CA2256365A1

CA2256365A1 - Compositions, methods and devices for the transdermal delivery of drugs

Info

Publication number: CA2256365A1
Application number: CA002256365A
Authority: CA
Inventors: Edward M. Portman; Michael S. Christensen; Dennis L. Schmirler
Original assignee: DIVERSIFIED PHARMACEUTICALS Inc
Current assignee: Individual
Priority date: 1996-05-22
Filing date: 1997-05-22
Publication date: 1997-11-27
Also published as: JP2000513336A; WO1997043989A1; IL127189A0; AU3136897A; EP0954260A1

Abstract

The present invention is directed to compositions, and methods for the delivery of drugs. Devices for the transdermal delivery of drugs are also provided. Specifically, the present invention relates to hydrogel compositions comprising water and a base mixture, in which the base mixture comprises: (i) a gelling agent consisting of methylcellulose or at least one natural gum, or a mixture thereof; (ii) at least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl paraben; and (vi) sodium chloride. The compositions may further comprise pectin, glycolic, alcoholic or oil-based additives, a coloring, fragrance, or other pharmaceutically acceptable additive. The compositions may further comprise substituted ureas of the formula R-NH-CO-NH2 such as butylurea. The compositions may further comprise drugs such as hormones selected from progesterone, progestin, estrogen and testosterone. Methods for the treatment of disorders responsive to hormone therapy are also provided. The figure is a cross-sectional view of a membrane-moderated transdermal drug delivery system.

Description

CA 022~636~ 1998-11-23 COMPOSITIONS, METHODS AND DEVICES
FOR THE TR~NSDERMAL DE~IVERY OF DRUGS

1. INTRODUCTION
The present invention re}ates to compositions for the transdermal delivery of hormones comprising a hydrogel-forming base mixture and a skin permeation enhancer.
Methods for the treatment of disorders responsive to the ,q,~iminictration of hormones are also provided. The present invention further relates to devices for the transdermal delivery of drugs.

2. BACKGROUND
A recent trend in the pharmq.~eutiral indust;y has been the development of new drug delivery systems for both old and new drugs. Much of the current research in drug delivery technology is aimed at developing formulations and devices that improve 15 the IhelapeuLic effectiveness of drugs over conventional means of 3~mini~tration by controlling the rate, time and place of release of drugs in the body.
Conventional dosage types include sublingual (under the tongue), oral (cqpsule~,tablets, liquids), injectable, nasal and ~ale.ll~.dl (suppository and non-oral) forms.
While oral dosage forms comprise a substantial majority of all present dosage forms and 20 offer ease of v~iminictration and low cost-per-use, they can suffer from inconvenient dosing intervals, side effects and reduced efficacy. Conventional dosage forms have disadvantages in certain patients, including unpredictable blood levels, difficult or uncomfortable q.-lmini~tration and poor compliance. In order to mqint~in optimum blood levels, some conventional forms of drug delivery require frequent doses which can be 25 difficult to remember or understand, particularly for the elderly patient. Failure to comply with a recommended drug regimen can endanger a patient's health.
Controlled drug delivery systems have been introduced within the last decade to eliminqte or reduce the limitations of conventional dosage forms. One type of controlled delivery is transdermal delivery, which involves delivery of a therapeutic 30 agent through the skin for distribution within the body by the circulation of the blood.
Transdermal delivery can be compared to continuous, controlled intravenous delivery of CA 022~636~ 1998-ll-23 wo 97/43989 PcT/uss7/08636 a drug using the skin as a port of entry instead of an intravenous needle. The therapeutic agent passes through the outer layers of the skin, diffuses into thecapillaries, or tiny blood vessels in the skin, and then is transported into the main circulatory system.
Examples of drugs which have s~ccessfully been delivered transdermally include scopolamine for the treatment of motion sirkness, nitroglycerin for the trç~tment of angina, estrogen and combined estrogen/progestogen for menopausal symptoms and osteoporosis, isosorbide dinitrate for angina, clonidine for hypertension, nicotine for smoking cessation, fentanyl for pain management and testosterone for male 10 hypogonadism.
The horrnone progesterone is used in the treatment of premenstrual ~yndrvllle, menopausal hormone replacement therapy (in combination with estrogen). infertility and a variety of gynecological conditions. In ovulating females, progesterone is chiefly produced by the corpus luteum of the ovary with smaller amounts made in the adrenal 15 cortex in both sexes, and in the testes of males. Within the cytoplasm of cells are minute organelles called the mitochondria, which convert cholesterol to pregnenolone.
~,egnellolone, on being transferred to the cytoplasm, is converted to progei,lcrone or DHEA depending on cell type and body needs. With the development of the corpus luteum at ovulation, the ovarian production of proge~.Lcrolle rapidly rises from 2-3 mg 20 per day to an average of 22 mg per day, peak production being as high as 30 mg per day, a week or so after ovulation. After 10 to 12 days, if fertilization does not occur, ovarian production of progesterone falls dr~m~tir~lly. It is the sudden decline in progesterone levels which triggers the ~hPd~ing of the secretory endo,llcLli.lll, leading to a renewal of the entire menstrual cycle. During p,e~"all ;y, production of ~loge~Lerolle 25 is taken over by the placenta which secretes an ever h~clcasillg supply, leachillg 300-400 mg per day during the third trimester.
Proge~lerone as it is secreted into the blood stream is bound within a water soluble protein (termed cortisol binding globulin; CBG), being the same globulin used by cortisol for passage through the plasma. Only a small portion of progesterone (2-30 10%) circulates unbound through the plasma. A molecular framework of progesterone,having been derived from cholesterol, is very similar to the cholesterol molecule, and CA 022~636~ 1998-11-23 like cholesterol is fat soluble. As such, it would not be soluble in the watery plasma were it not for the CBG protein carrier. In close proximity to a cell, progesterone is freed from the CBG and passes easily through cell membranes into the cell cytoplasm where, if it encounters and binds to an accessible receptor, forms an activated complex 5 which migrates into the cell nucleus for binding with an accessible DNA segment (genome) resulting in the formation of a specific RNA by which the cellu}ar effects of progesterone are brought into being. If the progesterone passes into a cell lacking an a~l,r()~ te progesterone receptor, it will simply pass on through and out the cell again.
Eventually, progesterone molecules are carried by the blood through the liver 10 where they are inactivated and disposed of by the bile and urine. Progesterone, in addition to its own intrinsic hormonal effect is an important precursor in the biosynthesis of various hormones. Specialized cells in key organs throughout the body use progesterone to synthesize other hormones as needed, specifically the adrenal corticosteroids, estrogen and testosterone. This aspect of progesterone distinguishes it 15 from most other hormones which are at a metabolic endpoint. This means they are unable to be used in further metabolic functions, except to be metabolized for excretion.
More specifically, the various synthetic analogues of progesterone now being promoted heavily have undergone molecular alterations at unusual positions that inhibit further metabolism, and thus are not subject to feeclback control by the body to prevent20 excessive or improperly prolonged activity. Unfortunately, these molecular alterations carry a heavy burden of potential undesirable side effects.
The transdermal delivery of progesterone has been reported. However, due to the large size of the progesterone molecule, efforts to transdermally deliver progesterone in therapeutically effective amounts have often been un~llccescful. Progesterone is 25 known to be metabolized within the skin by the 5-~-re~ cta~e enzyme which converts it to inactive 5-~-dihydroxyprogesterone (R. Sitruk-Ware, 1995, "Transdermal Application of Steroid Hormones for Contraception," J. Steroid Biochem. Molec. Biol. 53 (1-6):247-251). Thus, relatively high, multiple doses are required to elicit the desired progestational effect. The desired goal of transdermal delivery of progesterone is to be 30 able to m~int~in consistent serum levels of progesterone at relatively low dosage levels without requiring multiple dosing.

CA 022~636~ 1998-ll-23 W O 97/43989 PCT~US97/08636 Low rates of transdermal delivery of progesterone have been reported by various researchers. For example, Guy et al. (1987, "Kinetics of Drug Absorption Across Human Skin In Vivo," Pharmacol. Skin 1:70-76), disclose that about 1.2 ~g/cm' penetrated in a 24-hour period, when the drug was applied as a thin film on the skin in 5 vivo. Barry and Bennett, (1987, "Effect of Penetration F.nh~nrers on the Permeation of Mannitol, Hydrocortisone, and Progesterone Through Human Skin," J. Pharm.
Pharmacol. 39:535-546), report a rate of 0.477 ~g/cm21 hour in vitro through excised human skin. Both Guy et al. and Barry and Bennett measured penetration through the skin after progesterone was applied in an acetone solution, the solvent was allowed to 10 evaporate, and the skin surface was hydrated, either by occlusion or by application of a small amount of water. Barry and Bennett reported higher rates of transdermal penetration of progesterone when penetration enhancers were applied to the skin following application of the acetone/progesterone solution and evaporation of the solvent. Rates of 11.4 (+/- 4.6) and 12.4 (+/- 4.4) ~4g/cm2/hour, respectively, were 15 observed after application of 2-pyrrolidone and N-methylform~micle permeationenh~nrers. However, neither the methods nor the solvent vehicles for application of progesterone to the skin disclosed by these references are apl)lol)liate or practical for use in a transderrnal patch delivery system, for number of reasons. Application of acetone to the skin commonly results in skin irritation, an effect that may also be 20 encountered with 2-pyrrolidone and N-methylform~mi~1e. Further, permeation enhancers such as 2-pyrrolidone and N-methylform~mirle may impose health risks.
Also, the volatile solvent carriers disclosed by these references can be difficult and impractical to incorporate into a patch system.
The transdermal delivery of progesterone, progestins, estrogens and testosterone25 from gel-like matrices has been reported. R. Sitruk-Ware (1988, "Innovative Technology for Hormonal Replacement Therapy," Maturitas, 10:79-81) discloses a progesterone cream for use as a topical therapy in benign breast (li~e~ces. R. Sitruk-Ware (1989, "Transdermal Delivery of Steroids," Contraception 39, (1):1-20) discloses that only small amounts of proge~Le~ul1e can be obtained in plasma via skin penetration, 30 but when applied on the breast, high amounts of progesterone can be obtained in the breast tissue. A five-fold increase in progesterone concentration was demonstrsted in CA 022~636~ l998-ll-23 wo 97/43989 PcT/Us97/08636 breast tissue of women treated topically with the steroid dissolved in an alcohol/water gel.
Compounds that act as permeation enhancers have been added to transdermal drug delivery systems for a number of drugs, including progesterone. Pfister and Hsieh 5 (1990, in "Permeation Fnh~nrers with Transdermal Drug Delivery Systems: Part II:
System Design Considerations," Pharmaceutical Technology, October 1990: 55-60), disclose a wide variety of perrneation enhancers. For example, isopropyl palmitate and isopropyl myristate are disclosed as cosolvents to enhance the solubility of nitroglycerin in a polymer matrix-type transdermal system, which in turn optimizes the release of the 10 drug from the system. Similarly, ethanol is disclosed as enhancing the solubility of 17-,B-estradiol in the reservoir compartment of a transdermal drug delivery device. Other skin penetration enhancers are disclosed, including stearyl alcohol, glycerol, 2-pyrrolidone, urea, propylene glycol, oleic acid, and palmitic acid. D.R. Friend (1990, "Transdermal Delivery of Contraceptives", Critical Reviews in Therapeutic Drug 15 Carrier Systems 7 (2):149-186), discloses dirnethyl sulfoxide, N,N-dimethyl ilcet~mille, N,N-dimethyl form~mi-le, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, N,N-dimethyl-m-toluamide, urea, ethyl acetate, 1-dodecyla~acycloheptan-2-one (azone), oleic acid and ethanol as permeation enhancers.
20 Butylurea has also been disclosed as a permeation enhancer. For example, U.S. Patent No. 5,128,376 discloses a method for percutaneous a~l nini~tration of a drug from a mixture of an adjuvant, a solvent and a diol/triol moderator, wherein the solvent, which enhances perrneation, may be a substituted urea such as butylurea. U.S. Patent No.
4,863,952 discloses an improved method of drug ~ mini~tration using a mixture 25 comprising pyrrolidone carboxylic acid esters as percutaneous promoters, and optionally, substituted ureas such as butylurea. S.K. Han et al. (1991, "Percutaneous Absorption-Enhancing Activity of Urea Derivatives," Arch. Pharm. Res. 14(1):12-18) disclose the use of urea derivatives, including butylurea, to enhance the percutaneous ~ absorption of salicylic acid and sodium salicylate from a vaseline base.
Hydrogels are well known in the art as vehicles for the controlled release of drugs. N.A. Peppas, ed., "Hydrogels in Medicine and Pharmacy," CRC Press, Inc.

CA 022~636~ 1998-11-23 (1987) Vol. II, discloses the use of water soluble cellulose ethers such as methylcellulose for controlled release drug delivery systems. Volume III of the same publication discloses the release of progesterone from rod-shaped monolithic hydrogel devices.
U.S. Patent Nos. 5,344,655 and 5,254,338 disclose that hydrogel bases cont~ining water soluble polymers such as cellulose derivatives are known in the art for delivery of drugs through the skin. U.S. Patent No. 4,693,887 discloses hydrogelcompositions for the controlled release of contraceptives such as progesterone. The hydrogels are blends of either N-vinyl lactam or a copolymer of N-vinyl lactam and may 10 further comprise sperrnicides such as urea. U.S. Patent No. 5,405,366 discloses an adhesive hydrogel comprising an aqueous mixture of a radiation cro~link~ble water-soluble polymer such as a polymer of N-vinyl-2-pyrrolidone and ethylene oxide and a hllm~ct~nl such as propylene glycol which may be used in a transdermal drug delivery system. The hydrogel may also contain preservatives such as propyl paraben and 15 methyl paraben. U.S. Patent No. 4,593,053 discloses a skin-compatible pressure-sensitive adhesive hydrogel comprising polyvinyl pyrrolidone and polyvinyl alcohol, a polar plasticizer or hllmect~nt such as propylene glycol, water and a drug. The composition may also contain cellulose derivatives to increase strength and guar gum to increase t~ iness.
The transdermal delivery of progesterone, progestins, estrogens and testosteronefrom hydrogel matrices comprising permeation enhancers is also known. For example, U.S. Patent No. 5,030,629 discloses transdermal formulations cont~ining progesl~.one, ethanol, saline and an imidazoline penetration enhancer. Dosage forms of the formulations for application to the skin include gels, which may comprise inert carriers 25 such as propylene glycol, urea and methylcellulose. U.S. Patent No. 5,362,497discloses compositions for transdermal delivery of, inter alia, androgens such as testosterone and estrogens such as estradiol comprising water- and fat-soluble absorption enhancers, and a water-absorbent resin such as a vinyl acetate-acrylic acid ester copolymer that swells to form a hydrogel upon contact with water. U.S. Patent No.
30 5,064,654 discloses a transdermal drug formulation comprising a drug such as progesterone or estradiol, water and ethanol. The formulation may also contain an CA 022~636~ 1998-11-23 adhesive or gelling agent such as pectin, guar gum or methyl cellulose. U.S. Patent No. 4,942,158 discloses a composition comprising a combination of isopropyl alcohol and isobutyl alcohol to enhance the transdermal penetration of steroids such as estradiol, or a combination of estradiol with a progestogen. The composition may also include 5 water and a gelling agent such as methyl cellulose. U.S. Patent No. 4,865,84~
discloses compositions for enhancing the transdermal delivery of drugs, including progesterone, comprising sucrose esters as penetration enhancers. Preferably, the permeation enhancer and the drug are dispersed in a matrix which may be a gel or a hydrophilic polymer.
Despite their advantages, conventional transdermal delivery systems have been limited due to barrier properties of the stratum corneum, the skin's protective outer layer. Large, high molecular weight drugs such as progesterone are difficult to deliver through the skin in effective amounts. In general, the skin is highly resistant to permeation by chemicals, including drugs. Although the skin is only a few millimeters 15 thick, the stratum corneum serves as a highly protective barrier against physical, chemical and bacterial penetration. This barrier primarily consists of dead skin cells bound together by certain fatty (lipid) materials. Generally, only drugs that are effective in the body at very low concentrations or that have particular physical properties have been successfully delivered through the skin in Ihe,apelltically effective amounts. High 20 molecular weight drugs and drugs which are either charged or highly polar remain difficult to ~minict~r transdermally.
Natural proge~Lelone, which is the form of progesterone that is produced by the body, has been a~imini~tered in oral, injectable and suppository forms. The disadvantages of injectable and suppository forms are obvious: they are burdensome to 25 aflminicter. The disadvantage of oral forms is that they are short acting, and to m~int~in a~leqll~te blood levels, they have to be dosed throughout the day. The bulk of orally a(lminict~red progesterone is metabolized by the digestive system and excreted before it can be used by the body. In fact, progesterone, whether ~-~minictered orally, vaginally or rectally, has a half life in the body of only about 2.2 hours. Therefore, much larger 30 amounts than the body actually requires must be dosed to m~int~in effective blood levels.

CA 022~636~ 1998-11-23 To address the problems associated with conventional means of ~lmini.~tration ofnatural progesterone, a variety of synthetic forms, known as progestins, have been developed. Progestins fall primarily into two categories. The first group, pregnanes, is derived from 17-~-acetoxy progesterone. A classic example is medroxy progesterone 5 acetate (Provera). With an increased affinity for progesterone receptors, these compounds have marked progestational activity. They possess anti-estrogenic anti-gonadotropic, and no significant androgenic properties. A second group, estranes, derived from 17-c~-ethinyl-1-nortestosterone, includes norethindrone acetate (aygestin).
Besides progestational activity, these compounds have marked anti-estrogenic, some 10 anabolic, moderate androgenic, and as a result, pronounced anti-gonadotropic activities.
Synthetic progesterones are 10-100 times more potent than natural progesterone, and thus are effective at much lower doses. However, synthetic progesterones (i.e., progestins) can cause many negative side effects, such as sudden or partial loss of vision, thrombophlebitis, pulmonary embolism, cerebral thrombosis, salt and fluid 15 retention, epilepsy, migraine, asthma, cardiac or renal dysfunction, weight gain, rise in blood pressure, headaches, depression, decreased glucose tolerance leading to diabetes in predisposed individuals, acne, alopecia, hirsutism, decrease in T3 uptake and thyroid regulation.
A disadvantage of conventional patch systems is that many of them either 20 incorporate drugs in an adhesive or require an adhesive to affix the patch to patient's skin. These adhesives can irritate the skin, causing patient non-compliance. Thus, there is a need for a non-adhesive transdermal delivery system that can deliver th~ldl~c~lic~lly effective amounts of hormones such as natural progesterone, progestins, estrogens and testosterone that will reduce or e]imin~te the skin irritation experienced by 25 many patients using current adhesive patch transdermal delivery systems. This need is satisfied by a particular embodiment of the invention.
Although patches for the transdermal delivery of estrogen and testosterone are currently commercially available, progesterone can be obtained co-,ll,lel.;ially at present only in oral, injectable and suppository forms. The transdermal delivery of natural 30 progesterone from hydrogel matrix systems with potential for use in patches has been demonstrated; however, none of these systems has proven adequate for administration of CA 022~636~ 1998-11-23 therapeutically effective amounts of progesterone. Accordingly, there is a need in the art for a matrix composition that can transdermally deliver and m~int~in therapeutically effective levels of hormones such as natural progesterone, progestins, estrogens and testosterone in the bloodstream from a convenient, reliable patch system.
Citation of the references hereinabove shall not be construed as an admission that such references are prior art to the present invention.

