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WO1995034303A1 - Procede pour traiter, prevenir ou reduire au minimum la chute des cheveux - Google Patents

Procede pour traiter, prevenir ou reduire au minimum la chute des cheveux Download PDF

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Publication number
WO1995034303A1
WO1995034303A1 PCT/US1995/007470 US9507470W WO9534303A1 WO 1995034303 A1 WO1995034303 A1 WO 1995034303A1 US 9507470 W US9507470 W US 9507470W WO 9534303 A1 WO9534303 A1 WO 9534303A1
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Prior art keywords
acid
residue
group
compound
acetylcysteine
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English (en)
Inventor
Richard J. Sharpe
Maureen H. Mccaloon
Kenneth A. Arndt
Stephen J. Galli
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Arcturus Pharmaceutical Corp
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Arcturus Pharmaceutical Corp
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Priority to AU28252/95A priority Critical patent/AU2825295A/en
Publication of WO1995034303A1 publication Critical patent/WO1995034303A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/265—Esters, e.g. nitroglycerine, selenocyanates of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • A61K31/65—Tetracyclines
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A61K8/447—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof containing sulfur
    • 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

Definitions

  • This invention is a method for the treatment of alopecia (hair loss) by the topical administration of a thioester or thioether of N-acetylcysteine or a derivative or a salt thereof.
  • Alopecia is defined as the loss, miniaturization, involution, or increased fragility of the hair at any hair bearing site (i.e., scalp, face (bearded area) , eyebrows, eyelashes or body) .
  • Alopecia can be caused by many internal and external factors, including genetic factors, chemotherapy, burns, stress, infections, cutaneous and systemic diseases, ionizing radiation exposure, and other unknown factors.
  • hair loss is thought to result at least in part, from the formation of free radicals which, by producing oxidative damage, disrupt the hair's normal growth cycles.
  • the life cycle of hair consists of three phases. In humans, the growing phase, anagen, usually lasts about 1000 days. The resting phase, which lasts approximately 100 days in humans, is called telogen. The third phase is the dying phase, named catagen.
  • the length of hair is genetically determined and is dependent upon both the duration of anagen and the rate of hair growth, human scalp hair usually averages 1 cm per month. Approximately 10 percent of the 100,000 hair follicles on the scalp are in telogen phase at any given time. Therefore, typically no more than 100 hairs are ordinarily shed per day (Birnbau , P.S. in Manual of Clinical Problems in Dermatology, First Edition, Olbricht, S.M., Bigby, M.E., Arndt, K.A. eds. Little, Brown and Co., Boston: 1992, pg. 114).
  • Alopecia is generally divided into androgenetic alopecia, telogen effluvium (shed) , anagen effluvium, and alopecia areata.
  • the most common form of alopecia is androgenetic alopecia.
  • Synonyms for this disorder include common baldness, hereditary baldness, male-pattern baldness, premature baldness, and diffuse alopecia.
  • It is a genetically determined form of gradual hair loss that begins as a receding hair line and/or thinning at the vertex (crest) of the scalp.
  • a gradual decrease in hair shaft length and diameter may eventually result in near total replacement of terminal hair with soft, short vellus hair.
  • a band of hair is usually retained along the peripheral scalp.
  • onset can begin as early as adolescence.
  • women the pattern is exhibited as thinning of the parietal and vertex regions, and the age of onset is usually two decades after the onset in men.
  • a topical solution of minoxidil is available for the treatment of androgenetic alopecia.
  • the utility of this treatment is modest at best.
  • approximately 25%, 7%, and 0.7% of patients achieve minimal, moderate and dense regrowth of hair, respectively.
  • the response appears to be more favorable in women and men under 40, in those who have been bald for less than 10 years, and when the affected area is less than 10 cm in diameter (Price, V.H., Rogaine in the management of male-pattern baldness and alopecia areata. Proceedings of a Symposium, J. Am. Acad. Dermatol., 1987, Vol 16, pp. 749-750).
  • Patients with severe hair loss are currently instructed that most therapeutic attempts to treat hair loss are ultimately unsuccessful, and physicians must simply help patients make the psychological adjustment to permanent hair loss.
  • Telogen effluvium is the second most common form of alopecia. It can be induced by such factors as childbirth, surgery, psychological stress, certain drugs, androgen excess, nutritional and metabolic disorders, autoimmune diseases, chronic infections, chronic scalp disease and chronic alopecia areata. Telogen effluvium usually affects less than 20 to 35 percent of the scalp hair, and occurs approximately 6 weeks to 3 months after a triggering event. Anagen effluvium usually affects more than 80-90 percent of the total body hair, and begins 1 to 2 weeks after a triggering event.
  • Anagen effluvium can be caused by anti ⁇ coagulants, anti-metabolites, cytotoxic agents, alkylating agents, and alopecia areata, or by poisoning with lead, arsenic, mercury, thallium, and certain chemotherapeutic agents as well as ionizing radiation.
  • Alopecia areata a non-cicatricial (non-scarring) alopecia, is a relatively common disorder of unknown cause or causes. It is characterized by well defined areas of total hair loss, typically affecting the scalp, although it may extend to effect the entire scalp or even hair follicles on the entire body. Alopecia areata occurs in patients with atopy or Down's syndrome, and usually occurs before age 25. The typical lesions usually appear over a 24 hour period as 3-4 cm asymptomatic smooth bald patches, commonly on the scalp. However, the beard, eyebrows, and/or eyelashes may also be affected. The course of the baldness is variable, and some patients experience regrowth of hair within one year.
