WO1988005653A1 - Topical composition for stimulating hair growth with stable free radicals - Google Patents
Topical composition for stimulating hair growth with stable free radicals Download PDFInfo
- Publication number
- WO1988005653A1 WO1988005653A1 PCT/US1988/000232 US8800232W WO8805653A1 WO 1988005653 A1 WO1988005653 A1 WO 1988005653A1 US 8800232 W US8800232 W US 8800232W WO 8805653 A1 WO8805653 A1 WO 8805653A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- proxyl
- compoεition
- benzothiadiazine
- dioxide
- free radical
- Prior art date
Links
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- MMNYKXJVNIIIEG-UHFFFAOYSA-N 3-(aminomethyl)-PROXYL Chemical group CC1(C)CC(CN)C(C)(C)N1[O] MMNYKXJVNIIIEG-UHFFFAOYSA-N 0.000 description 1
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- 125000001309 chloro group Chemical group Cl* 0.000 description 1
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- KANINNSSRWMGIP-UHFFFAOYSA-M sodium;butyl 4-hydroxybenzoate;dodecyl sulfate;hexadecan-1-ol;methyl 4-hydroxybenzoate;octadecan-1-ol;propane-1,2-diol;propyl 4-hydroxybenzoate Chemical compound [Na+].CC(O)CO.COC(=O)C1=CC=C(O)C=C1.CCCOC(=O)C1=CC=C(O)C=C1.CCCCOC(=O)C1=CC=C(O)C=C1.CCCCCCCCCCCCCCCCO.CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCCCCCCCO KANINNSSRWMGIP-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q7/00—Preparations for affecting hair growth
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/63—Steroids; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/67—Vitamins
- A61K8/676—Ascorbic acid, i.e. vitamin C
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q5/00—Preparations for care of the hair
- A61Q5/02—Preparations for cleaning the hair
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Birds (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Topical composition and method for stimulating hair growth. The composition contains, in an occlusive or semiocclusive pharmaceutical carrier, a stable free radical forming substance such as minoxidil, diphenyl hydantoin, diazoxide, porphyrin, proxyl, doxyl or tempo, an antiandrogen such as spironolactone, and optimally, a free radical scavenger such as dimethyl sulfoxide, a tertiary phosphine oxide or a retinoid. The method involves applying the composition to skin, preferably water-soaked skin, once or twice a day.
Description
TOPICAL COMPOSITION FOR STIMULATING HAIR GROWTH WITH STABLE FREE RADICALS
SPECIFICATION
Field of the Invention
This invention relates to a composition and method for treating baldness, particularly androgenic alopecia.
Background of the Invention Various treatments were available for conditions such as male and female pattern baldness and alopecia areata. Several substances were known to be effective when administered internally, but had undesirable concomitant systemic effects and the hypertrichosis was not confined to the scalp area. In an effort to avoid these side effects and to confine the hypertrichosis to the scalp area, several attempts were made to apply such substances in a topical preparation to the affected area. However, such attempts had generally been only marginally successful, and the results obtained with the topical preparation containing the orally effective substances
were comparable to and generally little better than those obtained with topical application of the carrier only. U.S. Patent 2,986,573 described a process for treating hypertension by administering a 1,2,4- benzothiadiazine 1,1-dioxide, otherwise unsubstituted in the heterocyclic portion of the nucleus, having a saturated lower aliphatic hydrocarbon radical in the 3-position and a chlorine atom or its equivalent on the benzenoid portion of the nucleus in the 6- or 7- position. U.S. Patent 4,184,039 described the development of uncontrolled hair growth in patients treated orally with 1,2,4-benzothiadiazine 1,1-dioxideε; and also described topical application of 6-chloro-3-dimethylaminoethoxymethyl- 2H-1,2,4-benzothiadiazine 1,1-dioxide and 6-chloro-3- cyclohexenyl-3,4-dihydro-2H-l,2, -benzothiadiazine
1,1-dioxide in DMSO and in suspension to promote hair growth.
U.S. Patents 4,139,619 and 4,596,812 described a process for stimulating the growth of mammalian hair by the application of 6-amino-4-(substituted amino)-1,2- dihydro-l-hydroxy-2-iminopyrimidines to mammalian skin in association with a topical pharmaceutical carrier.
U.S. Patent 4,347,245 described a composition containing spironolactone in a liquid carrier such as alcohol, urea, mineral oil or white petrolatum.
Stewart, M.E. et al., "Antiandrogenε and the Skin," International Journal of Dermatology, Vol. 17, pp. 167-179 (1978) described the application to the foreheads of acne patients of 10% cyproterone in 50% aqueous dimethyl sulfoxide, with no reduction in sebum secretion or improvement in acne being produced.
U.S. Patent 4,367,227 described a composition for reducing sebum secretion when applied to the skin, which composition contained cyproterone acetate dissolved in a C ~C Q aliphatic alcohol.
Summary of the Invention
The present invention provides a topical composition for stimulating the growth of hair including, in a pharmaceutical carrier, (i) a hair growth stimulant, (ii) an antiandrogen, and optimally (iii) a free radical scavenger.
In another aspect, the invention is a method of stimulating the growth of hair by applying to the skin to be treated a composition including, in a pharmaceutical carrier, (i) a hair growth stimulant, (ii) an antiandrogen, and optimally (iii) a free radical scavenger.
Detailed Description of the Invention
Briefly, the composition of the invention includes a pharmaceutical carrier, a hair growth stimulant described in more detail hereinbelow, an antiandrogen and optimally, a free radical scavenger.
The carrier of the composition, in which the hair growth stimulant, antiandrogen and any scavenger will generally be substantially homogenously dispersed, is preferably an occluεive or εemi-occluεive preparation which may be a water-in-oil emulsion, but is most preferably an oil-in-water emulsion. As used herein, the terms "occluεive" or "semi-occlusive" are used in reference to a carrier which substantially prevents or inhibits, respectively, evaporation of water from the skin to which it is applied. As examples of non-occlusive carriers, there may be mentioned water, urea, alcohols and glycolε such as methanol, ethanol, propanol, butanol, ethylene glycol and propylene glycol, and the like.
