US20170042859A1 - Compositions and methods for treating alopecia - Google Patents

Compositions and methods for treating alopecia Download PDF

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US20170042859A1
US20170042859A1 US15/233,057 US201615233057A US2017042859A1 US 20170042859 A1 US20170042859 A1 US 20170042859A1 US 201615233057 A US201615233057 A US 201615233057A US 2017042859 A1 US2017042859 A1 US 2017042859A1
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composition
concentration
alopecia
minoxidil
cyclosporine
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David Weinstein
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David Weinstein Consulting Inc
Rivertown Therapeutics Inc
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Rivertown Therapeutics Inc
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Priority to US15/233,057 priority Critical patent/US20170042859A1/en
Publication of US20170042859A1 publication Critical patent/US20170042859A1/en
Priority to US15/478,547 priority patent/US10285977B2/en
Assigned to DAVID WEINSTEIN CONSULTING, INC. reassignment DAVID WEINSTEIN CONSULTING, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WEINSTEIN, DAVID E
Priority to US15/848,628 priority patent/US10363240B2/en
Priority to US16/356,660 priority patent/US20190216775A1/en
Priority to US16/358,781 priority patent/US20190216777A1/en
Priority to US16/877,485 priority patent/US20200276158A1/en
Priority to US16/877,484 priority patent/US20200276157A1/en
Priority to US17/124,572 priority patent/US20210100772A1/en
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K8/42—Amides
    • A—HUMAN NECESSITIES
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    • 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
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
    • 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
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • 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
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/0616—Skin treatment other than tanning
    • A61N5/0617—Hair treatment
    • A—HUMAN NECESSITIES
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    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/067—Radiation therapy using light using laser light

Definitions

  • the present invention is directed to a composition for treating alopecia containing a compound that binds FK506 binding protein 4 suitable for administration to humans.
  • the present invention is further directed to treating alopecia in humans by administering a composition of the invention.
  • Androgenic alopecia i.e. male pattern baldness
  • alopecia poses serious psycho-social issues for millions of effected individuals. These individuals include 54% of all US men aged 30 or more and 50 to 75% of US women over the age of 65.
  • Testosterone a lipophilic molecule that diffuses the cell membrane, is converted into its more active form, dihydrotestosterone (“DHT”), by cytoplasmic 5-AR.
  • DHT dihydrotestosterone
  • 5-AR cytoplasmic 5-AR
  • type 2 5-AR found in the skin and the inner root sheath of hair follicles. Burkhart C. G., et al., 5 alpha-reductase and finasteride in pattern alopecia and acne, Journal of Drugs in Dermatology, 2004, 3, 363-364.
  • DHT Once DHT enters the nucleus it binds to the androgen receptor, regulating gene expression.
  • the genes involved in mediating male pattern baldness have yet to be identified.
  • Minoxidil was originally developed as a systemic vasodilating agent to treat hypertension, however many patients suffered with disseminated hypertrichosis as a result of treatment. Bienova M., et al, Androgenetic alopecia and current methods of treatment, Acta Dermatovenerologica Alpina, Pannonica, et Adriatica, 2005, 14, 5-8. It was soon discovered that topical application of minoxidil results in limited hair restoration, largely confined to the sites of application.
  • DPCs dermal papilla cells
  • VEGF vascular endothelial growth factor
  • HGF hepatocyte growth factor
  • IGF-1 insulin-like growth factor 1
  • BMP-4 bone morphogenic protein 4
  • minoxidil is known to potentiate HGF and IGF-1 actions through the activation of uncoupled sulfonylurea receptor (“SUR”) on the plasma membrane of DPCs.
  • SUR uncoupled sulfonylurea receptor
  • Minoxidil has been shown to be effective in maintaining existing hair follicles, but ineffective in stimulating new follicles.
  • Sinclair has shown that only 15% of those treated with minoxidil had new hair growth, while 50% of those treated maintained existing hair, with no additional loss at 6-months.