  • An alternative therapy is the combination of Psoralen and ultraviolet radiation treatments (photochemotherapy, PUVA) .
  • This therapy has had some effect in certain severe cases.of alopecia areata.
  • the inconvenience and long-term toxicity and low rate of response of this treatment make it impractical for most patients.
  • the induction of irritant dermatitis or allergic contact dermatitis in areas affected by alopecia areata can sometimes promote hair regrowth.
  • the local pain and discomfort associated with this therapy renders it essentially useless.
  • a wide range of inflammatory disorders can cause hair loss as a result of scarring that produces complete destruction of the pilosebaceous unit.
  • These disorders include discoid lupus erythematosus (DLE) , lichen planopilaris (LPP) , morphea, cicatricial pemphigoid, and follicular mucinosis.
  • Basal cell carcinoma, infections (e.g., herpes zoster, leprosy), and physical injury (e.g., burns, radiodermatitis) may also result in scarring and hair loss.
  • Radiation and chemotherapy treatments for cancers may also cause alopecia, which may be transient or permanent.
  • the loss of hair due to radiation therapy is dose dependent, but usually occurs in the range of 200-800 rads. Follicles in the anagen phase are about 3 times more sensitive to this disruption than are follicles in the telogen phase. Free radicals generated as part of the cytotoxic mechanisms of action of chemotherapeutic agents and ionizing radiation are thought to have a major role in the hair loss associated with these modalities of cancer therapy.
  • Cytotoxic drugs may also produce partial or complete inhibition of mitosis or impairment of metabolic processes in the hair matrix, resulting in a thinned, weakened hair shaft.
  • This form of alopecia only affects hairs in the anagen phase of growth, and is therefore classified as a type of anagen effluvium. Hair loss due to chemotherapy is most pronounced in the scalp. Other terminal hairs, such as facial or pubic hairs, are variably affected. Hair loss is usually first observed 1-2 weeks after initiation of chemotherapy, but becomes progressively more marked 1-2 months later.
  • these antioxidants produce numerous side effects when applied to the skin and they are further limited in their ability to penetrate the epidermis (Thiele, F.A.J. British J. of Dermatology, 1975, Vol. 92, pg. 355).
  • U.S. Patent No. 2,986,573 describes a method to promote hair growth that includes the topical application of 6-chloro-3- dimethylaminoethoxymethyl-2H-l,2,4-benzothiadiazine 1,1-dioxide and 6-chloro-3-cyclohexenyl-3,4-dihydro-2H-l,2 ,4-benzothiazine 1,1-dioxide in DMSO or a suspension.
  • U.S. Patent Nos. 4,139,619 and 4,596,812 describe a process for stimulating the growth of mammalian hair by the application of 6-amino-4-(substituted amino)-1,2-dihydro-1- hydroxy-2-iminopyrimidines in combination with a topical pharmaceutical carrier.
  • N-acetylcysteine in preventing the alopecia induced by the chemotherapeutic agents cyclophosphamide, cytarabine or adriamycin (Jiminez, J. J., et al., Cancer Investigation, 1992, Vol. 10(4), pp. 271-276).
  • the results of this study illustrate that the sub-cutaneous injection of N-acetylcysteine can effectively prevent cyclophosphamide induced alopecia.
  • N-acetylcysteine did not prevent the alopecia when it was applied topically in the same alopecia model.
  • N-acetylcysteine in conjunction with a biological response modifier ImuVert (a membrane vesicle-ribosome preparation derived from the bacterium Serratia marcescens, sold by Cell Technology, Inc., Boulder, Colorado) may have enhanced the penetration of N-acetylcysteine into the skin resulting in slight prevention of alopecia.
  • ImuVert a membrane vesicle-ribosome preparation derived from the bacterium Serratia marcescens, sold by Cell Technology, Inc., Boulder, Colorado
  • N-acetylcysteine (a charged amino acid derivative) , however, is probably not suitable for topical treatment of alopecia because it is insufficiently lipid soluble to penetrate through the stratum corneum (outer most layer of skin) . Due to this, an effective means of topical delivery of N-acetylcysteine through the stratum corneum could be of enormous therapeutic benefit.
  • One embodiment of the present invention is a pharmaceutical composition for the topical treatment of alopecia which contains an effective amount of a lipid soluble thioester or thioether of N-acetylcysteine or a pharmaceutically acceptable salt or derivative thereof.
  • Another embodiment of the present invention is a method for treating alopecia via the topical administration of a lipid soluble thioether or thioester of N-acetylcysteine or its pharmaceutically acceptable salt or derivative optionally in a pharmaceutically acceptable carrier to induce regrowth of hair, and/or to prevent further loss of hair.
  • the thioesters and thioethers disclosed herein represent a new prodrug form of N-acetylcysteine which facilitate the transdermal or topical delivery of N-acetylcysteine for treatment of alopecia.
  • the thioester derivatives of N-acetylcysteine are stable in non-biological aqueous solutions such as saline, phosphate buffered saline, lactated Ringer's solution, sterile water and water-containing creams, gels, lotions, foams, and suspended particles.
  • non-biological aqueous solutions such as saline, phosphate buffered saline, lactated Ringer's solution, sterile water and water-containing creams, gels, lotions, foams, and suspended particles.
  • biological fluids such as plasma or tissue samples
  • the thioester of N-acetylcysteine is cleaved, releasing N-acetylcysteine, which exhibits antioxidant properties.
