HK1066724B - Drug delivery compositions for improved stability of steroids - Google Patents

Description

Pharmaceutical delivery composition for enhanced stability of steroids

Background

In general, the present invention relates to a drug delivery composition for improving the stability of a steroid drug having a 3-oxo-4-ene functional group in its A ring. More particularly, the present invention relates to a stable transdermal steroid drug delivery patch and a method for improving the stability of steroid drugs in the transdermal drug delivery patch during storage.

Steroids with 3-oxo-4-ene functionality include certain sex hormones and certain corticoids (corticosterioids). Adrenocortical hormones have many different physiological functions and pharmacological effects. They affect the metabolism of carbohydrates, proteins, fats, and purines, affecting the balance of electrolytes and water; and affect the function of the cardiovascular system, kidneys, skeletal muscles, nervous system, and other organs and tissues. Therapeutically, corticoids are used to treat hormonal deficiencies, inflammation, and other diseases, where sex hormones are widely used for contraception and hormonal deficiencies, as well as for the treatment of other diseases.

Progesterone is secreted by the ovary, mainly the corpus luteum, during the latter half of the menstrual cycle. The sudden decrease in the release of progesterone from the corpus luteum at the end of the cycle is the main determinant of the onset of menstruation. It is well known that progesterone during the luteal phase of the cycle can cause endometrial changes and produce a secreted endometrium. Endocervical glands are also affected by progesterone. In addition, the maturation of human vaginal epithelium induced by estrogen is shifted to a pregnant state by the action of progesterone, and progesterone causes a body temperature rise phenomenon associated with ovulation. During pregnancy, the growing placenta secretes progesterone until a large amount of progesterone is secreted before delivery, and during pregnancy, in rare cases during the luteal phase of the menstrual cycle, progesterone reacts with estrogen, resulting in hyperplasia of the mammary glands. At the end of pregnancy, these glands are filled with secretions and the vasculature of the mammary gland is significantly enlarged; however, the effects of estrogen and progesterone immediately cease after delivery and the lactation period begins.

Progestagens are used in therapy for the replacement of postmenopausal hormones to neutralize estrogen proliferation on the endometrium, for functional uterine bleeding, dysmenorrhea, premenstrual tension, endometriosis, and for threatened and habitual abortion. Diagnostically, progestagens are used for the evaluation of ovarian function. They are also useful in oral contraceptives. The progestogen can be formulated into a dosage form suitable for oral administration and injection, however, as known to those skilled in the art, the hormone can also be administered transdermally through a liquid reservoir and a matrix patch. However, the stability of these drugs during storage is a very important issue, which will be explained more fully below, testosterone.

Testosterone is normally synthesized under the control of the testes, ovaries, and adrenal cortex. It is well known that the normal function of testosterone is to produce a significant change in puberty, which allows boys to grow a man. Androgens are also known to be involved in aggressive and sexual behavior in men. Changes in plasma testosterone levels have been observed in women during the menstrual cycle. Androgens secreted by the ovary and adrenal cortex are likely to be of physiological interest to women. Clinically, testosterone was first used to treat hypogonadism in men and to promote the anabolism in men and women.

Delivery of drugs through the skin, i.e., skin and mucosa, has many advantages over other routes of administration. First, transdermal administration is a comfortable, convenient, and non-invasive way of administering drugs. Variable rates of absorption metabolism associated with oral treatment as well as other inherent inconveniences such as gastrointestinal irritation and the like can be avoided. Transdermal administration also provides increased control of the blood level of any particular drug, which enhances patient compliance and increases the safety and efficacy of the drug.

The skin is a complex, thick membrane, and molecules entering and passing through intact skin from the environment must first pass through the stratum corneum and any material on its surface. The molecule must then pass through the viable epidermis, papillary dermis, and capillary wall into the blood or lymphatic vessels. To achieve such absorption, the molecules must overcome different resistances, passing through various types of tissue. Thus, transport across the skin membrane is a complex phenomenon. However, the primary barrier to absorption of topical compositions or drugs administered to the skin is the stratum corneum. Recently there has been much interest in using mucous membranes as the site of administration because it is more permeable than the skin due to the lack of stratum corneum which impedes penetration.

Transdermal drug delivery devices are typically reservoir patch-based patches. In reservoir patches, the drug is stored in a liquid form in a reservoir from which it diffuses to the skin. The patch includes an outer layer that may include a rate controlling membrane to control the rate of release of the drug. In matrix patches, the drug is stored in a polymer matrix that is in one or more layers to store the drug, control the release rate, and adhere to the skin. Liquid reservoir patches were developed earlier than matrix patches due to few problems such as contraindication of drug compounding with polymeric materials. However, matrix patches are easier to manufacture than liquid reservoir patches and are more comfortable and convenient to use.