  • Sinclair R. Male pattern androgenetic alopecia, BMJ, 1998, 317, 865-869. Notably, discontinuation of minoxidil treatment results in the resumption of hair loss, presumably through the loss of trophic support.
  • Finasteride unlike minoxidil, is an oral medication, with potentially severe side effects including erectile dysfunction, gynecomastia, and loss of libido. Finasteride is a competitive 5-AR inhibitor that inhibits the conversion of testosterone to DHT, resulting in a decrease in androgenic alopecia. Price V. H., Treatment of hair loss, The New England Journal of Medicine, 1999, 341, 964-973.
  • cyclosporine A (“CSA”), an immunosuppressive drug intended to prevent rejection of solid organ allografts, promotes robust hair growth in up to 80% of transplant patients receiving systemic treatment.
  • CSA cyclosporine A
  • CSA is highly effective in preventing graft rejection, it has severe and undesirable side effects when taken orally or parenterally.
  • CSA is a poor choice for systemic administration in all but the most life threatening situations.
  • the topical administration of low-dose, topical CSA is not associated with immune suppression, hypertension, renal toxicity or the other severe or life-threatening side effects seen with oral CSA administration.
  • CSA binds to the calmodulin-dependent, serine/threonine protein phosphatase calcineurin, which in turn binds to NFAT, and relieves the repression on the follicular stem cell. With the NFAT repression relieved, the follicular stem cells proliferate, resulting in precocious follicular growth.
  • RT175 is a 241 Dalton molecule having the following chemical structure
  • RT175 has been shown to re-grow hair in rats that have undergone craniotomy prior to neurosurgery.
  • RT175 has also been shown to induce hair growth in shaved mice.
  • RT175 binds with high affinity to FK506 binding protein 4 (“FKBP52”).
  • FKBP52 is known to act as a molecular chaperone for the glucocorticoid receptor (“GR”).
  • RT175/GR complex After binding to ligand, the RT175/GR complex translocates to the nucleus. Banerjee A., et al. Control of glucocorticoid and progesterone receptor subcellular localization by the ligand-binding domain is mediated by distinct interactions with tetratricopeptide repeat proteins, Biochemistry, 2008, 47, 10471-10480. It has been shown that that RT175 treatment of fibroblasts for 2 hours results in the translocation of FKBP52 to the nucleus, presumably with its cargo.
  • WNT5A is regulated by PAX2 and may be involved in blastemal predominant Wilms tumorigenesis, Neoplasia, 2008, 10, 1470-1480; Nakao K., et al., IGF2 modulates the microenvironment for osteoclastogenesis, Biochem Biophys Res Commun, 2009, 378, 462-466; Sun Y., et al., Evolutionarily conserved transcriptional co-expression guiding embryonic stem cell differentiation, PLoS ONE, 2008, 3, e3406; Andl T., et al., WNT signals are required for the initiation of hair follicle development, Developmental Cell, 2002, 2, 643-653.
  • the present invention is directed to a composition for the treatment of alopecia comprising a compound that binds FK506 binding protein 4.
  • the present invention is directed to a composition for the treatment of alopecia comprising a compound that binds FK506 binding protein 4 and one or more additional active agents selected from the group consisting of minoxidil, cyclosporine A, and a combination thereof.
  • the present invention is directed to a composition for the treatment of alopecia comprising a compound of formula (I)
  • R 1 is COOH, a methoxy, a phenyl, a benzyl, a substituted phenyl or a substituted benzyl.
  • substituted phenyl and substituted benzyl of the compound of formula (I) are each individually substituted with an alkyl group, a methoxy group or a halogen.
  • the compound of formula (I) is selected from the group consisting of
  • the compound of formula (I) is RT175.
  • the present invention is directed to a composition for the treatment of alopecia comprising a compound of formula (II)
  • compositions of the present invention further comprise one or more excipients selected from the group consisting of urea, polyoxyl 40 stearate, a carbomer, cetyl alcohol, glyceryl monostearate, mineral oil, ethanol, propylene glycol, polyglycol 300, citric acid, sodium phosphate dibasic, stearyl alcohol, isopropyl myristate, sodium hydroxide, petroleum jelly, xanthan gum, white petrolatum, sorbitol solution, cetearyl alcohol, ceteareth-20, simethicone, sodium benzoate, glyceryl monostearate, polyethylene glycol monostearate, sorbic acid, butylated hydroxytoluene and water.