  • N-acetylcysteine through the skin in the form of a thioester or thioether is useful in the treatment, prevention or minimization of all types of alopecia, including androgenetic alopecia, alopecia areata, telogen effluvium, anagen effluvium, and other, non-specific types of hair loss which are caused by oxidative damage.
  • Figure 1 is a graph of the percentage of S-lauryl-N-acetylcysteine remaining over time in (a) a solution of 80% PBS and 20% methanol; and (b) a solution of 80% PBS and 20% methanol containing skin fragments.
  • alkyl refers to a saturated straight, branched or cyclic (or a combination thereof) hydrocarbon of C, to C 22 , and specifically includes methyl, ethyl, propyl, isopropyl, cyclopropylmethyl, cyclobutylmethyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, heptyl, octyl, nonyl, and decyl.
  • aryl or aromatic refers to phenyl, or substituted phenyl, wherein the substituent is halo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, alkoxyalkyl, methylenedioxy, cyano, C(0) (alkyl), carboxylic acid, C0 2 alkyl, amide, amino, alkylamino or dialkylamino, and wherein the aryl group can have up to 3 substituents.
  • aralkyl refers to an aryl group with an alkyl substituent.
  • halo refers to chloro, fluoro, bromo and iodo groups.
  • alkaryl refers to an alkyl group with an aryl substituent, including benzyl, substituted benzyl, phenethyl or substituted phenethyl, wherein the substituents are as defined above for aryl groups.
  • alkoxyalkyl refers to an alkyl group joined to another alkyl group through an oxygen atom. Non-limiting examples of this group include methoxymethyl.
  • aryloxyalkyl refers to an aryl group joined to an alkyl group through an oxygen atom.
  • Non-limiting examples of this type of group include phenoxymethy1.
  • acyloxyalkyl refers to an acyl group (aliphatic-C(O) )- which is linked to an alkyl group through an oxygen atom.
  • amino acid refers to an aliphatic compound containing both an amino group and a carboxylic acid group.
  • Non-limiting examples of suitable amino acids include alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, and histidinyl.
  • fatty acid refers to a long chain (C 6 to C 24 ) aliphatic carboxylic acid.
  • suitable fatty acids include lauric, oleic, caproic, linoleic, linolenic, caprylic, capric, perlargonic, neononanoic, neodecanoic, palmitelaidoic, myristic, palmitic, stearic, arachidic, behenic, lignoceric, heptanoic, nonanoic, undecanoic, tridecanoic, pentadecanoic, heptadecanoic, nonadecanoic, heneicosanoic, tricosanoic, arachidonic, docosahexanoic, elaidic, erucic, nervonic, palmitoleic or petriselinic acid, undecylenic and other trans fatty acids.
  • lauric oleic, caproic
  • aromatic or alkyl dicarboxylic acid refers to an alkyl or aryl moiety which is substituted with two carboxylic acid groups.
  • suitable dicarboxylic acids include azelaic acid, sebacic acid, phthalic acid, terephthalic acid, isophthalic acid, adipic acid, 1,10- dodecanoic acid, fumaric acid, l,4-diphenylenediacrylic acid, azeleic acid, pimelic acid, suberic acid, itaconic acid, bipheny1-4,4'-dicarboxylic acid, benzophenone-4,4'-dicarboxylic acid, hydroquinone-0, ⁇ -diacetic acid, 2,2-bis-(4- hydroxyphenyl)propane- ⁇ , ⁇ -diacetic acid, 1,4-phenylene- dipropionic acid, and cyclohexane dicarboxylic acid.
  • residue for example of an acid, refers to the remainder of the named molecule after the thioester or thioether is formed with the N-acetylcysteine.
  • residue of a carboxylic acid would be the remainder of the relevant molecule except for the -OH moiety of the carboxylic acid which was displaced during the formation of the thioester or thioether.
  • biologically active molecule refers to a molecule which exhibits a biological activity, for example, as an antioxidant or a free radical inhibitor.
  • this type of molecule include vitamin E, ascorbic acid, vitamin D, including l ⁇ ,25-dihydroxy vitamin D 3 , (l ⁇ ,24,25)-trihydroxy vitamin D 3 , l ⁇ -hydroxy vitamin D 3 , (l ⁇ ,25,26)-trihydroxy vitamin D 3 , and derivatives thereof.
  • suitable derivatives of these molecules are well known to those skilled in the art of organic and medicinal chemistry.
  • suitable derivatives include hydroxylated, alkylated, and acylated derivatives of these vitamins.
  • aliphatic refers to a hydrocarbon, typically of C, to C ⁇ o, that can contain one or a combination of alkyl, alkenyl, or alkynyl moieties, and which can be straight, branched, or cyclic, or a combination thereof.
  • enantiomerically enriched composition or compound refers to a composition or compound that includes at least 95% and optimally 97, 98, 99 or 100% by weight of a single enantiomer of the compound.
  • Cysteine is an amino acid with one chiral carbon atom. It can exist as an L-enantiomer, a D-enantiomer or a racemic mixture of the L and D enantiomers. The L-enantiomer is the naturally occurring configuration. Cysteine is an important substrate in the growth of hair.
  • N-acetylcysteine (acetamido-mercaptopropionic acid, NAC) is the N-acetylated derivative of cysteine having the formula
  • L-enantiomer It exists as an L-enantiomer, a D-enantiomer, an enantiomerically enriched composition of one of the enantiomers, or a racemic mixture of the L and D enantiomers.
  • Any of these forms of N-acetylcysteine can be delivered as a lipophilic derivative for the treatment, prevention or minimization of hair loss caused by oxidative damage or free radical mediated processes.
