lllllllllllllllllllllllllllllllllllll||||l||l||llllllllllllllllllllllllllll USOO5512555A United States Patent [191 [11] Patent Number: 5,512,555 Waldstreicher [45] Date of Patent: Apr. 30, 1996

[54] lVIETHOD OF TREATING SWEAT-RELATED Mortimer et al. “A double-blind controlled cross~over trial CONDITIONS USING FINASTERIDE, of cyrpoterone acetate in females with hidradenitis suppu EPRISTERIDE AND A CHOLESTAN-3-ONE rativa” British J. Dermatology, vol. 115, pp. 263-268 (1986). [75] Inventor: Joanne Waldstreicher, Scotch Plains, NJ. Sawers et a1. “Control of hidradenitis suppurativa in women using combined antiandrogen(cyproterone acetate) and [73] Assignee: Merck & Co., Inc., Rahway, NJ. oestrogen therapy” British J. Dermatology, vol. 115, pp. 269-274 (1986). [21] Appl. N0.: 278,434 Harris, et al. “Identi?cation and selective inhibition of an [22] Filed: Jul. 21, 1994 isozyme of steroid 5 alpha reductase in human scalp” Proc. Natl. Acad. Sci., vol. 89, PP. 10787-10792 (1992). [51] Int. Cl.6 ...... A61K 31/59; A61K 31/44; A61K 7/34 [52] US. Cl...... 514/168; 514/284; 514/176; Primary Examiner—Theodore J. Criares 424/65; 424/69 Attorney, Agent, or Firm-Catherine D. Fitch; Carol S. [58] Field of Search ...... 514/167, 176, Quagliato 514/284; 424/69, 65 [56] References Cited [57] ABSTRACT U.S. PATENT DOCUMENTS The instant invention involves methods of treating sweat 4,760,071 7/1988 Rasmusson et a1...... 514/284 related conditions with compounds that are Sa-reductase inhibitors. The Stx-reductase inhibitors may be administered FOREIGN PATENT DOCUMENTS alone or in combination with other active agents to treat WO93/23419 11/1993 WIPO . conditions such as apocrine gland sweating, hyperhidrosis, and hydradenitis suppurativa. OTHER PUBLICATIONS Takayasu et 21. “Activity of Testosterone 5a1pha-reductase in Various Tissues of Human Skin” 1. Invest. DennatoL, v01. 74, pp. 187-191 (1980). 14 Claims, No Drawings 5,512,555 1 2 METHOD OF TREATING SWEAT-RELAT ED occlusion, bacterial colonization, androgenic stimulation CONDITIONS USING FINASTERIDE, and in?ammation all seem to be important. Although its EPRISTERIDE AND A CHOLESTAN-S-ONE etiology is multifactorial, it is likely that a change in any one of the four etiologic factors will have a signi?cant impact on The present invention is concerned with the treatment of the course of the disease. Antibiotics (affecting bacterial sweat-related conditions with compounds that are Soc-reduc colonization) and isotretinoin (ACCUTANE®) (aifecting tase inhibitors. the keratinous plugging of the sweat duct) are used to treat this disorder. Antiandrogens such as cyproterone (not avail BACKGROUND OF THE INVENTION able in the US.) and estrogen have also been used to control 10 HS. Apocrine sweat glands, comprised of ducts that open The enzyme Sou-reductase converts testosterone (“T”) to directly into the hair follicle, are largely con?ned to regions dihydrotestosterone in certain target organs as well as in the of the axilla and perineum (genital-anal area) and become circulating blood serum. It is known that inhibitors ‘of functional just before puberty. Although this suggests that Son-reductase will serve to prevent or lessen symptoms of gonadal steroids (i.e. androgens and estrogens) play a role in hyperandrogenic stimulation such as acne vulgaris, sebor their development, the exact hormones have not been iden rhea, female hirsutism, androgenic alopecia, and benign ti?ed. prostatic hyperplasia. See especially US. Pat. Nos. 4,377, In man, the role of the apocrine gland is unclear, since the 584 and 4,760,07 1, both assigned to Merck & Co., Inc. It eccrine sweat glands (which open directly onto the surface is also now known that two isozymes of 560 -reductase of the skin and which are distributed over nearly the entire exist: isozyme type 2 which principally interacts within body surface) perform the thermoregulatory function. The prostatic tissues, and isozyme type 1, discovered more odor, which results from bacterial action on aprocrine sweat, recently, which principally interacts within skin tissues. See, may have had a role in man in the past, but is now clearly e.g., G. Hams, et al., Proc. Natl. ACad. Sci. USA, vol. 89, pp. vestigial. Sweat collected from the surface of the skin is 10787-10791 (November 1992). contaminated by sebum (since there is a common opening to 25 Since androgens are felt to play a role in the pubertal onset the surface of the skin), secretions from eccrine sweat of aprocrine gland function and the pathogenesis of HS and glands, as