Release hormone reservoir patches are known in the art. For example, U.S. patent No.3,964,482 to Gerstel et al discloses a drug delivery device for transdermal administration comprising a plurality of protrusions and a drug-containing reservoir, wherein the protrusions extend from the reservoir and the drug in the reservoir is adapted to penetrate the stratum corneum for transdermal administration. Matrix patches for steroid administration are also known in the art. For example, Chiang et al, in U.S. patent No.5,252,334, disclose transdermal delivery of steroids, preferably estradiol, using an adhesive matrix patch containing an acrylate adhesive, the steroid, and optionally a permeation enhancer and a water-soluble polymer. U.S. patent No.5,232,703 to Blank discloses a non-crosslinked, water-insoluble matrix of vinylpyrrolidone copolymer for transdermal delivery of estradiol. U.S. patent No.5,019,008 to Sinnreich et al discloses a polyisobutylene matrix for transdermal drug delivery in combination with a penetration enhancer of oleyl alcohol and N-methyl-2-pyrrolidone. U.S. patent No.5,023,084 to Chien discloses a progestogen/estrogen transdermal matrix patch for fertility control wherein the progestogen and estrogen are dispersed in a polymeric adhesive. What has not been disclosed in the art are steroids containing 3-oxo-4-ene functional groups, including many sex hormones and corticosteroids that are unstable in the presence of acid functional group containing adhesives, penetration enhancers, excipients, and other patch components, such instability significantly reducing the amount of such steroids stored in a dosage form containing such acid functional groups.

In view of the above, it would be apparent to a significant advance in the art to provide steroid-containing pharmaceutical compositions, and in particular steroid-containing matrices and storage reservoirs, in which the problems of shelf-life drug stability are greatly reduced.

Objects and summary of the invention

It is an object of the present invention to provide a pharmaceutical composition comprising a steroid compound, wherein the steroid compound comprising a 3-oxo-4-en functional group is stable during storage.

It is another object of the present invention to provide a pharmaceutical dosage form for transdermal administration wherein the steroid containing a 3-oxo-4-en functional group is stable during storage.

It is another object of the present invention to provide a matrix and stock dosage form for the manufacture and use of steroid compounds containing 3-oxo-4-en functional groups for transdermal administration, wherein the steroid compound is stable during the shelf life of the dosage form.

These and other objects are achieved by providing a stable patch for transdermal administration of a steroid drug containing a 3-oxo-4-en functional group, wherein the steroid drug is stable during long term storage of the patch, the patch comprising an effective amount of the steroid drug and a carrier, wherein the carrier does not contain an acid functional group and does not generate an acid functional group during storage. Preferably, the steroid drug is selected from the group consisting of sex hormones, corticosteroids, and mixtures thereof, the steroid drug containing a 3-oxo-4-ene functional group may also be mixed with steroids lacking such functional group, such as certain estrogens (e.g., estradiol), progestins, androgens, and corticosteroids. The stabilized patch may be either a matrix patch or a reservoir patch. In the matrix patch, the carrier comprises a biocompatible polymeric adhesive in which the steroid drug is intimately mixed, e.g. dissolved or suspended in the adhesive, preferably the polymeric adhesive is selected from acrylic polymers and copolymers. In a reservoir patch, the carrier comprises a viscosity-controlling composition into which the steroid drug is intimately mixed. The viscosity-controlling composition may contain a diluent or thickener. Additives such as penetration enhancers or excipients are also included in the carrier, provided that the additives also do not contain acid functional groups.

A method of stabilizing a steroid drug having a 3-oxo-4-ene functional group during storage in a transdermal patch comprising the steroid drug, comprising the steps of: an effective amount of a steroid drug is first intimately admixed with an effective amount of a carrier which does not have acid functional groups and which does not form acid functional groups during storage, and the admixed steroid drug and carrier are then incorporated into a transdermal drug delivery patch as a source of steroid drug.

Brief description of the drawings

Fig. 1 shows a partially schematic cross-sectional view of an illustrative example of a matrix patch according to the present invention.

FIG. 2 is a diagram showing a graph comprising: a-no gelling agent; b-1.5% hydroxypropyl cellulose; graphical representation of the results of HPLC analysis of NEA and its degradation products after storage in a liquid formulation of C-1.5% crosslinked polyacrylic acid.

FIG. 3 shows a graph containing A-81% (w/w) Duro TaK80-1196, 4% (w/w) NEA, 15% (w/w) sorbitan monooleate, B-81% (w/w) TSR, 4% (w/w) NEA, 15% sorbitan monooleate; graphical representation of the results of HPLC analysis of NEA and its degradation products after storage for 114 weeks at room temperature in a matrix formulation of C-81% (w/w) GEL-VA737, 4% (w/w) NEA, 15% (w/w) sorbitan monooleate.

Detailed description of the invention

Before the stabilized steroid containing patch of the present invention and the method of stabilizing the steroid drug during storage of the patch are disclosed or described, it is to be understood that the present invention is not limited to the particular process steps and materials described herein, as such process steps and materials may, in some instances, vary. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims and equivalents thereof.

It must be noted that, unless clearly indicated otherwise, the singular forms "a", "an", and "the" include plural referents. Thus, for example, the concept adhesive lamination "a (a) steroid drug" includes a mixture of two or more steroid drugs, the concept "an adhesive" includes one or more adhesives, and the concept "a (a) penetration enhancer" includes a mixture of two or more penetration enhancers.

In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below.

The terms "facilitate", "penetration facilitate", and "penetration facilitate" as used herein refer to increasing the permeability of a biological membrane (i.e., skin or mucosa) to a drug, so as to increase the rate at which the drug permeates through the membrane. "penetration enhancer", "penetration enhancer" or similar terms mean a substance that achieves such penetration enhancement.