  • a single isomer or an enantiomerically enriched composition of a thioester or thioether of N-acetylcysteine or its salt is used for the treatment, prevention or minimization of hair loss.
  • a preferred isomer is the naturally occurring L-enantiomer.
  • N-Acetylcysteine is known to exhibit antioxidant activity (Smilkstein, Knapp, Kulig and Rumack, N. Engl. J. Med. 1988, Vol. 319, pp. 1557-1562; Knight, K.R. , MacPhadyen, K., Lepore, D.A. , Kuwata, N. , Eadie, P.A. , O'Brien, B. Clinical Sci., 1991, Vol. 81, pp. 31-36; Ellis, E.F., Dodson, L.Y., police, R.J., J. Neurosurg. , 1991, Vol. 75, pp. 774-779).
  • the sulfhydryl functional group is a well characterized, highly reactive free radical scavenger.
  • N-acetylcysteine may behave as an oxygen radical scavenger through a pharmacodynamic pathway.
  • N-acetylcysteine is also known to promote the formation of glutathione (a tri-peptide, also known as g-glutamyl- cysteinylglycine) , which is important in maintaining cellular constituents in the reduced state (Berggren, M. , Dawson, J. , Moldeus, P. FEBS Lett., 1984, Vol. 176, pp. 189-192).
  • glutathione may enhance the activity of glutathione peroxidase, an enzyme which inactivates hydrogen peroxide, a known precursor to hydroxyl radicals (Lalitha, T. , Kerem, D., Yanni, S., Pharmacology and Toxicology, 1990, Vol. 66, pp. 56-61) .
  • N-acetylcysteine is also an effective mucolytic agent, due to the reactive sulfhydryl group in the molecule (Lightowler, J.E. and Lightowler, N.M. , Arch. Int. Pharmacodyn. Ther. 1971, Vol. 189, pp. 53-58). The sulfhydryl group probably opens sulfide linkages in mucus, thereby lowering mucosal viscosity.
  • N-acetylcysteine is also used for the treatment of acetaminophen overdoses (Smilkstein, M.J., Knapp, G.L., Kulig, K.W. and Rumack, B.H., N. Engl. J. Med.
  • acetaminophen results in a larger portion of the drug being metabolized via a free radical (cytochrome P-450) pathway, which in turn results in hepatic cellular necrosis.
  • N-acetylcysteine when administered within the first few hours of acetaminophen overdose, protects the liver by acting as an alternate substrate for conjugation with, and detoxification of, the reactive metabolite.
  • N-acetylcysteine has been reported to be an effective collagenase inhibitor (Lemp, M.A. and Roddy, M. , Ann.
  • N-acetylcysteine can reduce the activity of porcine proteolytic enzymes, leukocyte elastase and pancreatic elastase by greater than 55% in vitro (Morrison, H.M. , Burnett, D. and Stockley, R.A. , Biol. Chem. Hoppe Seyler 1986, Vol. 367, pp. 177-182). In yet another capacity, N-acetylcysteine can act as an inhibitor of tumor necrosis factor-alpha production in vivo (Peristeris, P. et al, Cell. Immunol. 1992, Vol. 140, pp. 390-399).
  • N-acetylcysteine possesses many other properties which may contribute to its therapeutic benefit in the treatment, prevention or minimization of hair loss. For example,
  • N-acetylcysteine exhibits anti-inflammatory activity (see U.S.S.N. 08/147,864, entitled “Topical Application of a Lipid Soluble Thioester or Thioether of N-Acetylcysteine for Treatment of Pathological Conditions Associated with Immune Responses or Inflammatory Conditions”) .
  • the present invention focuses on two discoveries: first, N-acetylcysteine can be converted into lipid soluble derivatives that are capable of penetrating the stratum corneum, and second, that these lipid soluble derivatives can be broken down in vivo to the active parent compound, N-acetylcysteine, at the site of application for treatment of hair loss.
  • the ester or ether residue of the selected N-acetylcysteine derivative can be either an inert substance or a biologically active substance which itself can have therapeutic benefit for the treatment of alopecia or associated disorders.
  • lipophilic thioester or thioether derivative of N-acetylcysteine refers to any thioester or thioether that is capable of passing through the stratum corneum in a therapeutically effective concentration and includes, but is not limited to, either:
  • R 1 is hydrogen, alkyl, aryl, alkaryl, aralkyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl, an amino acid salt formed by the reaction of the amino group of a naturally occurring amino acid with the carboxylic acid group of the N-acetylcysteine or derivative thereof; an amine salt formed by the reaction of an amine- containing antibiotic with the carboxylic acid group of the N-acetylcysteine, or an inorganic cation including but not limited to sodium, potassium, magnesium, calcium, zinc, bismuth, barium, aluminum, copper, cobalt, nickel, and cadmium; and wherein the amino acid includes but is not limited to alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl , tryptophanyl, ethioninyl, glycinyl, serinyl
  • R 2 is alkyl, aryl, alkaryl, aralkyl, alkyloxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl, C(0 or S)alkyl, C(0 or S)aryl, C(0 or S)alkaryl, C(0 or S)aralkyl, C( ⁇ or S)alkyloxyalkyl, C(0 or S)acyloxyalkyl, phosphate., the residue of a saturated or unsaturated fatty acid, including but not limited to lauric, oleic, caproic, linoleic, linolenic, caprylic, capric, perlargonic, neononanoic, neodecanoic, palmitelaidoic, myristic, palmitic, stearic, arachidic, behenic, lignoceric, heptanoic, nonanoic, undecanoic, tridecanoic, pentade
  • 1,4-phenylene-dipropionic acid 1,4-phenylene-dipropionic acid, cyclohexane dicarboxylic acid, branched monomers such as 1,3,5-benzenetricarboxylic acid, the residue of another active molecule such as vitamin D including but not limited to l ⁇ ,25-dihydroxy vitamin D 3 , (l ⁇ ,24,25)- trihydroxy vitamin D 3 , l ⁇ -hydroxy vitamin D 3 , (l ⁇ ,25,26)- trihydroxy vitamin D 3 ) and other derivatives of vitamin D 3 , including but not limited to hydroxylated, alkylated, and acylated derivatives thereof, and vitamin E.
