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WO2025069091A1 - Nouvelle composition pharmaceutique topique pour la prévention et le traitement de la chute des cheveux - Google Patents

Nouvelle composition pharmaceutique topique pour la prévention et le traitement de la chute des cheveux Download PDF

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Publication number
WO2025069091A1
WO2025069091A1 PCT/IN2024/051888 IN2024051888W WO2025069091A1 WO 2025069091 A1 WO2025069091 A1 WO 2025069091A1 IN 2024051888 W IN2024051888 W IN 2024051888W WO 2025069091 A1 WO2025069091 A1 WO 2025069091A1
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weight
percent
topical
composition
levocetirizine
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PCT/IN2024/051888
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English (en)
Inventor
Fredrik Enqvist
Desomayanandam PRABAKARAN
Kamalanathan SRINIVASAN
Mandapati Ravindhar REDDY
Ananya De BHOWMICK
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Pdfe Pharma Innovations Fzco
Sterin Labs Private Ltd
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Pdfe Pharma Innovations Fzco
Sterin Labs Private Ltd
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Publication of WO2025069091A1 publication Critical patent/WO2025069091A1/fr
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Anticipated expiration legal-status Critical

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    • 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
    • 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
    • A61K31/495—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
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • 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
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone

Definitions

  • the present invention relates to a synergistic topical hair growth formulation comprising Levocetirizine and Bimatoprost for promoting hair growth and treating Androgenic Alopecia.
  • AGA Androgenetic alopecia
  • AGA is an androgen-dependent hereditary disorder influenced by a variety of genetic and environmental factors.
  • AGA is the most common type of alopecia and has a chronic disease course, with its main symptoms being progressive hair loss and hair follicle atrophy, which may be accompanied by greasy scalp, dandruff, and itching. Since hair loss directly affects the patient’s appearance, it often has a significant impact on the patient's social activities and mental health and may lead to a decreased quality of life, while worsening social barriers and causing depression in severe cases (Yamazaki M et al., J Dermatol 2011;38:773-7.). With recent years of socioeconomic development, many patients have pursued a more positive outcome, and the role of AGA treatment has thus been increasingly recognized.
  • AGA hair follicle atrophy, miniaturization, shortened anagen phase, prolonged telogen phase, hair follicle involvement, and abnormal growth cycle may be the key links during its pathogenesis. It is well believed that the occurrence and development of AGA are closely related to endocrine disorders, especially the abnormal metabolism of androgen in the hair follicles on the scalp (Urysiak-Czubatka I et al., Postepy Dermatol Alergol 2014;31 :207-15.). Drugs for AGA include hormone regulators, vasodilators, and immunomodulators; however, few drugs that can effectively promote hair growth have been available.
  • the drugs that are commonly used for AGA are still Finasteride and Minoxidil; however, Finasteride has been reported to cause sexual side effects such as loss of libido and impotence, whereas the use of minoxidil has been associated with irritant dermatitis, allergic contact dermatitis, headache, and hypotension (Zhang Y, Second Military Medical University, 2016).
  • Many new methods have been developed for AGA treatment including autologous hair transplantation, hair follicle reconstruction, and low-energy laser therapy (Ghanaat M. South Med J 2010;103:917-21), these are expensive and invasive and thus cannot be widely applied.
  • Prostaglandins are a group of unsaturated fatty acids that are enzymatically metabolized. They are widely distributed in various tissues and body fluids and can mediate multiple physiological functions and inflammatory reactions such as cell proliferation, differentiation, and apoptosis.
  • Cyclooxygenase induces PGs to be converted from arachidonic acid to unstable prostaglandin H2 and then further processed into various biologically active prostaglandins (e.g., prostacyclin, PGD2, PGE2, PGF2a, and PGI2) by the corresponding prostaglandin synthetases.
  • PGE2 and PGF2a can promote hair growth, whereas PGD2 can inhibit hair growth and aggravate hair follicle miniaturization (Heilmann S et al., Br J Dermatol 2013;169:222-4).
  • Jeong et al. Jeong KH, Jung JH, Kim JE, et al. nt. J. Mol. Sci. 2018, 79(2), 556) have found that PGD2 leads to the activation of androgen receptors by regulating the DP2 and AKT/GSK3P signaling pathways on hDPCs.
  • Levocetirizine is a safe, highly selective, and highly affinitive new-generation histamine Hl receptor antagonist that has been widely used in the treatment of skin, respiratory, and ocular allergies.
  • XYZAL® an FDA approved Marketed Product of Levocetirizine dihydrochloride is indicated for the relief of symptoms associated with allergic rhinitis (seasonal and perennial) in adults and children 6 years of age and older. Further it is indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 years of age and older.
  • Bimatoprost is a synthetic prostamide F2a analog (PGF2a).