Suitable water-in-oil emulsions are commercially available under the designations Aguaphor, cold cream, Eucerin, hydrous lanolin, Hydrosorb, hydrophilic petrolatum, Nivea, Polysorb, ualatum and Velvachol. Suitable oil-in-water emulsions are available commercially under the designations acid mantle cream, Almay emulsion
crea , Cetaphil, Dermabase, Dermovan, hydrophilic ointment, Keri cream, Lubrider cream, Multibaεe cream, Neobase cream, Univase cream, Vanibaεe cream, and Wibi. The carrier may further contain various other emollients, emulsifierε, water, perfumes, colorants, preservatives and the like. In a preferred embodiment, the carrier comprises the Dermovan emulsion, propylene glycol and water.
A hair growth stimulant is broadly defined herein as any substance other than the carrier, the antiandrogen and the free radical scavenger which is effective in the preεent topical composition to promote the growth of hair, especially for treating conditions such as male pattern baldness. In general, pharmacologically acceptable substances which form stable free radicals are contemplated as being suitable hair growth stimulants. The formation of stable free radicals in a substance is attributable to electron acceptance or donation from other radicals or reducing and/or oxidizing species, and is generally confirmed by electron spin resonance εpectrometry. Several of such subεtanceε, such as minoxidil, diphenyl hydantoin, and diazoxide, are known to promote hair growth when administered internally.
Hair growth εtimulantε contemplated as suitable in the preεent composition include minoxidil and the compoundε related thereto described in U.S. Patent 3,461,461; 3,382,247 and 3,644,364 which are hereby incorporated herein by reference. Alεo contemplated as suitable hair growth stimulants are the porphyrins; 5,5-di-substituted- hydantoins; substituted
1,2,4-benzothiadiazine 1,1-dioxides; nitroxide spin labels and spin traps such as doxyl, proxyl and tempo nitroxides; and various nitrones and nitroso εpin labels and spin traps described in more detail hereinbelow. Porphyrins are physiologically active nitrogenous compounds, many of which occur naturally. Porphyrins are
also known as substituted porphines and are derived from the following structure:
Specific representative examples of contemplated porphyrins include uroporphyrin, coproporphyrin, protoporphyrin and the like.
Hydantoinε contemplated as suitable have the general formula:
wherein R5 and R6 are independently alkyl, aryl, alkaryl, haloaryl, alkoxyaryl, heteroaryl, aminoaryl or the like, or together are diarylene, and X1 is hydrogen, alkali metal, alkaline earth metal, ammonium, alkylamine, alkanolamine, polymethylene diamine or the like. Specific representative examples include 5, 5-diphenylhydantoin, 5-phenyl-5-(p-bromophenyl)- hydantoin, 5-phenyl-5-(p- chlorophenyl)-hydantoin, 5, 5-di-(p-dimethylaminophenyl)- hydantoin, 5-diphenylene-hydantoin, 5-xylenyl-5- phenylhydantoin, 5, 5-(di-p-tolyl )-hydantoin, 5-phenyl-5-
anisylhydantoin, 5-phenyl-5-(2-thienyl)-hydantoin, εodium salts thereof and the like. Such compounds and their preparation are described, for example, in U.S. Patents 2,366,221 and 2,409,754, which are incorporated herein by reference.
Diazoxide is 7-chloro-3-methyl-2H-l,2,4-benzo¬ thiadiazine 1,1-dioxide. Also contemplated as suitable hair growth stimulants in the composition are the substituted 1,2,4-benzothiadiazine 1,1-dioxides of the general formulae:
wherein X2 iε chlorine, bromine or trifluoromethyl in the 6, 7, 8 or 9 poεition or lower alkyl or lower alkoxy in the 6 poεition, and R7 is alkyl, dialkylaminoalkoxyalkyl, or aralkyl, or a pharmacologically acceptable acid addition salt thereof.
Specific representative examples of contemplated 1,2,4-benzothiadiazine 1,1-dioxides include:
3-methyl-7-chloro-2H-l,2,4-benzothiadiazine 1,1-dioxide;
3-ethyl-7-chloro-2H-l,2,4-benzothiadiazine 1,1-dioxide;
3-methyl-6-chloro-2H-l,2,4-benzothiadiazine 1,1-dioxide;
3-ethyl-6-chloro-2H-l,2,4-benzothiadiazine 1,1-dioxide; 3-n-pentyl-6-chloro-2H-l,2,4-benzothiadiazine 1,1-dioxide;
3-cyclopentyl-6-chloro-2H-l,2,4-benzothiadiazine 1,1-dioxide;
3-n-butyl-7-chloro-2H-l,2,4-benzothiadiazine 1,1-dioxide;
3-methyl-6-trifluoromethyl-2H-l,2,4-benzothiadiazine 1,1-dioxide;
3-methyl-6-trifluoromethyl-2H-l,2, -benzothiadiazine 1,1-dioxide; 3,6-dimethyl-7-chloro-2H-l,2,4-benzothiadiazine 1,1-dioxide;
3,7-dimethyl-6-chloro-2H-l,2,4-benzothiadiazine 1,1-dioxide;
3-(2,4,4-trimethylpentyl)-6-chloro-2H-l,2,4- benzothiadiazine 1,1-dioxide;
3-octyl-6-chloro-2H-l,2,4-benzothiadiazine 1,1-dioxide;
3-dimethylaminoethoxymethyl-6-chloro-2H-l,2,4- benzothiadiazine 1,1-dioxide; 3-cyclohexenyl-6-chloro-3,4-dihydro-2H-l,2,4- benzothiadiazine 1,1-dioxide;
3-heptyl-8-chloro-2H-l,2,4-benzothiadiazine 1,1-dioxide;
3-εtyryl-8-chloro-3,4 dihydro-2H-l,2,4- benzothiadiazine 1,1-dioxide;
3-propyl-6-methyl-2H-l,2,4-benzothiadiazine 1,1-dioxide; and
3-methoxy-6-ethyl-2H-l,2,4-benzothiadiazine 1,1-dioxide. Such compounds and their preparation are described, for example, in U.S. Patents 2,986,572 and 4,184,039 which are hereby incorporated herein by reference.