As used herein, "transdermal" or "transdermal" administration refers to the release of a drug into and through the skin or mucosal tissue. The terms "transdermal" or "transmucosal" are used interchangeably herein unless otherwise specifically indicated. Also, unless otherwise specifically indicated, the terms "skin", "skin" (constituent words), "epidermis", "mucosa", etc. may be used interchangeably.

As used herein, "steroid drug" means a steroid compound containing a 3-oxo-4-ene functional group in its A ring. Such steroid drugs include certain sex hormones, including progestagens and androgens, as well as certain corticosteroids. Examples of progestogens include progesterone, 17-ethinyltestosterone (17 α -ethynyltestosterone), medroxyprogesterone hydroxyprogesterone, norethindrone (17 α -ethynyl-19-demethyltestosterone), norethindrone acetate (17 α -ethynyl-19-nortestosterone acetate), dehydroprogesterone (9 β 10 α -pregna-4, 6-diene-3, 20-dione), dynorgestrel (6 α -methyl-17 α - [ 1-propynyl ] -testosterone), chlormadinone acetate (6-chloro-6-dehydro-17 α -acetoxyprogesterone), norethindrone (13 β -ethyl-) 17 α -ethynyl-17 β -hydroxysteroid-4-en-3-one), and esters and mixtures thereof. Norethindrone (NEA) is a preferred progestin with 3-oxo-4-ene functionality. Examples of androgens include testosterone, methyltestosterone, fluoxymethyltestosterone, metatestosterone, nandrolone, enolone, and esters and mixtures thereof. Testosterone and esters thereof are preferred androgens with the desired 3-oxo-4-ene functionality. Examples of corticosteroids include hydrocortisone, cortisone, deoxycorticosterone, fludrocortisone, betamethasone, dexamethasone, prednisolone, prednisone, methylprednisolone, paramethasone, triamcinolone acetonide, diflunisal, fluocinolone acetonide, fluocinolone acetate, fluocinolone acetonide, clobetasol, fluroxypyr, methylprednisolone, 6 alpha-methyl-1-beta hydroxyprogesterone, and esters and mixtures thereof.

As used herein, "carrier" means a formulation component of a transdermal delivery patch including, but not limited to, biologically acceptable polymeric binders, viscosity controlling compositions, penetration enhancers, excipients, diluents, emollients, plasticizers, anti-irritants, opacifiers, and the like, and mixtures thereof.

As used herein, "matrix", "matrix system", or "matrix patch" means a drug intimately mixed, i.e., dissolved in suspension, in a biologically acceptable polymer phase, preferably a pressure sensitive adhesive, which may also contain other components, or in which an enhancer may also be dissolved or suspended. The definition comprises the following specific scheme: the polymer phase is pressed into a sheet and applied to a pressure sensitive adhesive or a capping adhesive is used. Matrix patches known in the transdermal delivery art typically include an impermeable film backing pressed against the outer surface of their polymer phase and, prior to transdermal administration, a release liner on the inner surface of the polymer phase. Obviously, the matrix patch according to the invention also comprises such backing and release liner or functional equivalents thereof, and should also be free of acid functional groups in this part. U.S. patent No.5,122,383, incorporated herein by reference, describes such backings and liners. Thus, the matrix system is a pharmaceutical composition in a single dosage form in a polymeric carrier and contains, without being aggressive, an enhancer and other components or additives formulated to facilitate sustained transdermal, i.e., dermal or mucosal, drug delivery of the pharmaceutical composition in the polymeric layer.

The term "reservoir patch" refers to a drug intimately mixed in a composition of controlled viscosity and in an occlusive device having an impermeable backing and an inner surface suitably shaped by a permeable membrane and adhesive for transdermal administration. A releasable release liner protects the film and adhesive prior to use. Thus, one reservoir system is a single dose of a pharmaceutical composition in a controlled viscosity composition, which also contains an enhancer and optionally other components, formulated to facilitate sustained dermal, i.e., skin or mucosal, drug delivery of the pharmaceutical composition in the occlusive device. In application, the releasable release liner is removed to adhere the patch to the skin surface. The enhancer/drug together seeps out of the gel or ointment across the membrane and adhesive, if present, to the skin surface, the enhancer enhancing the penetration of the drug through the skin. Preferably, the reservoir patch is a reservoir patch having a peripheral adhesive ring adhered to the skin as claimed in U.S. patent 4,829,224 and U.S. patent 4,983,395, which are hereby incorporated by reference.

The term "viscosity-controlling composition" means a composition comprising a steroid drug and an accelerator, and any other optional additives, such as a solvent, excipient or carrier in a single phase or phase separated state, the viscosity of which can be controlled by the addition of a diluent or thickener to achieve a selected viscosity. The viscosity-controlling composition may be used as a solvent itself, or a solvent or co-solvent may be added thereto. Such viscosity-controlling compositions may be water-or organic-based and may contain a mixture of liquids or solvents that are suitably gelled or thickened. In other words, the controlled viscosity composition may include, but is not limited to, a solution, a suspension, an emulsion, a gel, an ointment, a cream, a paste or any other similar state that allows for the outward diffusion of the selected steroid drug, and optionally, an accelerator and/or a solvent or other additive. Suitable thickeners for viscosity control include any suitable material such as mineral oil, petrolatum, and various aqueous gelling agents and hydrophilic polymers such as methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, acrylic acid polymer thickeners, (e.g., AM-SCO 6038A)^TM(ii) a Uncacal), low molecular weight polymers, and the like, and mixtures thereof.