well as bacteria. Based on animal data, it is there is?a large amount of Soc-reductase activity in apocrine thought that aprocrine sweat contains protein, nitrogen, sweat glands, apocrine sweat gland production should be potassium, sodium, calcium, magnesium, chloride, bicar decreased by Soc-reductase inhibitors, such as ?nasteride bonate and lactate. Sweat is secreted in a pulsatile manner, (marketed in the U.S. under the tradename PROSCAR® for presumably due to synchronous contraction of myoepithelial the treatment of benign prostatic hyperplasia) and 4,75 cells across the body. dimethyl-4-aza-5ot-cholestan-3-one (also known as Unlike eccrine glands which are under cholinergic con MK-386). A decrease in sweat production, should be trol, apocrine gland secretion is largely under adrenergic observed with either oral administration or topical applica control. Both local and circulating epinephrine and norepi tion'of 5ot-reductase inhibitors to the axillae or perineum. nephrine can stimulate secretion. Emotional stimuli, after Therefore, these agents will be useful as antiperspirants and puberty, are strong inducers of secretion. Drugs that affect for the treatment of other androgenmediated conditions the adrenergic system (such as reserpine) affect apocrine related to sweat glands, such as local hyperhidrosis and HS. gland secretion. Son-Reductase levels are very high in apo crine glands. Therefore, activity of this enzyme is believed 40 SUlVIMARY OF THE INVENTION to play a role in controlling secretion. However, a Sot-re ductase inhibitor has not been previously studied as an The instant invention involves a novel method of treating inhibitor of apocrine secretion. sweat-related conditions, such as apocrine gland sweating, also known as perspiration, hyperhidrosis and HS compris Hyperhidrosis is de?ned as an increase above normal in 45 ing the administration of a therapeutically elfective amount sweat production. This is diagnosed when sweating occurs of a Soc-reductase inhibitor. Also provided are pharmaceu under conditions where it would not normally be expected or tical compositions comprising a pharmaceutically accept is excessive in response to emotional or thermal stimuli. able carrier, a SOL-reductase inhibitor and additional active Localized hyperhidrosis of the axilla is most likely due to agents such as aluminum hydroxide, anticholinergic agents, a combination of increased eccrine and apocrine sweat 50 antibiotics, and isotretinoin which are useful for the treat production. This disorder is usually most problematic when ment of sweat-related conditions. " there is both an increased ambient temperature and emo tional stimulation. Axillary sweating, unlike eccrine sweat DETAILED DESCRIPTION OF THE ing, is largely resistant to most common antiperspirant INVENTION regimens. Aluminum salts or anticholinergic agents produce 55 only a 50% decrease in armpit sweating, but nearly a 100% The present invention has the objective of providing decrease in eccrine sweating elsewhere. However, Shelley methods of treating sweat-related conditions including apro described a regimen of aluminum chloride in absolute crine gland sweating, hyperhidrosis and hydradenitis sup ethanol or isopropyl alcohol under occlusive plastic wrap at purativa (HS) by oral, systemic, parenteral or topical admin bedtime which more effectively inhibits axillary sweat. 60 istration of a 5ot-reductase inhibitor or a combination of Other reported treatments are sympathectomy of the ?fth Soc-reductase inhibitors, either alone or in combination with thoracic ganglion, local excision of affected axillary skin, other active agents such as aluminum hydroxide, anticho cryosurgery, tranquilizers and anticholinergic agents. linergic agents, antibiotics and isotretinoin. Hydradenitis suppurativa (HS) is a chronic in?arnmatory The term “Soc-reductase inhibitor” as used herein is disorder of apocrine sweat glands in which abscesses and 65 intended to include compounds which are active as inhibi drainage sinuses develop in the axilla and/or perineal area. tors of either or both of the isozymes of 5ot~reductase, such The pathogenesis of HS is felt to be similar to acne: poral as, e.g., inhibitors of Soc-reductase type 1, such as e.g., 5,512,555 3 4 4,7l5-dimethyl-4-aza-5ot-cholestan-3-one (also known as peritoneal, subcutaneous, topical with or without occlusion, MK-386; as disclosed in WO 93/23420 to Merck & Co. or intramuscular form, all using forms well known to those Inc.), inhibitors of Soc-reductase type 2, such as e.g., ?nas