Other stable free radical forming compounds contemplated aε being useful aε hair growth εtimulantε in the preεent invention include spin labelε and spin traps. Exemplary of theεe are: melanin; 4,4-dimethyl-3- oxazolinyloxy (hereinafter "doxyl") and derivativeε εuch as 3-doxyl-5α-choleεtane, 3-doxyl-17β-hydroxy-5α-androstane, 5-doxylεtearic acid, 7-doxylstearic acid, 12-doxylεtearic acid, 16-doxylεtearic acid, 5-doxylεtearic acid methyl ester, 7-doxylstearic acid methyl ester, 12-doxylεtearic acid methyl ester, 16-doxylstearic acid methyl eεter and the like; 2,2,5,5-tetramethyl-l-pyrrolidinyloxyl (hereinafter "proxyl") and derivativeε εuch as 3-(aminomethyl)-proxyl, 3-(2-[2-bromoacetamido]-acetamido)-proxyl, 3-(2-[2-2- bromoacetamido)-ethoxyethyl]-carbamoyl)-proxyl, 3-(2- bromoacetamido]-methyl)-proxyl, 3-(3-[2-bromoacetamido]- propylcarbamoyl)-proxyl, 3-(2-bromoacetamido)-proxyl, 3-carbamoyl-proxyl, 3-carboxy-proxyl, 3-cyano-proxyl, 3-(5-[dimethylamino]-1-naphthalene-sulfonamido)-proxyl, 3-(5-fluoro-2,4-dinitroanilino)-proxyl, 3-(2-[2- iodoacetamido]-acetamido)-proxyl, 3-(2-[2-(2- iodoacetamido)-ethoxyethyl]-carbamoyl)-proxyl, 3-(2- iodoacetamidomethyl)-proxyl, 3-(3-[2-iodoacetamido]- propylcarbamoyl)-proxyl, 3-(2-iodoacetamido)-proxyl, 3-(2-[2-iεothiocyanatoethoxy]-ethylcarbamoyl)-proxyl, 3-(2-isothiocyanatoethylcarbamoyl)-proxyl, 3-
(iεothiocyanatomethyl)-proxyl, 3-(3-iεothiocyanato- propyl carbamoyl)-proxyl, 3-(2-[2-maleimidoethoxy]- ethylcarbamoyl)-proxyl, 3-(2-maleimidoethyl-carbamoyl)- proxyl, 3-(maleimidomethyl)-proxyl, 3-(3-maleimidopropy1- carbamoyl)-proxyl, 3-maleimidoproxyl, 3-(4-nitrophenoxy carbonyl)-proxyl, and the like; 2,2,6,6,-tetramethyl- 1-piperidinyloxyl (hereinafter "tempo") and derivativeε such aε 4-amino-tempo, 4-(2-bromoacetamido)-tempo, 4-(ethoxyfluorophoεphinylox )-tempo, 4-hydroxy- empo, 4-(2-iodoacetamido)-tempo, 4-isothiocyanato-tempo,
4-maleimido-tempo, 4-( -nitrobenzoyloxy)-tempo, 4-oxo-tempo, 4-phoεphonooxy-tempo, and the like; other spin labels such aε 2-(acetoxymercuri)-4,4,5,5- tetramethyl-2-imidazolin-l-yloxy-3-oxide, 3-carbamoyl- 2,5-dihydro-2,2,5,5-tetramethyl-lH-pyrrol-l-yloxy,
3, ( [ethoxycarbonyl]-oxycarbonyl)-2,5-dihydro-2,2,5,5- tetramethyl-lH-pyrrol-1-yloxy and the like; and nitrone and nitroεo spin traps εuch aε N-t-butyl-α-phenyl-nitrone, 3,5-dibromo-4-nitroεo-benzeneεulfonic acid; 5,5-dimethyl -1-pyrroline N-oxide, 2-methyl-2-nitroεo-propane, nitrosobenzene, nitroεodiεulfonic acid, α-(4-pyridyl-l- oxide)-N-t-butylnitrone, 3,3,5,5-tetramethyl-pyrroline N-oxide, 2,4,6-tri-t-butylnitroεobenzene, and the like. Such spin labels and spin traps are commercially available.
Effective amounts of the hair growth stimulant generally range from about 0.01 to about 20 percent by weight of the composition, more preferably from about 0.1 to about 10 percent by weight, most preferably from about 0.5 to about 3 percent by weight, and especially about 2 percent by weight, but more or less may be present in the composition depending on the particular hair growth stimulant. For convenience, reference iε made hereinbelow to diphenyl hydantoin, but it iε to be understood that the suitable subεtituteε therefor described above may be present partially or entirely in lieu of diphenyl hydantoin itself.
The second essential ingredient is an antiandrogen, preferably one which interferes with the binding of androgenε εuch as dihydrotestosterone to receptors in hair follicles. However, antiandrogens which interfere with or inhibit the synthesis of androgenic compounds are also contemplated. The preferred compounds function primarily to block dihydroteεtosterone receptorε rather than to inhibit the reduction of teεtosterone, and are also known as DHT blockerε. Exemplary of such antiandrogens are spironolactone, cyproterone, cyproterone acetate, and the
like. Of theεe, εpironolactone iε preferred becauεe its effects from topical application are generally more limited to the local εite of application.
Effective amounts of the antiandrogen generally range from about 0.01 to about 5 percent by weight of the composition, but more or less than thiε may be used depending on the particular antiandrogen. The optimum amount iε about one percent by weight of the compoεition for εpironolactone and about 0.1 percent for cyproterone and cyproterone acetate. Quite surprisingly, at amounts above theεe optimums, the effect of the antiandrogens iε not aε great, and for unknown reaεonε, in some cases the presence of the antiandrogen in the compoεition in amountε in εubstantial excess of the optimum may result in a reduced effectiveneεε in εtimulating hair growth in comparison to the composition containing no antiandrogen. The hair growth stimulation effected by the preεent compoεition is improved when a free radical scavenger, preferably a hydroxyl radical scavenger, iε present. Aε used herein, the term "free radical scavenger" includes compoundε which εuppreεε free radical generation as well aε compoundε which react with free radicalε in biological εyεtemε. Hydroxyl radical εcavengers are, for example, sulfoxideε, phosphine oxides, retinoids, purines, pyrimidineε, thiolε, halide ionε, aromatic hydrocarbonε and the like. Free radical εcavengerε preferred in the composition of the present invention include those pharmaceutically acceptable hydroxyl radical scavengers which have a εubstantial effectiveneεs as a hydroxyl radical εcavenger, and eεpecially compoundε having an effectiveneεε aε a hydroxyl radical scavenger εubstantially equivalent to or better than DMSO.