  • LATISSE® is an FDA Approved Bimatoprost ophthalmic solution, 0.03% (Allergan Inc, Irvine, CA) indicated to treat hypotrichosis of the eyelashes by increasing their growth including length, thickness and darkness. Although the precise mechanism of action is unknown the growth of eyelashes is believed to occur by increasing the percent of hairs in, and the duration of the anagen or growth phase.
  • Eyelashes are highly specialized, short hairs that have evolved to protect the eyes from foreign objects. They have marked differences to scalp hairs, and their follicles lack the normal arrector pili muscle. Nevertheless, eyelashes are produced by hair follicles and are replaced regularly via the hair follicle cycle like all other hairs (Karzan G. Khidhir et al., FASEB J. 2013, Feb; 27(2): 557-567). The difference between producing a long or short human hair is primarily due to alterations in the length of anagen, the growing part of the hair growth cycle, rather than the rate of hair growth, which is relatively constant in vivo.
  • Bimatoprost stimulates human scalp follicles in culture and rodent pelage follicles in vivo, mirroring eyelash behaviour, and scalp follicles contain Bimatoprost-sensitive prostamide receptors in vivo.
  • Bimatoprost is an effective alternative to treat scalp alopecia, as part of a novel therapeutic approach involving direct prostamide F2a receptor-mediated stimulation of dermal papilla cells within hair follicles (L Subedi et al., 2022, Drug Delivery).
  • the present invention intends to provide a synergistic combination of Levocetirizine that possess potential to counter Prostaglandin D2 (PGD2) mediated suppression of hair growth and Bimatoprost that possess potential to promote PGE2/Prostaglandin F2a mediated Enhancement of Hair Growth.
  • PPD2 Prostaglandin D2
  • Levocetirizine protects the hair follicle from micro inflammation which is thought to be the cause of irreversible damage in androgenic alopecia (AGA).
  • AGA irreversible damage in androgenic alopecia
  • the present invention broadens the pharmacotherapeutic approaches available for the treatment of hair loss. Further there is a need for a topical formulation comprising synergistic combination of Levocetirizine and Bimatoprost for improved efficacy in Androgenic Alopecia.
  • the present invention provides the solution for long term requirement of effective treatment of Androgenic Alopecia.
  • the current invention is pertaining to a topical pharmaceutical formulation containing a novel synergistic combination of Levocetirizine and Bimatoprost to prevent hair loss and improve hair growth parameters by acting on mechanisms that mediate anagen, catagen and telogen balance.
  • the current invention is a critical contribution to the pharmacotherapeutic approach for treating hair loss.
  • Levocetirizine of the combination provides an anti-inflammatory coverage and antiallergic effect against the inflammatory infiltrates that are notably observed in the regions affected with baldness in addition to inhibit the PGD2 at DP2 receptors and thereby neutralize the suppressive effects of PGD2 at the hair follicle.
  • Bimatoprost, the Prostaglandin (PGF2a) analog, of the combination directly acts on prostaglandin F2a receptor (FP) on dermal papillae and outer root sheath of the hair follicle to promote hair growth.
  • the synergistic combination of present invention restores the appropriate anagen to telogen balance and contributes to healthy hair.
  • the proposed topical pharmaceutical composition comprises Levocetirizine and Bimatoprost.
  • the topical pharmaceutical composition comprises suitable pharmaceutically acceptable excipients.
  • the present invention provides a topical pharmaceutical composition comprising Levocetirizine and Bimatoprost for promoting healthy hair growth in Androgenic Alopecia, which is harmless to the human body.
  • the present invention provides a topical pharmaceutical composition comprising Levocetirizine and Bimatoprost wherein the topical pharmaceutical compositions of present invention are topical solutions or topical solutions for spray.
  • the present invention provides a topical pharmaceutical composition comprising Levocetirizine and Bimatoprost wherein the topical pharmaceutical compositions of present invention are topical gels, topical creams and topical foams.
  • the present invention provides a topical pharmaceutical composition comprising Levocetirizine and Bimatoprost, wherein presence of Levocetirizine ranging from about 0.001%-10% (w/w) and Bimatoprost ranging from about 0.0001%-10% (w/w) with pharmaceutically acceptable excipients.
  • the present invention provides a method of treating androgenic alopecia comprising administering to the skin of a human requiring such treatment an effective amount of a composition of the present invention.
  • the present invention relates to the use of the compositions described herein for the preparation of a medicament for the treatment of androgenic alopecia.
  • the synergistic topical composition for present invention comprising Levocetirizine a “Hl Receptor Antagonist” is to is to activate the Wnt/p-catenin pathway (increasing PGE2 and decreasing PGD2 activities) that drives the anagen (active) phase of the hair follicle and Bimatoprost a “prostaglandin analog” deactivate the Bone morphogenetic protein (increasing PGF2a activity) pathway that drives the Catagen (passive) phase of the hair follicle and also protects the hair follicle from micro inflammation.