3. SUl\IMARY OF THE INVENTION
The present invention is directed to compositions for the transderrnal delivery of 10 a hormone selected from the group consisting of progesterone, progestin, estrogen, and testosterone, or a combination thereof, said compositions comprising or alternatively consisting or consisting essentially of: (a) a hydrogel, or a base mixture that when combined with water forms a hydrogel; (b) a perrneation enhancer selected from the group consisting of urea, hydroxyurea, or an alkylurea; and (c) a hormone selected from 15 the group consisting of progesterone, progestin, estrogen, and testosterone, or a combination thereof. In a preferred embodiment, the hormone is natural progesterone.
Natural progesterone is superior to synthetic forms of progesterone, known as progestins, in treating gynecological conditions. The invention also provides apparatuses for transdermal hormone delivery cont:~ining the compositions of the20 invention. Methods of transderrnal drug delivery, and of treatment of disorders responsive to the ~-lmini~tration of hormones, are also provided.
Transdermal delivery according to the invention offers signifi~nt advantages over conventional means of drug ~mini~tration It is a comfortable, convenient and noninvasive means of drug delivery. The variable rates of absorption and metabolism 25 encountered in oral treatment are avoided, and side effects such as gastroint-?stinql irritation and the like are elimin~ted. Transdermal drug delivery also makes possible a high degree of control over blood concentrations of particular drugs.
Transdermal drug delivery according to the invention also helps provide patientswith a drug's maximum therapeutic effect and decreases the risk of adverse side effects 30 or dimini~hPd therapeutic effect due to excessive or insufficient blood concentrations.
The therapeutic effect of a drug is typically achieved only when the drug is within a , CA 022~636~ 1998-11-23 specific concentration range in the bloodstream. This blood concentration range is often called the drug's "therapeutic window." Below this range the drug may be ineffective, and above it the drug may cause unwanted side effects. Many conventional forms of drug delivery a/tmini~ter higher concentrations than are required in order to m~in~in 5 effective blood levels between doses. However, blood levels often fall below effective concentrations prior to aclmini~tration of the next dose. Transdermal drug delivery systems using the compositions of the present invention are designed to m~int~in a precise and continuous flow of drug into the bloodstream. This results in more stable blood concentrations which consistently remain within a drug's therapeutic window.
In contrast to oral a~lmini~tration, transdermal drug delivery can frequently maximize a drug's therapeutic effect by avoiding the gastrointestinal ("GI") tract and "first pass" liver metabolism. Oral drug delivery is often unreliable because the achievement of therapeutic blood levels depends on several factors, including the drug's chemical composition, the patient's physical condition, chemical and physical reactions 15 between the drug and substances in the GI tract and the timing of drug ~tlmini.ctration.
Upon GI tract absorption a drug must pass through the liver before entering the bloodstream. In many in~t:~n~es, the liver metabolizes a large portion of the drug. As a result, orally dosed drugs must generally be ~dministered at levels which exceed optimal therapeutic levels, potentially resulting in adverse side effects.
Transdermal drug delivery systems according to the invention avoid many of the problems associated with conventional drug delivery, and are capable of conveniently and consistently delivering drugs over a number of hours or days. The transdermal drug delivery systems of the invention may also improve the safety of drug ~lministration~ since they can be removed quickly and easily. If a patient has an 25 adverse reaction to a drug, rapid removal of the transdermal drug delivery device can minimi7e the extent of such an adverse reaction.
The present invention provides compositions complisillg (i) a gelling agent consisting of methylcellulose or at least one natural gum, or a mixture thereof; (ii) at least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl paraben; and 30 (vi) sodium chloride. The compositions of the present invention may further comprise a glycolic, alcoholic or oil-based additive such as propylene glycol. The compositions CA 022~636~ 1998-11-23 WO 97/43989 PCT/US97tO8636 may further comprise coloring, fragrance or other pharmaceutically acceptable additives.
The compositions of the present invention may also comprise pectin.
In a preferred embodiment, compositions of the present invention consist essentially of methyl cellulose, a natural gum selected from the xanthan and guar gums, 5 glucose, propyl paraben, methyl paraben, sodium chloride and pectin.
Preferably, compositions of the present invention comprise 50-80% (by weight) methyl cellulose,15-25% of a natural gum selected from the xanthan and guar gums, 3-7% glucose, 2-3.5% propylparaben, 1.5-3% methylparaben, 1-3% sodium chloride and0.75-3 .5 % pectin.
Even more preferably, the compositions comprise about 63% methylcellulose, about 21% guar gum, about 5% glucose, about 3.5% propylparaben, about 3% methyl paraben, about 3% pectin and about 1.5% sodium chloride.
In one embodiment, the compositions of the present invention further comprise a drug selected from the group consisting of nicotine, nitroglycerin, albuterol, 15 VERAPAMIL~, scopolamine, n-butylurea, fentanyl, morphine, butaconazole, acetylsalicylic acid, MINOXIDIL~, lidocaine, racemic menthol, methyl salicylate,benzalkonium chloride, DEET~, phenobarbital, iodine, insulin, salicylic acid, nonoxynol-9, erythromycin, tetracycline, cephalosporins, and acetaminophen.
In a preferred embodiment, the compositions of the present invention further 20 comprise a substituted urea of the formula R-NH-CO-NH2 wherein R is hydrogen,hydroxyl, or a lower alkyl having from 1 to 8 carbon atoms selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl.
Preferably, the substituted urea is butylurea.
The compositions of the present invention may be provided in the form of a hydrogel comprising water and a base mixture, said base mixture comprising: (i) a gelling agent consisting of methylcellulose or at least one natural gum, or a mixture thereof; (ii) at least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl paraben; and (vi) sodium chloride.
The compositions of the present invention may be provided in the form of a dry powder conll)lising CA 022~636~ 1998-ll-23 WO 97/43989 PCT/USg7/08636 (a) a drug; and (b) a base mixture comprising (i) a gelling agent consisting of methylcellulose or at least one natural gum, or a mixture thereof; (ii) at least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl paraben; and (vi) sodium chloride.
The compositions of the present invention may also be provided in the form of a paste comprising (a) a drug; and (b) a base mixture comprising (i) a gelling agent consisting of methylcellulose or at least one natural gum, or a mixture thereof; (ii) at least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl paraben; and (vi) sodium chloride.
The present invention further provides compositions comprising:
(a) a hydrogel comprising water and a base mixture, said base mixture comprising or consisting essentially of: (i) a gelling agent consisting of methylcellulose or at least one natural gum, or a mixture thereof; (ii) at least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl paraben; and (vi) sodium chloride;
(b) a substituted urea of the formula R-NH-CO-NH2 wherein R is hydrogen, hydroxyl or a lower alkyl having from 1 to 8 carbon atoms; and (c) a hormone selected from the group consisting of progesterone, progestin, estrogen, and testosterone, or a mixture of any two or more of the foregoing.
The compositions of the present invention may further complise a glycolic, 25 alcoholic or oil-based additive such as propylene glycol. The compositions may further comprise coloring, fragrance, or other pharmq~eutic~lly acceptable additives. The compositions of the present invention may also comprise pectin.
Preferably, the hydrogel-forrning base mixture of the present invention consistsessentially of methyl cellulose, a natural gum selected from the xanthan and guar gums, 30 glucose, propyl paraben, methyl paraben, pectin and sodium chloride.

CA 022~636~ 1998-ll-23 W O 97/43989 PCT~US97/08636 More preferably, the hydrogel-forming base mixture of the present invention consists essentially of 50-80% (by weight) methyl cellulose, 15-25% of a natural gum selected from the x~n~h~n and guar gums, 3-7 % glucose, 2-3.5% propylparaben, 1.5-3% methylparaben, 0.75-3.5 % pectin, and 1-3 % sodium chloride. Even more 5 preferably, the base mixture consists essentially of about 63% methylcellulose, about 21% guar gum, about 5% glucose, about 3.5% propylparaben, about 3% methyl paraben, about 3% pectin and about 1.5% sodium chloride.
Preferably, the compositions of the present invention consist essentially of:
(a) 3-12% of a base mixture as described above;
(b) 0.5-15% by weight of a substituted urea permeation enhancer of the formula R-NH-CO-NH2, wherein R is hydrogen, hydroxyl or lower alkyl having from 1 to 8 carbon atoms;
(c) 5-20% by weight of a horrnone selected from the group consisting of progesterone, progestin, estrogen, and testosterone, and a mixture of any two or more of the foregoing;
(d) 0-20% by weight propylene glycol; and (e) 20-80% water; in which said base mixture and water form a hydrogel.
Even more preferably, the compositions of the present invention consist essentially of:
(a) about 9% by weight of a base mixture consisting essentially of: about63% (by weight) methyl cellulose, about 21% guar gum, about 5%
glucose, about 3.5% propylparaben, about 3% methylparaben, about 1.5% sodium chloride and about 3% pectin;
(b) about 2% by weight of a substituted urea of the formula R-NH-CO-NH2, wherein R is hydrogen, hydroxyl or lower alkyl having from 1 to 8 carbon atoms;
(c) about 10% by weight of progesterone;
(d) about 20% by weight propylene glycol; and (e) about 59% by weight water; in which said base mixture and water form a hydrogel.

CA 022~636~ 1998-11-23 The compositions of the present invention may be used as vehicles or carriers for the delivery of a wide variety of drugs to a subject. Drugs that can be delivered using the compositions of the present invention include, but are not limited to nicotine, nitroglycerin, albuterol, VERAPAMIL~, scopolamine, n-butylurea, fentanyl, morphine, 5 butaconazole, acetylsalicylic acid, MINOXIDIL~, lidocaine, racemic menthol, methyl salicylate, benzalkonium chloride, DEET~3, phenobarbital, iodine, insulin, salicylic acid, nonoxynol-9, erythromycin, tetracycline, cephalosporins, and acet~minophen.
The compositions of the present invention are particularly useful as pharm~reutic~lly acceptable bases for the delivery of drugs such as hormones selected 10 from the group consisting of progesterone, progestin, estrogen, testosterone, and mixtures of any two or more of the foregoing. The compositions of the present invention are particularly useful for the transdermal delivery of these hormones. In a preferred embodiment, compositions of the present invention are particularly useful for the transdermal delivery of progesterone.
In another embodiment, the compositions of the present invention are useful in avariety of vaginal applications. Por example, compositions of the present invention are useful as vaginal lubricants, spermicides, and to treat vaginal yeast infections.
In specific embo~limentc, the present invention provides devices for transdermaldelivery of drugs that do not require the use of an adhesive that has the potential to 20 irritate the skin.
Devices in accordance with the invention may comprise a watch, or are in the form of a watch. In one embodiment, a watch or watch-like device of the invention has a watch-case with a recessed chamber on the back face of the watch-case in contact with the skin. The recessed chamber contains a wafer having a top face and a bottom face 25 cont~ining a drug and a pharm~re~ltically acceptable base. In another embodiment, the recessed chamber of the watch-case comprises a fluid-filled or hydrogel cushion later .~itl-~tçd against the top face of the drug-cont~ining wafer. In another embodiment, the recessed chamber of the watch-case comprises a heating layer having a top face and a bottom face in which the bottom face of the heating layer is situated against the top face 30 of the drug-cont~ining wafer. In still another embodiment, the recessed chamber of the CA 022~636~ 1998-11-23 watch-case comprises permanent, closed cell having a top face and a bottom face, the bottom face of which is situated against the top face of the heating layer.
In another embodiment, a device for the transdermal delivery of a drug to a subject is provided which comprises a disc-shaped drug reservoir. The reservoir has a 5 recessed chamber which can contain a wafer having a top face and a bottom facecomprising a drug and a pharmaceutically acceptable base. In one embodiment, thereservoir clips on to the back face of a watch or watch-like device such that drug-conr~ining wafer is m~int~in~d in contact with the subject's skin. In another embodiment, the reservoir slides onto a band capable of being ~tt~cll~d to the limb of a 10 subject such that the drug-cont~ining wafer is m~int~in~d in contact with the skin of the subject's limb. In another embodiment, the recessed chamber of the clip-on or slide-on drug reservoir comprises a fluid-filled or hydrogel cushion later situated against the top face of the drug-cont:~ining wafer. In another embodiment, the recessed chamber of the clip-on or slide-on drug reservoir comprises a heating layer having a top face and a 15 bottom face in which the bottom face of the heating layer is situated against the top face of the drug-cont~ining wafer. In still another embodiment, the recessed chamber of the clip-on or slide-on drug reservoir col"p,ises permanent, closed cell having a top face and a bottom face, the bottom face of which is shuated against the top face of the heating layer.
In another embodiment, a device for the transdermal delivery of a drug to a subject in accordance with the present invention comprises a glove wherein the inside of the glove is lined with a layer cont~ining a composition of the invention comprising a pharm~cel~tically acceptable hydrogel base and a drug.
In still another embodimPnt, a device for the transdermal delivery of a drug to a 25 subject in accordance with the present invention comprises a band or a strap having a surface coated with a drug-cont~ining composition of the present invention, wherein the band or strap is capable of being attached to the limb of a subject such that the drug-cont~ining composition is m~int~in~d in contact with the skin of the subject's limb.
The present invention also provides kits comprising the recessed chamber-type, 30 the clip-on drug reservoir-type, the slide-on drug reservoir-type, the glove-type or the band-type of transdermal drug delivery devices.

CA 022~636~ 1998-11-23 The present invention also provides methods for the treatment of conditions responsive to hormone replacement therapy such as premenstrual syndrome, menopause, infertility, dysfunctional bleeding, corpus luteum failure, senile vulvo-vaginitis, hypogonadism and osteoporosis. The invention also provides methods of contraception 5 in males and females. The invention further provides a method of delivering a hormone or mixture of hormones to a subject. These methods of the invention involve placing a composition of the invention in contact with the skin of a subject such that an effective amount of the hormone or mixture of hormones is delivered transdermally to said subject.
The present invention also provides methods for the treatment of vaginal disorders such as yeast infections. The present invention also provides methods of providing contraception using spermicides. The present invention further provides methods for providing vaginal lubrication. These methods involve placing a composition of the present invention inside the vagina of a subject.

4. DESCRIP~ION OF THE FIGURES
Figure 1. Cross-sectional view of a Membrane-Moderated Transdermal Drug Delivery System. The system comprises: a drug reservoir 1 that may contain a composition of the present invention; a drug-impermeable backing layer 2, which can be 20 plastic, metal, metallic l~min~te or any other pharm~eutir~lly acceptable material; a rate-controlling polymeric membrane 3; and an adhesive layer 4, which can be anyadhesive known in the art. Arrows S show an exemplary route of passage of the drug out the device into the skin. Figure 1 is adapted from R. Sitruk-Ware, 1989, "Transdermal Delivery of Steroids," Contraception 39 (1):1-20, at page 9, Figure 5.
Figure 2. Cross-sectional view of an Adhesive Diffusion-Controlled Transdermal Drug Delivery System. The system comprises: a drug reservoir layer 1 which may comprise a composition of the present invention; a drug-impermeable backing layer 2, which can be plastic, metal, metallic l~min~te or any other pharm~eu~ically acceptable material; a rate-controlling adhesive layer 3; and an adhesive layer 4. The adhesive 30 layers may comprise any adhesive known in the art. Arrows 5 show an exemplaryroute of passage of the drug out the device into the skin. Figure 2 is adapted from R.

CA 022~636~ 1998-ll-23 W O 97/43989 PCT~US97/08636 Sitruk-Ware, 1989, "Transdermal Delivery of Steroids," Contraception 39 (1):1-20, at page 10, Figure 6.
Figure 3. Cross-sectional view of a Microreservoir-Type Transdermal Drug Delivery System. The system comprises: an adhesive foam pad 1 made of flexible 5 polyurethane; an occlusive baseplate 2 comprising an alllmin~m foil disc; an adhesive rim 3; microscopic drug reservoirs 4; and a polymer matrix 5 which may comprise a composition of the present invention. Arrows 6 show an exemplary route of passage of the drug out the device into the skin. Figure 3 is adapted from R. Sitruk-Ware, 1989, "Transdermal Delivery of Steroids," Contraception 39 (1):1-20, at page 12, Figure 8.
Figure 4. Cross-sectional view of a Matrix Dispersion-Type Transdermal Drug Delivery System. The system comprises: a drug-impermeable backing layer 1, whichmay be plastic, metal, met~llir. l~min~e or any other pharm~ellti~lly acceptablematerial; an absorbent pad 2; an occlusive baseplate 3 comprising an alllmin~lm foil disc; a drug reservoir 4 which may contain a composition of the present invention; and 15 an adhesive rim 5. Arrows 6 depict an exemplary route of passage of the drug out the device into the skin. Figure 4 is adapted from R. Sitruk-Ware, 1989, "Transdermal Delivery of Steroids," Contraception 39 (1):1-20, at page 11, Figure 7.
Figure 5. Perspective view of the top face of a recessed-chamber type of transdermal drug delivery device of the present invention, comprising: a watch case 1 20 and a band or strap 2.
Figure 6. Perspective view of the back face of one embodiment of the recessed-chamber type of transdermal drug delivery device of the present invention, comprising:
a watch case 1; a recessed chamber 2 capable of cont~ining a wafer comprising a drug and a pharn n~e~ltically acceptable base, which may comprise a composition of the 25 present invention; and a band or strap 3.
Figure 7. Cross-sectional view of one embodiment of the recessed-chamber type of transdermal drug delivery device of the present invention, comprising: a watch case 1; a recessed chamber 2; a band or strap 3; and a wafer 4 comprising a drug and a pharm~reutic~lly acceptable base which may comprise a composition of the present30 invention.

CA 022~636~ 1998-11-23 WO g7/~3989 PCT/US97/08636 Figure 8. Cross-sectional view of another embodiment of the recessed-chamber type of transdermal drug delivery device of the present invention, conlplisillg: a watch case 1; a recessed chamber 2; a band or strap 3; a fluid-filled cushion 4; a wafer S
comprising a drug and a pharmaceutically acceptable base which may comprise a S composition of the present invention; and a non-slip material 6 on the rim of the recessed chamber.
Figure 9. Perspective view of one embodiment of the top face of a watch or watch-like device having the clip-on drug reservoir type of transdermal drug delivery device of the present invention attached to its back face comprising: a watch case l; a 10 band or strap 2; and a clip-on drug reservoir 3.
Figure 10. Cross-sectional view of one embodiment of the clip-on or slide-on drug reservoir type of transdermal drug delivery device of the present invention, comprising: a plurality of clips 1 capable of attaching the clip-on drug reservoir to the back face of a watch or watch-like device; a recessed chamber 2; a wafer 3 comprising 15 a drug and a pharm~e~tically acceptable base which may comprise a composition of the present invention; and a soft flair skin seal 4.
Figure 11. Cross-sectional view of another embodiment of the clip-on or slide-on drug reservoir type of transdermal drug delivery device of the present invention, comprising: a plurality of clips 1 capable of attaching the drug reservoir to the back 20 face of a watch or watch-like device; a recessed chamber 2; a permanent closed cell 3 comprising dense polyethylene capable of providing slight downward pressure on the drug-cont;lining wafer; a heating layer 4 comprising a means for heating the drug-cont~ining wafer; a wafer 5 comprising a drug and a pharmnceutically acceptable base which may comprise a composition of the present invention; and a soft flair skin seal 6.
Figure 12. Perspective view of the bottom face of one embodiment of the clip-on or slide-on drug reservoir type of transdermal drug delivery device of the present invention, comprising: a plurality of clips 1 capable of attaching the clip-on drug reservoir to the back face of a watch or watch-like device; a recessed chamber 2; a soft flair skin seal 3; and a plurality of slots 4 that are capable of having a band or strap 30 threaded through them.