  • vitamin D including but not limited to l ⁇ ,25-dihydroxy vitamin D 3 , (l ⁇ ,24,25)- trihydroxy vitamin D 3 , l ⁇ -hydroxy vitamin D 3 , (l ⁇ ,25,26)- trihydroxy vitamin D 3 ) and other derivatives of vitamin D 3 , including but not limited to hydroxy
  • Non-limiting examples of amine-containing antibiotics that can be used to form a salt with N-acetylcysteine include, but are not limited to erythromycin, propionylerythromycin, neomycin, gentamycin, tobramycin, kanamycin and mechlocycline, clarithromycin and azithromycin.
  • N-acetylcysteine that contains a combination of R 1 and R 2 as described herein, as well as combinations of N-acetylcysteine derivatives, can be used for the delivery of N-acetylcysteine to treat, prevent or minimize all types of alopecias.
  • Vitamin E which is a known antioxidant
  • ascorbic acid ⁇ carotene (provitamin A)
  • catalase superoxide dismutase
  • glutathione glutathione peroxidase
  • glutathione reductase glutathione reductase
  • Vitamin E is known to be a scavenger of both lipid peroxyl radicals and oxygen radicals, and to have membrane stabilizing action.
  • a thioester, thioether or ether of N-acetylcysteine is provided in which the thioester, thioether or ether moiety is one of the compounds naturally used by the body to minimize oxidative damage, including, but not limited to an enzyme, vitamin, or other biological molecule with antioxidant properties or that mediates antioxidant processes.
  • the material can be linked to N-acetylcysteine through a biodegradable linking moiety, as well as through methods known to those skilled in the art of organic synthesis and biochemistry.
  • Humans, equines, canines, bovines and other animals, and in particular, mammals, with alopecia, and in particular, alopecia caused by oxidative stress or free radicals, arising from either external factors, chemicals, ionizing radiation, or endogenous sources, can be treated by delivery of an effective amount of a pharmaceutically acceptable lipid soluble thioester or thioether of N-acetylcysteine or salt thereof, optionally in a pharmaceutically acceptable carrier or diluent.
  • pharmaceutically acceptable salts or complexes refers to salts or complexes that retain the desired biological activity of the above-identified compounds and exhibit minimal undesired toxicological effects.
  • Pharmaceutically acceptable carboxylic acid and mercaptyl salts are known to those skilled in the art, including inorganic salts with cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with a cation formed with a nitrogenous base such as ammonia, N,N-dibenzylethylene-diamine, D-glucosamine, or ethylenediamine.
  • the derivatives of N-acetylcysteine disclosed herein are "prodrugs" of N-acetylcysteine, that are either active in the prodrug form or that are cleaved in vivo to provide the parent N-acetylcysteine as well as an inert or active ester or ether moiety.
  • Modifications of the active compound can affect the bioavailability and rate of metabolism of the active species, thus providing control over the delivery of the active species through the stratum corneum.
  • various modifications of the active molecule such as alteration of charge, can effect water and lipid solubility and thus alter the potential for crossing the stratum corneum.
  • modifications can affect the bioactivity of the compound, in some cases increasing the activity over the parent compound or increasing the permeability of the parent compound through the stratum corneum. This can easily be assessed by synthesizing the derivative and testing its activity according to the methods described herein, or other methods known to those skilled in the art.
  • Preferred derivatives include, but are not limited to the thioester or thioether of N-acetylcysteine and the residue of oleic acid (S-oleoyl-N-acetyl-L-cysteine) , lauric acid (S-lauryl- N-acetyl-L-cysteine) , myristic acid (S-myristoyl-N-acetyl-L- cysteine) , capric acid (S-caprolyl-N-acetyl-L-cysteine) , retinoic acid (S-3,7-dimethyl-9-(2,6,6-trimethyl-l-cyclohexen-l- yl)-2,4,6,8-nonatetraenoyl-N-acetyl-L-cysteine) , lactic acid (S- lactoyl-N-acetyl-L-cysteine) and other ⁇ -hydroxy acids, ascorbic acid
  • the active compound is preferably included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount of the drug for any of the above conditions without causing serious toxic effects in the patient treated. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
  • the concentration of active compound in the drug composition will depend on absorption, distribution, deactivation, and excretion rates of the drug as well as other factors known to those skilled in the art. Dosage values will also vary with the severity of the condition to be alleviated. For any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. The concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the active ingredient can be administered at once, or can be divided into a number of smaller doses to be administered at varying time intervals.
  • the N-acetylcysteine prodrug is administered in an amount of 0.001 to 50 g/kg/day.
  • the active compound or pharmaceutically acceptable derivatives or salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antioxidants, antibiotics, anti-fungals, anti-inflammatories, disinfectants, or anti-viral compounds.
  • a topical formulation containing an effective amount of N-acetylcysteine derivative is administered typically in an aqueous solution that can include polymers, aqueous suspension, ointment, gel or cream vehicle. Except ointments, these vehicles may contain liposomes for creating a reservoir of dissolved agent.