  • topical administration of a topical pharmaceutical composition of Levocetirizine and Bimatoprost with Pharmaceutically acceptable excipients can be useful for promoting hair growth in androgenic alopecia and to provide a synergistic efficacy for the treatment of androgenic alopecia by multiple pathways.
  • Hl Receptor Antagonists as employed herein is intended to include the Cetirizine, Levocetirizine, Cetirizine, Levocetirizine, Olopatadine, Desloratadine, Azalestine, Rupatadine, Mizolastine, Ebastine and Meclozine and their salts, isomers, polymorphs, solvates and hydrates.
  • prostaglandin analogs as employed herein is intended to include Bimatoprost, Latanoprost, Carboprost, Travoprost and Tafluprost and their salts, isomers, polymorphs, solvates and hydrates.
  • Topical application refers to being applied to a surface such as skin.
  • Topically active refers to the composition or medicament for topical application which treats predominately the surface on which it is applied.
  • Topical pharmaceutical composition includes creams, ointments, lotions, liniment, gels, solutions, foams, sprays, and the like.
  • Percutaneous penetration or “transdermally available” means that the medicament of the composition is absorbed through skin when applied topically. Typically, although not necessarily, the medicament will then be distributed throughout the body resulting in systemic action as opposed to being only locally active.
  • Permeation Enhancer refers to a component used to enhance the penetration rate of drugs through the skin, preferably by temporarily diminishing the impermeability of the skin. Permeation enhancers have also been called “accelerants” and “sorption promoters.”
  • the topical compositions of the present invention contain Levocetirizine ranging from about 0.001%-10% (w/w) and Bimatoprost ranging from about 0.0001%-10% (w/w), preferably Levocetirizine ranging from about 0.1%-5% (w/w) and Bimatoprost ranging from about 0.01%-5% (w/w), most preferably Levocetirizine ranging from about 0. l%-3% (w/w) and Bimatoprost ranging from about 0.01%- 3% (w/w) with pharmaceutically acceptable excipients.
  • Preferred formulations according to the present invention are topical solutions, topical solution for sprays, gels, creams, foams, ointments, liniments and lotions. Most preferred formulations according to the present invention are topical solutions, topical solutions for sprays, gels, creams and foams.
  • the topical pharmaceutical composition of the present invention may additionally contain pharmaceutically acceptable excipients selected from the group consisting of solvents, permeation enhancers, surfactants, plasticizers, film-forming agents, preservatives, moisturizing agents, stabilizers, antifoaming agents, antioxidants, pressure-sensitive adhesives, gelling agents, softening agents, astringents, propellants, buffering agents and opacifying agents.
  • pharmaceutically acceptable excipients selected from the group consisting of solvents, permeation enhancers, surfactants, plasticizers, film-forming agents, preservatives, moisturizing agents, stabilizers, antifoaming agents, antioxidants, pressure-sensitive adhesives, gelling agents, softening agents, astringents, propellants, buffering agents and opacifying agents.
  • the present invention includes topical solutions or topical solution for spray composition
  • composition comprising Levocetirizine and Bimatoprost, dissolved or dispersed in one or more vehicles which comprise up to 95% of the composition (e.g., 1% to about 95%).
  • the composition further may contain permeation enhancer, humectants, surfactants, antioxidants, film-forming agents, preservatives, buffers and optionally propellants.
  • the composition may contain one or more of these additives in amounts of vehicles 1% to about 95%, humectants 1% to about 80%, permeation enhancer 1% to about 30%, surfactants 1% to about 10%, preservatives 1% to about 5%, film-forming agents 0.5% to about 10% and optionally propellants 5% to about 25% w/w of the total compositions.
  • the inventive composition may be applied topically or sprayed on a topical site to act locally on the surface or are trans-dermally available.
  • the compositions can be dispensed from any dispenser, preferably a dispenser which provides the composition as a spray.
  • the vehicle used in the can be water or a non-aqueous solvent.
  • Preferred nonaqueous vehicles include water, ethyl alcohol, acetone, isopropyl alcohol, methylene chloride, methyl-ethyl-ketone, ethyl acetate and tri chloromonofluoromethane (PH), methylene dimethyl ether or any two or more of the above in combination.
  • the aqueous or non-aqueous vehicle may additionally comprise (weight/weight of vehicle) up to 80% of one or more humectants.
  • Preferred humectants include polyhydric alcohols and polyvinyl pyrrolidone.
  • Preferred polyhydric alcohols are propylene glycol, butylene glycol, polyethylene glycol, glycerol and sorbitol.