As used herein, an "effective amount" of a drug refers to an amount of the drug that is non-toxic but sufficient to provide a selected effect. An "effective amount" of a penetration enhancer refers to an amount of the enhancer that provides a selected increase in membrane permeability, and correspondingly, a selected depth of penetration, rate of administration, and amount of drug.

It has been found that steroid drugs, i.e. steroids containing a 3-oxo-4-en functional group, are unstable and can be degraded in the presence of acid functional groups. This phenomenon occurs in any formulation, oral, injectable, or transdermal, as long as the acid functional group is present. Thus, stable steroid pharmaceutical formulations can be prepared by combining the steroid drug with components that do not contain acid functional energy, such as other drugs, carriers, excipients, and the like. Formulations containing a non-steroidal drug mixed with a "steroidal drug" or a steroidal compound without a 3-oxo-4-ene functional group are included within the scope of the present invention. Such mixtures may include estradiol or other estrogens mixed with progestogens having 3-oxo-4-en functionality, such as norethindrone acetate, norethindrone, or progesterone, or androgens having 3-oxo-4-en functionality, such as testosterone and its esters. The invention also includes transdermal administration of the aforementioned steroid drugs in ataxia.

The flux of the drug through the skin or mucosa can be increased by changing the resistance (diffusion coefficient) or the kinetics (diffusion gradient). Flow rates can be increased by using a flow-through promoter. Penetration enhancers comprise two main classes of components, namely cell membrane imbalance compounds and solvents. Binary systems containing two classes of cell membrane imbalance compounds are known in the art, e.g., U.S. patent No.4,863,970, hereby incorporated by reference.

It is known in the art that cell membrane imbalance compounds are useful in topical agents, which are believed to aid in penetration of the skin by imbalance of the lipid layer of the stratum corneum cell membrane. A general list of these compounds is described in European patent publication No.43,738, 6/13/1982, which is hereby incorporated by reference. It is believed that any cell membrane imbalance compound that does not contain acid functional groups or does not generate acid functional groups during storage or aging may be suitable for the purposes of the present invention. Preferred cell membrane disregulating compounds include isopropyl myristate, methyl laurate, oleyl alcohol, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, glyceryl monostearate, glyceryl monolaurate, propylene glycol monolaurate, sorbitan esters and mixtures thereof.

Likewise, the solvents useful in the present invention should be free of acid functional groups. Suitable solvents include water; glycols, such as propylene glycol and glycerol; mono-alcohols, such as ethanol, propanol, and higher alcohols; DMSO; dimethylformamide; n, N-dimethylacetamide; 2-pyrrolidone; n- (2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, 1-dodecylazacycloheptan-2-one and other N-substituted-alkyl-azacycloalkyl-2-ones (azones), and the like, and mixtures thereof.

Other chemical promoters not necessarily associated with binary systems include DMSO or DM-SO in water. Such as U.S. patent 3,551,554 to Hersohler; U.S. patent 3,711,602 to Hersehler and U.S. patent 3,711,606 to herschelr, and azones (n-substituted-alkyl-azacycloalkyl-2-ones), such as U.S. patent 4,557,943 to Cooper.

Certain chemical promoter systems can have negative side effects such as toxicity and skin irritation. U.S. patent 4,855,298 discloses compositions for reducing skin irritation caused by chemical enhancers containing compositions having skin irritation properties using a sufficient amount of glycerin having an anti-irritation effect. Thus, anti-irritants may be advantageously added to the drug-containing compositions of the present invention.

Transdermal drug delivery systems often suffer from "burst effects," i.e., immediate release of high doses of drug when the transdermal drug delivery system is applied to the skin or mucosa. After a period of time, this burst or very high level of release is reduced or leveled out to an acceptable level of drug in the plasma. Thus, a very inhomogeneous drug release profile is formed. Co-pending application No. 07/897,269 describes that this problem is solved by the advantages found from glycerol, which when added to a transdermal formulation, effectively reduces the initial dose of drug, while at the same time providing a more uniform amount of drug penetration into the plasma over the expected period of use without significantly reducing the dose administered. Thus, agents to combat the explosive effect may advantageously be added to the drug/enhancer within the scope of the present invention.

With respect to fig. 1, a schematic representation of a matrix patch according to the present invention is generally shown in fig. 10. The patch 10 is a patch in the form of a layered drug-containing polymer layer adapted to adhere to the application site. The layers of the patch 10 include a substantially drug impermeable backing 14, a drug-loaded polymer layer 18 adapted to adhere to skin or mucous membranes, and a substantially drug impermeable release liner 22.

The backing layer 14, in use, is secured to the side of the patch facing the environment, i.e. away from the skin or mucosa. The function of the backing layer 14 is to protect the patch and provide an impermeable layer to prevent the loss of the drug to the environment, and therefore, the material chosen should be substantially impermeable to the drug. Preferably, the backing material may be opaque to protect the drug from decomposition upon exposure to light. In addition, the backing 14 should be capable of bonding to and supporting the other layers of the patch, and should be flexible to accommodate movement of the person using the patch 10. Materials that may be used, with or without modification, are selected from the group consisting of metal foils, metallized polymer foils, polytetrafluoroethylene-containing ("TEFLON)") composite foils or films of type one materials or their equivalents, polyether amide block copolymers (e.g.," PEBAX "copolymers), polyurethane such as PELLATHANE" or ESTANE "polymers, polyterephthalic acid dichloride (Saran)) Nylon, silicone elastomers, rubber-based polyisobutylene, styrene-butadiene and styrene-isoprene copolymers, polyethylene, polypropylene, polyester, and other materials used in the transdermal delivery field. As with the other components of the patch, the backing material selected should be free of acid functional groups or should not generate acid functional groups during aging.