  • excipients selected from the group consisting of urea, polyoxyl 40 stearate, a carbomer, cetyl alcohol, glyceryl monostearate, mineral oil, ethanol, propylene glycol, polyglycol 300,
  • the one or more excipients are a combination of white petrolatum, sorbitol solution, propylene glycol, cetearyl alcohol, ceteareth-20, simethicone, glyceryl monostearate, polyethylene glycol monostearate, sorbic acid and butylated hydroxytoluene.
  • the one or more excipients are a combination of urea, polyoxyl 40 stearate, propylene glycol, polyglycol 300 (Medibase C available from Medisca), citric acid, sodium phosphate dibasic, cetyl alcohol, stearyl alcohol, isopropyl myristate, sodium benzoate and water.
  • the one or more excipients are a combination of about 1,200 grams of urea, about 103 grams polyoxyl 40 stearate, about 63 milliliters of propylene glycol, about 47 milliliters of polyglycol 300, about 1 gram of citric acid, about 2 grams of sodium phosphate, about 94 grams of cetyl alcohol, about 200 grams of stearyl alcohol, about 219 grams of isopropyl myristate, about 3 grams of sodium benzoate and about 1,000 to about 1,500 milliliters of water.
  • the present invention is directed to a composition for the treatment of alopecia comprising minoxidil at a concentration from about 1% to about 10% w/v, cyclosporine A at a concentration from about 0.01% to about 1% w/v and RT175 at a concentration from about 0.000001% to about 0.0001% w/v.
  • the present invention is directed to a composition for the treatment of alopecia comprising minoxidil at a concentration from about 1% to about 10% w/v, cyclosporine A at a concentration from about 0.01% to about 1% w/v, RT175 or a pharmaceutically acceptable salt or ester thereof at a concentration from about 0.000001% to about 0.0001% w/v, ethanol at a concentration from about 10% to about 50% w/v, propylene glycol at a concentration from about 10% to about 70% w/v and water at a concentration from about 10% to about 50% w/v.
  • the present invention is directed to a composition for the treatment of alopecia comprising minoxidil at a concentration of about 5% w/v, cyclosporine A at a concentration of about 0.12% w/v and RT175 or a pharmaceutically acceptable salt or ester thereof at a concentration of about 0.000012% w/v.
  • the present invention is directed to a composition for the treatment of alopecia comprising minoxidil at a concentration of about 5% w/v, cyclosporine A at a concentration of about 0.12% w/v, RT175 or a pharmaceutically acceptable salt or ester thereof at a concentration of about 0.000012% w/v, ethanol at a concentration of about 28% w/v, propylene glycol at a concentration of about 47% w/v and water at a concentration of about 19% w/v.
  • the present invention is directed to a method of treating alopecia comprising topically administering to a human in need thereof an effective amount of a composition of the present invention.
  • the present invention is directed to a method of treating androgenic alopecia comprising topically administering to a human in need thereof an effective amount of a composition of the present invention.
  • the present invention is directed to a method of treating alopecia in a human in need thereof comprising topically administering concurrently or sequentially minoxidil, cyclosporine A and a compound that binds FK506 binding protein 4.
  • the human in need of alopecia treatment suffers from achromotrichia and the method provides regrowth of pigmented hair, preferably the achromotrichia is due to aging.
  • the present invention is directed to a method of enhancing facial hair (including eye brow) growth comprising topically administering to a human in need thereof an effective amount of the compositions of the present invention.
  • the present invention is directed to a method of treating alopecia in a human in need thereof comprising topically administering concurrently or sequentially minoxidil at a concentration from about 1% to about 10% w/v, cyclosporine A at a concentration from about 0.01% to about 1% w/v and RT175 or a pharmaceutically acceptable salt or ester thereof at a concentration from about 0.000001% to about 0.0001% w/v.