A preferred clasε of free radical εcavengerε includeε εulfoxideε of the formula R8R9S0 wherein R8 iε alkyl, alkenyl, heteroalkyl (e.g. thiaalkyl or azaalkyl), hydroxyalkyl, or alkoxyalkyl having up to about 14 carbon atoms, and R9 iε independently alkyl or hydroxyalkyl
having from 1 to about 8 carbon atomε. Examples of R8 suitable herein include octyl, nonyl, decyl, undecyl, dodecyl, 3-decenyl, 2-dodecenyl, 3-undecenyl, 3-octenyl, 2-ketooctyl, 2-ketodecyl, 2-ketoundecyl, 2-ketododecyl, 2-hydroxyoctyl, 2-hydroxydecyl, 2-hydroxyundecyl, 2-hydroxydodecyl, 3-hydroxyundecyl, 3-methoxyundecyl, 2-methoxydodecyl, 3,6-dioxadodecyl, 2-ethylhexyl, and branched chain nonyl and dodecyl resulting from polymerization of three and four moles of propylene, respectively. Examples of R9 include methyl, ethyl, propyl, butyl, hydroxymethyl, 2-hyroxyeth l, 3-hydroxypropyl, and 4-hydroxybutyl.
Especially preferred εulfoxideε for the purposes of this invention are the dialkyl εulfoxideε where R8 iε a hydrocarbyl alkyl or hydroxy-subεtituted alkyl group containing from 8 to 12 carbon atoms and R9 is methyl, ethyl or propyl. As examples of these preferred sulfoxides there may be mentioned octyl methyl sulfoxide, nonyl methyl sulfoxide, decyl methyl sulfoxide, undecyl methyl sulfoxide, dodecyl methyl sulfoxide, 2-hydroxydecyl methyl sulfoxide, 2-hydroxyundecyl methyl εulfoxide and 2-hydroxydodecyl methyl sulfoxide.
Another preferred class of hydroxyl radical εcavengerε includes the tertiary phoεpine oxides of the formula R10R11R12P0 wherein R10 is alkyl, aralkyl, heteroalkyl (e.g. azaalkyl or thiaalkyl), hydroxyalkyl, alkoxyalkyl, or ketoalkyl of from 1 to 14 carbon atomε, or aryl of from 6 to 12 carbon atomε, and R11 and R12 are independently alkyl, hydroxyalkyl, alkoxyalkyl or ketoalkyl of from 1 to 4 carbon atomε. Examples of R10 include methyl, ethyl, propyl, butyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, 2-propenyl, 3-decenyl, 2-dodecenyl, 3-undecenyl, 3-octenyl, 2-ketobutyl, 2-ketohexyl, 2-ketoocotyl, 2-ketodecyl, 2-ketoundecyl, 2-ketododecyl, 2-hydroxypropyl, 2-hydroxyhexyl, 3-hydroxyheptyl, 2-hydroxyoctyl, 2-hydroxyundecyl, 2-hydroxydodecyl, 3-hydroxyundecyl,
2-methoxybutyl, 3-methoxyundecyl, 2-methoxydodecyl, 2-chlorodecyl, 3-chlorobutyl, 2-thiomethylhexyl, 3,6-dioxadodecyl, 2-oxaheptyl, 3-azahexyl, 2-thiadecyl, 2-ethylhexyl, phenyl, naphthyl, m-tolyl, benzyl, and branched chain nonyl and dodecyl resulting from polymerization of three and four moles of propylene, respectively.
Examples of R11 and R12 include methyl, ethyl, propyl, hydroxymethyl, 1-hydroxypropyl, 2-hydroxyethyl, and the like.
Especially preferred phosphine oxides for the purpose of this invention are those in which R10 iε a hydrocarbyl alkyl or hydroxy-substituted alkyl subεtituent containing from 8 to 12 carbon atomε and R1 x and R12 are each methyl, ethyl or propyl. Aε examples of these preferred phospine oxideε there may be mentioned octyl dimethyl phoεpine oxide, nonyl diethyl phosphine oxide, decyl dimethyl phosphine oxide, undecyl dimethyl phosphine oxide, dodecyl dimethyl phoεpine oxide, 2-hydroxydecyl dimethyl phosphine oxide, 2-hydroxyundecyl dimethyl phosphine oxide and 2-hydroxydodecyl dimethyl phospine oxide. Dodecyl dimethyl phospine oxide is especially preferred.
The retinoidε compriεe another preferred claεε of free radical scavengers. Exemplary retinoids include carotene, tretinoin, isotretinoin, 9-ciε-tretinoin, retinol, retinol acetate, retinol palmitate, dehydroretinol, 9-cis-dehydroretinol,
13-cis-dehydroretinol, 9,13-di-cis-dehydroretinol, retinal, etretinate, retinyl acetate, 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,
8-nonatetraenoic acid and the like. Especially preferred retinoids include tretinoin and 9-(4-methoxy-2,3,6- trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid. The free radical scavenger iε preferably preεent in the compoεition in a proportion effective to, εynergiεtically with the diphenyl hydantoin and . antiandrogen, εtimulate the growth of hair. The effective
amount depends on the particular free radical scavenger and its scavenging effectiveneεε, but is generally in the range of from 0.01 up to 50 percent by weight of the composition. For the sulfoxides such as DMSO, the effective amount iε generally from about 5 to about 25 percent by weight of the compoεition, preferably about 15-20 percent by weight. Depending on the particular carrier, the amount of DMSO preεent may be adjusted to avoid phase separation. With free radical scavengers εuch aε tretinoin, the effective amount iε aε little as
0.01-0.5 percent by weight. For convenience, reference iε made hereinbelow to DMSO, but it iε to be underεtood that other suitable free radical scavengers may be present, partially or entirely, in lieu of DMSO. In some instanceε, the combined effect of the antiandrogen and free radical scavenger in the composition iε εufficient to obtain acceptable hair growth εtimulation without the preεence of a hair growth stimulant per se. Aε examples of such compositions, there may be mentioned the combination of spironolactone with a sulfoxide such aε DMSO or with a retinoid εuch aε tretinoin. Such compositions, while generally less effective from the standpoint of the amount of hair growth and length of time to response, are generally nearly aε effective aε the compoεition with the hair growth εtimulant from the standpoint of the proportion of those treated who eventually respond.
According to the method of the invention, the composition of the invention described above iε applied topically to the skin to be treated, such as the scalp. Preferably, the application iε once a day with a sufficient amount of the composition to cover the area at which the stimulation of hair growth iε deεired. It iε contemplated that results are improved when the composition iε applied after water-soaking the skin.
Thus, a preferred embodiment of the method iε convenient
in that the composition can be applied once daily immediately following bathing.