  • N-acetylcysteine can be easily prepared using standard methods known to organic chemists.
  • a general synthetic route is outlined below. N-acetylcysteine in dry tetrahydrofuran (THF) is stirred under inert atmosphere. One equivalent of triethylamine is added and the reaction mixture is chilled to 5°C. One equivalent of the desired acid chloride, dissolved in THF, is added slowly to the reaction mixture. After addition, the reaction mixture is stirred for three hours, and reaction progress monitored by thin-layer chromatography until the reaction approaches completion.
  • THF dry tetrahydrofuran
  • Desired acid chlorides are formed by the addition of an excess of thionyl chloride to the fatty acid (for example) under inert, dry conditions according to methods known to those skilled in the art.
  • Thioethers can be formed using a variety of synthetic methods known to those skilled in the art, including by the Williamson ether synthesis, where the sodium salt of N-acetylcysteine is formed by treatment with base, and further reacted with an alcohol.
  • lipid soluble thioester e.g., S-lauryl-N-acetylcysteine
  • ether/ester e.g., S-lauryl-N-acetylcysteine
  • the reaction mixture was stirred overnight under N 2 .
  • the end of the reaction was observed by the disappearance of the methyl-(S)-lactate by gas chromatography ( t 0.7 min. , 1 ; 9.0 mins., 2.; 10.5 mins., 3.) •
  • the reaction mixture was cooled with an ice bath before adding 200 mL of water and 200 mL of ether.
  • the product was further extracted with 2 x 150 mL of ether.
  • the organic layers were combined and washed with 2 x 150 L of water, 2 x 150 mL of ammonium chloride solution until the pH reached 5, dried with magnesium sulfate, filtered by gravity, and concentrated under reduced pressure. The residue was further pumped under high vacuum overnight.
  • the basic aqueous solution was washed with 3 x 300 mL of ether to remove silanol impurities from the previous step.
  • the aqueous solution was then acidified with cone. HCl until the pH reached 2, and then was extracted with 3 x 400 mL of ether.
  • the organic layer was dried with sodium sulfate, filtered by gravity and concentrated under reduced pressure. The residue was dried under high vacuum for several days. A viscous oil was collected which crystallized upon heating and triturating as a white waxy solid, 142.1 g (overall yield: 87%).
  • N-Acetyl-(l)-cysteine (119 mmol, 19.5 g) was then added through a funnel in two portions while keeping the temperature of the reaction mixture from rising, via a water bath. Then 80 L of THF was added to the reaction mixture to help dissolve all of the material. The reaction mixture was stirred for two hours (a thin layer chromatogram (tic) sample showed complete conversion of the starting material) . Half of the solvent was evaporated and 200 mL of water was added to the reaction mixture. The pH was lowered to two with cone. HCl. The product was then extracted with 3 x 250 mL of ethyl acetate.
  • N-acetyl-S-(L) -lactoyl-fL)-cysteine N-acetyl-S- (O-(t-butyldiphenylsilyl)-(L)-lactoyl)-(L)-cysteine (compound 5., 89.5 mmol, 42.4 g) was dissolved in 150 ml of THF. To this solution was added a commercially available THF solution of tetrabutyl ammonium fluoride, 1M (130 mmol, 130 mL) . The reaction mixture was stirred for eight hours at room temperature.
  • the crude material was dissolved in minimum ethyl acetate and loaded on top of a column packed with thirty times the weight of crude product of silica in hexane:acetic acid (98:2).
  • the polarity of the solvent was increased from hexane:acetic acid (98:2), to hexane:ethyl acetate:acetic acid (48:50:2). All the fractions were collected in the dark.
  • Product 2 was eluted with a solvent polarity ranging from hexane:ethyl acetate:acetic acid (68:30:2) to hexane:ethyl acetate:acetic acid (48:50:2).
  • Triethylamine (Aldrich, 5.73 g, 56.6 mmol) was added, and the reaction mixture chilled in an ice bath.
  • Oleoyl chloride (Nu-Chek-Prep, 17.0 g, 56.4 mmol) was dissolved in 100 mL of THF and placed in the addition funnel. This solution was added dropwise over 0.5 hours. A white solid precipitated from the solution. The ice bath was allowed to melt, and the resulting suspension stirred at 25°C for 3 hours, by which time TLC (eluted with a mixture of ethylacetate and acetic acid) showed the reaction was nearly complete.
  • Example 4 Regeneration of N-Acetylcysteine From S-Lauryl-N- acetylcysteine
  • the sulfhydryl group which is protected as a thioester, must be regenerated by cleavage of the ester.
  • Figure 1 illustrates the stability of S-lauryl-N-acetylcysteine after 1 and 24 hours at
  • Example 5 Treatment of Alopecia Induced by Chemotherapeutic Agents: Rodent (Young Rat) Model The systemic administration of cyclophosphamide, cytarabine or adriamycin chemotherapeutic agents to 8 day old rats induces hair loss in these young animals.
  • the assay set forth in Jiminez, J.J. , et al . , Cancer Investigation. 1992, Vol. 10(4), pp. 271-276 was used to assess the efficacy of the lipid soluble N-acetylcysteine prodrug in treating chemotherapeutically induced alopecia.
  • Lactating Fisher rats with 8-day old pups were purchased from Charles River Laboratories, Inc., Wilmington, MA. Rat pups used for each experiment were of the same age and weight ⁇ 1 g.