  • the present invention is directed to a method of treating alopecia in a human in need thereof comprising topically administering concurrently or sequentially minoxidil at a concentration of about 5% w/v, cyclosporine A at a concentration of about 0.12% w/v and RT175 or a pharmaceutically acceptable salt or ester thereof at a concentration of about 0.000012% w/v.
  • the present invention is directed to a method of treating alopecia in a human in need thereof comprising topically administering to a human in need thereof an effective amount of the composition comprising minoxidil, cyclosporine and RT175 or a pharmaceutically acceptable salt or ester thereof, and urea.
  • the present invention is directed to a method of treating alopecia in a human in need thereof comprising the steps of:
  • the present invention is directed to a method of treating alopecia in a human in need thereof comprising the steps of:
  • the present invention is directed to a method of treating alopecia comprising topically administering concomitantly or sequentially a compound that binds FK506 binding protein 4 and at least one compound selected from the group consisting of minoxidil and cyclosporine A.
  • the present invention is directed to a method of treating alopecia comprising topically administering concomitantly or sequentially a compound that binds FK506 binding protein 4, minoxidil and cyclosporine A.
  • FIG. 1 Punch biopsies of mouse dorsal skin treated topically with RT175.
  • FIG. 2 Scalp closure following craniotomy in rats treated topically with RT175.
  • FIG. 3 Skin lesions in pigs treated topically with RT175.
  • FIG. 4 59-year-old male with androgenic alopecia treated topically with RT175 and RT175/minoxidil.
  • FIG. 5 57-year-old male with androgenic alopecia treated topically with RT175/minoxidil/cyclosporine A.
  • FIG. 6 57-year-old male with androgenic alopecia and achromotrichia treated topically with RT175/minoxidil/cyclosporine A.
  • FIG. 7 24-year-old male with inadequate facial hair growth treated with RT175/minoxidil/cyclosporine A.
  • FIG. 8 Skin regeneration and hair regrowth following shaving and rasping of mice dorsal skin and 10-day treatment with RT1061.
  • composition for the treatment of alopecia which has reduced side effects and prolonged effects over available treatments.
  • minoxidil refers to the compound of the formula
  • cyclosporine A refers to the compound of the formula
  • RT175 refers to the compound of the formula
  • alopecia refers to the loss of hair from the body, whether on the scalp, body, face or eyebrows, and due to a pathological condition.
  • pharmaceutically acceptable refers to ingredients that are not biologically or otherwise undesirable in a topical application.
  • the term “effective amount” refers to the amount necessary to treat a patient in need thereof.
  • Androgenic alopecia refers to an autosomal disorder which begins in puberty in genetically disposed individuals. Androgenic alopecia is also known as hereditary baldness, male pattern baldness, and seborrheic alopecia. Androgenic alopecia may occur in males and females.
  • achromotrichia refers to an absence or loss of pigment in the hair shaft. Achromotrichia may be due to aging, stress, diet or disease.
  • fractional laser therapy or “fractional laser treatment” refers to application of a laser beam that is divided into thousands of zones and is capable of reacting with both the epidermis and dermis. This treatment is sometimes referred to as fractional laser photothermolysis.
  • Fractional lasers may be based on, but are not limited to, erbium, carbon dioxide, diode, yttrium aluminum garnet (YAG), neodymium-doped yttrium aluminum garnet, yttrium scandium gallium garnet (YSGG) or combinations thereof.
  • fractional lasers sufficient for the present invention include, but are not limited to, Profractional (Sciton, Inc.), Halo (Sciton, Inc.), Emerge (Cynosure Palomar), Lux1540 (Cynosure Palomar), Lux2940 (Cynosure Palomar), Deep FX (Lumenis), Active FX (Lumenis), Fraxel re:Pair® (Fraxel re:pair is a registered trademark of Reliant Technologies LLC; available through Solta Medical), Fraxel re:Store® (Fraxel re:store is a registered trademark of Reliant Technologies LLC; available through Solta Medical), Clear+Brilliant (Solta Medical), Fraxel® Dual 1550/1027 (Fraxel® is a registered trademark of Reliant Technologies LLC; available through Solta Medical) and Pearl® Fractional (Pearl is a registered trademark of Cutera, Inc.).