Generally, best results are obtained in treatment of bald or thinly-haired scalp areas in which hair loεε haε not occurred for a period of time εubεtantially in excess of about 3-5 years . The effectiveneεε also depends , although to a leεεer degree, inverεely on the age of the user .
The preparation and use of the compoεition iε illustrated by way of the following examples .
Preparation of the Composition Example 1 A composition according to the invention was prepared with the ingredientε and proportionε listed in Table I . Table I
Ingredient Proportion
Dermovan emulsion 15 pounds
DMSO 3 pints Water 2 pints
Propylene glycol 2 pints
Diphenyl hydantoin 0 .5 wt . %
Spironolactone 0.5 wt . %
Notes for Table I :
1. Obtained from Owen Laboratories ; Dermovan emulsion contains water , glycerol stearate , glycerin, mineral oil , synthetic spermaceti , cetyl alcohol , butylparaben, propylparaben and methylparaben.
The water and propylene glycol were added to the diphenyl hydantoin in a suitable container . The DMSO was then added and the mixture waε thoroughly mixed and
allowed to stand overnight. Then, with constant εtirring the Dermovan emulεion was added slowly. The mixture was then allowed to stand at least 24 hours with occasional stirring. Example 2
A composition iε prepared aε in Example 1 except that 2.0 percent by weight of εodium diazoxide iε εubεtituted in place of the diazoxide and the proportion of spironolactone iε decreased to 0.01 percent by weight. Example 3
A topical gel was prepared with the following ingredients and proportionε:
Table II
Ingredient Propo rtion
DMSO 3 Pi- nts
Propylene glycol 3 pints Water 3 pi: tits
Spironolactone 1 wt Diphenyl hydantoin 1 t 7 Hydroxypropyl 1 wt • /o cellulose (M.W. 100,000-1,000,000)
The ingredientε were combined with εtirring and allowed to εit for 3-5 dayε until the mixture formed a gel.
Example 4 A lotion waε prepared with the following ingredientε and proportionε:
Table I I I
Ingredient Proportion
Propylene glycol 2 pints
Wa er 2 pints
Ethyl alcohol 6 pints
Urea 10 wt.%
Spironolactone 1 wt.%
Diphenyl hydantoin 1 wt.%
The ingredients were combined with stirring to form a lotion.
Example 5 A cream was prepared aε in Example 1, except, that 1 pint of propylene glycol waε uεed inεtead of 2 pints, 1 wt.% minoxidil was used inεtead of diphenyl hydantoin, 1 wt.% εpironolactone inεtead of 0.5 wt.%, and also contained 0.01 wt.% tretinoin added with the minoxidil and spironolactone. Use of the Compoεition
Example 6 The compoεition of Example 1 waε applied topically to the scalpε of male patientε with 2-5 years of hair losε who had all been previouεly treated with 2 wt.% minoxidil in a solution of water (70 vol.%), ethanol (15 vol.%) and propylene glycol (15 vol.%) without any significant promotion of hair growth. The composition of Example 1 waε applied to the εcalp twice daily at a rate of 1 • ml/day. About half of the εubjectε reεponded with photographically verifiable hair growth after 2-6 monthε of treatment. In contrast, a control group similarly administered the composition of Example 1, but without any diphenyl hydantoin, exhibited lesε hair growth and had a
longer response time, although the number of subjects eventually responding waε also about half of the group.
While I have described the composition and method of my invention above, many variations in the ingredients, proportionε, and manner of preparation will occur to those skilled in the art. It is intended that all εuch variations which fall within the scope and spirit of the appended claims be embraced thereby.
Claims
1. A composition for topical application to the skin to stimulate hair growth, comprising: (a) a hair growth stimulant; (b) an antiandrogen; and (c) a pharmaceutical carrier in which said hair growth stimulant and said antiandrogen are εubεtantially homogenously dispersed.
2. The composition of claim 1, wherein said hair growth εtimulant iε a subεtance which formε a εtable free radical.
3. The composition of claim 2, wherein said hair growth εtimulant iε selected from the group consisting of: 6-amino-4-(substituted amino)-l,2-dihydro-l-hydroxy- 2-iminopyridineε, porphryinε, 1,2,4-benzothiadiazine 1,1-dioxideε, 5,5-diaryl hydantoinε, and nitroxide, nitroso and nitrone spin labels and spin traps.
4. The composition of claim 1, wherein said antiandrogen interferes with the binding of dihydrotestoεterone to receptorε.
5. The compoεition of claim 2, further comprising a free radical scavenger.
6. The composition of claim 5, wherein said free radical scavenger is selected from the group consisting of: sulfoxides, tertiary phosphine oxides, and retinoids.
7. A compoεition for topical application to the skin to εtimulate hair growth, comprising: (a) a pharmacologically acceptable subεtance which formε a εtable free radical;
(b) an antiandrogen; and (c) a pharmaceutical carrier in which said hair growth εtimulant and εaid antiandrogen are εubstantially homogenously dispersed.
8. The composition of claim 7, wherein said stable free radical forming stubεtance iε εelected from the group conεiεting of: 6-amino-4-(εubεtituted amino)-l,2-dihydro- l-hydroxy-2-iminopyrimidineε, porphoryns, 5,5-diaryl hydantoins, 1, 2,4-benzothiadiazine 1, 1-dioxideε, nitroxide, nitroso and nitrone spin labels and traps.
9. The composition of claim 7, wherein said stable free radical forming substance is a 1, 2-dihydro-l- hydroxypyrimidine compound εelected from the group conεiεting of compoundε of the formula:
wherein R„ and R. are selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower aralkyl, and lower cycloalkyl, and taken together, R-. and R4 may be a heterocyclic moiety selected from the group consiεting of aziridinyl, azetidinyl, pyrrolidinyl, piperidino, hexahydroazepinyl, heptamethylenimino, octamethylenimino, morpholino and 4-lower-alkyl-piperazinyl, each of said
hetrocyclic moieties having attached as subεtituents on the carbon atoms thereof 0-3 lower alkyl groups, hydroxy or alkoxy, and wherein R_ is εelected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkoxyalkyl, lower cycloalkyl, lower aryl, lower aralkyl, lower alkaryl, lower alkoxyaralkyl, and lower haloaralkyl, and the tautomers and pharmacologically acceptable acid addition salts thereof.
10. The compoεition of claim 9, wherein εaid εtable free radical forming substance is minoxidil.
11. The compoεition of claim 7, wherein said stable free radical forming εubstance iε a porphyrin.
12. The compoεition of claim 11, wherein εaid porphyrin is selected from the group conεiεting of: uroporphyrin, coproporphyrin and protoporphyrin.
