Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-25
2001-05-22
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S315000, C514S428000, C514S628000
Reexamination Certificate
active
06235737
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to reducing hair growth in mammals, particularly for cosmetic purposes.
A main function of mammalian hair is to provide environmental protection. However, that function has largely been lost in humans, in whom hair is kept or removed from various parts of the body essentially for cosmetic reasons. For example, it is generally preferred to have hair on the scalp but not on the face.
Various procedures have been employed to remove unwanted hair, including shaving, electrolysis, depilatory creams or lotions, waxing, plucking, and therapeutic antiandrogens. These conventional procedures generally have drawbacks associated with them. Shaving, for instance, can cause nicks and cuts, and can leave a perception of an increase in the rate of hair regrowth. Shaving also can leave an undesirable stubble. Electrolysis, on the other hand, can keep a treated area free of hair for prolonged periods of time, but can be expensive, painful, and sometimes leaves scarring. Depilatory creams, though very effective, typically are not recommended for frequent use due to their high irritancy potential. Waxing and plucking can cause pain, discomfort, and poor removal of short hair. Finally, antiandrogens—which have been used to treat female hirsutism—can have unwanted side effects.
It has previously been disclosed that the rate and character of hair growth can be altered by applying to the skin inhibitors of certain enzymes. These inhibitors include inhibitors of 5-alpha reductase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, gamma-glutamyl transpeptidase, and transglutaminase. See, for example, Breuer et al., U.S. Pat. No. 4,885,289; Shander, U.S. Pat. No. 4,720,489; Ahluwalia, U.S. Pat. No. 5,095,007; Ahluwalia et al., U.S. Pat. No. 5,096,911; and Shander et al., U.S. Pat. No. 5,132,293.
Ceramide is a naturally occurring sphingolipid metabolite present in skin and other tissues both intra- and extra-cellularly. Biosynthesis of ceramide in cells generally starts by the condensation of the amino acid serine and palmitoyl-CoA resulting in the formation of 3-ketodihydrosphingosine, which is subsequently reduced to dihydrosphingosine. The amide linkage of fatty acyl groups to dihydrosphingosine forms dihydroceramide. The dihydroceramide is converted to ceramide by the introduction of a trans-4,5-double bond. Once formed, ceramide acts as a precursor for the synthesis of other complex sphingolipids such as galactosylceramide, glucosylceramide, and acyl ceramide. Most glycosphingolipids are synthesized from ceramide via glucosylceramide, the formation of which is catalyzed by glucosylceramide synthase.
Ceramide is also formed in cells by pathways of complex glycosphingolipid catabolism. For example, the breakdown of sphingomyelin through the action of sphingomyelinases results in the formation of ceramide. Another set of enzymes that may regulate cellular ceramide levels are ceramidases, which break down ceramide to sphingosine.
SUMMARY OF THE INVENTION
The invention features reducing unwanted mammalian (including human) hair growth—particularly androgen-stimulated hair growth—by increasing cellular ceramide levels. Cellular ceramide levels may be increased, for example, by applying to the skin a composition including (1) an inhibitor of glucosylceramide synthase, (2) an inhibitor of ceramidase; (3) ceramide (N-acyl-trans-D-erythro-2-amino-4-octadecene-1,3-diol); (4) a ceramide analog; and/or (5) an inducer of spingomylinase. A ceramide analog is a chemical derivative of the ceramide molecule that either behaves as ceramide or is degraded in cells to ceramide. The unwanted hair growth which is reduced may be normal hair growth, or hair growth that results from an abnormal or diseased condition. For purposes of this application, glucosylceramide synthase includes glucosyl ceramide transferase.
Other features and advantages of the invention may be apparent from the description of the preferred embodiments thereof, and from the claims.
DESCRIPTION OF THE EMBODIMENTS
A preferred composition includes at least one compound that increases cellular ceramide levels when applied topically in a cosmetically and/or dermatologically acceptable vehicle. The composition may be a solid, semi-solid, or liquid. The composition may be, for example, a cosmetic and dermatologic product in the form of an, for example, ointment, lotion, foam, cream, gel, or hydroalcoholic solution. The composition may also be in the form of a shaving preparation or an aftershave. The vehicle itself can be inert or it can possess cosmetic, physiological and/or pharmaceutical benefits of its own.