  • S-oleoyl-N-acetylcysteine (NACO) was synthesized according to the method described in Example 3.
  • Rats in the 5% group were partially protected from the alopecia at the site of application, i.e., their backs, but unprotected from the hair loss on their heads.
  • Rats in the 10% group were almost entirely protected from hair loss on their backs, but again were unprotected from the alopecia on their heads. It is significant that the hair is lost on the heads of these animals in all groups.
  • the local effect which we are observing is desirable in the management of chemotherapeutically induced hair loss.
  • the androchronogenic alopecia (AGA) mouse as a model for male-pattern baldness, with baldness being induced by the injection of testosterone or dihydrotestosterone.
  • AGA androchronogenic alopecia
  • One group receives a topical application of the lipid soluble N-acetylcysteine derivative (e.g., S-lauryl-N-acetylcysteine), in a suitable vehicle several times daily.
  • Another group receives topical application of vehicle control at the same dosing schedule. The degree of alopecia can then be measured.
  • lipid soluble thioester derivative of N-acetylcysteine in protecting mice from this form of alopecia may be limited to site of application or, if significant systemic absorption occurs, may result in a more generalized protection against hair loss and/or regrowth of hair.
  • the model disclosed by Rittmaster et al. (J. Clin. Endocrinol Metab. , 1987, 65, 188-193) can be used to evaluate the effectiveness of the N-acetylcysteine derivatives in the treatment of stump tailed macaque monkeys by replacing the N,N- diethyl-4-methyl-3-oxo-4-aza-5 ⁇ -androstane-17jS-carboxamide with the N-acetylcysteine derivatives.

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Abstract

Cette invention se rapporte à une composition et à un procédé pour traiter, prévenir ou réduire au minimum la chute des cheveux, ce procédé consistant à administrer de façon topique une quantité efficace d'un thioester ou thioéther de N-acétylcystéine soluble en liquide.
PCT/US1995/007470 1994-06-13 1995-06-13 Procede pour traiter, prevenir ou reduire au minimum la chute des cheveux Ceased WO1995034303A1 (fr)

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999062485A1 (fr) * 1998-06-03 1999-12-09 Gpi Nil Holdings, Inc. Compositions pour la croissance des cheveux a base d'urees ou de carbamates a liaison n de thioesters heterocycliques, et utilisation de ces compositions
WO2003049774A1 (fr) * 2001-12-13 2003-06-19 Vital Health Sciences Pty Ltd Transport transdermique de composes
AU764073B2 (en) * 1997-06-04 2003-08-07 Gpi Nil Holdings, Inc. N-linked urea or carbamate of heterocyclic thioester hair growth compositions and uses
US6943187B2 (en) 1997-06-04 2005-09-13 Gpi Nil Holdings, Inc. Pyrrolidine derivative hair growth compositions and uses
EP1491181A3 (fr) * 2003-06-27 2006-03-22 L'oreal Composition cosmétique à base de précurseur(s) de radical thiyl pour la déformation permanente des fibres kératiniques
US7078424B2 (en) 1998-06-03 2006-07-18 Gpi Nil Holdings, Inc. N-linked sulfonamides of N-heterocyclic carboxylic acids or carboxylic acid isosteres
US7153883B2 (en) 1998-06-03 2006-12-26 Gpi Nil Holdings Inc. Carboxylic acids and carboxylic acid isosteres of N-heterocyclic compounds
US20130115177A1 (en) * 2004-06-12 2013-05-09 Signum Biosciences, Inc. Topical compositions and methods for epithelial-related conditions
US8841342B2 (en) 2002-08-09 2014-09-23 Vital Health Sciences Pty. Ltd. Carrier
US9168216B2 (en) 2005-06-17 2015-10-27 Vital Health Sciences Pty. Ltd. Carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
US9314527B2 (en) 2010-03-30 2016-04-19 Phosphagenics Limited Transdermal delivery patch
US9561243B2 (en) 2011-03-15 2017-02-07 Phosphagenics Limited Composition comprising non-neutralised tocol phosphate and a vitamin A compound
US9630937B2 (en) 2013-11-08 2017-04-25 Promentis Pharmaceuticals, Inc. Substituted N-acetyl-L-cysteine derivatives and related compounds
WO2017220998A1 (fr) * 2016-06-22 2017-12-28 Paxman Coolers Ltd Traitement de l'alopécie secondaire à la chimiothérapie.