  • treatment refers to preventing hair loss and growing, regrowing and regenerating hair.
  • pharmaceutically acceptable refers to ingredients that are not biologically or otherwise undesirable in a topical application.
  • the term “effective amount” refers to the amount necessary to treat a patient in need thereof.
  • % w/v and “percent w/v” refer to the percent weight of the total formulation.
  • R 1 refers to a substituent selected from the group consisting of COOH, a methoxy, a phenyl, a benzyl, a substituted phenyl and a substituted benzyl.
  • substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • alkyl refers to a branched or straight-chain alkyl consisting of a saturated hydrocarbon group of 1 to 24 carbon atoms (C 1 -C 24 ) unless otherwise stated.
  • the alkyl group can be cyclic or acyclic.
  • all numerical values relating to amounts, weights, and the like, that are defined as “about” each particular value is plus or minus 10%.
  • the phrase “about 10% w/v” is to be understood as “9% to 11% w/v.” Therefore, amounts within 10% of the claimed value are encompassed by the scope of the claims.
  • compositions of the present invention may contain a solvent.
  • Solvents of the present invention include, but are not limited to, ethanol, propylene glycol, water, polyethylene glycol, glycerol, isostearic acid, oleic acid, trolamine, tromethamine, triacetin, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, butanol, iso-amyl acetate, methanol, propanol, isobutene, pentane, hexane, chlorobutanol, turpentine, cytopentasiloxane, cyclomethicone, methyl ethyl ketone and mixtures thereof.
  • Total solvents of the present invention may be at concentrations from about 10% to about 99% w/v, preferably from about 50% to about 99% w/v and more preferably from about 80% to about 95% w/v.
  • the solvent is a mixture of ethanol, propylene glycol and water, more preferably from about 10% to about 50% w/v ethanol, from about 10% to about 70% w/v propylene glycol and from about 10% to about 50% w/v water and even more preferably about 28% w/v ethanol, about 47% w/v propylene glycol and about 19% w/v water.
  • the present invention is directed to a composition for the treatment of alopecia comprising a compound that binds FK506 binding protein 4.
  • the present invention is directed to a composition for the treatment of alopecia comprising a compound that binds FK506 binding protein 4 and one or more additional active agents selected from the group consisting of minoxidil, cyclosporine A, and a combination thereof.
  • the present invention is directed to a composition for the treatment of alopecia comprising a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, minoxidil and cyclosporine A,
  • R1 is COOH, a methoxy, a phenyl, a benzyl, a substituted phenyl or a substituted benzyl.
  • substituted phenyl and substituted benzyl of the compound of formula (I) are each individually substituted with an alkyl group, a methoxy group or a halogen.
  • the compound of formula (I) is selected from the group consisting of (“RT175”), (“RT1061”), (“RT1062”) and (“RT1063”) and a pharmaceutically acceptable salt or ester thereof.
  • the compound of formula (I) is RT175.
  • the present invention is directed to a composition for the treatment of alopecia comprising a compound of formula (II) or a pharmaceutically acceptable salt or ester thereof, minoxidil and cyclosporine A.
  • compositions of the present invention further comprise one or more excipients selected from the group consisting of urea, polyoxyl 40 stearate, a carbomer, cetyl alcohol, glyceryl monostearate, mineral oil, ethanol, propylene glycol, polyglycol 300, citric acid, sodium phosphate dibasic, stearyl alcohol, isopropyl myristate, sodium hydroxide, petroleum jelly, xanthan gum, white petrolatum, sorbitol solution, cetearyl alcohol, ceteareth-20, simethicone, sodium benzoate, glyceryl monostearate, polyethylene glycol monostearate, sorbic acid, butylated hydroxytoluene and water.