13. The compoεition of claim 7, wherein said stable free radical forming substance is εelected from hydantoinε of the formula:
wherein R5 and R6 are independently aryl, alkaryl, haloaryl, alkoxyaryl, heteroaryl, aminoaryl, or taken together, R5 and R6 are diarylene, and X2 iε hydrogen, alkali metal, alkaline earth metal, ammonium, alkylamine, alkanolamine or polymethylenediamine.
14. The composition of claim 13, wherein εaid hydantoin iε selected from the group consisting of: 5, 5-diphenylhydantoin, 5-phenyl-5-(p-bromophenyl )- hydantoin, 5-phenyl-5-(p-chlorophenyl)-hydantoin, 5,5-di- (p-dimethylaminophenyl)-hydantoin, 5-diphenylene- hydantoin, 5-xylenyl-5-phenylhydantoin, 5, 5-(di-p-tolyl)- hydantoin, 5-phenyl-5-anisylhydantoin, 5-phenyl-5-(2- thienyl)-hydantoin, and salts thereof.
15. The composition of claim 7, wherein said εtable free radical forming εubεtance iε 5, 5-diphenylhydantoin or a εalt thereof.
16. The compoεition of claim 7, wherein said stable free radical forming substance is a 1,2,4-benzothiadiazine 1,1-dioxide.
17. The composition of claim 16, wherein εaid 1,2,4-benzothiadiazine 1,1-dioxide iε selected from compounds of the formulae:
H
18. The compoεition of claim 17 wherein εaid 1,2,4-benzothiadiazine 1,1-dioxide iε εelected from the group conεiεting of: 3-methyl-7-chloro-2H-l,2,4-benzothiadiazine 1,1- dioxide; 3-ethyl-7-chloro-2H-l,2,4-benzothiadiazine 1,1- dioxide; 3-methyl-6-chloro-2H-l,2,4-benzothiadiazine 1,1- dioxide; 3-ethyl-6-chloro-2H-l,2,4-benzothiadiazine 1,1- dioxide; 3-n-pentyl-6-chloro-2H-l,2,4-benzothiadiazine 1,1- dioxide; 3-cyclopentyl-6-chloro-2H-l,2,4-benzothiadiazine 1,1-dioxide; 3-n-butyl-7-chloro-2H-l,2,4-benzothiadiazine 1,1- dioxide; 3-methyl-6-trifluoromethyl-2H-l,2,4-benzothiadiazin 1,1-dioxide; 3-methyl-6-trifluoromethyl-2H-l,2,4-benzothiadiazi 1,1-dioxide; 3,6-dimethyl-7-chloro-2H-l,2,4-benzothiadiazine 1,1 dioxide; 3,7-dimethyl-6-chloro-2H-l,2,4-benzothiadiazine 1,1 dioxide; 3-(2,4,4-trimethylpentyl)-6-chloro-2H-l,2,4- benzothiadiazine 1,1-dioxide; 3-octyl-6-chloro-2H-l,2,4-benzothiadiazine 1,1- dioxide; 3-dimethylaminoethoxymethyl-6-chloro-2H-l,2,4- benzothiadiazine 1,1-dioxide;
3-cyclohexenyl-6-chloro-3,4-dihydro-2H-l,2,4- benzothiadiazine 1,1-dioxide; 3-heptyl-8-chloro-2H-l,2,4-benzothiadiazine 1,1- dioxide; 3-εtyryl-8-chloro-3,4 dihydro-2H-l,2,4- benzothiadiazine 1,1-dioxide; 3-propyl-6-methyl-2H-l,2,4-benzothiadiazine 1,1- dioxide; 3-methoxy-6-ethyl-2H-l,2,4-benzothiadiazine 1,1- dioxide; and pharmacologically acceptable acid addition salts thereof.
19. The compoεition of claim 17, wherein said εtable free radical forming εubεtance is 7-chloro-3-methyl-2H-l,2, 4-benzothiadiazine 1,1,-dioxide or a salt thereof.
20. The composition of claim 7, wherein said stable free radical forming substance is selected from the group conεiεting of derivativeε of 4,4-dimethyl-3-oxazolinyloxy, 2,2,5,5-tetramethyl-l-pyrrolidonyloxy and 2,2,6,6-tetramethyl-l-piperidinyloxy.
21. The compoεition of claim 20, wherein εaid εtable free radical forming εubεtance iε selected from the group consisting of: 3-doxyl-5α-cholestane, 3-doxyl-17β-hydroxy-5α-androεtane, 5-doxylεtearic acid, 7-doxylstearic acid, 12-doxylstearic acid, 16-doxylstearic acid, 5-doxylstearic acid methyl eεter, 7-doxylstearic acid methyl eεter, 12-doxylstearic acid methyl ester and 16-doxylstearic acid methyl eεter.
22. The compoεition of claim 20, wherein εaid εtable free radical forming εubεtance iε εelected from the group conεisting of: 3-(aminomethy1)-proxyl, 3-(2-[2- bromoacetamido]-acetamido)-proxyl,
3-(2-[2-2-bromoacetamido)-ethoxyethyl]-carbamoyl)-proxyl, 3-(2-bromoacetamido]-methyl)-proxyl, 3-(3-[2- bromoacetamido]-propylcarbamoyl)-proxyl, 3-(2- bromoacetamido)-proxyl, 3-carbamoyl-proxyl, 3-carboxy- proxyl, 3-cyano-proxyl, 3-(5-[dimethy1amino]-l- naphthalene-εulfonamido)-proxyl, 3-(5-fluoro-2,4- dinitroanilino)-proxyl, 3-(2-[2-iodoacetamido]-acetamido) -proxyl, 3-(2-[2-(2-iodoacetamido)-ethoxyethyl]-carbamoyl) -proxyl, 3-(2-iodoacetamidomethyl)-proxyl, 3-(3-[2- iodoacetamido]-propylcarbamoyl)-proxyl, 3-(2- iodoacetamido)-proxyl, 3-(2-[2-iεothiocyanatoethoxy]- ethylcarbamoyl)-proxyl, 3-(2-isothiocyanatoethylcarbamoyl)- proxyl, 3-(isothiocyanatomethyl)-proxyl, 3-(3-iεothiocyanato- propyl carbamoyl)-proxyl, 3-(2-[2-maleimidoethoxy]- ethylcarbamoyl)-proxyl, 3-(2-maleimidoethyl-carbamoyl)- proxyl, 3-(maleimidomethyl)-proxyl, 3-(3-maleimidopropyl- carbamoyl)-proxyl and 3-maleimidoproxyl, 3-(4-nitrophenoxy carbonyl)-proxyl.