The polymer used to form the polymer/drug composite layer 18 should be compatible with the drug and allow the drug used to flow. The material included in the polymer layer 18 is preferably a pressure sensitive skin contact adhesive comprising a pharmaceutically acceptable material that does not have acid functional groups and does not generate acid functional groups during storage. General criteria that should be met by adhesives used in transdermal patches include biocompatibility, ease of use, and ease of removal. The preferred binder material should be one in which the drug has intermediate diffusivity. Upon equilibration, the drug will diffuse through the adhesive layer 18, which aids in the modulation of the release kinetics. Thus, by careful selection of the materials used for the adhesive 18, the distribution of the drug throughout the patch 10 can be adjusted. Other useful criteria include proper solubility of the drug in the adhesive layer 10 to provide storage capacity. Adhesives suitable for use in the present invention include natural and synthetic rubbers including polyisobutylene, neoprene, polybutadiene, and polyisoprene. Other suitable materials include polysiloxanes, polyurethanes, plasticizer-weighted polyether amide block copolymers ("PEBAX" copolymers), and certain crosslinked or non-crosslinked acrylic polymers and copolymers. Crosslinked and uncrosslinked acrylic polymers and copolymers may be preferred as polymeric adhesives because they are flexible, inexpensive, provide large area adhesive formulations, and provide better drug solubility than other adhesives, such as polyisobutylene ("PIB") adhesives. Two preferred binders are block copolymers of N-vinylpyrrolidone and 2-ethyl-hexyl acrylate (TSR, Sekisui chemical Co., Osaka, Japan) and hydroxyl functional acrylate binders (GELVA737, Monsanto Polymer Prod-ucts Co., St.Louis, Missouri). While the preferred polymer is an adhesive, the use of a non-adhesive polymer is also within the scope of the present invention. In this case, the polymer layer may be pressed onto the adhesive or may be faced with the adhesive. In any event, the components of the matrix patch that come into contact with the drug should not contain acid functional groups or generate acid functional groups during aging.

A release liner or release film 22 covers the skin-facing or adjacent side of the patch 10 until the time of use of the patch 10. The release liner or release film 22 should therefore have similar properties to, and preferably the same material as, the backing 14. Prior to use of the patch, the release liner 22 is removed, exposing the drug-containing polymer layer 18 to contact and adhere to the skin or mucosal surface. Thus, the release liner should be suitable for removal from the patch 10.

A method of stabilizing a steroid compound having a 3-oxo-4-ene functional group during storage in a transdermal patch containing the steroid compound, comprising the steps of: an effective amount of a steroid drug is first intimately admixed with an effective amount of a carrier which does not have acid functional groups and which does not generate acid functional groups during storage, and the admixed steroid drug and carrier are then incorporated into a transdermal drug delivery patch as a source of steroid drug. According to this method, the patch may be either a matrix patch or a reservoir patch, and the carrier may be any suitable carrier selected from those described above. The patch may be manufactured according to methods known in the art.

Example 1

Selected amounts of glycerol, Glycerol Monooleate (GMO). Methyl dodecanoate (ML), was mixed with ethanol to give a homogeneous solution. Water was added to give a stock solution containing 56/20/20/2/2 volume percent ethanol/water/glycerol/GMO/ML. An aliquot (100ml) of this stock solution was transferred to a vial and NEA was added to give a final concentration of approximately 10mg/ml for each vial. These NEA-containing solutions were analyzed for drug content, and then each vial was sealed and incubated at Room Temperature (RT) or 45 ℃ for a selected time before analysis for NEA content. Samples were incubated at 45 ℃ to accelerate disintegration, which of course would also occur if time were sufficient at RT. That is, the decomposition experiment can be accelerated by culturing at a higher temperature. NEA content was determined by HPLC analysis. The results of this experiment are shown in Table 1

TABLE 1

Time (week)	RT(mg NEA/ml)	45℃(mg NEA/ml)
			0	10.31±0.21	-
12	10.34±0.14	10.13±0.14

a is average + -SD, n is 4

These results indicate that NEA is fairly stable in pharmaceutical compositions without acid functional groups at RT or 45 ℃ over 12 weeks.

Example 2

The procedure of example 1 was followed except that 1.5% by weight of hydroxypropyl cellulose, (KLUCEL HXF, Aqnalon co., Wilmington, Delaware) was added to each bottle. The drug content in the gel obtained in the previous step was determined by placing a known amount of the gel in a jar, extracting the gel with methanol overnight with shaking, and determining the drug content in an aliquot of the methanol extract by HPLC. The results of this experiment are shown in table 2.

TABLE 2

Time (week)	RT(mg NEA/g gel)	45℃(mg NEA/g gel)
			0	10.27±0.15	-
12	10.17±0.10	10.17±0.07

a is average + -SD, n is 4

These results indicate that NEA is fairly stable in gelling drug/enhancer compositions without acid functional groups at RT or 45 ℃ for 12 weeks. Such gelled compositions may be used in reservoir patches or transdermal delivery systems in free form.