  • excipients selected from the group consisting of urea, polyoxyl 40 stearate, a carbomer, cetyl alcohol, glyceryl monostearate, mineral oil, ethanol, propylene glycol, polyglycol 300,
  • the one or more excipients are a combination of white petrolatum, sorbitol solution, propylene glycol, cetearyl alcohol, ceteareth-20, simethicone, glyceryl monostearate, polyethylene glycol monostearate, sorbic acid and butylated hydroxytoluene.
  • the one or more excipients are a combination of urea, polyoxyl 40 stearate, propylene glycol, polyglycol 300 (Medibase C available from Medisca), citric acid, sodium phosphate dibasic, cetyl alcohol, stearyl alcohol, isopropyl myristate, sodium benzoate and water.
  • the one or more excipients are a combination of about 1,200 grams of urea, about 103 grams polyoxyl 40 stearate, about 63 milliliters of propylene glycol, about 47 milliliters of polyglycol 300, about 1 gram of citric acid, about 2 grams of sodium phosphate, about 94 grams of cetyl alcohol, about 200 grams of stearyl alcohol, about 219 grams of isopropyl myristate, about 3 grams of sodium benzoate and about 1,000 to about 1,500 milliliters of water.
  • the present invention is directed to a composition for the treatment of alopecia comprising minoxidil at a concentration from about 1% to about 10% w/v, cyclosporine A at a concentration from about 0.01% to about 1% w/v and RT175 at a concentration from about 0.000001% to about 0.0001% w/v.
  • the present invention is directed to a composition for the treatment of alopecia comprising minoxidil at a concentration from about 1% to about 10% w/v, cyclosporine A at a concentration from about 0.01% to about 1% w/v, RT175 or a pharmaceutically acceptable salt or ester thereof at a concentration from about 0.000001% to about 0.0001% w/v, ethanol at a concentration from about 10% to about 50% w/v, propylene glycol at a concentration from about 10% to about 70% w/v and water at a concentration from about 10% to about 50% w/v.
  • the present invention is directed to a composition for the treatment of alopecia comprising minoxidil at a concentration of about 5% w/v, cyclosporine A at a concentration of about 0.12% w/v and RT175 or a pharmaceutically acceptable salt or ester thereof at a concentration of about 0.000012% w/v.
  • the present invention is directed to a composition for the treatment of alopecia comprising minoxidil at a concentration of about 5% w/v, cyclosporine A at a concentration of about 0.12% w/v, RT175 or a pharmaceutically acceptable salt or ester thereof at a concentration of about 0.000012% w/v, ethanol at a concentration of about 28% w/v, propylene glycol at a concentration of about 47% w/v and water at a concentration of about 19% w/v.
  • the present invention is directed to a method of treating alopecia comprising topically administering to a human in need thereof an effective amount of a composition of the present invention.
  • the present invention is directed to a method of treating androgenic alopecia comprising topically administering to a human in need thereof an effective amount of a composition of the present invention.
  • the present invention is directed to a method of treating alopecia in a human in need thereof comprising topically administering concurrently or sequentially minoxidil, cyclosporine A and a compound that binds FK506 binding protein 4.
  • the human in need of alopecia treatment suffers from achromotrichia and the method provides regrowth of pigmented hair, preferably the achromotrichia is due to aging.
  • the present invention is directed to a method of enhancing facial hair growth (including but not limited to eye brows) comprising topically administering to a human in need thereof an effective amount of the compositions of the present invention.
  • the present invention is directed to a method of treating alopecia in a human in need thereof comprising topically administering concurrently or sequentially minoxidil at a concentration from about 1% to about 10% w/v, cyclosporine A at a concentration from about 0.01% to about 1% w/v and RT175 or a pharmaceutically acceptable salt or ester thereof at a concentration from about 0.000001% to about 0.0001% w/v.
  • the present invention is directed to a method of treating alopecia in a human in need thereof comprising topically administering concurrently or sequentially minoxidil at a concentration of about 5% w/v, cyclosporine A at a concentration of about 0.12% w/v and RT175 or a pharmaceutically acceptable salt or ester thereof at a concentration of about 0.000012% w/v.