23. The compoεition of claim 20, wherein εaid stable free radical forming subεtance is selected from the group consisting of: 4-amino-tempo, 4-(2-bromoacetamido)-tempo, 4-(ethoxyfluorophosphinyloxy)-tempo, 4-hydroxy-tempo, 4-(2- iodoacetamido)-tempo, 4-iεothiocyanato-tempo, 4-maleimido- tempo, 4-(4-nitrobenzoyloxy)-tempo, 4-oxo-tempo, and 4-phosphonooxy-tempo.
24. The composition of claim 7, wherein εaid stable free radical forming substance is selected from the group consisting of: 2-(acetoxymercuri)-4,4,5,5-tetramethyl-2- imidazolin-l-yloxy-3-oxide, 3-carbamoyl-2,5-dihydro-2,2,5, 5-tetramethyl-lH-pyrrol-l-yloxy, and 3, ( [ethoxycarbonyl]- oxycarbonyl)-2,5-dihydro-2,2,5,5-tetramethyl-lH-pyrrol- 1-yloxy.
25. The compoεition of claim 7, wherein εaid εtable free radical forming εubstance iε εelected from the group consiεting of: N-t-butyl-α-phenyl-nitrone, 3,5-dibromo- 4-nitroεo-benzeneεulfonic acid; 5,5-dimethyl-l-pyrroline N-oxide, 2-methyl-2-nitroεo-propane, nitrosobenzene, nitrosodisulfonic acid, α-(4-pyridyl-l-oxide)-N-t- butylnitrone, 3,3,5,5-tetramethyl-pyrroline N-oxide, and 2,4,6-tri-t-butylnitrosobenzene.
26. The composition of claim 7, wherein said antiandrogen interferes with the binding of dihydrotestosterone to receptors.
27. The composition of claim 7, wherein said antiandrogen is selected from the group consiεting of: εpironolactone, cyproterone, cyproterone acetate, and combinations thereof.
28. The composition of claim 7, wherein εaid carrier is an occlusive or semioccluεive carrier selected from the group consiεting of water-in-oil emulsions and oil-in-water emulsions.
29. The composition of claim 7, further comprising a free radical scavenger homogenouεly dispersed in εaid carrier in an amount leεε than 50 percent by weight of the composition.
20. The compoεition of claim 29, wherein said free radical scavenger is selected from the group consisting of sulfoxides, tertiary phosphine oxides and retinoids.
31. The composition of claim 29, wherein said free radical scavenger is a sulfoxide of the formula R8R9SO wherein R8 is alkyl, alkenyl, heteroalkyl, hydroxyalkyl or alkoxyalkyl having up 1 to about 14 carbon atoms, and R9
iε independently alkyl or hydroxyalkyl having from 1 to 8 carbon atoms.
32. The compoεition of claim 31, wherein R8 iε alkyl or β-hydroxyalkyl having up to 14 carbon atomε and R9 iε methyl.
33. The compoεition of claim 32, wherein R8 is methyl.
34. The compoεition of claim 30, wherein εaid free radical εcavenger iε a tertiary phoεphine oxide of the formula R10R11R12PO wherein R10 iε alkyl, aryl, aralkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, or ketoalkyl having up to 14 carbon atoms and R11 and R12 are independently alkyl, hydroxyalkyl, alkoxyalkyl or ketoalkyl having up to 4 carbon atomε.
35. The compoεition of claim 29, wherein εaid free radical εcavenger iε an alcohol selected from the group conεiεting of methanol, ethanol, propanol, butanol, ethylene glycol, and propylene glycol.
36. The compoεition of claim 7, further compriεing a retinoid.
37. The compoεition of claim 36, wherein said retinoid iε εelected from the group conεisting of: carotene, tretinoin, isotretinoin, 9-cis-tretinoin, retinol, retinol acetate, retinol palmitate, dehydroretinol, 9-ciε-dehydroretinol, 13-cis- dehydroretinol, 9,13-di-cis-dehydroretinol, retinal, etretinate, retinyl acetate, and 9-(4-methoxy-2,3,6- trimeth lphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid.
38. The composition of claim 36, wherein said retinoid is tretinoin or 9-(4-methoxy-2,3,6- tri ethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid.
39. A topical hair growth stimulating composition, comprising: from about 0.5 to about 3 percent by weight 5,5,-diphenyl hydantoi ; from about 0.01 to about 5 percent by weight εprionolactone; and from about 5 to about 25 percent by weight dimethyl sulfoxide; substantially homogenouεly dispersed in a pharmaceutical carrier.
40. A topical hair growth stimulating compoεition, compriεing: from about 0.5 to about 3 percent by weight 5,5,-diphenyl hydantoin; from about 0.01 to about 5 percent by weight εprionolactone; and from about 0.01 to about 0.5 percent by weight tretinoin; substantially homogenouεly dispersed in a pharmaceutical carrier.
41. A topical hair growth stimulating composition, comprising: from about 0.01 to about 5 percent by weight sprionolactone; and from about 5 to about 25 percent by weight dimethyl sulfoxide; substantially homogenously diεperεed in a pharmaceutical carrier.
42. A topical hair growth εtimulating compoεition, compriεing: from about 0.01 to about 5 percent by weight εprionolactone; and from about 0.01 to about 0.5 percent by weight tretinoin; εubεtantially homogenously disperεed in a pharmaceutical carrier.
43. A topical hair growth εtimulating compoεition, compriεing: from about 0.5 to about 3 percent by weight diazoxide; from about 0.01 to about 5 percent by weight spironolactone; and from about 5 to about 25 percent by weight dimethyl sulfoxide; εubεtantially homogenously dispersed in a pharmaceutical carrier.
44. A topical hair growth εtimulating compoεition, compriεing: from about 0.5 to about 3 percent by weight diazoxide; from .about 0.01 to about 5 percent by weight sprionolactone; and from about 0.01 to about 0.5 percent by weight tretinoin; substantially homogenously diεperεed in a pharmaceutical carrier.
45. A topical hair growth εtimulating compoεition, compriεing: from about 0.5 to about 3 percent by weight minoxidil; from about 0.01 to about 5 percent by weight εpironolactone; and
from about 5 to about 25 percent by weight dimethyl εulfoxide; εubεtantially homogenously dispersed in a pharmaceutical carrier.