Example 3

The procedure of example 2 was followed except that 1.5% by weight of 15 allyl ether crosslinked polyacrylic acid (CARBOPOL 1342, BF Goodrich Co., clereland, Ohio) was added to each bottle. Since the crosslinked polyacrylic acid lowered the pH of the drug/enhancer formulation, sufficient 2N NaOH was added to adjust the pH to about 5.5, similar to the pH of the drug/enhancer of examples 1 and 2. The results of this experiment are shown in table 3.

TABLE 3

Time (week)	RT(mg NEA/g gel)	45℃(mg NEA/g gel)
			0	10.16±0.12	-
12	9.92±0.07	9.21±0.05

a is average + -SD, n is 4

These results indicate that about 9% of the NEA is lost in the acid functional group containing gel after 12 weeks storage at 45 ℃. These results are in contrast to the results of examples 1 and 2, where no acid functional groups were present in the formulation, there was no significant loss of drug.

HPLC analysis showed the presence of degradation products of NEA in the acid functional group containing gel, but not in the acid functional group free formulation. The Relative Retention Times (RRTS) of these decomposition products compared to NEA were 0.47 and 0.52. These degradation products were collected from the HPLC effluent, concentrated under reduced pressure, redissolved in chloroform, and analyzed by mass spectrometry. The analysis showed that the degradation product was a hydroxy derivative of NEA. The position of hydroxylation is not determined, but is likely at the 6, 8, and/or 10 positions. This result demonstrates that the formation of these degradation products is related to the presence of acid functional moieties. The degradation of NEA in the presence of acid functional groups is not a simple ester hydrolysis of norethindrone but a nuclear substitution of the NEA molecular backbone.

Example 4

The NEA-containing matrix transdermal patch was prepared as described below. A small amount of Duro-Tak 80-1196 adhesive solution (acid functional group-containing acrylic adhesive, national starch & Chemical co., Bridgewater, n.j.) was dispensed into pre-weighed aluminum pans and the weight was measured. The dish and its contents were weighed after drying overnight in a convection oven at 70 ℃ to evaporate the solvent. The percent solids is calculated by dividing the dry weight by the wet weight and multiplying by 100. A known amount of the DuroTak80-1196 adhesive solution was weighed in a glass bottle. The amount of binder in the solution was calculated from the binder solution weight and percent solids content. Appropriate amounts of NEA (Schering AG, Berlin, Germany) and sorbitan monooleate penetration enhancer (ARLACEL 80, ICI America, Wilmington, Delaware) were added to give a composition containing 81% DuroTak80-1196, 4% NEA, and 15% sorbitan monooleate, all percentages being by dry weight. The individual vials were then capped tightly, sealed with a laboratory film (PARAFILM "M", American National Can co., Greenwich, CT) and shaken gently overnight until all components were completely dissolved and the dissolution became clear.

Approximately 8ml of DuroTak 80-1196/NEA/sorbitan monooleate solution was then dispensed onto a silanized polyester Release liner (Release technologies. Inc., W.Chicago, Illinois) and cast with a casting knife with a 10mil gap. The cast mixture was dried in a convection oven at 70 ℃ for 15 minutes to give a dry film of about 2mil thickness, and a polyethylene backing film (3M corp., st. paul, Minnesota) was then pressed onto the dried adhesive film using a rubber roller. The film product is used for rapid drug stability evaluation.

The stability of NEA in matrix patches formulated according to this example was determined as follows. Mixing patch (10 cm)²) Cut from the base film article and placed in a white 3 x 3 inch box (SVRLYN film, aluminum foil, low density polyethylene, and paper; WRAPS, inc., eastlorange, n.j.), heat-sealed in a box and stored at Room Temperature (RT) or at 45 ℃. The patch samples were analyzed for drug content at time zero and after selected intervals. Before peeling the release liner from the adhesive patchThereafter, three samples stored at each temperature were weighed. The average weight of backing film was determined by weighing 10 backing film samples of the same area of patch. The weight of each patch adhesive was calculated by subtracting the weight of the backing film from the weight of the patch with the release liner removed. The peeled patch was then extracted with 50ml of methanol in a sealed container for 24 hours. The methanol extracts were analyzed by HPLC to determine the drug content of each patch. The results of this rapid stability study are shown in table 4.

TABLE 4

Time (week)	RT(％/w/w)	45℃(％w/w)
			0	3.88±0.03	-
14	3.80±0.02	2.5±0.00

a mean ± SD (n ═ 3)

These results show that in the presence of a binder containing acid functional groups, about 36% of the NEA is lost due to decomposition after 14 weeks of storage at 45 ℃. Figure 3 shows that this drug loss on storage in the presence of an acid functional group is related to the formation of RRTS as degradation products identical to those of example 3 (figure 2), indicating that the mechanism of NEA degradation is identical to that of example 3.

Example 5

A matrix transdermal drug delivery patch containing NEA was prepared by following the procedure of example 4 except that the adhesive was an acrylic copolymer (2-ethylhexyl acrylate and n-vinyl-2-pyrrolidone copolymer; TSR, Sekisui Chemical Co., Osaka, Japan) containing no acid functional group. The formulations were prepared with the following dry weight percent components. 81% RST, 4% NEA, 15% sorbitan monooleate. The stability of these patches was measured according to the procedure of example 4, and the results are shown in Table 5.