CA 022~636~ l998-ll-23 wo 97/43989 PCT/USg7/08636 Figure 13. Cross-sectional view of a watch having one embodiment of the clip-on drug reservoir type of transdermal drug delivery device of the present invention attached to its back face, comprising: a watch case l; a band or strap 2; a clip-on drug reservoir 3; a recessed chamber 4; a wafer 5 comprising a drug and a pharmaceutically 5 acceptable base which may comprise a composition of the present invention; and a soft flair skin seal 6.
Figure 14. Cross-sectional view of one embodiment of the slide-on drug reservoir type of transdermal drug delivery device of the present invention attached to a band, comprising- a slide-on drug reservoir 1; a band or strap 2; a recessed chamber 3;
10 a wafer 4 comprising a drug and a pharm~relltir:llly acceptable base which may comprise a composition of the present invention; and a soft flair skin seal 5.
Figure 15. Perspective view of the bottom face of one embodiment of the slide-on drug reservoir type of transdermal drug delivery device of the present invention, comprising. a plurality of slots 1 that are capable of having a band or strap threaded lS through them; a wafer 2 comprising a drug and a pharm~eutically acceptable base which may comprise a composition of the present invention; a soft flair skin seal 3; and a band or strap 4.
Figure 16. Cross-sectional view of the Single-Chamber Diffusion Cell used in the skin permeation measurements described in Section 6.2. The cell comprises: a 20 retaining nut 1; a flanged PVC washer 2 with alnmimlm foil coating 3,~an o-ring 4; a skin disc 5, which is cemented to a nylon washer 6; a teflon-coated magnetic stirring button 7; receptor fluid 8; and a stopper 9 comprising a foil-coated flanged washer.
Figure 17. A graph depicting the cl~mlll~tive amount of progesterone penetrated,(~g/cm2, y-axis) against time, (hours x-axis), from sample A-1 through a dialysis 2S membrane, as described in Section 6.2.2. The graph shows a penetration rate of 30.8 ~g/cm2 of progesterone through the dialysis membrane.
Figure 18. A graph depicting the cum-~ ive amount of progesterone penetrated, (~g/cm2, y-axis) against time, (hours, x-axis), from covered and not-covered samples of A-l through human skin, as described in Section 6.2.3. Curve 1 corresponds to the 30 covered sample of A-1 and Curve 2 corresponds to the not-covered sample of A-1.

CA 022~636~ l998-ll-23 Figure 19. A graph depicting the cumulative amount of progesterone penetrated, (~gtcm2, y-axis) against time, (hours, x-axis), from samples A-1, A-2, and A-3 through human skin, as described in Section 6.2.4. Curve 1, corresponding to sample A-1,shows a rate of 3.1 ,ug/cm2/hr. Curve 2, corresponding to sample A-2, shows a rate of 5 1.9 ~g/cm2/hr. Curve 3, corresponding to sample A-3, shows a rate of 9.8 ~g/cm2/hr.
Figure 20. Cross-sectional view of the redesigned Diffusion Cell Assembly used in the skin permeation measurements described in Section 6.4. The cell comprises: a glass receptor 1; a magnetic stirrer 2; saline 3; a teflon washer 4; a notch which elimin~tes air bubbles 5; an assembled donor 6; a donor chamber 7; test material on 10 epidermal membrane cemented to nylon washer 8; a foil cover 9; an O-ring 10; a flanged washer 11; and a nut 12.
Figure 21. Progesterone penetration of human skin in vitro. A graph depicting the cumulative amount of progesterone penetrated ~g/cm2, y-axis) against time (hours, x-axis) from samples A-4 (curve 2) and B-4 (curve 1), as described in Section 6.4. The graph shows a mean penetration rate (m) of 6.1 ~g/cm2/hr for sample A-4 (R2 =
0.9989) and a mean penetration rate (m) of 3.2 ~g/cm2/hr for sample B-4 (R2 =
0.9984).

5. DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compositions comprising (i) a gelling agent consisting of methylcellulose or at least one natural gum, or a mixture thereof; (ii) at least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl paraben; and (vi) sodium chloride.
The compositions of the present invention may further comprise a glycolic, 25 alcoholic or oil-based additive. Examples of the glycolic, alcoholic, or oil-based additives that may be used in the compositions of the present invention include, but are not limited to propylene glycol, glycerin, mineral oil, corn oil, bran oil, rice oil, soy oil, ethylene glycol, xylene and alcohols such as ethyl alcohol. A ~ fe.led additive is propylene glycol. The compositions may further comprise coloring, fragrance or other 30 ph~ reutically acceptable additives. The compositions of the present invention may also comprise pectin.

CA 022~636~ 1998-11-23 WO 97/43989 PCTtUS97tO8636 In a preferred embodiment, compositions of the present invention consist essentially of methyl cellulose, a natural gum selected from the xanthan and guar gums, glucose, propyl paraben, methyl paraben, sodium chloride and pectin.
Preferably, compositions of the present invention comprise 50-80% (by weight) 5 methyl cellulose,15-25% of a natural gum selected from the xanthan and guar gums, 3-7% glucose, 2-3.5% propylparaben, 1.5-3% methylparaben, 1-3% sodium chloride and0.75-3.5% pectin. Even more preferably, the compositions comprise about 63%
methylcellulose, about 21% guar gum, about 5% glucose, about 3.5% propylparaben,about 3% methyl paraben, about 3% pectin and about 1.5% sodium chloride.
In specific embodiments, drugs are included in the compositions of the present invention.
In a preferred embodiment, the compositions of the present invention further comprise a substituted urea of the formula R-NH-CO-NH2 wherein R is hydrogen, hydroxyl, or a lower alkyl having from 1 to 8 carbon atoms selected from the group 15 consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl. Preferably, the substituted urea is butylurea.
The compositions of the present invention may be provided in the form of a dry powder comprising (a) a drug; and (b) a base mixture comprising (i) a gelling agent consisting of methylcellulose or at least one natural gum, or a mixture thereof; (ii) at least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl paraben; and (vi) sodium chloride.
The compositions of the present invention may also be provided in the form of a 25 paste comprising (a) a drug; and (b) a base mixture comprising (i) a gelling agent consisting of methylcellulose or at least one natural gum, or a mixture thereof; (ii) at least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl paraben; and (vi) sodium chloride.

CA 022~636~ 1998-ll-23 wo 97/43989 PcT/uss7/08636 Dry powder and paste compositions of the present invention can form hydrogels upon the addition of water.
The present invention provides compositions for the transderrnal delivery or hormones such as progesterone, progestin, estrogen, testosterone, or combinations 5 thereof, said compositions alternatively consisting of or consisting essentially of: (a) a hydrogel, or a base mixture that when combined with water forms a hydrogel; (b) a permeation enhancer selected from the group consisting of urea, hydroxyurea, or an alkylurea; and (c) a hormone selected from the group consisting of progesterone,progestin, estrogen, testosterone, or combinations thereof. In preferred embodiment, 10 the hormone is natural progesterone. Natural progesterone is superior to synthetic forms of progesterone, known as progestins, in treating gynecological conditions.
The invention also provides apparatuses for transdermal hormone delivery cont~ining the compositions of the invention. Methods of transdermal delivery, and of treatment of disorders responsive to the a~ ini~tration of hormones are also provided.
15 The compositions of the invention provide more effective and efficient means for delivery of a therapeutically effective amount of the hormone(s) contained therein to the bloodstream of a patient.
The present invention further provides compositions comprising:
(a) a hydrogel conlplisillg water and a base mixture, said base mixture comprising or consisting essenti~lly of: (i) a gelling agent consisting of methylcellulose or at least one natural gum, or a mixture thereof; (ii) at least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl paraben; and (vi) sodium chloride;
(b) a substituted urea of the formula R-NH-CO-NH2 wherein R is hydrogen, hydroxyl or a lower alkyl having from 1 to 8 carbon atoms; and (c) a hormone selected from the group consisting of progesterone, progestin, estrogen, and testosterone, or a mixture of any two or more of the foregoing.
The composition may also optionally contain a glycolic, alcoholic or oil-based 30 additive. Examples of the glycolic, alcoholic or oil-based additives that may be used in the compositions of the present invention include propylene glycol, glycerin, mineral CA 022~636~ 1998-11-23 oil, corn oil, bran oil, rice oil, soy oil, ethylene glycol, xylene, and alcohols such as ethyl alcohol. A preferred additive is propylene glycol. The compositions may also contain colorings, fragrances or other pharmaceutically acceptable additives.
Preferably, the water used in the inventive compositions is distilled water. The5 compositions of the present invention may also comprise pectin.
Preferably, the hydrogel-forming base mixture of the present invention consists essentially of methyl cellulose, a natural gum selected from the xanthan and guar gums, glucose, propyl paraben, methyl paraben, pectin and sodium chloride.
More preferably, the hydrogel-forming base mixture of the present invention 10 consists essentially of 50-80% (by weight) methyl cellulose, 15-25% of a natural gum selected from the xanthan and guar gums, 3-7% glucose, 2-3.5% propylparaben, 1.5-3% methylparaben, 0.75-3.5% pectin, and 1-3% sodium chloride. Even more preferably, the base mixture consists essentially of about 63 % methylcellulose, about 21% guar gum, about 5% glucose, about 3.5% propylparaben, about 3% methyl 15 paraben, about 3% pectin and about 1.5% sodium chloride.
Preferably, the compositions of the present invention consist essentially of:
(a) 3-12% of a base mixture as described above;
(b) 0.5-15% by weight of a substituted urea permeation enhancer of the formula R-NH-CO-NH2, wherein R is hydrogen, hydroxyl or lower alkyl having from 1 to 8 carbon atoms;
(c) S-20% by weight of a hormone selected from the group consisting of progesterone, progestin, estrogen, and testosterone, and a mixture of any two or more of the foregoing;
(d) 0-20% by weight propylene glycol; and (e) 20-80% water; in which said base mixture and water form a hydrogel.
Even more preferably, the compositions of the present invention consist essentially of:
(a) about 9% by weight of a base mixture consisting essentially of: about 63% (by weight) methyl cellulose, about 21% guar gum, about 5%
glucose, about 3.5% propylparaben, about 3% methylparaben, about 1.5% sodium chloride and about 3% pectin;

CA 022~636~ 1998-11-23 (b) about 2% by weight of a substituted urea of the formula R-NH-CO-NH2, wherein R is hydrogen, hydroxyl or lower alkyl having from 1 to 8 carbon atoms;
(c) about 10% by weight of progesterone;
(d) about 20% by weight propylene glycol; and (e) about 59% by weight water; in which said base mixture and water form a hydrogel.

5.1 HYDROGEL BASE MIXTURE
The hydrogel-forming base mixture may optionally include pectin.
Natural gums which may be used in the hydrogel-forming base mixture include guar gum and xanthin gum. The hydrogel-forming base mixture preferably comprises a methylcellulose gelling agent; however inclusion of methylcellulose is not required. In place of the methylcellulose gelling agent, additional amounts of natural gums such as 15 guar or xanthin gums, or mixtures thereof, may be substituted.
The hydrogel-forming base mixture of the present invention is preferably made by way of example as follows: A dry powder form is mixed together of each of thenatural gum, glucose, propylparaben, methylparaben, and sodium chloride ingredients.
Methyl cellulose and pectin dry powders are optionally included. The dry powder 20 mixture is then micronized to a size of approximately one micron. Upon the addition of water, the mixture forms a hydrogel, which varies from a semi-fluid to a solid rubber consistency, depending on the amount of water added.
Preferably, the hydrogel-forming base mixture of the present invention consists essentially of 50-80% (percentages are by weight) methyl cellulose, 15-25% of a natural 25 gum, 3-7% glucose, 2-3.5% propylparaben, 1.5-3% methylparaben, and 1-3% sodium chloride. Optionally, the mixture may include 0.75-3.5% pectin. Even more preferably, the base mixture consists essentially of 63% methylcellulose, 21% guar gum, 5% glucose, 3.5% propylparaben, 3% methyl paraben, 3% pectin and 1.5%
sodium chloride. All seven of these ingredients that may be used in the base mixture of 30 the present invention are well known materials which are readily available from a wide CA 022~636~ 1998-11-23 WO 97t43989 PCT/US97108636 variety of commercial sources such as the Aldrich Chemical Co. (Milwaukee, WI), or the Sigma Chemical Co. (St. Louis, MO), etc.
In preferred embodiment, the present invention provides a composition for the transdermal delivery of natural progesterone comprising, or alternatively, consisting S essentiallY ofi (a) 3-12% of a base mixture comprising: (i) a gelling agent consisting of methylcellulose or at least one natural gum, or mixtures thereof; (ii) at least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl paraben; and (vi) sodium chloride; which may optionally include pectin;
(b) 0.5-15% by weight of a substituted urea permeation enhancer of the formula R-NH-CO-NH2, wherein R is hydrogen, hydroxyl or lower alkyl having from 1 to 8 carbon atoms;
(c) 5-20% by weight of a hormone selected from the group consisting of progesterone, progestins, estrogens, and testosterone, or mixtures thereof;
(d) 0-20% by weight propylene glycol; and (e) 20-80% water; in which said base mixture and water combine to form a hydrogel.
A particularly preferred embodiment of the present invention is directed to a composition for the transdermal delivery of natural progesterone consisting of:
(a) 9% by weight of a base mixture consisting essentially of (1) methylcellulose; (2) guar gum; (3) glucose; (4) propylparaben; (5) methyl paraben; (6) pectin; and (7) sodium chloride;
(b) 2 % by weight of a substituted urea permeation enhancer of the formula R-NH-CO-NH2, wherein R is hydrogen, hydroxyl or lower alkyl having from 1 to 8 carbon atoms;
(c) 10% by weight of natural progesterone;
(d) 20% by weight propylene glycol; and (e) 59% by weight water; in which said base mixture and water form a - hydrogel.
In a preferred embodiment, the above composition of the present invention is formed by first mixing the base mixture powder, substituted alkyl urea and progesterone CA 022~636~ 1998-11-23 in propylene glycol to form a paste. The paste is then heated without boiling until the progesterone and substituted alkyl urea are dissolved and the paste becomes a liquid.
This hot glycol mixture is then added to tepid water while stirring with a blade type stirring unit at a speed sufficient to from a vortex at the surface. The hot glycol 5 mixture is added to the stirring water in this manner for 5 to 15 minutes, or until the proper or desired viscosity is achieved. The mixture is then removed from the stirred container and placed in a barrier container for storage to prevent evaporation. Shelf life of the finished product should be several years.

5.2 PERMEATION ENHANCERS
The compositions enhancers of the present invention can comprise monosubstituted lower-alkyl ureas of the formula:

wherein R is hydrogen, hydroxyl or lower alkyl having from 1 to 8 carbon atoms.
15 Preferably, the lower alkyl group has from 1 to 6 carbon atoms; more preferably from 1 to 4 carbon atoms; and most preferably from 3 to 4 carbon atoms. Specific examples of the lower alkyl group R include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl. A particularly preferred monosubstituted lower-alkyl urea useful in the present invention is butylurea. The monosubstituted lower alkyl 20 ureas are known compounds and are readily available from commercia~sources such as the Aldrich Chemical Co. (Milwaukee, WI). In a preferred embodiment, the permeation enhancer is butylurea. When the compositions of the present inventioncomprising urea derivatives are used for the transdermal delivery of drugs, the urea derivatives may function as transdermal penetration enhancers. Urea derivatives such as 25 butylurea can also function as spermicides when the compositions of the present invention are used in vaginal applications.

5.3 DRUGS
Drugs which may be used in the compositions of the present invention and the 30 disorders which such compositions may be used to treat include, but are not limited to nicotine for smoking cessation, nitroglycerin for angina pectoris, albuterol as an CA 022~636~ 1998-11-23 antiasthmatic, VERAPAMIL~ for hypertension, scopolamine for motion sickness, n-butylurea for herpes sores, fentanyl for acute pain, morphine for pain, steroid hormones t'or osteoporosis, estrogen and progestin for hormonal replacement, butaconazole for vaginal yeast infection, acetylsalicylic acid as aspirin for pain, 5 MINOXIDIL~ for hair growth. Iidocaine for pain, racemic menthol for pain, methyl salicylate for pain, benzalkonium chloride as a germicide, DEET~ for insect control, phenobarbital as a sedative, iodine as an antiseptic, insulin as an antidiabetic, salicylic acid as a topical keratolytic, nonoxynol-9 as a spermicide, erythromycin as an anti-biotic, tetracycline as an antibiotic, cephalosporins as an antibiotic, and a~et~minophen 10 for pain. In a specific embodiment, the drug has utility in the treatment of a human disease or animal disorder. The present invention also provides methods for treating the above-listed disorders.
Examples of hormones that may be delivered to a subject using the compositions of the present invention include progesterone, progestin, estrogen and testosterone, or a 15 mixture of any two or more of the foregoing. Depending on the application, the present invention may be used to deliver each of these hormones alone, or in various combinations. In a preferred embodiment, the hormones are delivered transdermally using the compositions of the present invention. Specific examples of progestins useful in the present invention include but are not limited to are medroxy progesterone acetate, 20 norethindrone, norethindrone acetate, norgestrel, and ethynodiol di~et~tP. Specific examples of estrogens useful in the present invention include but are not limited to 17-,B-estradiol, diethylstilbestrol, estropipate (formerly known as piperazine estrone sulfate), estrone and estriol.
A most preferred hormone is pregn4-ene-3,20-dione, which has a molecular 25 weight of 314.47, and is also known as "natural progesterone", or simply, "progesterone." Natural progesterone is produced in the human body, but it can be also be isolated from certain plants, and is available commercially. For example, micronized powder forms of natural progesterone useful in the present invention are available from both the Upjohn Chemical Co. (~ m:1700, MI) and the Berlex Chemical Co. (North 30 Surburban, IL).

CA 022~636~ 1998-11-23 As discussed above, the compositions of the present invention are also suitable for delivery, transdermal and otherwise, of synthetic progestins, estrogens such as 17-~-estradiol and testosterone. Synthetic progestins, estrogens and testosterone which may be used in the present invention are readily available from a variety of commercial 5 sources well known to those skilled in the art.