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
WO2019083288A1 (fr) * 2017-10-25 2019-05-02 연세대학교 산학협력단 Composition comprenant de l'acide subérique en tant que principe actif pour prévenir la chute des cheveux ou activer la pousse des cheveux
US10973761B2 (en) 2015-12-09 2021-04-13 Phosphagenics Limited Pharmaceutical formulation
US11753435B2 (en) 2016-12-21 2023-09-12 Avecho Biotechnology Limited Process

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4567163A (en) * 1981-11-20 1986-01-28 Pietro Ismardi & C. S.P.A. Salicyclic acid derivatives of N-acetylcysteine and pharmacological use thereof
EP0415598A1 (fr) * 1989-08-16 1991-03-06 Unilever Plc Composition cosmétique
US5296500A (en) * 1991-08-30 1994-03-22 The Procter & Gamble Company Use of N-acetyl-cysteine and derivatives for regulating skin wrinkles and/or skin atrophy

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4567163A (en) * 1981-11-20 1986-01-28 Pietro Ismardi & C. S.P.A. Salicyclic acid derivatives of N-acetylcysteine and pharmacological use thereof
EP0415598A1 (fr) * 1989-08-16 1991-03-06 Unilever Plc Composition cosmétique
US5296500A (en) * 1991-08-30 1994-03-22 The Procter & Gamble Company Use of N-acetyl-cysteine and derivatives for regulating skin wrinkles and/or skin atrophy

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CANCER INVESTIGATION, Volume 10, No. 4, issued April 1992, JIMENEZ et al., "Treament With ImuVert/N-Acetylcysteine Protects Rats from Cyclophosphamide/Cytarabine-Indufed Alopecia", pages 271-276. *
CELLULAR IMMUNOLOGY, Volume 140, issued 1992, P. PERISTERIS et al., "N-Acetylcysteine and Flutathione as Inhibitors of Tumor Necrosis Factor Production", pages 390-399. *
H. BUNDGARRD, "Design of Prodrugs", Published 1985, by ELSEVIER (AMSTERDAM), pages 1-3 and 79. *
PHARMACOLOGY & TOXICOLOGY, Volume 66, issued 1990, T. LALITHA et al., "Effect of N-Acetyl-Cysteine, D-Penicillamine and Buthionine Dulfoximine on Glutathione Levels and CNSoxygen Toxicity in Rats", pages 56-61. *

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AU764073B2 (en) * 1997-06-04 2003-08-07 Gpi Nil Holdings, Inc. N-linked urea or carbamate of heterocyclic thioester hair growth compositions and uses
US6943187B2 (en) 1997-06-04 2005-09-13 Gpi Nil Holdings, Inc. Pyrrolidine derivative hair growth compositions and uses
US7078424B2 (en) 1998-06-03 2006-07-18 Gpi Nil Holdings, Inc. N-linked sulfonamides of N-heterocyclic carboxylic acids or carboxylic acid isosteres
WO1999062485A1 (fr) * 1998-06-03 1999-12-09 Gpi Nil Holdings, Inc. Compositions pour la croissance des cheveux a base d'urees ou de carbamates a liaison n de thioesters heterocycliques, et utilisation de ces compositions
US7153883B2 (en) 1998-06-03 2006-12-26 Gpi Nil Holdings Inc. Carboxylic acids and carboxylic acid isosteres of N-heterocyclic compounds
JP2005511725A (ja) * 2001-12-13 2005-04-28 バイタル ヘルス サイエンシズ プロプライアタリー リミティド 化合物の経皮輸送
WO2003049774A1 (fr) * 2001-12-13 2003-06-19 Vital Health Sciences Pty Ltd Transport transdermique de composes
US8841342B2 (en) 2002-08-09 2014-09-23 Vital Health Sciences Pty. Ltd. Carrier
EP1491181A3 (fr) * 2003-06-27 2006-03-22 L'oreal Composition cosmétique à base de précurseur(s) de radical thiyl pour la déformation permanente des fibres kératiniques
US20130115177A1 (en) * 2004-06-12 2013-05-09 Signum Biosciences, Inc. Topical compositions and methods for epithelial-related conditions
US9168216B2 (en) 2005-06-17 2015-10-27 Vital Health Sciences Pty. Ltd. Carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
US9314527B2 (en) 2010-03-30 2016-04-19 Phosphagenics Limited Transdermal delivery patch
US9561243B2 (en) 2011-03-15 2017-02-07 Phosphagenics Limited Composition comprising non-neutralised tocol phosphate and a vitamin A compound
US10188670B2 (en) 2011-03-15 2019-01-29 Phosphagenics Limited Composition
US10358414B2 (en) 2013-11-08 2019-07-23 Promentis Pharmaceuticals, Inc. Substituted N-acetyl-L-cysteine derivatives and related compounds
US10112897B2 (en) 2013-11-08 2018-10-30 Promentis Pharmaceuticals, Inc. Substituted N-acetyl-L-cysteine derivatives and related compounds
US9630937B2 (en) 2013-11-08 2017-04-25 Promentis Pharmaceuticals, Inc. Substituted N-acetyl-L-cysteine derivatives and related compounds
US10961187B2 (en) 2013-11-08 2021-03-30 Promentis Pharmaceuticals, Inc. Substituted N-acetyl-L-cysteine derivatives and related compounds
US10973761B2 (en) 2015-12-09 2021-04-13 Phosphagenics Limited Pharmaceutical formulation
CN109475428A (zh) * 2016-06-22 2019-03-15 帕克斯曼冷却器有限公司 用于治疗化学治疗诱发的脱发的组合物和装置
WO2017220998A1 (fr) * 2016-06-22 2017-12-28 Paxman Coolers Ltd Traitement de l'alopécie secondaire à la chimiothérapie.
JP2019524664A (ja) * 2016-06-22 2019-09-05 パックスマン クーラーズ リミテッドＰａｘｍａｎ Ｃｏｏｌｅｒｓ Ｌｉｍｉｔｅｄ 化学療法誘発性脱毛症の治療のための組成物および装置
CN109475428B (zh) * 2016-06-22 2022-07-05 帕克斯曼冷却器有限公司 用于治疗化学治疗诱发的脱发的组合物和装置
JP7555692B2 (ja) 2016-06-22 2024-09-25 パックスマン クーラーズ リミテッド 化学療法誘発性脱毛症の治療のための組成物および装置
US11753435B2 (en) 2016-12-21 2023-09-12 Avecho Biotechnology Limited Process
WO2019083288A1 (fr) * 2017-10-25 2019-05-02 연세대학교 산학협력단 Composition comprenant de l'acide subérique en tant que principe actif pour prévenir la chute des cheveux ou activer la pousse des cheveux

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