TABLE 5

Time (week)	RT(％/w/w)	45℃(％w/w)
			0	4.14±0.04	-
8.5	4.08±0.06	3.91±0.07

a mean ± SD (n ═ 3)

These results show that the NEA content in the base patch without acid functional groups is quite stable after 8.5 weeks storage at room temperature or 45 ℃. It has also been found that NEA can be stored stably at room temperature for more than 2 years in the absence of acid functional groups. Compared to patches containing acid functional groups, degradation of NEA by hydroxylation was inhibited (fig. 3).

Example 6

A NEA-containing matrix transdermal drug delivery patch was prepared by following the procedure of example 4, except that the adhesive was an acrylic copolymer without acid functional groups (GELVA737, Mon-santo polymer Products co., st. louis, Missouri). The following formulations were obtained in weight percent of each component: 81% (GELVA737, 4% NEA, 15% sorbitan monooleate. the stability of NEA in the obtained patch was measured, and the results are shown in Table 6.

TABLE 6

Time (week)	RT(％/w/w)	45℃(％w/w)
			0	3.99±0.06	-
8.5	3.87±0.10	3.82±0.12

a mean. + -. SD

These results show that in the absence of acid functional groups, there is no significant loss of NEA after 8 weeks of storage at room temperature or 45 ℃. Further studies have demonstrated that the drug in this formulation can be stored stably at room temperature for more than 2 years. In addition, the generation of NEA degradation products was inhibited compared to the acid functional group containing formulations (fig. 3).

Example 7

A matrix transdermal patch containing Testosterone (TS) was prepared according to the procedure of example 4. The following formulations were obtained in weight percent of each component: 83% Duro Tak80-1196, 2% TS, 15% sorbitan monooleate. The stability of TS in the patch prepared as described above was measured, and the results are shown in table 7.

TABLE 7

Time (week)	RT(％/w/w)	45℃(％w/w)
			0	1.94±0.03	-
4	2.05±0.03	1.88±0.03
			12	2.05±0.01	1.75±0.03
26	1.98±0.04	1.52±0.05

a mean. + -. SD

These results show a clear change in TS content over different times between patches stored at RT and patches stored at 45 ℃. In the acid functional group containing adhesive, TS unstable, and compared with RT sample, TS content at 45 degrees C loss 12% and 24%. Loss of TS content in the DuroTak80-1196 binder indicates that it produces TS degradation products, and the production of at least one TS hydroxy derivative can be determined by comparing the degradation products to a reliable curve of chromatography of 6 β -OM testosterone. This example illustrates the degradation of the steroid drug testosterone in an acid functional group containing adhesive by a nucleophilic substitution mechanism similar to that observed in NEA.

Example 8

A matrix transdermal patch containing TS was prepared as in example 7, except that DuroTak 87-2287 (an acrylic adhesive without acid functional groups) was used in place of DuroTak 80-1196. The following formulations were obtained in weight percent of each component: 88% DuroTak 87-2287.2% TS, 10% sorbitan monooleate. The TS stability in these patches was measured, and the results are shown in table 8.

TABLE 8

Time (week)	RT(％/w/w)	45℃(％w/w)
			0	2.03±0.02	-
4	1.97±0.01	2.01±0.02
			12	2.00±0.01	2.02±0.01
26	1.97±0.02	1.91±0.02

a mean. + -. SD

These data show that the TS content of the patch is not significantly different after 26 weeks of storage between RT and 45 ℃ and that the drug is stable in the acid functional group free DuroTak 87-2287 adhesive after 26 weeks of storage at 45 ℃. These results show that the steroid drug testosterone is stable when stored in a formulation without acid functional groups.

Example 9

A patch containing Norethindrone (NE) for transdermal administration as a matrix was prepared by following the procedure of example 4. The following formulations were obtained in weight percent of each component: 88% DuroTak80-1196, 2% NE, 10% sorbitan monooleate. The stability of NE in the prepared patch was measured, and the results are shown in table 9.

TABLE 9

Time (week)	RT(％/w/w)	45℃(％w/w)
			0	1.95±0.06	-
11	1.97±0.04	1.77±0.05

a mean. + -. SD

These results show that the patch has a significant difference in steroid content, about 11%, between RT storage and storage at 45 ℃. The steroid drug norethindrone is therefore unstable in acid functional group-containing adhesives.

Example 10

A matrix transdermal patch containing NE was prepared by following the procedure of example 9 except that DuroTak80-1196 was replaced with a TSR adhesive not containing an acid functional group. The following formulations were obtained in weight percent of each component: 88% TSR, 2% NE, 10% sorbitan monooleate. The stability of NE in the obtained patch was measured, and the results are shown in table 10.

Watch 10

Time (week)	RT(％/w/w)	45℃(％w/w)
			0	1.96±0.07	-
11	1.99±0.08	1.96±0.03

a mean. + -. SD

Comparison of the data at each time point shows that there was no significant difference in steroid drug content between RT and 45 ℃ after 11 weeks of storage of the patch, and that the steroid drug remained stable after 11 weeks of storage at 45 ℃ in an adhesive without acid functional groups.