  • the present invention is directed to a method of treating alopecia comprising topically administering concomitantly or sequentially a compound that binds FK506 binding protein 4 and at least one compound selected from the group consisting of minoxidil and cyclosporine A.
  • the present invention is directed to a method of treating alopecia comprising topically administering concomitantly or sequentially a compound that binds FK506 binding protein 4, minoxidil and cyclosporine A.
  • the present invention is directed to a composition for the treatment of alopecia comprising minoxidil at a concentration of about 5% w/v, cyclosporine A at a concentration of about 0.12% w/v and RT175 or a pharmaceutically acceptable salt or ester thereof, an analog thereof or a derivative thereof at a concentration of about 0.000012% w/v.
  • the present invention is directed to a composition for the treatment of alopecia comprising minoxidil at a concentration of about 5% w/v, cyclosporine A at a concentration of about 0.12% w/v, RT175 or a pharmaceutically acceptable salt or ester thereof, an analog thereof or a derivative thereof at a concentration of about 0.000012% w/v, ethanol at a concentration of about 28% w/v, propylene glycol at a concentration of about 47% w/v and water at a concentration of about 19% w/v.
  • the present invention is directed to a composition for the treatment of alopecia comprising minoxidil at a concentration of about 5% w/v, cyclosporine A at a concentration of about 0.12% w/v, RT175 or a pharmaceutically acceptable salt or ester thereof, an analog thereof or a derivative thereof at a concentration of about 0.000012% w/v, and one or more excipients selected from the group consisting of urea, a carbomer, cetyl alcohol, glyceryl monostearate, mineral oil, propylene glycol, sodium hydroxide, petroleum jelly, xanthan gum and water, in a preferred embodiment the urea is at a concentration of about 40% w/v.
  • the present invention is directed to a composition for the treatment of alopecia comprising minoxidil, cyclosporine A, RT175 or a pharmaceutically acceptable salt or ester thereof, an analog thereof or a derivative thereof and one or more excipients selected from the group consisting of urea, a carbomer, cetyl alcohol, glyceryl monostearate, mineral oil, propylene glycol, sodium hydroxide, petroleum jelly, xanthan gum and water.
  • the urea is at a concentration of about 40% w/v.
  • mice underwent 5 millimeter, full thickness, punch biopsies of their dorsal skin. Mice were then treated topically with 120 nanograms (“ng”) of RT175, daily.
  • ng nanograms
  • mice receiving RT175 over vehicle 5 days after punch biopsy healing of the wound site is clearly accelerated in mice receiving RT175 over vehicle. See FIG. 1 .
  • 9 days after punch biopsy the RT175 treated wounds displayed robust hair regeneration, with intact follicles even in the middle of the wound. See FIG. 1 .
  • the vehicle treated tissue has yet to regenerate follicles in the center of the wound site.
  • a single pig underwent bilateral, slit thickness, skin surgery leaving lesions on opposite sides of the pig. One of these lesions was then treated topically with 120 ng of RT175, daily. The other lesion was treated with vehicle only. The lesion treated with RT175, and not the lesion treated with vehicle only, exhibited early and transient appearance of granulation tissue, followed by rapid revascularization, invasion of newly formed skin from wound edges, accelerated repigmentation and regeneration of hair. See FIG. 3 and compare 3 ( b ) to 3 ( a ). The de novo hair growth is consistent with the regeneration of the upper hair follicles, most of which would have been removed as the microtome sliced through the skin in creating the split thickness wounds.
  • a 59-year-old white with androgenic alopecia was treated twice daily with 1 milliliter of a composition containing 120 nanograms/milliliter (“ng/mL”) of RT175 in 30% w/v ethanol, 50% w/v propylene glycol and 20% w/v water.
  • the composition was applied directly to the bald skin on the crown of the head once in the morning after showering and once before going to bed. Baseline hair distribution is shown in FIG. 4( a ) .
  • FIG. 4( b ) shows an absence of hair growth 4 months after RT175 treatment.