5.4 TRANSDERMAL DELIVERY DEVICES
The means for a~lminictration of the compositions of the present invention to a patient may vary. In one embodiment, compositions of the present invention are 10 ~flmini.ctçred vaginally. ln another embodiment, the compositions are delivered transdermally, which but n~cess~rily involves application of the composition to a selected intact surface of the skin for a period of time sufficient to provide the desired blood level of the drug. Preferably, the composition is a-~mini~rered to a patient via use of a transdermal delivery device. Various transdermal systems are known and may be 15 used to ~lmini~ter therape~-tic~lly effective amounts of hormones using the compositions of the invention. Four general types of transdermal drug delivery devices are taught, for example, by R. Sitruk-Ware (1989, "Transdermal Delivery of Steroids,"
Contraception 39 (1):1-20. Transdermal delivery devices are also disclosed by Pfister and Hsieh (1990, "Permeation F.nh~nf~ers Compatible with Transdermal Drug Delivery 20 Systems: Part II: System Design Considerations," Pharmaceutical Technology (October 1990): 55-60.
For example, the composition of the present invention may be a~lmini~tered usinga membrane-moderated transdermal dr~g delivery system, as shown in Figure 1. In this type of system, the inventive composition is contained within the drug reservoir 1. The 2~ rate of delivery of the hormone through the skin is simultaneously enh~nred by use of the hydrogel and the monosubstituted alkyl urea penetration enhancer of the invention and moderated by a rate-controlling polymeric membrane 3. The inventive composition may also be a~lmini.stered to a patient via an adhesive diffusion-controlled transdermal drug delivery system, (see Figure 2) in which the rate of delivery of the hormone 30 through the skin is simultaneously enhanced by use of the hydrogel and the -CA 022~636~ 1998-11-23 monosubstituted alkyl urea penetration enhancer of the invention and moderated by a rate-controlling adhesive layer 3.
Another type of transdermal drug delivery device suitable for use with the present invention is the microreservoir-type system (see Figure 3). As applied to the 5 present invention, this type of system consists of a suspension of the solid hormone in the inventive hydrogel-forming base mixture. The hormone suspension is dispersedhomogeneously in a lipophilic polymer to form numerous microscopic spheres of drug reservoir 4. This dispersion is thermodyn~mirally unstable and is stabilized by cross-linking the polymer chains in situ. The mixture is formed into a disc and is then 10 covered by an occlusive baseplate 2 and optionally surrounded by an adhesive rim 3.
A preferred transdermal delivery device useful for application of the compositions of the present invention is a matrix dispersion type system (Figure 4). For use in this type of system, the composition of the present invention is molded into a disc of a certain thickness and is applied onto an occlusive baseplate 3 in a compartment 15 fabricated from a drug-impermeable plastic backing 1. An adhesive may be applied along the circumference of the device to form an adhesive rim 5 around the disc.Generally, adhesives used in transdermal delivery devices have the potential to cause skin irritation. Accordingly, in specific embodiments, the present invention provides transdermal delivery devices in form of a watch or watch-like device which 20 have the advantage that an adhesive is not n~cess~ry to m~int~in contact of a drug-cont~ining transdermal delivery composition with the patient's skin.
In one embodiment, a watch or watch-like device of the invention has a watch-case with a recessed chamber on the back face of the watch-case in contact with the skin. The recessed chamber contains a wafer having a top face and a bottom face 25 cont~ining a drug and a pharmaceutic~lly acceptable base. In another embodiment, the recessed chamber of the watch-case comprises a fluid-filled or hydrogel cushion later situated against the top face of the drug-cont~ining wafer. In another embodiment, the recessed chamber of the watch-case comprises a heating layer having a top face and a bottom face in which the bottom face of the heating layer is situated against the top face 30 of the drug-cont~ining wafer. In still another embodiment, the recessed chamber of the CA 022~636~ 1998-11-23 watch-case comprises permanent, closed cell having a top face and a bottom face, the bottom face of which is situated against the top face of the heating layer~
The heating layer of the inventive devices can comprise a printed circuit board or a plastic or metallic layer which contains a plurality of metal electrical wires or lines 5 comprising circuitry which provide heating. The heating layer of the inventive devices can be battery-powered or solar-powered. In one embodiment the heating layer is powered via the battery of the watch. In another embodiment, the heating layer is powered by a solar cell.
The perm~nPnr, closed cell layer of the inventive devices can comprise a dense 10 polymeric material. The permanent closed cell layer provides sight downward pressure on the drug filled wafer, to aid in m~int~ining contact of the wafer with the subject's skin.
In another embodiment, a device for the transdermal delivery of a drug to a subject is provided which comprises a disc-shaped drug reservoir. The reservoir has a 15 recessed chamber which can contain a wafer having a top face and a bottom face comprising a drug and a pharm~re~-ric~lly acceptable base. The drug reservoir may comprise clear plastic or vinyl.
In one embodiment, the reservoir clips on to the back face of a watch or watch-like device such that drug-cont~ining wafer is m~int~inPd in contact with the subject's 20 skin. In a specific embodiment, the reservoir clips over the posts and band of the wafer. In another embodiment, the reservoir slides onto a band capable of being attached to the limb of a subject such that the drug-cont~ining wafer is m~int~inPd in contact with the skin of the subject's limb. In another embodiment, the recessedchamber of the clip-on or slide-on drug reservoir comprises a fluid-filled or hydrogel 2S cushion later situated against the top face of the drug-cont~inin~ wafer. In another embodiment, the recessed chamber of the clip-on or slide-on drug reservoir comprises a heating layer as described above having a top face and a bottom face in which the bottom face of the heating layer is situated against the top face of the drug-cont~ining wafer. In still another embodiment, the recessed chamber of the clip-on or slide-on 30 drug reservoir comprises permanent, closed cell as described above having a top face CA 022~636~ 1998-11-23 and a bottom face, the bottom face of which is situated against the top face of the heating layer.
In another embodiment, a device for the transdermal delivery of a drug to a subject in accordance with the present invention comprises a glove wherein the inside of 5 the glove is lined with a layer cont~ining a composition of the invention comprising a pharmaceutically acceptable hydrogel base and a drug.
In still another embodiment, a device for the transdermal delivery of a drug to a subject in accordance with the present invention comprises a band or a strap having a surface coated with a drug-cont~ining composition of the present invention, wherein the 10 band or strap is capable of being attached to the limb of a subject such that the drug-cont~ining composition is m~int~inf~d in contact with the skin of the subject's limb.
The present invention also provides kits comprising the recessed chamber-type, the clip-on drug reservoir-type, the slide-on drug reservoir-type, the glove-type or the band-type of transdermal drug delivery devices.
lS In the case of the recessed-chamber water type of transdermal drug delivery device, the kit may comprise a watch or watch-like device with a recessed chamber and comprising a band or strap, and a plurality of drug-cont~ining wafers. The wafers may be provided in sealed packages for long shelf life. In the case of the clip-on or slide-on type of transdermal drug delivery device, the kit may comprise at least one drug20 reservoir, which may be clear plastic, vinyl or some other acceptable màterial, and a plurality of drug-cont~ining wafers. Again, the wafers may be provided in sealedpackages for long shelf life.
One embodiment of the watch-like device of the present invention provides a recessed-chamber type of transdermal drug delivery device. A perspective view of the 2S front face of this device is shown in Figure 5. The device comprises a watch case (1) and a band or strap (2) to attach the device to a limb (e.g., wrist, arm or leg) of the user. The back face (Figure 6) of the device has a recessed-chamber capable (2) of cont~ining a drug-cont~ining wafer, which may comprise a composition of the present invention. In a specific embodiment, the recessed chamber of the watch is 30 approximately 3.6 cm in diameter, corresponding to an area of about 10 cm~. The chamber is at least deep enough to accommodate a drug-cont~ining wafer approximately CA 022~636~ 1998-11-23 1.5 mm thick. When the wafer loses its ability to deliver the drug, the patient can simply replace it with another "refill" wafer.
The watch case may comprise stainless steel or plastic, and the recessed chambermay be lined with teflon or some other inert material. Optionally, the rim of the 5 recessed chamber is coated with a non-slip or a soft flair slcin seal material to aid in m~int~ining contact of the drug-cont~ining wafer with the user's skin, and to prevent the drug-cont:~ining wafer from drying out. The front face of the watch need not actually contain a functional watch dial, although such can be the case.
Another embodiment of the recessed-chamber type of transdermal drug delivery 10 device, shown in Figure 8, comprises a recessed chamber 2 deep enough to contain both a drug-cont~ining wafer 2 and a fluid-filled cushion 4. The fluid-filled cushion may comprise the hydrogel alone, without the hormone. In a specific embodiment, the recessed chamber is deep enough to accornmodate both a 1.5 rnm thick hormone-cont~ining wafer and a fluid-filled cushion on the roof of the chamber. This fluid 15 cushion prevents the wafer from buckling and minimi7es air bubbles. The device of this embodiment may also comprise a soft, non-slip material 6 on the rim of the recessed chamber.
Another embodiment of the watch-like device of the present invention provides a clip-on drug reservoir type of transdermal drug delivery device. A perspective view of 20 the top face of the clip-on drug reservoir type transdermal drug delivery device of the present invention is shown in Figure 9, comprising a watch case 1, a band or strap 2 and a clip-on drug reservoir 3. The clip-on drug reservoir transdermal drug delivery device of the present invention (Figure 10) comprises a plurality of clips 1 capable of ~tt~r~ing the clip-on drug reservoir to the back face of a watch; a recessed chamber 2; a 25 drug-cont~ining wafer 3 which may comprise a composition of the present invention;
and a soft flair skin seal 4. The front face of the watch need not actually contain a functional watch dial, although such can be the case.
Figure 13 shows a cross-sectional view of a watch having the clip-on drug reservoir type of transdermal drug delivery device of the present invention attached to 30 its back face, comprising: a watch case 1; a band or strap 2; the clip-on drug reservoir CA 022~636~ 1998-11-23 3 of the present invention; a recessed chamber 4, a drug-cont~ining wafer 5; and a soft flair skin seal 6.
Another preferred embodiment of the present invention which also elimin~tes the need for an adhesive is a glove lined with the hormone-containing composition of the 5 present invention. The glove may be latex or any material that is compatible with the compositions of the present invention. This embodiment of the invention is suitable when 24 hour contact of patient's skin with the hormone-cont~ining composition of the invention is not necessary to achieve therapeutically effective blood levels of the hormone. The patient simply wears the lined gloves to bed and then removes them in 10 the morning and washes their hands.
In another preferred embodiment of the invention, a means is provided for heating the hormone-cont~ining composition while it is in contact with the patient's skin.
Such heating increases the rate of penetration of the drug into the patient's bloodstream.
For example, a battery-powered heater capable of warming the system approximately 15 10~ F above ambient temperature can be built into the watch-like transdermal device of the present invention to increase the delivery rate of the hormone through the patient's skin.
In preferred embodiments, use of the compositions of the invention does not involve topical pre-atlmini.~tration of acetone or similar solvents in order to achieve 20 transdermal delivery of therapeutically effective amounts to the bloodstream 5.5 THERAPEUTIC USES
As ~ cu.~se(l above, the compositions of the present invention may contain a wide variety of drugs, and may be used to treat a wide variety of disorders. In a 25 preferred embodiments, the present invention provides methods for tre~tmPnt of disorders responsive to the ~(lmini~tration of hormones comprising ~(lmini~tering to the patient transdermally a composition of the invention comprising a therapeutically effective amount of a hormone selected from the group consisting of progesterone, progestin, estrogen, and testosterone, and a mixture of any two or more of the 30 foregoing.

_ CA 022~636~ 1998-11-23 The compositions of the present invention are useful for treating a variety of disorders which benefit from hormone replacement therapy, including premenstrualsyndrome, menopausal symptoms, infertility, and osteoporosis. A variety of gynecological problems in women such as dysfunctional bleeding, corpus luteum failure, 5 and post-menopausal senile vulvo-vaginitis may also be treated with the compositions of the present invention, as well as male disorders such as hypogonadism. The compositions of the present invention may also be used to provide contraception to male and female subjects.
The subject is preferably an animal, including but not limited to animals such as 10 cows, pigs, chickens, etc., and is preferably a m~mrn~l, and most preferably human.
Human subjects may be male or female. Obviously, when the condition being treated is one specific to women, such as premenstrual syndrome, menopausal symptoms, and gynecological problems, the subject is a woman.
The present invention provides compositions useful for providing contraception 15 to female subjects comprising progesterone, progestins, estrogens and mixtures thereof.
Specifically, compositions of the presen~ invention comprising progesterone, mixtures of progesterone and one or more estrogens, or mixtures of one or more estrogens and one or more progestins may be used to provide contraception to females. Compositions of the present invention comprising testosterone are useful for providing contraception to 20 male subjects.
Compositions of the present invention comprising estrogen are particularly useful in treatment of menopause. At the onset of menopause, women lose their ability to produce estrogen. A ~limini~h~d estrogen supply in post-menopausal women can cause such symptoms as hot flashes, insomnia, vaginal atrophy, irritability, anxiety, 25 moodiness and excessive sweating. Natural or synthetic estrogens may be formnl~ted into the compositions of the present invention for the treatment of these menopausal symptoms. Estrogen alone may be used to treat menopause in some women. However, women who use estrogen and who have an intact uterus preferably also take progesterone to prevent uterine cancer.
Compositions of the present invention comprising estrogen, progesterone or mixtures thereof may be used to treat or prevent osteoporosis. Estrogen is known to CA 022~636~ 1998-11-23 prevent bone loss, while progesterone is known to stim~ e bone growth. Osteoporosis is a progressive deterioration of the skeletal system through the loss of bone mass, and is related to the inability to produce estrogen. According to the National Osteoporosis Foundation, osteoporosis currently affects approximately 25 million people in the United 5 States. It is estim~Pd that 80% of all hip fractures in elderly patients are associated with osteoporosis.
Corpus luteum failure is another condition that the compositions of the present invention may be used to treat, and can result in infertility and/or irregular bleeding.
Compositions of the present invention comprising low dosages of testosterone can10 be used to treat senile vulvo-vaginitis, a post-menopausal condition.
Compositions of the present invention comprising natural progesterone, syntheticprogestins, estrogens and mixtures thereof may be used to provide contraception to a subject.
Accordingly, the present invention provides methods for the treatment of premenstrual syndrome, menopausal symptoms, infertility, osteoporosis, dysfunctional bleeding, corpus luteum failure, post-menopausal senile vulvo-vaginitis and hypogonadism, and methods for providing contraception, by using compositions of the present invention cont~ining one or more hormones. The methods entail providing a composition of the present invention comprising a hydrogel-forming base mixture, a 20 skin permeation enhancer, a hormone selected from the group consisting of natural progesterone, progestins, estrogens, testosterone and mixtures thereof, an optional glycolic, alcoholic or oil-based additive, and water, and cont~cting said composition to the skin of a patient to perrnit the hormone in the composition to be absorbed into the skin.
In one embodiment, the present invention provides a method for the treatment of premenstrual syndrome in which a composition of the present invention comprisingnatural progesterone is contacted with the skin of a patient suffering from premenstrual ~ylldlollle. In another embodiment, the present invention provides a method for the treatment of menopausal symptoms such as hot flashes, insomnia, vaginal atrophy,30 irritability, anxiety, moodiness and excessive sweating in which a composition of the present invention comprising a horrnone selected from the group consisting of natural CA 022~636~ 1998-11-23 progesterone, progestins, estrogens, testosterone, and mixtures thereof, is contacted with the skin of a patient suffering from any of such symptoms. In another embodiment, the present invention provides a method for the treatment of infertility in which a composition of the present invention comprising natural progesterone is contacted with 5 the skin of a patient suffering from any of such symptoms.
In still another embodiment, the present invention provides a method for the treatment of osteoporosis in which a composition of the present invention comprising natural progesterone, estrogen, or a mixture thereof is contacted with the skin of a patient suffering from osteoporosis. In still another embodiment, the present invention 10 provides a method for the prevention of osteoporosis in which a composition of the present invention comprising natural progesterone, estrogen, or a mixture thereof is contacted with the skin of a patient who has the potential to develop osteoporosis.
In another embodiment, the present invention provides a method for the treatment of dysfunctional bleeding in which a composition of the present invention 15 comprising natural progesterone or a mixture of natural progesterone and an estrogen is contacted with the skin of a patient suffering from dysfunctional bleeding. In another embodiment, the present invention provides a method for the treatment of corpus luteum failure in which a composition of the present invention colllplisillg natural progesterone or a mixture of natural progesterone and an estrogen is contacted with the skin of a 20 patient suffering from corpus luteum failure.
In another embodiment, the present invention provides a method for the treatment of post-menopausal senile vulvo-vaginitis in which a composition of the present invention comprising testosterone is contacted with the skin of a patient suffering from senile vulvo-vaginitis.
In another embodiment, the present invention provides a method for the treatment of hypogonadism in which a composition of the present invention comprising testosterone is contacted with the skin of a patient suffering from hypogonadism.
In another embodiment, the present invention provides a method for providing contraception in which a composition of the present invention comprising natural30 progesterone, synthetic progestins, estrogens or mixtures thereof is contacted with the CA 022~636~ 1998-11-23 skin of a subject in need of contraception. The compositions of the invention may be sued to provide contraception to both ma}es and f'emales.
In the methods of this invention, the inventive composition comprising the appropriate hormone or hormone mixture is contacted with the subject's skin for a 5 period of time sufficient to permit a therapeutically effective amount of the horrnone or mixture of hormones to be absorbed through the skin into the subject's bloodstream.
The amount of progesterone in the blood which will be considered therapeuticallyeffective will, of course, vary from patient to patient, and with the type of condition being treated. As a general rule, a therapeutically effective amount can be considered 10 the level of progesterone one would anticipate during the second half of the luteal phase of the menstrual cycle. However, other levels produced by the normal functions of the body may also be effective, depending on the circumstances. For example, a mean serum level of 2 ng/ml progesterone gives an optimal effect in the treatment of menopause using a combination of progesterone and estrogen.
According to W.S. Maxon (1987, "Use of Progesterone in the Treatment o~
PMS," J. Clin. Obstetrics & Gynecology 30 (2): 465-480), the adrenal gland produces small amounts of progesterone from cholesterol and pregenelone as an intermediate in the biosynthesis of corticosteroids. During the proliferative phase of the menstrual cycle, most of the circul~ting progesterone is adrenal in origin and is produced in 20 quantities of about 0.75 mg/day. During the follicular phase, serum co'n'centrations of progesterone range between 0.1 and 1 ng/ml.
During the luteal phase, progesterone production by the ovarian corpus luteum dr~m~tic~lly increases and may reach 50 mg per day. When the conceptus is expected to implant during the mid-luteal phase, serum concentrations of progesterone average S
25 to 25 ng/ml. Progesterone is released in a pulsatile fashion, which correlates with LH
pulsatility. During pregnancy the placenta contributes an additional 25 to 40 mg/day of progesterone. Concentrations during gestation increase progressively to a mean of 175 ng/ml at term.
Thus, blood level of progesterone can fluctuate widely during the luteal phase of 30 the cycle, i.e. at least from 0-50 ng/ml. Generally, however, the fluctuation is on the order of 0-18 ng/ml. The preferred method of assaying the level of progesterone in the CA 022~636~ 1998-11-23 WO 97/43g89 PCT/US97/08636 blood is by standard radioimmunoassay, which is well known to those skilled in the art.
Compositions of the present invention are also useful for treating vaginal conditions such as yeast infections and vaginal dryness. Compositions of the present invention are also useful as sperrnicides. For example, compositions of the present 5 invention comprising a drug selected from butylurea and butaconazole can be used to treat vaginal yeast infections. Compositions of the invention comprising butylurea can also be used as spermicides. Compositions of the present invention, with or without drug(s), may be used to treat vaginal dryness.
Compositions of the present invention comprising progesterone, estrogen, 10 progestin, testosterone and a mixture of any two or more of the foregoing may also be administered vaginally to treat a variety of vaginal or gynecological conditions.
Accordingly, the present invention provides methods for treating vaginal yeast infections. The present invention also provides methods for treating vaginal dryness.
The invention also provides methods for contraception which involve the vaginal 15 ~lmini~tration of compositions of the present invention CO~"p~iSil~g urea or urea derivatives such as butylurea. These methods involve the placement of a composition of the present invention inside the vagina of a subject.