of ordinary skill in the pharmaceutical arts. teride, epristeride (also known as SKF-105657, SmithKline The daily dosage of the compounds may be varied over a Beecham), ONO-3805 (Ono Pharmaceutical Co., Ltd.), range from 0.01 to 1,000 mg per adult human/per day. For FK-143 (Fujisawa), and TZP-4238 (Teikokuzoki), and those oral administration, the compositions are preferably pro which are active as dual inhibitors of both isozymes type 1 vided in the fonn of tablets containing 0.01, 0.05, 0.1, 0.5, and 2, such as e.g., those disclosed in W0 94/00121 and 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, and 50.0 milligrams of the W094/00125 to SmithKline Beecham. Also encompassed active ingredient for the symptomatic adjustment of the by the instant method invention is the use of a combination dosage to the patient to be treated. An effective amount of of an inhibitor of Soc-reductase type 1 with an inhibitor of Set-reductase type 2, such as e.g., the use of a combination the drug is ordinarily supplied at a dosage level of from of ?nasteride with MK-386. Many compounds which are about 0.0002 mg./kg. to about 50 mgJkg. of body weight per Soc-reductase inhibitors have been described in the art; day. The range is more particularly from about 0.001 mg./kg. compounds which are 5ot-reductase inhibitors can also be to 7 mgJkg. of body weight per day. detennined by the Soc-reductase assay further described 15 Advantageously, compounds of the present invention may below. be administered in a single daily dose, or the total daily Examples of compounds speci?cally and generically dosage may be administered in divided doses of two, three which are Stx-reductase inhibitors and the use of which are or four times daily. Furthermore, compounds for the present encompassed within the present invention, include, but are invention can be administered in intranasal form via use of not limited to, those described in the following patents and suitable intranasal vehicles, or via transdermal routes, using publications: U.S. Pat. Nos. 4,377,584; 4,760,071; 4,845, those forms of transdermal skin patches well known to those 104; 4,859,681; 5,049,562; 5,120,742; 5,138,063; and of ordinary skill in that art. To be administered in the form 5,151,429; and WO 93/23038, W0 93/23039,_ W0 of a transdermal delivery system, the dosage administration 93/23040, W0 93/23041, WO 93/23048, W0 93/23050, will, of course, be continuous rather than intermittent WO 93/23051, W0 93/234 19, WO 93/23420, WO throughout the dosage regimen. 93/16996, W0 93/23042, W0 94/00121, W0 94/00125, For the treatment of sweat-related conditions, the com W0 94/03474, W0 94/03475, WO 94/03476, W0 pounds of the present invention may be administered in a 94/07909, W0 93/13124, U.S. Pat. No. 5,302,528, B? pharmaceutical composition comprising the active com 532,190, EP 291,245. The above list is not intended to be pound in combination with a pharmaceutically acceptable exhaustive, and there are many other publications which 30 carrier adapted for topical administration. Topical pharma describe inhibitors of 5ot-reductase. ceutical compositions may be, e. g., in the form of a solution, The term “therapeutically effective amount” means that cream, ointment, gel, lotion, or aerosol formulation adapted amount of a drug or pharmaceutical agent that will elicit the for application to the skin. These topical pharmaceutical biological or medical response of a tissue, system, animal or compositions containing the compounds of the present 35 human that is being sought by a researcher, veterinarian, invention ordinarily include about 0.005% to 5% by weight medical doctor or their clinician. The novel methods of of the active compound in admixture with a pharmaceuti treatment of this invention are for conditions known to those cally acceptable vehicle. skilled in the art. In fact, apocrine gland sweating, ‘or For the treatment of apocrine gland‘ sweating and hyper perspiration, is a condition commonly known and under 40 hidrosis, the Su-reductase inhibitor compounds can be used stood by average consumers who lack any specialized in combination with a therapeutically effective amount of a medical skills. topical antiperspirant such as an aluminum salt, e. g. alumi In particular, with regard to treating the disorders of num hydroxide and/or a topical or oral anti-cholinergic hyperhidrosis and hydradenitis suppurativa, the term “thera agent and optionally including a deodorant. For the treat peutically eifective amount” is intended to mean that amount 45 