46. A topical hair growth stimulating compoεition, compriεing: from about 0.5 to about 3 percent by weight minoxidil; from about 0.01 to about 5 percent by weight εprionolactone; and from about 0.01 to about 0.5 percent by weight tretinoin; εubεtantially homogenouεly diεperεed in a pharmaceutical carrier.
Applications Claiming Priority (2)
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US818687A | 1987-01-28 | 1987-01-28 | |
US008,186 | 1987-01-28 |
Publications (1)
Publication Number | Publication Date |
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WO1988005653A1 true WO1988005653A1 (en) | 1988-08-11 |
Family
ID=21730221
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1988/000232 WO1988005653A1 (en) | 1987-01-28 | 1988-01-27 | Topical composition for stimulating hair growth with stable free radicals |
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AU (1) | AU1362488A (en) |
WO (1) | WO1988005653A1 (en) |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2620619A1 (en) * | 1987-07-01 | 1989-03-24 | Keunwha Pharmaceutical Co Ltd | Novel pharmaceutical process for obtaining a unique formula for novel and improved therapeutic applications and safety |
DE3915133A1 (en) * | 1987-11-13 | 1990-11-15 | Luderschmidt Christoph | Hair growth promoter compsns. - contain anti-androgenic agent and minoxidil |
WO1992022290A1 (en) * | 1991-06-18 | 1992-12-23 | Oklahoma Medical Research Foundation | Use of spin trapping for the treatment of diseases associated with oxidation of lipids and proteins |
EP0520005A1 (en) * | 1990-03-16 | 1992-12-30 | Us Health | Nitroxides as protectors against oxidative stress. |
DE4213314A1 (en) * | 1992-04-23 | 1993-10-28 | Ingeborg Zingraf | Hair lotion and hair treatment process to reduce hair loss and promote hair growth in androgenetic hair loss |
US5405874A (en) * | 1989-10-17 | 1995-04-11 | Oklahoma Medical Research Foundation | PBN, DMPO, and POBN compositions and method of use thereof for inhibition of age-associated oxidation |
US5538945A (en) * | 1994-06-17 | 1996-07-23 | Procyte Corporation | Stimulation of hair growth by peptide copper complexes |
WO1996040127A1 (en) * | 1995-06-07 | 1996-12-19 | The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Nitroxides as protectors against oxidative stress |
US5681845A (en) * | 1989-10-17 | 1997-10-28 | Oklahoma Medical Research Foundation | DMPO spin trapping compositions and methods of use thereof |
US5900227A (en) * | 1996-06-17 | 1999-05-04 | Oklahoma Medical Research Foundation | Multicyclic nitrone spin trapping compositions |
EP0684809A4 (en) * | 1993-02-19 | 1999-07-28 | Ringler Steven L | Compositions and methods for promoting hair growth. |
WO2001046195A1 (en) * | 1999-12-21 | 2001-06-28 | Gpi Nil Holdings, Inc. | Hydantoin derivative compounds, pharmaceutical compositions, and methods of using same |
EP1194150A1 (en) * | 1999-06-23 | 2002-04-10 | Eric F. Bernstein | Use of nitroxides in wound healing and in the prevention of photodamage |
WO2003039597A1 (en) * | 2001-11-09 | 2003-05-15 | Qlt Inc. | Compositions comprising a photosensitizer and a skin-penetration enhancer and their use in photodynamic treatment |
EP1313479A1 (en) * | 2000-07-19 | 2003-05-28 | W. Roy Knowles | Hair loss prevention |
US6639051B2 (en) * | 1997-10-20 | 2003-10-28 | Curis, Inc. | Regulation of epithelial tissue by hedgehog-like polypeptides, and formulations and uses related thereto |
WO2005041905A2 (en) * | 2003-10-30 | 2005-05-12 | Ciba Specialty Chemicals Holding Inc. | Stabilized body care products, household products, textiles and fabrics |
EP1637135A1 (en) * | 2004-09-15 | 2006-03-22 | Albert Aebi | Compositions comprising dimethylsulfoxide and tretinoin for treating skin disorders |
US7264629B2 (en) | 2001-11-09 | 2007-09-04 | Qlt, Inc. | Photodynamic therapy for the treatment of hair loss |
EP2985017B1 (en) * | 2013-04-11 | 2020-01-22 | Osaka Organic Chemical Industry Ltd. | 1,2-alkane polyol-containing composition |
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FR2620619A1 (en) * | 1987-07-01 | 1989-03-24 | Keunwha Pharmaceutical Co Ltd | Novel pharmaceutical process for obtaining a unique formula for novel and improved therapeutic applications and safety |
DE3915133A1 (en) * | 1987-11-13 | 1990-11-15 | Luderschmidt Christoph | Hair growth promoter compsns. - contain anti-androgenic agent and minoxidil |
DE3915133C2 (en) * | 1987-11-13 | 2003-04-03 | Christoph Luderschmidt | Hair restorer |
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US5578617A (en) * | 1989-10-17 | 1996-11-26 | Oklahoma Medical Research Foundation | Method and compositions for treating age related disorders |
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EP0787492A1 (en) * | 1990-03-16 | 1997-08-06 | THE UNITED STATES OF AMERICA as represented by the Secretary UNITED STATES DEPARTMENT OF COMMERCE | Use of nitroxides and oxazolidines for protection against ionising radiation and oxidative stress |
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EP1313479A1 (en) * | 2000-07-19 | 2003-05-28 | W. Roy Knowles | Hair loss prevention |
EP1313479A4 (en) * | 2000-07-19 | 2005-09-21 | W Roy Knowles | Hair loss prevention |
WO2003039597A1 (en) * | 2001-11-09 | 2003-05-15 | Qlt Inc. | Compositions comprising a photosensitizer and a skin-penetration enhancer and their use in photodynamic treatment |
US7090691B2 (en) | 2001-11-09 | 2006-08-15 | Qlt Inc. | Photodynamic therapy for the treatment of hair loss |
US7264629B2 (en) | 2001-11-09 | 2007-09-04 | Qlt, Inc. | Photodynamic therapy for the treatment of hair loss |
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JP2007513875A (en) * | 2003-10-30 | 2007-05-31 | チバ スペシャルティ ケミカルズ ホールディング インコーポレーテッド | Stabilized body care products, household products, fabrics and textiles |
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