each comprising approximately 164.8 mg Duro Tak® 8 and 2.6 mg levonorgestrel (LNG), after drying, with and without PVP/VA and DMSO, were prepared to test the oxidative effects of a polyacrylate PSA, PVP, and DMSO.

Table 11. Compositions PVP/VA (mg) DMSO (mg) 60mgPVPNA WM In the case of compositions 1 — 4 and 6, the PSA was pre-heated at 78°C for 8 hours prior to addition of PVP/VA and DMSO. In the case of preparations 3 and 4, the PVP/VA was pre- heated at 80°C for 48 hours in the presence of air and nitrogen, respectively.

All preparations were then placed in an oven at 80°C for 4 days and 8 days. ants were analyzed by HPLC. Degradant percentage data are provided in Table 12.

Table 12. Peak Area Percentage of Total Degradants ition # Degradants (%) ants (%) Day 4 Day 8 0.78 1.16 1.21 1.60 _1.12 1.67 1.65 1.78 As shown in Table 12, presence of PVP/VA increased degradants roughly by two-fold. Pre- treatment of PVP/VA did not show signiﬁcant difference. Heating the compositions for 8 days produced slightly more degradants than for 4 days. Pre-heating the PSA d the amount of degradants. Addition ofDMSO increased the amount of degradants.

Example 6 A master blend utilizing the formula listed in Table 13 was produced. The master blend was then divided and spiked with BHT as shown in Table 14. Each test blend was then coated on a release liner at a target coat weight of 200 g/m2 and dried at 60°C for 17.5 mins using a fan speed of 2300 rpm. The sheets were then laminated, cut into 15 cm2 samples, placed between two release liners, pouched, and then stored at 80°C. Samples were evaluated on Days 0, 4, and 8..

Table 13. Master Blend Formula 037% Ethinyl estradiol 0.333% Penetration Enhancers, 39-55 8 4)0 PVP/VA, Ethyl Acetate 59-730% * PSA = polyacrylate adhesive mer having a 2-ethylhexyl acrylate monomer and approximately 50-60% w/w of vinyl acetate as a co-monomer [Duro-Tak 8] Table 14. Test Blends Batch #1 Vlaster Blend Batch #2 Vlaster Blend -- BHT, 1.712 mg/15 cm 2.481 g/kg Batch #3 Vlaster Blend -- BHT, 1.000 mg/15 cm 1.449 g/kg Batch #4 Vlaster Blend -- BHT, 0.428 mg/15 cm 0.620 g/kg Batch #5 r Blend -- BHT, 0.300 mg/15 cm 0.435 g/kg Batch #6 Vlaster Blend -- BHT, 0.150 mg/15 cm 0.217 g/kg The amounts of levonorgestrel and ethinyl estradiol were determined by HPLC. The results (% LC) for each test blend are shown in Table 15 as an average of 5 s per test blend, with %-Relative Standard Deviations (%RSD).

Table 15. Results _——— EE LNG EE LNG EE LNG (% RSD) (% RSD) (% RSD) (% RSD) (% RSD) (% RSD) (1.9) (2.1) (1.0) (3.1) (9.1) (57.0) (2.2) (2.2) (1.3) (1.5) (2.4) (8.1) It is understood that the examples and embodiments described herein are for rative purposes only and that various modiﬁcations or changes in light f will be suggested to persons skilled in the art and are to be included Within the spirit and purview of this application and the scope of the appended claims.

[Link] http://www.wanchem.com.cn/products/Antioxidant-168.html

Claims

1. A composition for transdermal delivery of levonorgestrel that comprises: a) a polymeric pressure-sensitive adhesive (PSA), b) the levonorgestrel, c) a skin permeation enhancer comprising an organic solvent, d) polyvinyl pyrrolodone (PVP) or a PVP copolymer, and e) an anti-oxidant that is not an estrogen or is in addition to an estrogen; n the anti-oxidant protects against oxidative degradation of the rgestrel by the organic solvent or the PVP or PVP copolymer.