ment of HS, the SOt-reductase inhibitor compounds can be of a 50ot-reductase inhibitor or combination of inhibitors used in combination with an anticholinergic agent, antibi that will prevent or alleviate the symptoms of the disorder. otics and/or isotretinoin each of which can be administered With regard to treating the condition of aprocn'ne gland topically or orally. Where combination treatment is sweating, i.e., for use of a Soc-reductase inhibitor or com employed, the active agents may be administered in a single bination of inhibitors as an anti-perspirant, the term “thera 50 pharmaceutical dosage formulation. Alternatively, a com peutically eifective amount” is intended to mean that amount bined therapy can be employed wherein the active agents are of inhibitor that will prevent or reduce the amount of administered in separate dosage formulations. For example, apocrine gland secretions. a Son-reductase inhibitor and aluminum hydroxide can be The present invention also has the objective of providing administered in a single topical dosage formulation, or each suitable topical, oral, systemic and parenteral pharmaceuti 55 active agent can be administered in a separate dosage cal s formulations for use in the novel methods of treatment formulation, e.g., an oral dosage formulation of the Sou-re of the present invention. The compositions containing ductase inhibitor in combination with a topical dosage 5ot-reductase inhibitor compounds as the active ingredient formulation of aluminum hydroxide. See, e.g., U.S. Pat. for use in the treatment of the above-noted conditions can be Nos. 4,377,584 and 4,760,071 which describe dosages and administered in a wide variety of therapeutic dosage forms 60 formulations for 5ot-reductase inhibitors. in conventional vehicles for systemic administration. For For combination treatment with more than one active example, the compounds can be administered in such oral agent, where the active agents are in separate dosage for dosage forms as tablets, capsules (each including timed mulations, the active agents can be administered concur release and sustained release formulations), pills, powders, rently, or they each can be administered at separately stag granules, elixirs, tinctures, solutions, suspensions, syrups 65 gered times. and emulsions, or by injection. Likewise, they may also be The dosage regimen utilizing the compounds of the administered in intravenous (both bolus and infusion), intra present invention is selected in accordance with a variety of 5,512,555 5 6 factors including type, species, age, weight, sex and medical EXAMPLE 1 condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic BIOLOGICAL ASSAYS function of the patient; and the particular compound thereof employed. A physician or veterinarian of ordinary skill can 5 Preparation of Human prostatic and scalp Su-reductases readily determine and prescribe the eifective amount of the Samples of human tissue were pulverized using a freezer drug required to prevent, counter or arrest the progress of the mill and homogenized in 40 mM potassium phosphate, pH condition. Optimal precision in achieving concentration of 6.5, 5 mM magnesium sulfate, 25 mM potassium chloride, drug within the range that yields e?icacy without toxicity 1 mM phenylmethylsulfonyl ?uoride, 1 mM dithiothreitol requires a regimen based on the kinetics of the drug’s 10 (DTT) containing 0.25M sucrose using a Potter-Elvehjem homogenizer. A crude nuclear pellet was prepared by cen availability to target sites. This involves a consideration of trifugation of the homogenate at 1.500Xg for 15 min. The the distribution, equilibrium, and elimination of a drug. crude nuclear pellet was washed two times and resuspended In the methods of the present invention, the compounds in two volumes of buifer. Glycerol was added to the resus herein described in detail can form the active ingredient, and 15 pended pellet to a ?nal concentration of 20%. The enzyme are typically administered in admixture with suitable phar suspension was frozen in aliquots at ~80° C. The prostatic maceutical diluents, excipients or carders (collectively and scalp reductases were stable for at least 4 months when referred to herein as “carder” materials) suitably selected stored under these conditions. with respect to the intended form of administration, that is, Sou-reductase assay oral tablets, capsules, elixirs, syrups and the like, and 20 The reaction mixture for the type 1 Sa-reductase con consistent with conventional pharmaceutical practices. tained 40 