Examples of inhibitors of glucosylceramide synthase: 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP); 1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol (PPMP); 1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol (PPPP); 1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (P4); D-threo-4′-hydroxy-P4; D-threo-3′,4′-methylenedioxyphenyl-P4; D-threo-trimethylenedioxyphenyl-P4; D-threo-3′,4′-ethylenedioxyphenyl-P4; N-butyldeoxynojirimycin (NBDN); and N-(5-adamantane)-1-yl-methoxy)pentyl)-deoxy norjirimycin. See Rani et al., J. Biol. Chem. 270: 2859-2867, 1995; Olshefski and Ladisch, J. Neurochem. 70: 467-472, 1998; Lee et al., J. Biol. Chem. 274: 14662-14669, 1999; Neises et al., Biol. Cell 89: 123-131, 1997; and Platt et al. J. Biol Chem. 269: 8362-8365, 1994.
Examples of inhibitors of ceramidase include the following: D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol (D-erythro-MAPP); N-oleoyl ethanolamine; and (1S,2R)-(+)-phenylpropanolamine. See Spinedi et al., Biochem. Biophys. Res. Commun. 255: 456-459, 1999; Bielawska et al., J. Biol. Chem. 271: 12646-12654, 1996.
Examples of ceramide analogs include the following: N-acetylsphingosine (C2-ceramide); N-hexanoylsphingosine (C6-ceramide); N-octanoylsphingosine (C8-ceramide); N-octanoyl-DL-erythro dihydrosphingosine; N-octyl-D-erythro-sphingosine; and N-thioacetylsphingosine; and 4-dodecanoylamino-decan-5-ol. See Park et al., Exp. Mol. Med. 31: 142-150, 1999; Irie and Hirabayashi, J. Neurosci. Res., 54: 475-485, 1998; Karasavvas et al., Eur. J. Biochem. 236: 729-737, 1996; and Bektas et al., Exp. Dermatol. 7: 342-249, 1998.
The composition may include more than one compound that increases cellular ceramide levels. In addition, the composition may include one or more other types of hair growth reducing agents, such as those described in U.S. Pat. Nos. 4,885,289; 4,720,489; 5,132,293; 5,096,911; 5,095,007; 5,143,925; 5,328,686; 5,440,090; 5,364,885; 5,411,991; 5,648,394; 5,468,476; 5,475,763; 5,554,608; 5,674,477; 5,728,736; 5,652,273; WO 94/27586; WO 94/27563; and WO 98/03149, all of which are incorporated herein by reference.
The concentration of the compound that increases cellular ceramide levels in the composition may be varied over a wide range up to a saturated solution, preferably from 0.1% to 30% by weight or even more; the reduction of hair growth increases as the amount of compound applied increases per unit area of skin. The maximum amount effectively applied is limited only by the rate at which the compound penetrates the skin. The effective amounts may range, for example, from 10 to 3000 micrograms or more per square centimeter of skin.
Vehicles can be formulated with liquid or solid emollients, solvents, thickeners, humectants and/or powders. Emollients include stearyl alcohol, mink oil, cetyl alcohol, oleyl alcohol, isopropyl laurate, polyethylene glycol, olive oil, petroleum jelly, palmitic acid, oleic acid, and myristyl myristate. Solvents may include ethyl alcohol, isopropanol, acetone, diethylene glycol, ethylene glycol, dimethyl sulfoxide, and dimethyl formamide.
The composition also may include components that enhance the penetration of the compound into the skin and/or to the site of action. Examples of penetration enhancers include urea, polyoxyethylene ethers (e.g., Brij-30 and Laureth-4), 3-hydroxy-3,7,11-trimethyl-1,6,10-dodecatriene, terpenes, cis-fatty acids (e.g., ol
Ahluwalia Gurpreet S.
Styczynski Peter
Cook Rebecca
Fish & Richardson P.C.
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