2. The composition of claim 1, wherein the anti-oxidant is ed from vitamins A, C, D, and E, carotenoids, flavanoids, vanoids, beta-carotene, ted hydroxytoluene (“BHT”), ted hydroxyanisole (“BHA”), glutathione, lycopene, gallic acid and esters thereof, salicylic acid and esters thereof, sulfites, alcohols, amines, amides, sulfoxides, surfactants, or any combination thereof.

3. The composition of claim 1, wherein the anti-oxidant is sodium bisulfite, sodium sulfite, isopropyl gallate, vitamin C, n E, or BHT; or any combination of two or more of said anti-oxidants.

4. The composition of claim 1, n the anti-oxidant comprises one or more phenolic anti-oxidants.

5. The composition of claim 1, wherein the anti-oxidant is BHT, pentaerythritol tetrakis(3- (3,5-di-tert-butylhydroxyphenyl)propionate), or tris(2,4-di-tert-butylphenyl) phosphite.

6. The composition of any one of the ing claims, wherein the PSA is selected from a polyacrylate adhesive, a polyisobutylene adhesive, or a silicone adhesive.

7. The composition of any one of the ing claims, wherein the PSA is polymerized by free radical polymerization.

8. The composition of claim 7, n the PSA is a polyacrylate adhesive.

9. The composition of claim 8, wherein the PSA comprises a 2-ethylhexyl acrylate comonomer.

10. The composition of claim 8, wherein the polyacrylate adhesive further comprises about 50 to 60% w/w vinyl acetate co-monomer.

11. The composition of any one of the ing , further comprising one or more other skin permeation enhancers selected from: alcohols; alkanones; amides and other nitrogenous compounds; 1-substituted azacycloheptanones; bile salts; cholesterol; cyclodextrins and substituted cyclodextrins; ethers; saturated and unsaturated fatty acids; saturated and unsaturated fatty acid esters; saturated and unsaturated fatty alcohol esters; glycerides and monoglycerides; organic acids; methyl nicotinate; ecalactone; polyols and esters thereof; phospholipids; sulfoxides; surfactants; terpenes; and ations f.

12. The composition of claim 1, wherein the organic solvent is DMSO.

13. The composition of claim 1, comprising one or more skin permeation enhancers selected from: DMSO, a fatty (C8-C20) alcohol ester of a hydroxy acid, a lower (C1-C4) alkyl ester of a hydroxy acid, and a C6-C18 fatty acid.

14. The ition of claim 13, wherein the skin permeation er comprises one or more of: DMSO, lauryl lactate, ethyl lactate, and capric acid.

15. The composition of any one of the preceding claims, further comprising a humectant.

16. The composition of claim 15, wherein the humectant is PVP or PVP/VA.

17. The composition of any one of the ing claims, wherein the levonorgestrel is present in a concentration based on weight of the composition of 0.1% to 3.0% or 0.2% to 2.0% or 0.5% to 1.5%.

18. The composition of any one of the preceding claims, wherein the skin permeation enhancer is present in a concentration based on weight of the composition of 1% to 50% or 2% to 40%.

19. The composition of any one of the preceding claims, wherein the anti-oxidant is BHT.

20. The composition of claim 19, wherein the BHT is present in a tration based on weight of the hormone of 10% to 500%, 20% to 200%, or 50% to 150%.

21. The composition of any one of the preceding claims, which does not comprise an estrogen.

22. The ition of any one of the preceding claims, wherein the xidant is pentaerythritol tetrakis (3-(3,5-di-tert-butylhydroxyphenyl) propionate) or tris (2,4-ditert-butylphenyl ) phosphite.

23. A transdermal drug delivery device that comprises: a) a transdermal composition of any one of the ing claims, said composition comprising a PSA and having a skin contacting surface and a non-skin contacting b) a release liner adjacent the skin contacting surface of the transdermal composition; and c) a backing layer adjacent the in contacting surface.