6. EXAMPLES
6.1 MANUFACTURE OF A PREFERRED COMPOSITION OF THE
INVENTION
A hydrogel-forming base mixture of the invention is prepared a by mixing together the following seven dry powder ingredients:
63 % methyl cellulose 21 % guar gum 5 % glucose 3 % pectin 1.5% sodium chloride 3 .5 % propylparaben 3 % methyl paraben After mixing the above ingredients, the mixture is micronized to a size of approximately 30 one micron.
A composition for the transdermal delivery of natural progesterone cont~ining the ingredients:

CA 022~636~ 1998-11-23 2 % butylurea 9% base mixture hydrogel powder 10% progesterone 20 % propylene glycol 59% distilled water 5 is prepared as described below.
Mix the hydrogel, butylurea and progesterone powders with the propylene glycol forming a paste. Warm (do not boil) the paste until the ingredients totally dissolve and the paste becomes a thinned pourable liquid. Use a large enough container to accept the combined volume of thinned paste and tepid water. Cold or hot water may be used to 10 delay or accelerate the set-up time. Place the container with water in a stirring unit using a blade-type prop. Begin stirring water at a speed to form a vortex at the surface.
Add all the combined warrned glycol mixture to the stirring water. Continue to mix for 3 to 15 minutes or until the proper or desired viscosity is achieved. Place a cover over the finished mixture to prevent short terrn evaporation. To prevent long-term 15 evaporation, remove the finished mixture from the container and place in a vapor barrier container. Shelf life in the container should be several years.

6.2 SKIN PERMEATION ASSAYS: FULL THICKNESS HUMAN SKIN
6.2.1 MATERIALS AND METHODS
20 Materials Excised full-thickness human skin was obtained from elective surgery, (e.g., breast reductions) or occasionally, from amputated legs. The tissue was stored in plastic containers at refrigerator temperature until use, at which time the subcutaneous fat and connective tissue were carefully trimmed off. Skin specimen thickness was in the range 25 1.5 - 2.0 mm, with characteristic histological features preserved.
Tritium-labeled progesterone was obtained from NEN-DuPont (Wilmington, DE), with the label at ring positions 1, 2, 6, and 7. lt was incorporated in the test compositions in the range 100 to 500 DPM (Disintegration Per Minute) per microgram of progesterone. The labeled progesterone was incorporated at the pre-polymerization 30 stage, i.e., just as water is added to form the hydrogel polymer. Aliquots of the gelling mixtures were added to small amounts of tritiated progesterone in scintillation vials (after the solvent had been evaporated), and stirred briskly with a small spatula. The CA 022~636~ 1998-ll-23 wo 97/43989 PCT/US97/08636 vials were then tightly capped and stored at room temperature. Milligram portions of this mixture were then taken from widely-spaced sites from within the vials, rapidly weighed, and dispersed in scintillation cocktail for determination of specific activities.
Transdermal Penetration Transdermal penetration was performed in a single-chamber, solvent-replacement Diffusion Cell, held vertically and inverted (Figure 13). Half-inch diameter discs of skin to which nylon washers had been cemented with cyanoacrylate were used. The available diffusional area of each skin disc enclosed by the nylon washer was 0.495 cm2.
The cell was assembled from parts of a commercial PVC coupling m:~m~f~etured by 10 Genova Products, Inc., Davison, MI. The body of the coupling serves as the receptor chamber. The skin disc (5), kept flat by the nylon washer (6) cemented to its surface, is seated in the bottom end of the chamber, dermal side in contact with the receptor fluid (8). After test material is applied to the skin surface, an O-ring (4) and a flanged PVC washer (2) coated with all~min~lm foil (3) are positioned under the nylon washer on 15 the skin, and a ret~inin~ nut (1) is carefully tightened under all. A small, teflon-covered magnetic stirring button (7) and the receptor fluid are introduced, after which the top end of the coupling is stoppered with another foil-coated flanged washer (9). After assembly, the cell is held in a rack on a magnetic stirrer, in a 32~ C incubator. The magnetic stirring button is used to stir the receptor fluid in the inverted cell, and this 20 button spins in direct contact with the dermal side of the skin. In this configuration, the 1 ml of fluid in the receptor chamber is mixed instantaneously as stirring is begun, and continuously during the course of the experiment. The receptor fluid was physiological saline, and O.S ml samples were removed (with replacement) at one-hour intervals.
Intradermal r~ lion ~ntradermal penetration was ~ccessed with 0.5-inch diameter discs of skin, to which nylon washers were cemented, as described above. Discs with attached washers were placed in wells drilled in a plastic block. The block was then covered with a sheet of clear plastic to minimi7e dehydration of the skin. To terminate penetration, individual discs were removed from the block, and residual material removed from the 30 surface by a rinse/wipe procedure as follows: 1) a stream of ice-cold water was delivered to the skin surface confined within the washer for 10 seconds, and the surface CA 022~636~ 1998-11-23 then dried with absorbent paper. These steps were repeated, and then 2) a smaller disc of skin was punched out from within the cleansed area, and 3) dissolved for determination of tritiated progesterone. Dissolution was in lN NaOH for an hour at 100~ C followed by neutralization of the alkali solution with perchloric acid. If the 5 epidermis was to be separated from the dermis for measurement of radioactivity, this separation was done by exposing the disc to an infrared heat lamp, held at 4 inches from the surface for 30 seconds, and peeling off the epiderrnis with fine forceps. Scintillation cocktail was added to the dissolved tissue samples, for determination of radioactivity.
Thirteen formulations were used in the Examples described hereinbelow. The 10 formulations were prepared as described above by addition of radioactive progesterone during polymerization, before the final viscosity had developed. The thirteen formulations are give below. The hydrogel-forming base mixture used in all thirteen forrnulations consisted of: 63% methyl cellulose, 21% guar guam, 5% glucose, 3%
pectin, 1.5% sodium chloride, 3.5% propyl paraben, and 3% methyl paraben.

Sample A-1 Sample B-1 Sample C-1 20% propylene glycol 20% propylene glycol 20% propylene glycol 4 % natural 4 % natural 4 % natural progesterone progesterone progesterone 20 13% hydrogel-forming13% hydrogel-forming13% hydrogel-forming base mixture base mixture base mixture 3% oleic acid 3% oleic acid 3% oleic acid 60% water 59% water 59% water Sample A-2 Sample B-2 Sample C-2 20% propylene glycol 20% propylene glycol 20% propylene glycol 4% natural 20% natural 20% natural progesterone progesterone progesterone 13% hydrogel-forming13% hydrogel-forming 14% hydrogel-forming base mixture base mixture base mixture 3% Myristic acid 3% Myristic acid 1.5% Myristic acid 60% water 40% water 44.5% water CA 022~636~ 1998-11-23 Sample A-3 Sample B-3 Sample C-3 20% propylene g}ycol 20% propylene glycol 20% propylene glycol 4 % natural 4 % natural 4 % natural progesterone progesterone progesterone 5 13% hydrogel-forming base14% hydrogel-forming 14% hydrogel-forming mixture base mixture base mixture 3% n-butylurea 6% n-butylurea 1.5% n-butylurea 60% water 56% water 60.5% water 10 Sample W SamPle X
20% propylene glycol 20% propylene glycol 5 % natural progesterone 10% natural progesterone 13% hydrogel-forming base mixture 13% hydrogel-forming base mixture 1.5% n-butylurea 1.5% n-butylurea 60-5% water 55.5% water Sample Y Sample Z
20% propylene glycol 20% propylene glycol 15% natural progesterone 20% natural progesterone 20 11% hydrogel-forming base mixture 9% hydrogel-forming base mixture 1.5% n-butylurea 2.5% n-butylurea 52.5% water 48.5% water 6.2.2 PROGESTERONE PENETRATION THROUGH A DIALYSIS
MEMBRANE
Since the transdermal progesterone experiments were to be performed using physiological saline as the receptor fluid, it was first determined if penetration might be limited by solubility of progesterone in the physiological saline. Thus, penetration of progesterone through a dialysis membrane, which was ~sumed to be more permeable than the sl~in, was measured to see how much progesterone could acc~m~ te in the receptor of the diffusion cells. The dialysis membrane used was Spectra/PorR No. 1 dialysis tubing, purchased from Thomas Scientific, Swedesboro, NJ. The dialysis CA 022~636~ 1998-11-23 membrane was positioned in the diffusion cell as described above. The results are given in Figure 14, which is a plot of the cumulative amount of progesterone penetrated (~g/cm2) over a period of about 1.5 hours. Figure 14 shows that penetration occurred at a rate of about 30 ~g/cm2/Hr. Note that there appeared to be no lag time, i.e., the 5 rate of penetration appeared to be linear from the time of contact. Such a time course for penetration is consistent with diffusion through pores (i.e., the solvent-filled pores of the dialysis membrane).

6.2.3 TRANSDERMAL PENETRATION OF PROGESTERONE:
COMPARISON OF COVERED AND NOT-COVERED
SAMPLES
Using Sample A-1, rates of progesterone penetration through the skin were compared for covered with a layer of al--min-lm foil vs. not-covered samples. Figure 15 shows a plot of the cum~ tive amount of progesterone penetration (,ug/cm2) over a period of about 8 hours for uncovered and covered samples of A-1. Clearly, penetration proceeds more rapidly through the skin when the application site is covered.
Also note that there is a lag time, i.e., the steady-state rate of progesterone penetration was not established until 2-3 hours after application. This kind of time course is consistent with the drug having to partition into ~dissolve in) the skin before the transdermal diffusional process begins.

6.2.4 TRANSDERMAL PENETRATION OF PROGESTERONE:
COMPARISON OF OLEIC ACID~ MYRISTIC ACID AND
BUTYLUREA PENETRATION ENHANCERS
Rates of transdermal penetration of progesterone were determined for three 25 samples: A-1, A-2, and A-3. Each of these samples was of the same viscosity, but each contained a different kind of penetration enhancer. (The compositions of these samples are given above in Section 6.2.1). The penetration data for samples A-1, A-2 and A-3 are given in Table 1.

CA 022~636~ 1998-ll-23 WO 97/43989 PCT/USg7/08636 Table 1. Transdermal Penetration of Progesterone ~glcm2 Sample A-3 Hrs 1 2 3 4 5 6 7 Skin #1~ 1.3 3.9 9.2 18.0 28.0 37.4 48.257.6 Skin #2 0.49 5.~ 14.8 28.6 46.0 63.7 82.9105.2 Skin ~3 4.5 13.3 25.0 37.1 49.8 63.7 77.092.3 Steady-state Rates, ~g/cm2/HR: #1 = 9.8, #2 = 18.1, #3 = 13.4 Sample A-2 Hrs 1 2 3 4 5 6 7 8 Skin #1 0.29 0.97 1.8 4.1 5.6 7.7 9.7 11.5 Skin #2 0.35 1.2 2.6 5.1 8.0 11.3 14.6 18.9 Steady-state Rates, ~glcm~/HR: #1 = 1.9, ~2 = 3.2 Sample A-1 Hrs 1 2 3 4 ~ 6 7 8 Skin #1 0.53 1.4 2.9 .5.4 8.7 11.9 14.6 18.4 Skin #2 3.4 7.9 12.6 16.9 21.8 26.4 31.1 36.3 Steady-state Rates, ~glcm~/HR: # 1 = 1.9, #2 = 3.2 As may be seen in Table 1, n-butylurea was clearly the most efficacious of the three in promoting the penetration of progesterone through the skin. The highest rate observed, (18.1 ,ug/cm2/Hr, sample A-3, skin #1) was for the composition of the present invention cont~ining n-butylurea.
Note that the rate of 18.1 ~4g/cm~/Hr was substantially lower than that measuredthrough dialysis membrane (Section 6.3.2). Thus, the test system does not impose an upper limit on the rate of penetration, and therefore, the measured rates are a true indication of how fast the drug can be transferred through the skin from these formulations.
Some of the data from these determinations are plotted in Figure 16, to illustrate how the rates were determined. A linear regression analysis was performed for each of CA 022~636~ 1998-11-23 the three curves, corresponding to samples A-1, A-2 and A-3, respectively, using the points taken in the interval from 3-8 hours. The rates were derived from the slopes of the curves. The rate is defined as the slope of the plot of the cumulative amount of progesterone penetrated in ,ug/cm2, versus time in hours. It may be seen that the plots 5 are almost perfectly linear during this interval (regression coefficient ~ 0.99). The position of the x-intercepts indicates that there was a lag time of about two hours.
Table 3 gives the 3-8 hour steady state rates, the average for hours 1-8 of penetration and the average rates for hours 8-30 of penetration for samples A-1, A-2 and A-3. It is also clear from the data in Table 2 that the rate of penetration measured in the first eight 10 hours of contact with the skin was sustainable for more than a day (30 Hrs in this experiment).

Table 2 n~e of the Rate of ~ ~ ~ ~t~l o,~e ~..el~..tion (~g/cm2/Hr) (Skin #1) Steady-state, 3-~ HrsAv. Rate, 1st 8 hrsAv. Rate, 8-30 Hrs A-1 3.1 3.3 1.2 A-2 1.9 1.7 1.6 A-3 9.8 9.1 8.9 * Skin Donor Number, #1, #2, etc.

6.2.5 INTRADERMAL PENETRATION OF PROGESTERONE:
COMPARISON OF OLEIC ACID, MYRISTIC ACID AND
BUTYLUREA PENETRATION ENHANCERS
Since it had been observed that dilution o~ the receptor fluid seemed to decrease transdermal penetration, samples A-1, A-2, A-3, B-1, B-2, B-3, C-1, C-2, and C-325 were compared by measuring intradermal penetration rather than transderrnal penetration. The observed dilution-dependent decrease in transdermal penetration was contrary to expectation, since norrnally, lowering drug concentration the receptor increases penetration, as it increases the concentration gradient across the skin. The decrease was especially unexpected because in this model, the receptor volume is at a 30 minimum (only the fluid in the dermal compartment of the skin).

W O 97/43989 PCT~US97/0~636 All measurements were performed on skin from a single donor. Results are given in Table 3.

Table 3. Intradermal I~ tr~lion of Progesterone, over 20 Hrs, ~g/cm2 Sample Full-thickness Dermis A-l 71.4 36.3 A-1 * 47.3 29.0 A-2 72.6 33.6 A-3 44.5 34.0 B-1 91.0 19.6 B-2 59.1 40.0 10 B-3 54.5 37.0 C-1 50.5 33.0 C-Z 71.0 619.
C-3 56.5 27.6 Mean,+/- SD 61.8, ~/-14.4 31.0, +/-7.0 As Table 3 shows, a mean value of about 60 ,ug/cm2 could be recovered from "full thickness" skin after a 20-hr contact period, and about 30 ~g/cm2 from the derrnal portion of the slcin, the site of the dermal capillary network. These numbers indicate that only about 3 ~4glcm~/Hr penetrated the skin when there was no added receptor fluid in contact with the dermis, and that about half the penetrating material actually got into 20 the dermis, i.e., under these circum.ct~nres, about 1.5 ~g/cm2/Hr of progesterone was "available" for uptake into the capillaries. Further, the rate of differences observed with different enhancers in the fîrst set of comparisons (Section 6.2.4, Table 1, Figure 16), could not be demonstrated.

6.2.6 TRANSDERMAL PENETRATION OF PROGESTERONE:
COMPARISON OF OLEIC ACID AND BUTYLUREA
PENETRATION ENHANCERS
Transdermal penetration using samples A-3 and C-3 was measured using skin from the same donor as was used in Section 6.3.5. Measurements were performed in two ways: with the sampling from the diffusion cells during the first eight hours, and without such sampling (Table 4). In this experiment, the amounts that passed through the skin were much higher when the diffusion cells were not sampled, however the best CA 022~636~ 1998-ll-23 W O 97/43989 PCT/US97tOX636 hourly average for transdermal penetration rate (Sample C-3, 4.8 ,ug/cm2/Hr), was still only about one-half the lowest rate measured with n-butylurea in Section 6.2.4 (Table 1).

Table 4. Transdermal and Intradermal Penetration of Progesterone over 20 Hrs, ~g/cm2 A-3 A-3** C-3 C-3**
Transdennal 36.0 56.0 28.1 95.5 Intraderrnal, Dermis 23.0 81.4 Intraderrnal, Epidermis 18.6 20.3 * A duplicate of sample A-l.
** These cells were not sampled, whereas the other member of each pair, (A-3 and C-3) were sampled during the first eight hours.

6.2.7 TRANSDERMAL PENETRATION OF PROGESTERONE
USING BUTYLUREA PENETRATION ENHANCER:
COMPARISON OF VISCOSITIES
To access the effect of viscosity on transdermal penetration rate, rates were measured using samples of low viscosity (A-3) and high viscosity (C-3), both con~:~ining n-butylurea. The results, presented in Table 5, indicated that in the range tested, 20 viscosity did not affect the transdermal penetration rate. It is also clear that penetration rates through these skin samples (average 9-10 ,ug/cm2/Hr) were higher than the best rate shown in Table 4, providing some indication that the skin used in Section 6.2.5 for measurements of intradermal penetration and in Section 6.2.6 for transdermal penetration may have had atypically low permeability.

WO 97/43989 PCT~US97/0863 Table 5. Transdermal Penetration Progesterone, ~glcm2/Hr (20-Hr Assay, w/o Hourly Sampling) Test Article A-3 C-3 Skin # I ll I II

7.8 10.4 8.9 1 1.2 9.4 1 1 .9 6.7 1 l .4 7.2 9.5 9.8 10.0 Mean SD 8.13 10.56 8.47 10.87 1 . 14 1 . 16 1 .59 0.75 Mean, All Samples SD 9.35 9.67 l.68 1.72 6.2.8 TRANSDERMAL PENETRATION OF PROGESTEI~ONE:
EFFECT OF PROGESTERONE CONCENTR~TION
To access the effect of progesterone content of the inventive compositions upon transderrnal penetratian, tests were carried out using samples W, X, Y and Z in which lS the progesterone concentration was varied from S to 20%. The results are give in Table 6.