  • the subject went on treatment holiday for 1 month, before beginning treatment with 120 ng/mL of RT175 and 5% w/v minoxidil in 30% w/v ethanol, 50% w/v propylene glycol and 20% w/v water.
  • FIG. 4( c ) depicts the subjects scalp before initiation of the second round of treatment.
  • FIG. 4( d ) shows the failure of the combination of RT175 and minoxidil to induce new hair growth.
  • a 57-year-old male with androgenic alopecia was treated twice daily with 1 milliliter of a composition containing 120 ng/mL of RT175 (0.000012% w/v), 1.2 milligrams per milliliter (“mg/mL”) of cyclosporine A (0.12% w/v) and 5% w/v minoxidil in about 28% w/v ethanol, about 47% w/v propylene glycol, and about 19% w/v water.
  • the composition was applied directly to the bald skin on the crown of the head once in the morning after showering and once before going to bed. The extent of hair loss is depicted in FIG. 5 in the panel at the upper left (baseline).
  • FIG. 5 upper right panel shows an unexpected and extensive hair growth after 21 days.
  • FIG. 5 middle left panel shows continued hair growth after 28 days.
  • FIG. 5 middle right panel show continued hair growth after 35 days and lower left panel shows additional hair growth at 42 days.
  • a 57-year-old male with androgenic alopecia and who had already gone through achromotrichia was treated twice daily continuously for 20 weeks with 1 milliliter of a composition containing 120 ng/mL of RT175 (0.000012% w/v), 1.2 milligrams per milliliter (“mg/mL”) of cyclosporine A (0.12% w/v) and 5% w/v minoxidil in about 28% w/v ethanol, about 47% w/v propylene glycol, and about 19% w/v water.
  • the composition was initially applied directly to the bald skin at the crown of the head once after showering in the morning and once before going to bed.
  • composition of the invention not only regrows hair in patients with androgenic alopecia but also regrows pigmented hair in patients with androgenic alopecia who have undergone achromotrichia due to aging.
  • Subject 1 a 50-year-old male, was subjected to topical administration of RT175, once in the morning after showering and once before going to bed for 60 days. After 30 days-post treatment Subject 1 had not experienced significant hair regrowth. 60 days-post RT175 treatment Subject 1 was subjected to Fraxel® fractional laser treatment of areas of the scalp affected by alopecia using standard Fraxel® protocol. 45 day-post Fraxel® treatment Subject 1 had not experienced substantial hair regrowth. 7 days later, Subject 1 was retreated with Fraxel® followed 8 hours later by topical treatment with a composition containing RT175. Subject 1 then continued topical treatment with the RT175 composition for 60 days.
  • FIG. 7 shows baseline facial hair.
  • FIG. 7 lower panels, shows facial hair following three weeks of twice daily treatment with RT175/cyclosporine A/minoxidil.
  • mice of both sexes with weight between 45 and 50 grams were shaved and rasped to induce dermabrasion lesions.
  • the animals were then randomly assigned (5 per treatment arm) to one of two groups to receive either 5 ⁇ L of 100 nanomolar RT1061 or a vehicle control.
  • RT1061 or vehicle control was applied topically to the lesion site once each day including immediately after dermabrasion.

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US15/478,547 US10285977B2 (en) 2015-08-13 2017-04-04 Compositions and methods for treating alopecia
US15/848,628 US10363240B2 (en) 2015-08-13 2017-12-20 Compositions and methods for treating alopecia
US16/356,660 US20190216775A1 (en) 2015-08-13 2019-03-18 Compositions and methods for treating alopecia
US16/358,781 US20190216777A1 (en) 2015-08-13 2019-03-20 Compositions and methods for treating alopecia
US16/877,485 US20200276158A1 (en) 2015-08-13 2020-05-18 Compositions and methods for treating alopecia
US16/877,484 US20200276157A1 (en) 2015-08-13 2020-05-18 Compositions and methods for treating alopecia
US17/124,572 US20210100772A1 (en) 2015-08-13 2020-12-17 Methods for treating alopecia and achromotrichia

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