24. A method of improving the stability of a tin-only transdermal ry composition in which the progestin is levonorgestrel and wherein the composition comprises an oxidizing agent, the method sing adding an anti-oxidant other than an estrogen to the composition.

25. The method of claim 24, wherein the oxidizing agent is one or more of an c solvent, PVP, or a PVP copolymer.

26. The method of claim 25, wherein the composition comprises a PSA.

27. The method of any one of claims 24, 25, or 26, wherein the anti-oxidant is selected from vitamins A, C, D, and E, carotenoids, flavanoids, isoflavanoids, beta-carotene, butylated hydroxytoluene (“BHT”), butylated yanisole ), glutathione, lycopene, gallic acid and esters thereof, salicylic acid and esters thereof, sulfites, alcohols, amines, amides, sulfoxides, phenolics or surfactants, or any combination of two or more of said anti-oxidants.

28. The method of any one of claims 24, 25, or 26, wherein the anti-oxidant is sodium bisulfite, sodium sulfite, isopropyl gallate, vitamin C, vitamin E, or BHT, or any combination of two or more of said anti-oxidants.

29. The method of claim 24, 25, 26, 27 or 28, wherein the polymeric r is a PSA selected from a polyacrylate ve, a polyisobutylene adhesive, or a silicone adhesive.

30. The method of claim 29, wherein the PSA is polymerized by free radical polymerization.

31. The method of claim 30, wherein the PSA is a polyacrylate adhesive.

32. The method of claim 31, wherein the PSA comprises a 2-ethylhexyl acrylate monomer.

33. The method of claim 32, wherein the polyacrylate adhesive further comprises about 3 to 60% w/w vinyl acetate monomer.

34. The method of any one of claims 24 through 33, wherein the composition comprises a skin permeation enhancer selected from one or more of: alcohols; alkanones; amides and other nitrogenous compounds; 1-substituted azacycloheptanones; bile salts; cholesterol; cyclodextrins and tuted cyclodextrins; ethers; saturated and unsaturated fatty acids; saturated and unsaturated fatty acid esters; saturated and unsaturated fatty alcohol esters; glycerides and ycerides; organic acids; methyl nicotinate; pentadecalactone; polyols and esters thereof; phospholipids; sulfoxides; surfactants; terpenes; and combinations thereof.

35. The method of claim 34, wherein the enhancer comprises an organic solvent.

36. The method of claim 35, wherein the organic solvent is DMSO.

37. The method of claim 34, 35 or 36, wherein the enhancer comprises one or more of: DMSO, a fatty (C8-C20) alcohol ester of a y acid, a lower (C1-C4) alkyl ester of a hydroxy acid, and a C6-C18 fatty acid.

38. The method of claim 37, n the enhancer comprises DMSO, lauryl e, ethyl lactate, and capric acid.

39. The method of any one of claims 24 through 38, wherein the composition further comprises a humectant.

40. The method of claim 39, wherein the ant is PVP or PVP/VA.

41. The method of any one of claims 24 through 40, wherein the levonorgestrel is present in a tration based on weight of the composition of 0.1% to 3.0% or 0.2% to 2.0% or 0.5% to 1.5%.

42. The method of any one of claims 24 through 41, wherein the skin permeation enhancer is present in a tration based on weight of the composition of 1% to 50% or 2% to 40%.

43. The method of any one of claims 24 through 42, wherein the anti-oxidant is BHT.

44. The method of claim 43, wherein the BHT is present in a concentration based on weight of the hormone of 10% to 500%, 20% to 200%, or 50% to 150%.

45. The method of any one of claims 24 through 44, wherein the anti-oxidant is pentaerythritol tetrakis (3-(3,5-di-tert-butylhydroxyphenyl) propionate) or tris itert-butylphenyl ) phosphite.

46. A composition for transdermal delivery of levonorgestrel according to any one of claims 1-22 and substantially as herein described with reference to the Examples.

47. A method of improving the ity of a rgestrel only transdermal delivery composition according to any one of claims 24-46 and substantially as herein described with reference to the Examples.