Table 6. Transdermal ~g~lerone P~nlr~ion.
Initial and S--~t?~ine-l Rates, in ~g/cm21Hr Skin No I II III
Rate Initial 0-24Hr24-48Hr Initial Initial Pro,gesterone Conc ., ( % ) Sample W 5 5.2 4.9 5.0 4.7 6.2 X 10 6.7 6.1 6.0 5.8 8.1 Y 15 7.8 7.0 7.3 6.5 9.0 Z 20 1 1. 1 10.4 10.0 10.5 13.6 As may be seen in Table 6, a 4-fold increase in concentration resulted in a doubling of the penetration rate, both initially, and in the rate sustainable for up to 48 hours. While 30 the concentration dependency appears to be real, it should be noted that the highest rate observed here (about 14 ~g/cm2/hr) was not higher than the 18.1 ~g/cm2/Hr rate seen CA 022~636~ 1998-11-23 with a 4% progesterone formulation in Section 6.2.4 (see Table 1). This disparity may be due to skin-to-skin variation.

6.2.9 TRANSDERMAL PENETRATION OF PROGESTERONE:
COMPARISON OF FULL-THICKNESS SKIN AND SKIN
FROM WHICH THE EPIDERMIS HAD BEEN REMOVED
The transdermal penetration of the progesterone through full-thickness skin was compared to penetration through skin from which the epidermis had been removed. The rate increased only about 2-fold after this maneuver, indicating that the dermis is an important factor in limiting the rate of penetration through the skin.

6.3 DEMONSTRATION OF INTRADERMAL PENETRATION OF
PROGESTERONE BY AUTORADIOGRAPHY
Introduction It was not possible to demonstrate progesterone within the skin by conventional 15 histological techniques, as it appeared to be extracted by the alcohols used in processing.
Therefore, an alternative procedure was used to acquire skin surface biopsies (Marks and Dawber, 1971, Brit. J. Dermatol. 85:117-123). Surface biopsies consist of a sheet of the top 2-3 layers of the stratum corneum, which retain vellus hairs on the underside, along with fragments of the pilosebaceous ducts known as "follicular casts" (Lavker and 20 Leyden, 1979, "Lamellar Inclusions in Follicular Horny Cells: A New ~'spect of Abnormal Ker~tini7~ion," J. Ultrastruct. Res. 69: 362-370). These samples are produced by application of a drop of cyanoacrylate adhesive on a microscope slide to the surface of the skin, and after the adhesive sets, the slide with adhering tissue is carefully peeled off. When surface biopsy samples were taken from skin to which 25 radioactive progesterone had been applied, a time-dependent ~ccumul~ion of progesterone in the tissue could be demonstrated, by autoradiography.

Procedure Discs of skin were prepared as described in "Methods", for measurement of 30 intradermal penetration, but using much larger washers to provide test sites of about 10 cm~ in area. A test formula con~ining 20% progesterone (Sample Z) was applied, and CA 022~636~ 1998-11-23 wo 97l43989 PCT/US97108636 uptake into the skin was allowed to proceed for one hour, and for 20 hours. Surface residue was removed at the indicated times, using the rinse/wipe procedure described.
Skin surface biopsies were taken from 1 & 20-Hr skin discs, and coated with photographic emulsion (Illford K-2 emulsion, Illford, London), then allowed to develop 5 for 14 days. Rinsing and fixing were done as prescribed by the manufacturer.

Results Three surface biopsies were photographed with black-and-white film, on a white background, with sub-surface illumination. There was a distinct gradation in grayness, 10 increasing from the baseline level of the control sample to the 20-Hr sample, as would be expected with increasing numbers of silver grains. It is clear that the stratum corneum as a whole darkened with time, but the follicular fragments were much darker than the interfollicular stratum corneum, indicating a preferential ~cc~-m-~ ion of progesterone in the pilosebaceous follicles. This pattern was also obvious when sections 15 were photographed with incident light. Ridges and grooves that crisscrossed the undersurface were visible; these are the "negative" of the fine folds on the surface of the skin. A high magnification study of the sections was undertaken, to establish that the pattern of darkness, or opacity, seen in these low-magnification images was really due to silver grains. A view of the underside of a control biopsy, showed an uprooted 20 vellus hair enveloped by a mixture sebum and compacted corneocytes (keratinized stratum corneum cells). It resembled a horn with a collar, emerging from the background undersurface of the stratum corneum.
The horn is the coated hair, and the collar a portion of the infundibulum, or funnel-shaped opening of the pilosebaceous duct, that emerges on the surface of the 25 skin. The polygonal outlines of individual corneocytes are sometimes discernible, a convenient metric (about 40 microns) for the scale of the images. In distinct contrast to a control section, the underside of a section from skin which had been in contact with a tritiated 20% progesterone formula for 20 hours appeared to be stained a deep blue color, most intensely at follicular structures. At higher magnification, the blue stain 30 could be resolved into individual silver grains, seen as a stippling of blue dots about 500 nanometers in diameter. Where the wall of the follicle was perpendicular to the plane CA 022~636~ 1998-11-23 of the section (W), the stain was much more intense, a combination of a higher grain density, and effectively viewing a thicker section (imagine looking at the edge of a piece of stained glass). An image of a 0.2 mm-long follicular fragment showed that progesterone was distributed uniformly to this depth within the lipid-rich interior of the 5 follicle. Finally, stippling (and thus silver grains) was absent from a control biopsy, taken from tissue which had never been in contact with radioactive material.
Summary The disposition of tritiated progesterone in the surface biopsies ex~min~od is consistent with diffusion through the follicles, as well as diffusion through the 10 interfollicular stratum corneum. Accumulation in the follicles appeared to be faster than in the stratum corneum, but both were shown to be time-dependent. The contribution of each route to the combined rate of penetration is not easily determined, but it should noted that the surface area of the openings of the follicles is estim~ed to be only about 0.001% of the area in contact with the applied test formulation (about 30 follicles per 15 cm2, and about 100 micron2 per follicle). To have a real impact under these circumstances, movement through the follicular "shunt" route would have to be more than four orders of m~gni~l(le faster, per unit area. If, however, we invoke the length of the follicular shunts, the real interfacial area (follicle/dermis) could approach 1%, and under these circumstances, if the transfer rate from follicle to dermis were only 10 20 times as fast (or more) as the transfer rate from stratum corneum to dermis, then the shunt route could approach or even exceed the contribution of the transepidermal route to the total rate of penetration.
The Examples above demonstrate that progesterone penetration rates using compositions of the present invention are in the range 1-20 ,ug/cm21hr, and appear to be 25 sustainable for at least 48 hours (Table 6). The rate at the higher end of this range is in excess of two orders of m:~gnitn-le greater the 1.2 ~g/cm21day rate reported by Guy et al., (1987, "Kinetics of Drug Absorption Across Human Skin In Vivo," Pharmacol.
Skin 1: 70-76). (discussed supra). Although Barry and Bennett, (1987, "Effect ofPenetration Fnh~nrers on the Permeation of ~Iannitol, Hydrocortisone, and 30 Progesterone Through ~uman Skin," J. Pharm. Pharmacol. 39: 535-546), reportedsomewhat higher rates when certain permeation enhancers were used (supra), that CA 022~636~ 1998-11-23 method of application increases delivery by pretreatment of skin with acetone and thus that method of application to the skin is not amenable to a transdermal delivery patch system. Thus, the compositions of the present invention provide unexpectedly superior delivery to the blood of the hormone contained within them and a very promising aspect 5 of a su~t~in~d-released transdermal delivery system for progesterone.

6.4 SKIN PENETRATION ASSAYS: HUMAN EPIDEl~MAL
MEMBRANES
6.4.1 BACKGROUND AND SUMMARY
In these experiments, a revised in vitro percutaneous absorption model was used.
The ~pl)rop,iateness of full thickness skin as a diffusional barrier, the radioactive labeling of test formulations after they had been compounded, and establishing the identity of the radioactive species in the receptor of the diffusion cell after diffusion has occurred were addressed. These issues were dealt with as follows:
15 1. Heat-separated human epidermal membranes were used instead of full-~hickn~oss human skin.
2. The test formulations were compounded with progesterone which had been radiolabeled by mixing tritiated progesterone with "cold" progesterone dissolvedin propylene glycol at 100 ~C.
20 3. The radioactive species in the receptor of the diffusion cell was.extracted from the saline receptor fluid, and shown by thin layer chromatography to be indistinguishable from the progesterone which had been applied to the surface ofthe skin.
Two progesterone formulations were tested, one with 2% enhancer (Test Formulation 25 A-4) and one with 4% enhancer (Test Formulation B-4). Mean penetration rates of 3.2 and 6.1 micrograms per centimeter squared per hour were determined, for the 2% and the 4% enhancer formulations, respectively (see Figure 21). These results indicate that 1-1.5 mg (0.77-1.46 mg) per day can be delivered to the body, from a 10 cm2 patch, and that the penetration rate can be modulated by varying the concentration of enhancer.
30 Of particular interest is Test Formulation A-4, which is the same forrnula used in the in vivo study described in Section 6.5. Impressive (clinically significant) serum and saliva levels were achieved when Formulation A-4 was applied to human test subjects CA 022~636~ 1998-11-23 during a single 8-hour application using a 10 x 10 cm~ patch. It is likely that concentrations observed in vitro could rise substantially, with continuous in vivo application of a patch, using an optimized formula (e.g., with higher enhancer concentration). In such in.~t~nr.e, the patch could be reduced in size to something which 5 could be worn around the wrist, or applied at some other convenient body site. Test formulations A-4 and B-4 had the following compositions:

Natural Progesterone 0.200 g (16.3 wt %) Propylene Glycol 0.200 g (16.3 wt %) Butylurea 0.025 g (2.0 wt %) Polymer 0.090 g (7.3 wt %) Distilled Water 0.71 g (58.0 wt %) Natural Progesterone 0.195 g (15.7 wt %) Propylene Glycol 0.194 g (15.7 wt %) Butylurea 0.050 g (4.0 wt %) Polymer 0.090 g (7.3 wt %) Distilled Water 0.71 g (57.3 wt %) The polymer (hydrogel-forming base mixture) was composed of the following ingredients: 63% methyl cellulose, 21% guar gum, 5% glucose, 3% pectin, 1.5%
sodium chloride, 3.5% propyl paraben and 3% methyl paraben.

6.4.2 MATERIALS AND METHODS
Preparation of Epidermal Membranes: All membranes used in this series of experiments were isolated from skin samples obtained after breast reduction. Donors were Caucasian females, ages 26-48. The epidermis was peeled from the dermis after 30 the skin had been immersed in distilled water at 60~C, as described by R.J. Scheuplein (1986, "Mechanism of Percutaneous Absorption," J. Invest Dermatol. 45:334-346).
The membranes were spread corneum-side down on aluminllm foil, and stored over CA 022~636~ l998-ll-23 wo 97143989 PCT/US97108636 Drierite at room temperature. In this desiccated state they are brittle, and they were therefore carefully dehydrated before discs of tissue were punched out for placement on the diffusion cells.

Diffusion Cell Design and Assembly: Transepidermal penetration was measured using single chamber diffusion cells. The diffusion cell described in Section 6.2 was redesigned to work with epidennal membranes, which are much thinner and more fragile than the full-thickness skin from which they are isolated. For parts, the same polyvinyl chloride ("PVC") couplings described in Section 6.2 were used to 10 make a donor assembly (Figure 20) which could be partially immersed, so that the underside of the epidermal membrane was in contact with saline held in a glass receptor. A half-inch diameter epidermal membrance disc was positioned such that its dermal surface was in contact with normal saline (2.5 ml) held in a glass receptor. The diffusion area was 0.71 cm'. The saline was stirred continuously using a small stirring 15 bar. Diffusion cells were incubated at 32~C. The cells were covered with a plastic sheet to prevent evaporation from the receptor.
At each time point, a O.S ml aliquot of receptor fluid was removed and replaced with an equal volume of normal saline, prewarmed to 32~C. Progesterone penetration was estimated by measuring the amount of tritiated progesterone contained in each 20 aliquot, using standard techniques. Plots of the cumulative amount collected in the receptor with time were used to determine progesterone penetration rates, expressed in llg/cm~/hour (see Figure 21). Four separate determinations were made for each of the two formulations tested. The extracted labeled material was shown by thin layer chromatography to be int~i~tinguishable from fresh natural progesterone.
The membranes were ex~min~d visually with a hand lens before each experiment, to confirm that no visible defects were present. Following each experiment, Blue Dextran (molecular weight 2 million, obtained from Pharmacia Biotech) solution was added to the epidermal side of the membrane. There was no leakage of the Dextran into the receptor fluid after 24 hours.
As shown in Figure 21, formulations A-4 and B-4 resulted in steady-state, linearpenetration of natural progesterone through human epiderrnal membranes, following a CA 022~636~ 1998-11-23 lag time of about 1 hour. Formulation A-4, which contained 2% butylurea. had a steady state penetration rate of 3.2 ~g/cm21hr, while formulation B-4, which contained 4% butylurea, had a steady state penetration rate of 6.1 ~g/cm7/hr.

Compounding and Radiolabeling of Test Formulations A-4 and B-4. Tritiated progesterone was purchased from NEN-Dupont (96 Ci/mmole), and was labeled in ring positions 1, 2, 6, and 7. Compounding was as follows:
1. "Cold" progesterone (i.e., non-radioactive progesterone), radioactive progesterone~ and propylene glycol were mixed in a small screw-cap vial, which was immersed in boiling water for S-10 minutes, until an optically clear solution was obtained. The vial was removed from the bath and allowed to cool for 2 minutes, then added all at once to an aqueous mixture described in no. 2 below.
2. Fnh~n~er was dissolved in an appropliate volume of water, in a heavy 2~ounce "shot glass", stirred with a straight steel rod at 1500 RPM. A
weighed amount of polymer was then dusted onto the vortex of stirring solution, to ensure rapid, thorough mixing. As soon as thickening was evident, the progesterone-glycol solution from No. 1 above was added, and the stirring rate increased to 3000 RPM. Stirring was continued for 2-3 minutes, until the mixture was the consistency of dough, and adhered to the rod; then the stirrer was turned off. With the help of a small spatula, the labeled polymer mixture was transferred to a clean scintillation vial, which was then tightly capped. The final mixtures had 5-600 dpm/microgram of hormone.

Chromatographic Analysis of l~ro~e~lerone: Thin layer chromatography (TLC) of progesterone mixtures was performed on 250-micron silica gel GF plates (Analtech, Newcastle, DE) using a 1:1 mixture of cyclohexane and ethyl acetate as solvent. This system was recommended by NEN-Dupont. The plates were developed for about 30 mimltes Visualization of the chromatographed material was with short-wave UV, as 30 the silica on the TLC plates contained a bound fluor, which was quenched by the UV-absorbing progesterone.

... ... .

CA 022~636~ 1998-11-23 A stock solution of "cold" progesterone was prepared at 1 mg/ml in ethyl acetate. Five-,ul aliquots of this solution (about 50 llg) were spotted and run as described. After drying, UV ex:~min~rion disclosed a single spot, with an R, of 0.68.
Fifty mg of Test Forrnulation A-4 was extracted with 1 ml of ethyl acetate and 5-S ,ul aliquots spotted for analysis. These aliquots also yielded a single spot on vi~ li7~tion, with an R, that was indistinguishable from that obtained with the "cold"
stock solution. When the spots were scraped from the TLC p}ate and suspended in scintillation cocktail, spuriously high counts were observed because of the fluor bound to the silica gel. These counts were found to decrease as the silica settled, but as this 10 procedure was time-con~-lming, the practice was adopted of centrifuging the suspension at 1000xg for 5 minutes and counting the supernatant. As may be seen in Table 9, this procedure resulted in an apparent loss of counts (14%), which was significant, but reproducible. We were unable to detect radiolabel elsewhere on the track of the migrating progesterone, thus the loss is probably due to absorption of progesterone in the pelleted silica gel. (We also found that adding increasing amounts of silica to "hot"
(radioactive) progesterone dissolved in scintillation cocktail resulted in increasing losses of radioactivity in the supernatant after centrifugation).
Receptor fluid (2.5 ml) was removed from an assembled diffusion cell about S hours after Test Formulation A-4 had been applied. This fluid was extracted with 20 5 ml o~ ethyl acetate with vigorous shaking for 10 minutes. Five-~41 aliquots were counted or applied to a TLC plate to assess their identity and purity. On vi~ li7~tion with UV after the plates were developed, three UV-absorbing spots could be detected, one with R, 0.68. As may be seen in Table 10, about 75% of the applied counts were recovered in this "progesterone spot". No radioactivity could be detected in the other 25 UV-absorbing spots, or elsewhere on the TLC plate. The apparently lower percent recovery in the "progesterone spot" in this experiment vis-à-vis the recovery observed for the Test Formulation extract (see Table 9) is probably due to the fact that a smaller amount of material was spotted on the TLC plate.

, CA 022~636~ 1998-ll-23 wo 97/43989 PcT/uss7/08636 6.4.3 ~SULTS AND DISCUSSION
In Section 6.2 skin penetration of progesterone was assessed by measuring transdermal penetration rates; in this section, transepidermal penetration rates are described. Similar to the earlier measurements, a steady-state rate of penetration was 5 established within the first several hours of contact (Figure 21). The lag time was somewhat shorter, as might be expected for a thinner diffusional barrier. The rates (Table 7) are lower than those reported in Section 6.2, probably because the radioactive progesterone is now mixed with insoluble as well as soluble progesterone, whereas in the Section 6.2 experiments, only the soluble portion of the progesterone was labeled, 10 resulting in penetration values.
When the concentration of enhancer was doubled (Table 8), the rate increased proportionately, i.e., a approximate doubling of the rate.
Heating the progesterone in propylene glycol resulted in a true solution of the hormone, thus assuring a thorough mixing of the radioactive and non-radioactive forms.
15 A possible consequence of this heating was some decomposition of progesterone. We have checked this as follows:
Thin-layer chromatography (TLC) of the progesterone supplied by the manufacturer yielded only a single spot on the TLC plate, with an Rf of 0.68.
When Test Formulation compounded with heated "hot" and "cold" progesterone was extracted with ethyl acetate, one of the chromatographic solvents, the extract also yielded a single spot on the TLC plate, with an R, identical to the original material, and all the radioactivity recoverable from the TLC plate was confined to this spot; Table 9. This means that the heating did not cause any discerniblealteration of progesterone and that the "hot" progesterone is identical to the "cold" .

To establish the identity of the radiolabeled species in the receptor of the diffusion cell, receptor fluid was extracted with ethyl acetate after five hours of transepidermal penetration. This ethyl acetate extract was concentrated and then spotted 30 on a TLC plate. Visual ex~min~tion of the TLC plate then showed three spots, one of which was at R, 0.68. All of the radioactivity recoverable from the TLC plate was wo 97/43989 PCTrUS97/08636 (Table 10) again confined to this "progesterone spot." It thus appears that little chemical or enzymatic changes occur when progesterone passed through the epidermis, and that tritium in the receptor is a true indicator of progesterone penetrating.

Table 7 ~ oge~lero le Penetration through Epidermal Membranes from 3 Different Skin Samples (~glcm2/hr) Test Formulation A-4 Skin I Skin II Skin III

3.6 3.9 4.1 3.3 3.4 4.5 3.1 3.6 4.8 2.7 3.8 Mean 3.2 3.6 4.3 Table 8 ~ffect of F.nh~n-~er Conce.llldlion on Transdermal Penetration of Progesterone (~g/cm2/hr) Test Formulation Test Formulation 3.6 7.7 3.3 6.3 3.1 5.6 2.7 4.7 Mean 3.2 6.1 S.D. 0.378 1.266 B > A; 99.99 % (P < 0.001) Note: Four replicate determinations using membranes from a single skin sample obtained after breast redllction from a Caucasian female.