mM potassium phosphate, pH 6.5, 5 mM [7-3H] For instance, for oral administration in the form of a tablet -testosterone, 1 HM dithiothreitol and 500 M NADPH in a or capsule, the active drug component can be combined with ?nal volume of 100 pl. The reaction mixture for the type 2 an oral, non-toxic pharrnaceutically acceptable inert carrier Son-reductase contained 40 mM sodium citrate, pH 5.5, 0.3 such as ethanol, glycerol, water and the like. Moreover, 25 mM [7-3H]-testosterone, 1 mM dithiothreitol and 500 M when desired or necessary, suitable binders, lubricants, NADPH in a ?nal volume of 100 pl. Typically, the assay was disintegrating agents and coloring agents can also be incor initiated by the addition of 50-100 ug prostatic homogenate porated into the mixture. Suitable binders include, without or 75-200 pg scalp homogenate and incubated at 37° C. limitation, starch, gelatin, natural sugars such as glucose or After l0~50 min. the reaction was quenched by extraction beta-lactose, corn sweeteners, natural and synthetic gums 30 with 250 |il of a mixture of 70% cyclohexane: 30% ethyl such as acacia, tragacanth or sodium alginate, carboxym acetate containing 10 ug each DHT and T. The aqueous and ethylcellulose, polyethylene glycol, waxes and the like. organic layers were separated by centrifugation at 14,000 Lubricants used in these dosage forms include, without rpm in an Eppendorf rnicrofuge. The organic layer w, as limitation, sodium oleate, sodium stearate, magnesium stear subjected to normal phase HPLC (10 cm Whatman partisil ate, sodium benzoate, sodium acetate, sodium chloride and 35 5 silica column equilibrated in 1 ml/min 70% cyclohexane: the like. Disintegrators include, without limitation, starch, 30% ethyl acetate; retention times: DHT, 6.8-7.2 min.; methyl cellulose, agar, bentonite, xanthan gum and the like. androstanediol, 7.6-8.0 rnin.; T, 9.1-9.7 min.). The HPLC The liquid forms in suitably ?avored suspending or dis system consisted of a Waters Model 680 Gradient System persing agents such as the synthetic and natural gums, for equipped with a Hitachi Model 655otautosampler, Applied example, tragacanth, acacia, methyl-cellulose and the like. 40 Biosystems Model 757 variable UV detector, and a Radi Other dispersing agents which may be employed include omatic Model A120 radioactivity analyzer. The conversion glycerin and the like. For parenteral administration, sterile of T to DHT was monitored using the radioactivity ?ow suspensions and solutions are desired. Isotonic preparations detector by mixing the HPLC effluent with one volume of which generally contain suitable preservatives are employed Flo Scint l (Radiomatic). Under the conditions described, when intravenous administration is desired. 45 the production of DHT was linear for at least 25 min. The only steroids observed with the human prostate and scalp Topical preparations containing the active drug compo preparations were T, DHT and androstanediol. nent can be admixed with a variety of carrier materials well Inhibition studies known in the art, such as, e.g., alcohols, aloe vera gel, Compounds were dissolved in 100% ethanol. The com allanloin, glycerine, vitamin A and E oils, mineral oil, PPG2 pound to be tested was pre-incubated with the enzyme myristyl propionate, and the like, to form, e.g., alcoholic (either Son-reductase type 1 or 2) prior to initiation by solutions, topical cleansers, cleansing creams, skin gels, skin addition of substrate testosterone. IC50 values represent the lotions, aerosol or non-aerosal sprays, and shampoos in concentration of inhibitor required to decrease enzyme con cream or gel formulations. See, e.g., EP 0 285 382. version of testosterone to dihydrotestosterone by 50% of the The compounds of the present invention can also be 55 control. 1C50 values were determined using a 6 point titration administered in the form of liposome delivery systems, such where the concentration of the inhibitor was varied from 0.1 as small unilamellar vesicles, large unilamellar vesicles and to 1000 nM. multilamellar vesicles. Liposomes can be formed from a _ A compound referred to herein as a Son-reductase 2 variety of phospholipids, such as cholesterol, stearylamine inhibitor is a compound that shows inhibition of the Soc-re or phosphatidylcholines. ductase 2 isozyme in the above-described assay, having an The compounds of the present invention may be coupled IC50 value of about or under 100 nM. to a class of biodegradable polymers useful in achieving A compound referred to herein as a Soc-reductase