Example 11

A matrix transdermal patch containing NE was prepared in the same manner as in example 9, except that sorbitan monooleate was omitted, to obtain a preparation having the following dry weight percentages of the respective components: 98% DuroTak80-1196, 2% NE. The stability of NE in the obtained patch was measured, and the results are shown in table 11.

TABLE 11

Time (week)	RT(％/w/w)	45℃(％w/w)
			0	1.97±0.02	-
11	2.01±0.02	1.64±0.03

a mean. + -. SD

These results show a loss of NE content of about 14% after 11 weeks storage between RT and 45 ℃. Thus, the steroid drug is unstable in the acid functional group-containing formulation, and the amount of steroid drug lost is approximately the same as in the patch containing sorbitan monoglyceride (example 9). Thus, the stability of the steroid drug is related to the interaction of the acid functional group-containing binder and not to sorbitan monooleate.

Example 12

A matrix transdermal patch containing levo 18-methylnorethindrone (LVNG) was prepared according to the procedure of the examples. The following formulations were obtained in weight percent of each component: 89% DuroTak80-1196, 1% LVNG, 10% sorbitan monooleate. The stability of LVNG in the resulting patches was determined and the results are shown in Table 12.

TABLE 12

Time (week)	RT(％/w/w)	45℃(％w/w)
			0	1.94±0.02	-
11	0.98±0.01	0.84±0.02

a mean. + -. SD

These data show a significant loss of LVNG in the patch, about 14%, after 11 weeks of storage between RT and 45 ℃. LVNG is therefore unstable in acid functional group containing adhesives.

Example 13

A matrix transdermal patch containing levo-18-methylnorethindrone (LVNG) was prepared as in example 12 except that DuroTak80-1196 was replaced with an STR containing no acid functional groups. The following formulations were obtained in weight percent of each component: 89% TSr, 1% LVNG, 10% sorbitan monooleate. The stability of LVNG in the prepared patches was determined and the results are shown in table 13.

Watch 13

Time (week)	RT(％/w/w)	45℃(％w/w)
			0	0.91±0.03	-
11	0.89±0.02	0.89±0.03

a mean. + -. SD

Comparison of the data at each time indicated no significant difference in LVNG content between RT and patches stored for 11 weeks at 45 ℃. Thus, the steroid drug in the patch containing no acid functional group remained stable after storage at 45 ℃ for 11 weeks.

Example 14

A matrix transdermal patch containing LVNG was prepared as in example 12, except that sorbitan monooleate was not used. Obtaining the preparation with the dry weight percentage of each component: 99% DuroTok 80-1196, 1% LVNG. LVNG stability in the prepared patches was measured and the results are shown in table 14.

TABLE 14

Time (week)	RT(％/w/w)	45℃(％w/w)
			0	0.98±0.03	-
11	0.99±0.02	0.85±0.03

a mean. + -. SD

These data show that there is a significant loss of LVNG content in the patch, about 14%, after 11 weeks of storage of the patch between KT and 45 ℃. This indicates that steroid drugs are unstable in the presence of acid functional groups. Comparison with example 12 shows that this instability stems from interaction with the binder and not with the sorbitan monooleate in the formulation.

Claims (8)

1. A stable matrix patch for transdermal administration of testosterone having a 3-oxo-4-ene functional group, wherein said testosterone is stable during prolonged storage of the patch, comprising

(i) An effective amount of said testosterone intimately admixed with a biocompatible polymeric adhesive carrier, wherein said polymeric adhesive carrier is free of acid functional groups and does not generate acid functional groups during shelf life, and

(ii) an effective amount of a penetration enhancer, wherein the penetration enhancer is free of acid functional groups and does not generate acid functional groups during shelf life,

wherein the matrix patch is free of a substance having an acid functional group or generating an acid functional group during storage.

2. The stable matrix patch of claim 1 wherein said polymeric binder is selected from the group consisting of acrylic polymers and copolymers which are free of acid functional groups and do not generate acid functional groups during shelf life.

3. The stable matrix patch of claim 2 wherein said polymeric adhesive is free of acid functional groups and does not generate acid functional groups during shelf life and is a block copolymer of N-vinyl pyrrolidone and 2-ethyl-hexyl acrylic acid.

4. The stable matrix patch of claim 3 wherein said penetration enhancer is selected from the group consisting of cell membrane disregulating compounds, solvents, and mixtures thereof.

5. The stable matrix patch of claim 4 wherein said cell membrane disregulating compound is selected from the group consisting of isopropyl myristate, methyl dodecanoate, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol trioleate, glycerol monostearate, glycerol monododecanoate, propylene glycol monododecanoate, sorbitan ester and mixtures thereof and said solvent is selected from the group consisting of water, glycols, monoalcohols, DMSO, dimethylformamide, N, N-dimethylacetamide, 2-pyrrolidone, N-substituted-alkyl-azacycloalkyl-2-one, and mixtures thereof.

6. The stable matrix patch of claim 1 further comprising a steroid compound free of 3-oxo-4-en functional groups selected from the group consisting of estrogens, progestogens, androgens, and corticosteroids, wherein said steroid compound has no acid functional groups or produces no acid functional groups during storage.

7. The stable matrix patch of claim 6 wherein said steroid is an estrogen.

8. The stable matrix patch of claim 7 wherein said estrogen is estradiol.