CA 022~636~ 1998-11-23 Table 9 Ethyl Acetate Extract of Test Formulation A-4 Recovery of Tritium at TLC Progesterone Spot MEAN
DPM/5~1~ 27,986; 28,783; 28,331; 28,414; 28,269 28,339 DPM/Progesterone Spot~ 24,310; 25,083; 23,993; 24,690; 25,514 24,318 ~ Five-~l aliquots of extract (cont~ining about 38 micrograms of progesterone) were added to scintillation-counting vials cont~inin,J 10 ml of cocktail.

10 ~ Five-~l aliquots of the same extract were spotted on a TLC plate, which wasdeveloped for 30 minutes. After drying, the spot at Rf 0.68 was scraped off and added to 10 ml of cocktail. Samples were counted after the silica gel particles were removed by centrifugation, as described.
Note: "DMP" refers to "Disintegrations Per Minute", which is a measure of radioactivity.

Table 10 Ethyl Acetate Extract of Diffusion Cell Receptor Fluid:
Tritium Recovery at TLC Progesterone Spot MEAN
DPM/5~1~ 1207 1241 1086 1178 DPM/Progesterone Spot 848 966 821 878 After about 5 hours of diffusion, the receptor fluid (2.5 ml) from a diffusion cells was extracted with 5 ml of ethyl acetate, and concentrated to about 100 ~l.
Five-,ul aliquots were added directly to scintillation cocktail and counted, or spotted on a TLC plate. DPM in the second line of the Table represent the amount of progesterone recovered from the "Progesterone Spot" (R,0.68). UV-absorbing material appeared at two other spots on the TLC plate, but these were found to be non-radioactive.

, CA 022~636~ 1998-11-23 6.5 IN-V~VO STUDY OF TRANSDERMAL PENETRATION OF
NATURAL PROGESTERONE
6.5.1 BACKGROUND AND SUMMARY
This study was designed to measure the in-vivo transdermal penetration of 5 progesterone using compositions of the present invention. Serum and saliva sampling were elected as the cardinal indices of absorption. Urinary excretion of progesterone and its by-products are not a reliable index of total progesterone excretion, due to difficulties in analysis, and also because large amounts of progesterone are excreted into the bile. Measurement of salivary progesterone has an advantage over other assays 10 because it represents free unbound progesterone.
Three male candidates were chosen for this study. Males were selected for the study because only small amounts of progesterone are made in the adrenal cortex and in the testes.

6.5.2 MATERIALS AND METHODS
Studies were carried out under the guidelines of the Midtown Hospital (Atlanta, Georgia) human studies commitsPe, following review and approval of the study protocol.
Three normal males, ages 30, 40 and 49 were selected and informed consent was obtained. The subjects for the study were in good health and were screened to confirm 20 that each was free of any known medical problems and not taking any medications.
The transdermal progesterone formulation used in this study was the same as Test Formulation A-4, described in Section 6.4, supra, except that the formulation used in this study did not contain radioactive progesterone.
Just prior to application, approximately 45 g of the forrnulated material was 25 applied in a thin layer to a 100 cm2 square piece of plastic to form a crude patch. The site of application for the transdermal progesterone formulation was on the skinoverlying the pectoral muscle. The skin was prepared by gently shaving the existing hairs. The plastic patch receptacle cont~ining the test formulation was applied to the skin and taped in place. The system had no external pressure applied to the surface of 30 the receptacle.
Prior to the initiation of the study, baseline saliva and serum levels of progesterone were obtained from the candidates. Subsequent sampling was at 24 and CA 022~636~ 1998-ll-23 WO 97/43989 PcT/US97/08636 48 hours. Serum was obtained by venipuncture. Saliva was collected by asking thesubjects to expectorate into a sterile plastic container. The serum progesteroneconcentration was determined by SmithKline Laboratories, Atlanta, Georgia, using a standard clinical radioimmunoassay. Salivary progesterone assay was performed by5 Aeron Life Cycles, San Leandro, California. Aeron has considerable experience in the measurement of compounded natural progesterone products in saliva. In test populations previously studied by Aeron, males and postmenopausal females have basal salivary progesterone levels of <0.05 ng/ml, while that of premenopausal femalesranges from 0.05 to 0.5 ng/ml.
During the test period, subjects rested in the semisupine position, so as not todisturb the patches. Lunch was provided. Patches were applied between 8:30 and 9:30 AM and removed after 8-9 hours. Following patch removal, the rem~ining formulation was removed by gently washing the area with water. Skin was blotted dry with soft paper tissue. Subjects went home and returned on each of the following two mornings lS to provide the 24 and 48 hour samples.
Baseline progesterone ranges in both saliva and serum in men normally range from 0.02 to 0.05 nanograms per ml. The reason salivary levels of progesterone were chosen for measurements is that salivary levels reflect the free plasma fraction. Many factors may alter the level of binding proteins in the blood or affect the binding of 20 steroids to them. This greatly complicates the in~ etation of the total plasma steroid levels. Serum measurement of total progesterone must therefore be interpreted with caution. These considerations are not a significant problem in the current study, however, since the concentration of progesterone binding proteins would not be expected to change during the brief duration of the of the experiment. Saliva samples avoid these 25 problems by giving an index of the free plasma level.
The lipid, soluble, unconjugated steroids (such as cortisol, estriol, testosterone, progesterone, etc.,) enter saliva predominantly via the intracellular route. Their salivary concentrations are not dependent on saliva flow rate, and their salivary concentrations closely approximate their unbound concentration in plasma. Unconjugated steroids enter 30 saliva by diffusing through the cells of the saliva glands and their concentration in saliva does not depend on the rate of saliva production. Roth the saliva progesterone assay CA 022~636~ 1998-11-23 and serum assays for progesterone were performed hy radioimmunoassay which uses the competition between radioactive and non-radioactive progesterone for a fixed number of antihody binding sites to determine the progesterone concentration present in the speclmen.

6.5.3 RESULTS
Transdermal delivery of natural progesterone was assessed in three male volunteers by measurement of serum and salivary progesterone levels, at time points ranging from zero to 48 hours following patch application. The serum progesterone 10 data is shown in Table 11 and the saliva progesterone data is shown in Table 12. All three men showed baseline serum levels of 0.4 ng/ml and saliva values of 0.04, 0.04 and 0.02 ng/ml, consistent with established normal values in men.
Although the in-vivo transdermal penetration study described herein used an unsophisticated receptacle to apply the formulation to the skin, significant transdermal 15 penetration of progesterone was observed. By about 2 hours, serum progesterone increased about 10-fold in subject #3, but increased insignificantly in subjects #1 and #2. At approximately three hours, all of the subjects showed increased progesterone levels. Concentrations increased throughout the 8-9 hour experiment. There was no indication that either steady state or maximal serum levels had been reached.
Salivary progesterone levels also rose in a time dependent fashion, though the increases tended to lag those seen in the serum. Subjects #1 and #2 showed increases over basal of 60 and 33 fold at 24 hours, respectively. Subject #3's salivary progesterone level measured 25 ng/ml at around 8 hours in a single determination, with a lower value of 0.13 at 24 hours.
Subjects #1 and #2 showed decreases in serum progesterone at about 24 hours, around 9 hours following patch removal, the same time that their saliva horrnoneconcentration reached its highest value during the experiment. Both serum and salivary concentrations had decreased, but were still supernormal, at about 48 hours, 33 hours after discon~in--ing a~mini~tration of the hormone. Subject #3 showed a decline in both 30 serum and salivary concentrations at 24 hours; he was not tested at 48 hours.

CA 022~636~ 1998-11-23 6.5.4 DISCUSSION
The purpose of this study was to determine whether the transdermal formulation of natural progesterone of the present invention could provide a safe and effective method for the transdermal administration of natural progesterone to humans. Despite 5 the short duration of the study and the relative crudeness of the patch, the forrnulation delivered significant amount of hormone without skin irritation or any other detectable adverse effects. The results suggest that the formulation has utility as a safe and effective device to deliver natural progesterone.
Each of the three subjects showed increases in the levels of both circ~ ting and10 salivary progesterone. None appeared to reach steady state, so maximal transport rates could be significantly greater than observed. Subject ~3 showed a very large salivary concentration at about eight hours, but this value could be spurious. Clearly, more extensive evaluation of the formulation would be needed before establishing any firm conclusions about progesterone delivery rates. Questions obviously remain as to levels 15 of penetration that may have been accomplished if the system had remained on the skin for an extended period of time, i.e. 12 - 24 hours with serial saliva and serum samples being obtained during those intervals. Because of the simplicity of the vehicle for the formulation, the data suggest that the transdermal penetration of progesterone was predominantly dependent on the effects of the hydrogel polymer in combination with the 20 butylurea transdermal enhancer with progesterone. It should also be noted that the salivary levels of unbound progesterone achieved using the transdermal system are considerably higher than the peak ranges achieved historically by oral micronized progesterone (upper limits of 0.5 nanograms per ml), as measured by Aeron Life Cycles.
The results of this study correlate well with the results of the accompanying in vitro study performed on human skin described in Section 6.4. In this study, a similar preparation showed progesterone penetration rates of 3.2 ,~4g/cm2/hr through human skin samples. It is not possible, given the limits of the current data, to predict what steady state serum concentrations might be achieved with this preparation.
From the analysis of in-vivo studies performed on human male subjects using transdermal progesterone described above, the question obviously arises as to clinical CA 022~636~ l998-ll-23 Wo 97/43989 PcT/uss7to8636 efficacy of progesterone in the female who is using transdermal progesterone in combination with estrogen in the menopause. The major issue is whether sufficient progesterone levels are being achieved to prevent the risk of endometrial hyperplasia and adenocarcinoma.
A study performed by Joel T. Hargrove, et al., Obstetrics and GYnecology, Volume 7, D3, #4, April 1989, was the first to report the use of Natural estrogen and progesterone in combination for the management of the post-menopausal patient. The study revealed that oral a~lmini~tration of micronized progesterone in a complex oil base resulted in predictable reproducible increases in serum progesterone concentrations in a 10 dose-dependent fashion.
At the completion of the Hargrove study, all women on estrogen and natural progesterone had a thin endometrium with complete quiescence and atrophy. The mean level for serum progesterone at baseline in the study was under 1 nanogram per ml.
The mean level of progesterone at 12 months was less than 3 nanograms per ml. This 15 level was achieved by using a total of 200 mg of natural progesterone combined with estrogen in divided doses. The present study suggests that compaIable levels of natural progesterone could be achieved using compositions of the present invention. If one compares this data to the in-vivo and in-vitro studies described herein, it can be seen that suitable equivalent blood and saliva levels were achieved in a relatively short period of 20 time transdermally using the inventive composition. '' It should also be noted that despite the short half-life of progesterone in the orally ingested mP~ic~tion used in the Hargrove study, adequate conversion of the endometrium was achieved. It is expected that transdermal delivery of progesterone using compositions of the present invention will result in suct~inP~l blood levels of 25 progesterone, resulting in a more predictable endometrial response.

Table 11 _, Serum Progi~le. one Data ,~, Patient I Patient 2 Patient 3 Time Point (hr) Cùn~.. tlatiun Time Point (hr)Cunce.lllation Time Point (hr) Conc~.llJdtion (ng/ml) (ng/ml) (ng/ml) 0:00 0.4 0:00 0.4 0:00 0.4 I :5û 0.4 1:45 0.5 1:15 0.5 D
3:50 0.8 3:45 1 3:00 1 ~
u. I
4:50 1. 1 4:45 1.7 4: 15 1.2 6:50 1 6:45 1.6 6: 15 1.3 '~

8:50 1.3 8:45 2.1 8:15 1.8 24 Hour 1.1 24 Hour 1.1 24 Hour 0.9 48 Hour 0.5 48 Hour 0.6 Table 12 Saliva Progesterone Data 3 r Patient I Patient 2 Patient 3 Time Point (hr) c._- diullTime Point (hr) G,llce.~t~ ion Time Point ~r) Con~tl.~tion (ng/ml) (ng/rnl) (ng/ml) 0:00 0.040:00 0.040:00 0.02 1:45 0.041:45 0.171:15 0.48 3:45 0.023:45 0.163: 15 1.09 4:45 0.044:45 0.074: 15 0.21 o~
cr.6:45 0.046:45 2.246: 15 1.53 8:45 0.048:45 0.668: 15 24.62 24 Hour 2.3824 Hour 1.3324 Hour 0.13 .

48 Hour 0.16 48 Hour 0.19 CA 022~636~ 1998-11-23 The present invention is not to be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the invention inaddition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to 5 fall within the scope of the appended claims.
Various publications are cited herein, the disclosures of which are incorporatedby reference in their entireties.

... . . . .

Claims

WHAT IS CLAIMED IS:

1. A composition comprising (i) a gelling agent consisting of methylcellulose orat least one natural gum, or a mixture thereof; (ii) at least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl paraben; and (vi) sodium chloride.

2. The composition of claim 1 which further comprises a glycolic, alcoholic or oil-based additive selected from the group consisting of propylene glycol, glycerin, mineral oil, corn oil, bran oil, rice oil, soy oil, ethylene glycol, xylene, and ethyl alcohol.

3. The composition of claim 1 which further comprises pectin.

4. The composition of claim 1 consisting essentially of 50-80% (by weight) methyl cellulose, 15-25% of a natural gum selected from the xanthan and guar gums, 3-7% glucose, 2-3.5% propylparaben, 1.5-3% methylparaben, 1-3% sodium chloride and 0.75-3.5% pectin.

5. The composition of claim 1 consisting essentially of methyl cellulose, a natural gum selected from the xanthan and guar gums, glucose, propyl paraben, methyl paraben, sodium chloride and pectin.

6. The composition of claim 1 consisting essentially of about 63%
methylcellulose, about 21% guar gum, about 5% glucose, about 3.5% propylparaben,about 3% methyl paraben, about 3% pectin and about 1.5% sodium chloride.

7. The composition of claim 1 which further comprises a drug.

8. The composition of claim 7 wherein the drug is selected from the group consisting of nicotine, nitroglycerin, albuterol, VERAPAMIL R, scopolamine, n-butylurea, fentanyl, morphine, butaconazole, acetylsalicylic acid, MINOXIDIL R, lidocaine, racemic menthol, methyl salicylate, benzalkonium chloride, DEET R, phenobarbital, iodine, insulin, salicylic acid, nonoxynol -9, erythromycin, tetracycline, cephalosporins, and acetaminophen.

9. A hydrogel comprising water and a base mixture, said base mixture comprising: (i) a gelling agent consisting of methylcellulose or at least one natural gum, or a mixture thereof; (ii) at least one natural gum; (iii) glucose;
(iv) propylparaben; (v) methyl paraben; and (vi) sodium chloride.

10. The hydrogel of claim 9 which further comprises a glycolic, alcoholic or oil-based additive selected from the group consisting of propylene glycol, glycerin, mineral oil, corn oil, bran oil, rice oil, soy oil, ethylene glycol, xylene, and ethyl alcohol.

11. The hydrogel of claim 9 which further comprises coloring, fragrance, or other pharmaceutically acceptable additives.

12. The hydrogel of claim 9 wherein said base mixture further comprises pectin.

13. The hydrogel of claim 9 wherein said base mixture consists essentially of 50-80% (by weight) methyl cellulose, 15-25% of a natural gum selected from the xanthan and guar gums, 3-7% glucose, 2-3.5% propylparaben, 1.5-3% methylparaben,1-3% sodium chloride and 0.75-3.5% pectin.

14. The hydrogel of claim 9 wherein said base mixture consists essentially of about 63% methylcellulose, about 21% guar gum, about 5% glucose, about 3.5%
propylparaben, about 3% methyl paraben, about 3% pectin and about 1.5% sodium chloride.

15. The hydrogel of claim 9 which further comprises a substituted urea of the formula R-NH-CO-NH2 wherein R is hydrogen, hydroxyl or a lower alkyl having from1 to 8 carbon atoms.

16. The hydrogel of claim 15 wherein R is a lower alkyl group selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl.

17. The hydrogel of claim 15 wherein said substituted urea is butylurea.

18. The hydrogel of claim 9 which further comprises a drug.

19. The hydrogel of claim 18 wherein the drug is selected from the group consisting of nicotine, nitroglycerin, albuterol, VERAPAMIL R. scopolamine, n-butylurea, fentanyl, morphine, butaconazole, acetylsalicylic acid, MINOXIDIL R, lidocaine, racemic menthol, methyl salicylate, benzalkonium chloride, DEET R, phenobarbital, iodine, insulin, salicylic acid, nonoxynol-9, erythromycin, tetracycline, cephalosporins, and acetaminophen.

20. A composition in the form of a dry powder, said dry powder comprising (a) a drug; and (b) a base mixture comprising (i) a gelling agent consisting of methylcellulose or at least one natural gum, or a mixture thereof; (ii) at least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl paraben; and (vi) sodium chloride.

21. A composition in the form of a paste, said paste comprising (a) a drug;
(b) a glycolic, alcoholic or oil-based additive; and (c) a base mixture comprising (i) a gelling agent consisting of methylcellulose or at least one natural gum, or a mixture thereof; (ii) at least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl paraben; and (vi) sodium chloride.

22. The composition of claim 21 wherein said glycolic, alcoholic or oil-based additive is selected from the group consisting of propylene glycol, glycerin, mineral oil.
corn oil, bran oil, rice oil, soy oil, ethylene glycol, xylene, and ethyl alcohol.

23. The composition of claim 20 or 21 wherein said drug is selected from the group consisting of nicotine, nitroglycerin, albuterol, VERAPAMIL R, scopolamine, n-butylurea, fentanyl, morphine, butaconazole, acetylsalicylic acid, MINOXIDIL R, lidocaine, racemic menthol, methyl salicylate, benzalkonium chloride, DEET R, phenobarbital, iodine, insulin, salicylic acid, nonoxynol-9, erythromycin, tetracycline, cephalosporins, and acetaminophen.

24. The composition of claim 1, 20 or 21 which further comprises a coloring, fragrance, or other pharmaceutically acceptable additive.

25. The composition of claim 20 or 21 wherein said base mixture further comprises pectin.

26. The composition of claim 1, 20 or 21 further comprising a substituted urea of the formula R-NH-CO-NH2 wherein R is hydrogen, hydroxyl or a lower alkyl having from 1 to 8 carbon atoms.

27. The composition of claim 26 wherein R is a lower alkyl group selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl.

28. The composition of claim 26 wherein said substituted urea is butylurea.

29. The composition of claim 20 or 21 wherein said base mixture consists essentially of 50-80 % (by weight) methyl cellulose, 15-25% of a natural gum selected from the xanthan and guar gums, 3-7 % glucose, 2-3.5% propylparaben, 1.5-3 %
methylparaben, 1-3 % sodium chloride and 0.75-3.5 % pectin.

30. The composition of claim 20 or 21 wherein said base mixture consists essentially of methyl cellulose, a natural gum selected from the xanthan and guar gums, glucose, propyl paraben, methyl paraben, sodium chloride and pectin.