type 1 controlled release of a drug, for example, polylactic acid, inhibitor is a compound that shows inhibition of the Son-re polyepsilon caprolactone, polyhydroxy butyric acid, poly ductase type 1 isozyme in the above-described assay, having orthoesters, polyacetals, polydihydro-pyran's, polycy 65 an IC50 value of about or under 100 nM. anoacrylates and cross-linked or amphipathic block copoly A compound referred to herein as a dual 5ot-reductase mers of hydrogels. ' type 1 and 2 inhibitor is a compound that shows inhibition 5,512,555 7 8 of both the type 1 and type 2 isozymes, having an IC50 value (b) a therapeutically e?ective amount of the Sou-reductase of about or under 100 nM for each isozyme. type 1 inhibitor, 4,7B-dimethyl-4-aza-5ot-cholestan-3 While the invention has been described and illustrated one and a Sot-reductase type 2 inhibitor selected from with reference to certain'particular embodiments thereof, ?nasteride and epristeride, or those skilled in the art will appreciate that various changes, 5 (c) a therapeutically effective amount of an antiperspirant. modi?cations and substitutions can be made therein without 5. A method of treating a condition selected from apocrine departing from the spirit and scope of the invention. For gland sweating, hyperhidrosis, or hydradenitis suppurativa example, eiTective dosages other than the particular dosages comprising adrninstering to a person in need of such treat as set forth herein above may be applicable as a consequence ment a therapeutically effective amount of a Sot-reductase of variations in the responsiveness of the s mammal being 10 inhibitor selected from ?nasteride, epn'steride or 4,7[5-dim treated for any of the indications for the compounds of the ethyl-4-aza-Sot-cholestan-S-one. invention indicated above. Likewise, the speci?c pharma 6. The method of claim 5 wherein the inhibitor is a cological responses observed may vary according to and Set-reductase type 2 inhibitor selected from ?nasteride or depending upon the particular active compound selected or epristeride. 7. The method of claim 6 wherein the inhibitor is?nas whether there are present pharmaceutical carriers, as well as 15 teride. the type of formulation and mode of administration 8. The method of claim 5 wherein the inhibitor is the employed, and such expected variations or differences in the Stx-reductase type 1 inhibitor, 4,7B-dimethyl-4-aza-5ot results are contemplated in accordance with the objects and cholestan-3-one. practices of the present invention. It is intended, therefore, 9. The method of claim 6 further comprising the admin that the invention be de?ned by the scope of the claims istration of the Sot-reductase type 1 inhibitor, 4,7?-dimethyl which follow and that such claims be interpreted as broadly 4-aza-5rx-cholestan-3-one. as is reasonable. 10. The method of claim 9 wherein the Set-reductase type What is claimed is: 2 inhibitor is ?nasteride. 1. A pharmaceutical composition comprising 11. The method of claim 5 wherein the condition is (a) a pharmaceutically acceptable carrier, 25 apocrine gland sweating, and further comprising adminis tration of a therapeutically effective amount of aluminum (b) a therapeutically eifective amount of a Soc-reductase hydroxide. inhibitor selected from ?nasteride, epristeride or 4,7[3 12. The method of claim 5 wherein the condition is dimethyl-4-aza-5ot-cholestan-3-one, and hyperhidrosis, and further comprising administration of a (c) a therapeutically eifective amount of an antiperspirant. therapeutically effective amount of aluminum hydroxide. 2. A composition of claim 1 wherein the antiperspirant is 13. The method of claim 5 wherein the Soc-reductase an aluminum salt. inhibitor is administered orally. 3. A composition of claim 2 wherein the aluminum salt is 14. The method of claim 5 wherein the SOt-reductase aluminum hydroxide. inhibitor is administered topically. 4. A pharmaceutical composition comprising (a) a pharmaceutically acceptable carrier, * * * * * UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. 5,512,555

DATED 4/30/96

INVENTOFl(S) 2 JOANNE WALDSTREICHER

it is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown-below: _ in Claim 4, at Column 8, line 4, delete "finasteride and epristeride, or" and insert therefor -- finasteride or epristeride, and -- . '

In Claim 5, at Column 8, line 8, delete “adminstering" and insert therefor -- administering --.

Signed and Sealed this Thirtieth Day of July, 1996

BRUCE LEHMAN

Azteszing O?icer Commzssionzr of Parents and Trademarks