31. The composition of claim 20 or 21 wherein said base mixture consists essentially of about 63% methylcellulose, about 21% guar gum, about 5% glucose, about 3.5% propylparaben, about 3% methyl paraben, about 3% pectin and about 1.5%
sodium chloride.

32. The composition of claim 20 or 21 wherein said drug is a hormone selected from the group consisting of progesterone, progestin, estrogen and testosterone.

33. The composition of claim 20 or 21 wherein said drug is the hormone progesterone.

34. A composition comprising:
(a) a hydrogel comprising water and a base mixture, said base mixture comprising: (i) a gelling agent consisting of methylcellulose or at least one natural gum, or a mixture thereof; (ii) at least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl paraben; and (vi) sodium chloride;
(b) a substituted urea of the formula R-NH-CO-NH2 wherein R is hydrogen, hydroxyl or a lower alkyl having from 1 to 8 carbon atoms; and (c) a drug.

35. The composition of claim 34 wherein the drug is a hormone selected from the group consisting of progesterone, progestin, estrogen, and testosterone, or a mixture of any two or more of the foregoing.

36. A composition comprising:
(a) a hydrogel comprising water and a base mixture, said base mixture comprising: (i) a gelling agent consisting of methylcellulose or at least one natural gum, or a mixture thereof; (ii) at }east one natural gum;
(iii) glucose; (iv) propylparaben; (v) methyl paraben; and (vi) sodium chloride;
(b) a substituted urea of the formula R-NH-CO-NH2 wherein R is hydrogen.
hydroxyl or a lower alkyl having from 1 to 8 carbon atoms; and (c) a hormone selected from the group consisting of progesterone, progestin, estrogen, and testosterone, or a mixture of any two or more of the foregoing.

37. The composition of claim 36 which further comprises a glycolic, alcoholicor oil-based additive selected from the group consisting of propylene glycol, glycerin, mineral oil, corn oil, bran oil, rice oil, soy oil, ethylene glycol, xylene, and ethyl alcohol.

38. The composition of claim 36 which further comprises a coloring, fragrance, or other pharmaceutically acceptable additive.

39. The composition of claim 30 wherein said base mixture further comprises pectin.

40. The composition of claim 36 wherein said base mixture consists essentially of 50-80% (by weight) methyl cellulose, 15-25% of a natural gum selected from the xanthan and guar gums, 3-7% glucose, 2-3.5% propylparaben, 1.5-3%
methylparaben, 1-3% sodium chloride and 0.75-3.5% pectin.

41. The composition of claim 36 wherein said base mixture consists essentially of methyl cellulose, a natural gum selected from the xanthan and guar gums, glucose, propyl paraben, methyl paraben sodium chloride and pectin.

42. The composition of claim 36 wherein said base mixture consists essentially of about 63% methylcellulose, about 21% guar gum, about 5% glucose, about 3.5% propylparaben, about 3% methyl paraben, about 3% pectin and about 1.5%
sodium chloride.

43. The composition of claim 36 wherein R is a lower alkyl group selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl.

44. A composition consisting essentially of:
(a) 3-12% of a base mixture consisting essentially of: 50-80% (by weight) methyl cellulose, 15-25% of a natural gum selected from the xanthin and guar gums, 3-7% glucose, 2-3.5% propylparaben, 1.5-3% methylparaben, 1-3% sodium chloride and 0.75-3.5% pectin;
(b) 0.5-15% by weight of a substituted urea of the formula R-NH-CO-NH2, wherein R is hydrogen, hydroxyl or lower alkyl having from 1 to 8 carbon atoms selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl. heptyl and octyl;
(c) 5-20% by weight of a hormone selected from the group consisting of progesterone, progestin, estrogen, and testosterone, or a mixture of any two or more of the foregoing;
(d) 0-20% by weight propylene glycol; and (e) 20-80% by weight water;
in which said base mixture and water form a hydrogel.

45. A composition consisting essentially of:

(a) about 9% by weight of a base mixture consisting essentially of: about 63% (by weight) methyl cellulose, about 21% guar gum, about 5%
glucose, about 3.5% propylparaben, about 3% methylparaben, about 1.5% sodium chloride and about 3% pectin;
(b) about 2% by weight of a substituted urea of the formula: R-NH-CO-NH2, wherein R is hydrogen, hydroxyl or lower alkyl having from 1 to 8 carbon atoms selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl;
(c) about 10% by weight of progesterone;
(d) about 20% by weight propylene glycol; and (e) 59% by weight water; in which said base mixture and water form a hydrogel.

46. A composition consisting essentially of:
(a) about 9% by weight of a base mixture consisting essentially of: about 63% (by weight) methyl cellulose, about 21% guar gum, about 5%
glucose, about 3.5% propylparaben, about 3% methylparaben, about 1.5% sodium chloride and about 3% pectin;
(b) about 2% by weight butylurea;
(c) about 10% by weight of progesterone;
(d) about 20% by weight propylene glycol; and (e) about 59% by weight water;
in which said base mixture and water form a hydrogel.

47. A composition consisting essentially of:
(a) a base mixture consisting essentially of methyl cellulose, guar gum, glucose, propylparaben, methyl paraben, sodium chloride and pectin;
(b) butylurea (c) progesterone (d) propylene glycol; and (e) water;

in which said base mixture and water from a hydrogel.

48. A kit for the transdermal delivery of a drug to a subject comprising:
(a) a watch or a watch-like device comprising:
(i) a watch-case having a front face and a back face, the back face of said watch-case having a recessed chamber; and (ii) a band or strap affixed to said watch-case and capable of attaching said watch or watch-like device to a limb of a subject such that a wafer having a top face and a bottom face, when situated within said recessed chamber, can be maintained such that the bottom face of said wafer is held in contact with the skin of said limb; and (b) at least one of said wafer, said wafer (i) comprising a drug; and (ii) being capable of being situated within said recessed chamber and being removable from said chamber.

49. A kit for the transdermal delivery of a drug to a subject comprising a watchor a watch-like device comprising:
(a) a watch-case having a front face and a back face;
(b) a band or strap affixed to said watch-case and capable of attaching said watch or watch-like device to a limb of a subject;
(c) at least one disc-shaped drug reservoir comprising:
(i) a recessed chamber;
(ii) a plurality of clips that are capable of attaching said reservoir to the back face of said watch-case, such that a wafer having a top face and a bottom face, when situated within said recessed chamber, can be maintained such the bottom face of said wafer is held in contact with the skin of said limb; and (d) at least one of said wafer, said wafer (i) comprising a drug, and (ii) being capable of being situated within said recessed chamber and being removable from said chamber.

50. The kit of claim 49 wherein said reservoir further comprises a plurality of slots capable of having said band or strap threaded through said slots.

51. A kit for the transdermal delivery of a drug to a subject comprising:
(a) at least one disc-shaped drug reservoir comprising:
(i) a recessed chamber; and (ii) a plurality of slots;
(b) a band or a strap (i) capable of being affixed to said reservoir by threading said band or strap through the slots of said reservoir;
(ii) capable of attaching said reservoir to a limb of a subject such that a wafer having a top face and a bottom face, when situated within said recessed chamber, is maintained such the bottom face of said wafer is held in contact with the skin of said limb; and (c) at least one of said wafer, said wafer (i) comprising a drug, and (ii) being capable of being situated within said recessed chamber and being removable from said chamber.

52. The kit of claim 51 wherein said reservoir further comprises a plurality of clips that are capable of attaching said reservoir to a back face of a watch-case.

53. A device for the transdermal delivery of a drug to a subject comprising a watch or a watch-like device comprising:
(a) a watch-case having a front and a back face, the back-face of said watch-case having a recessed chamber;

(b) a wafer having a top face and a bottom face and comprising a drug, said wafer being situated within said recessed chamber and being removable from recessed chamber; and (c) a band or strap affixed to said watch-case and capable of attaching said watch or watch-like device to a limb of a subject such that said bottom face of said wafer is maintained in contact with the skin of said limb.

54. A device for the transdermal delivery of a drug to a subject comprising a watch, or a watch-like device comprising:
(a) a watch-case having a front face and a back face, (b) a disc-shaped drug reservoir comprising:
(i) a recessed chamber;
(ii) a wafer having a top face and a bottom face and comprising a drug, said wafer capable of being contained within said recessed chamber; and (iii) a plurality of clips that are capable of attaching said reservoir to the back face of said watch-case such that said bottom face of said wafer can be maintained in contact with the skin of a limb of a subject; and (c) a band or strap affixed to said watch-case capable of attaching said watch or watch-like device to the limb of said subject such that said bottom face of said wafer is maintained in contact with the skin of said limb.

55. The device of claim 54 wherein said reservoir further comprises a plurality of slots capable of having said band or strap threaded through said slots.

56. A device for the transdermal delivery of a drug to a subject comprising:
(a) a disc-shaped drug reservoir comprising:
(i) a recessed chamber;
(ii) a wafer having a top face and a bottom face and comprising a drug, said wafer being contained within said recessed chamber;

(iii) a plurality of slots; and (b) a band or a strap (i) threaded through said slots and thereby affixed to said reservoir;
and (ii) capable of attaching said reservoir to a limb of a subject such that said bottom face of said wafer is maintained such the bottom face of said wafer is held in contact with the skin of said limb.

57. The device of claim 48 wherein said reservoir further comprises a plurality of clips that are capable of attaching said reservoir to the back face of a watch-case.

58. The kit of claim 48, 49 or 51 wherein said wafer comprises:
(a) 3-12% of a base mixture consisting essentially of: 50-80% (by weight) methyl cellulose, 15-25% of a natural gum selected from the xanthan and guar gums, 3-7% glucose, 2-3.5%, propylparaben, 1.5-3% methylparaben, 1-3% sodium chloride and 0.75-3.5% pectin;
(b) 0.5-15% by weight of a substituted urea of the formula R-NH-CO-NH2, wherein R is hydrogen, hydroxyl or lower alkyl having from 1 to 8 carbon atoms selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl. hexyl, heptyl and octyl;
(c) 5-20% by weight of a hormone selected from the group consisting of progesterone, progestin, estrogen, and testosterone, or a mixture of any two or more of the foregoing;
(d) 0-20% by weight propylene glycol; and (e) 20-80% by weight water;
in which said base mixture and water form a hydrogel.

59. A kit according to claim 48, 49 or 51 wherein said wafer comprises:
(a) about 9% by weight of a base mixture consisting essentially of: about 63% (by weight) methyl cellulose, about 21% guar gum, about 5%

glucose, about 3.5% propylparaben, about 3% methylparaben, about 1.5% sodium chloride and about 3% pectin;
(b) about 2 % by weight butylurea;
(c) about 10% by weight of natural progesterone;
(d) about 20 % by weight propylene glycol; and (e) about 59% by weight water;
in which said base mixture and water form a hydrogel.

60. The device of claim 53, 54 or 56 wherein said wafer comprises:
(a) 3-12% of a base mixture consisting essentially of: 50-80% (by weight) methyl cellulose, 15-25% of a natural gum selected from the xanthan and guar gums, 3-7% glucose, 2-3.5% propylparaben, 1.5-3% methylparaben, 1-3% sodium chloride and 0.75-3.5% pectin;
(b) 0.5-15% by weight of a substituted urea of the formula R-NH-CO-NH2, wherein R is hydrogen, hydroxyl or lower alkyl having from 1 to 8 carbon atoms selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl;
(c) 5-20% by weight of a hormone selected from the group consisting of progesterone, progestin, estrogen, and testosterone, or a mixture of any two or more of the foregoing;
(d) 0-20% by weight propylene glycol; and (e) 20-80% by weight water;
in which said base mixture and water form a hydrogel.

61. The device of claim 53, 54 or 56 wherein said wafer comprises:
(a) about 9% by weight of a base mixture consisting essentially of: about 63% (by weight) methyl cellulose, about 21% guar gum, about 5%
glucose, about 3.5% propylparaben, about 3% methylparaben, about 1.5% sodium chloride and about 3% pectin;
(b) about 2% by weight butylurea;
(c) about 10% by weight of progesterone;

(d) about 20% by weight propylene glycol; and (e) about 59% by weight water;
in which said base mixture and water form a hydrogel.

62. The kit of claim 48 wherein said watch-case comprises a fluid-filled or hydrogel cushion layer capable of being situated within said recessed chamber and against said top face of said wafer.

63. The kit of claim 49 or 51 wherein said drug reservoir further comprises a fluid-filled or hydrogel cushion layer capable of being situated within said recessed chamber and against said top face of said wafer.

64. The device of claim 53 wherein said watch-case comprises a fluid-filled or hydrogel cushion layer capable of being situated within said recessed chamber and against said top face of said wafer.

65. The device of claim 54 or 56 wherein said drug reservoir further comprises a fluid-filled or hydrogel cushion layer capable of being situated within said recessed chamber and against said top face of said wafer.

66. The kit of claim 48 wherein said recessed chamber of said watch case comprises a heating layer having a top face and a bottom face, said heating layer comprising a means for heating said wafer, the bottom face of said heating layer being situated against the top face of said wafer.

67. The kit of claim 66 wherein said recessed chamber of said watch case further comprises a permanent closed cell having a top face and a bottom face, the bottom face of said permanent closed cell being situated against the top face of said heating layer.

68. The kit of claim 49 or 51 wherein said recessed chamber of said drug reservoir comprises a heating layer having a top face and a bottom face, said heating layer comprising a means for heating said wafer, the bottom face of said heating layer being situated against the top face of said wafer.

69. The kit of claim 68 wherein said recessed chamber of said drug reservoir further comprises a permanent closed cell having a top face and a bottom face, the bottom face of said permanent closed cell being situated against the top face of said heating layer.

70. The device of claim 53 wherein said recessed chamber of said watch case comprises a heating layer having a top face and a bottom face, said heating layer comprising a means for heating said wafer, the bottom face of said heating layer being situated against the top face of said wafer.

71. The device of claim 69 wherein said recessed chamber of said watch case further comprises a permanent closed cell having a top face and a bottom face, the bottom face of said permanent closed cell being situated against the top face of said heating layer.

72. The device of claim 54 or 56 wherein said recessed chamber of said drug reservoir comprises a heating layer having a top face and a bottom face, said heating layer comprising a means for heating said wafer, the bottom face of said heating layer being situated against the top face of said wafer.

73. The device of claim 71 wherein said recessed chamber of said drug reservoir further comprises a permanent closed cell having a top face and a bottom face, the bottom face of said permanent closed cell being situated against the top face of said heating layer.

74. A device for the transdermal delivery of a drug comprising a band or a straphaving a surface which is coated with a composition of claim 7 or 36, wherein said band or strap is capable of being attached to a limb of a subject such that the surface of said band or strap is maintained in contact with the skin of said limb.

75. A device for the transdermal delivery of a drug to a subject comprising a glove wherein the inside of said glove is lined with a layer consisting essentially of:
(a) 3-12% of a base mixture consisting essentially of: 50-80% (by weight) methyl cellulose, 15-25% of a natural gum selected from the xanthin and guar gums, 3-7% glucose, 2-3.5% propylparaben, 1.5-3% methylparaben, 1-3% sodium chloride and 0.75-3.5% pectin;
(b) 0.5-15% by weight of a substituted urea permeation enhancer of the formula R-NH-CO-NH2, wherein R is hydrogen, hydroxyl or lower alkyl having from 1 to 8 carbon atoms selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl;
(c) 5-20% by weight of a drug;
(d) 0-20% by weight propylene glycol; and (e) 20-80% by weight water; in which said base mixture and water form a hydrogel.

76. A method of treating or preventing a condition responsive to hormone replacement therapy comprising placing a composition of claim 36, 44, or 45, said composition comprising a therapeutically effective amount of said hormone or mixture of hormones, in contact with the skin of a subject in need of such treatment.

77. The method of claim 76 wherein said condition is selected from the group consisting of premenstrual syndrome, menopause, infertility, osteoporosis, dysfunctional bleeding, corpus luteum failure, senile vulvo-vaginitis, and hypogonadism.

78. A method of providing contraception to a male or female subject comprising placing a composition of claim 36, 44, or 45, said composition comprising a therapeutically effective amount of said hormone or mixture of hormones, in contact with the skin of a subject in need of contraception.

79. The method of claim 78 wherein said subject is female and said hormone or mixture of hormones is selected from the group consisting of progesterone, progestin, estrogen, and a mixture of any two or more of the foregoing.

80. The method of claim 79 wherein said hormone is a mixture of one or more estrogens and one or more progestins.

81. The method of claim 79 wherein said hormone is a mixture of progesterone and one or more estrogens.

82. The method of claim 79 wherein said hormone is selected from the group consisting of progesterone and progestins.

83. The method of claim 78 wherein said subject is a male and said hormone is testosterone.

84. A method of delivering a therapeutically effective amount of a hormone or mixture of hormones to the bloodstream of a subject comprising contacting the skin of said subject with a composition of claim 36, 44, or 45 comprising a therapeutically effective amount of said hormone or mixture of hormones.

85. The method of claim 76 wherein said hormone is selected from the group consisting of progesterone, progestin, estrogen, testosterone and a mixture of any two or more of the foregoing.

86. The method of claim 76 wherein said hormone is natural progesterone.

87. The method of claim 76 wherein said hormone is a progestin selected from the group consisting of medroxy progesterone acetate, norethindrone, norethindrone acetate, norgestrel, ethynodiol diacetate and mixtures thereof.

88. The method of claim 76 wherein said hormone is an estrogen selected from the group consisting of 17-.beta.-estradiol, diethylstilbestrol, estropipate, estrone estriol and mixtures thereof.

89. The method of claim 76 wherein said hormone is a mixture of a progestin selected from the group consisting of natural progesterone, medroxy progesteroneacetate, norethindrone, norethindrone acetate, norgestrel, ethynodiol diacetate and mixtures thereof; and an estrogen selected from the group consisting of 17-.beta.-estradiol, diethylstilbestrol, estropipate, estrone, estriol, and mixtures thereof.

90. The method of claim 76 wherein said hormone is testosterone.

91. A method for treating vaginal yeast infection comprising placing a composition of claim 7, 34, 36, 44 or 45 inside the vagina of a female subject suffering from yeast infection.

92. A method for providing contraception to a female subject comprising placing a composition of claim 7, 34, 36, 44 or 45 inside the vagina of a female subject in need of contraception.

93. A method for treating vaginal dryness comprising placing a composition of claim 7, 34, 36 44 or 45 inside the vagina of a female subject suffering from vaginal dryness.

94. A method for vaginal delivery of a drug comprising placing a composition of claim 7, 24, 36, 44 or 45 inside the vagina of a female subject.

95. A composition comprising:
(a) a base mixture that when combined with water forms a hydrogel;
(b) a permeation enhancer selected from the group consisting of urea, hydroxyurea, and an alkylurea; and (c) a hormone selected from the group consisting of progesterone, progestin, estrogen and testosterone, or a mixture of any two or more of the foregoing.

96. A composition comprising:
(a) a hydrogel;
(b) a permeation enhancer selected from the group consisting of urea, hydroxyurea, and an alkylurea; and (c) a hormone selected from the group consisting of progesterone, progestin, estrogen and testosterone, or a mixture of any two or more of the foregoing.

97. The composition of claim 95 or 96 wherein the alkylurea is butylurea.