  • the permeation enhancer is preferably a lipophilic solvent, for example, dimethyl sulfoxide, dimethyl formamide or isopropyl myristate; a surfactant, for example, Tweens or sodium lauryl sulfate; menthol; oleic acid, octyl dimethyl para-amino benzoic acid (Padimate 0); mixed esters of capric and caprylic acid; or fatty acid esters, or a polyhydric alcohol, for example, diethylene glycol monoethyl ether EP (Transcutol® P), a monoalkyl ether of diethylene glycol having a general formula C4H9O3 (CnEbn+l), wherein n is 1-4; or any two or more of the above in combination.
  • a lipophilic solvent for example, dimethyl sulfoxide, dimethyl formamide or isopropyl myristate
  • a surfactant for example, Tweens or sodium lauryl
  • the film-formers preferably include acrylic polymers or copolymers, including methacrylic polymers and copolymers.
  • Preferred film-formers include a non-ionic copolymer of methyl methacrylate and butyl methacrylate (Plastoid B®), a copolymer of dimethylamine ethyl methacrylate and a neutral methacrylic acid ester (Eudragit El 00®), ammonio methacrylate copolymer type B (Eudragit RS®, USP/NF), ammonio methacrylate copolymer type A (Eudragit RL®, USP/NF), methacrylic acid copolymer type A (Eudragit LI 00®, USP/NF), methacrylic acid copolymer type B (Eudragit SI 00® USP/NF), polyvinyl acetate, cellulose acetate, polyvinyl alcohol, povidone, povidone vinyl acetate, hydroxypropy
  • compositions may be dispensed from a pump dispenser or from an aerosol dispenser.
  • the composition additionally comprises from about 5% to 90% of propellant in order to provide a suitable pressure within the aerosol dispenser.
  • propellant is not required for compositions dispensed from a pump dispenser.
  • such compositions may also comprise from about 5% to 90% of a propellant which is liquid at room temperature, for example, trichloromonofluoromethane (PH).
  • the invention also provides a method of preparing a pump dispenser containing the spray composition of the invention comprising mixing the ingredients of the composition with or without liquid propellant and placing the mixed ingredients in a pump dispenser.
  • the invention provides a method of preparing an aerosol dispenser containing the spray composition of the invention comprising mixing the ingredients of the composition without propellant and charging the mixture together with propellant into an aerosol dispenser.
  • the composition is preferably dispensed from the chosen dispenser in a metered dose.
  • the vehicle When the composition is dispensed as an aerosol or spray, the vehicle partly comprises a propellant in an amount to provide from about 5% to about 90% (w/w) of the composition.
  • the propellant can be any pharmaceutically acceptable propellant which provides a suitable pressure within an aerosol dispenser, preferably a pressure of from about 20 p.s.i.g. to about 130 p.s.i.g.
  • Preferred propellants include hydrocarbons, for example, propane, butane, isobutane, or dimethylether; hydrofluorocarbons and hydrochlorofluorocarbons, for example, dichlorodifluoromethane (P12), trichloromonofluoromethane (PH), di chlorofluoroethane, monochlorodifluoromethane (P22), di chlorotetrafluoroethane (P114), difluoroethane (P152a), tetrafluoroethane (134a), heptafluoropropane (P227b); or compressed gases, for example, nitrogen or carbon dioxide.
  • hydrocarbons for example, propane, butane, isobutane, or dimethylether
  • hydrofluorocarbons and hydrochlorofluorocarbons for example, dichlorodifluoromethane (P12), trichloromonofluoromethane (PH), di chlorofluoro
  • the present invention includes topical gels, creams or foams comprising Levocetirizine and Bimatoprost, dissolved or dispersed can include an oil phase like hydrocarbon oils such as paraffin oil, purcellin oil, perhydrosqualene, microcrystalline wax, petrolatum, mineral oil (Paraffinum liquidum), polyalkene, cerasin, ozokerite, polyethylene, perhydrosqualene, stearic acid, palmitic acid, oleic acid, palmito-oleic acid, cetyl or oleyl alcohols, poly alpha olefin, hydrogenated polyisobutene, beeswax, and mixtures thereof; saturated esters such as isopropyl palmitate, alkyl myristates such as isopropyl, butyl and cetyl myristates, hexodecyl stearate, ethyl palmitate, octanoic and decanoic acid triglycerides and
  • the oil phase of the topical gel, cream or foam composition ranges from about 5% to about 40% or about 10% to about 30% or about 10% to about 20% by w/w of the topical pharmaceutical composition.
  • the aqueous phase of the topical gel, cream or foam pharmaceutical composition ranges from about 30% to about 95% of the topical pharmaceutical composition, or about 50% to about 90% or about 60% to about 90% w/w of the topical pharmaceutical composition.
  • the preferred ratio of oil phase to water phase in the topical pharmaceutical composition ranges from about 1 : 1 to 1 :9.
  • the present topical gel, cream and foam compositions may contain a surfactant selected from the group consisting of may be used.
  • the surfactants include, but are not limited to, lecithin; sorbitan esters; polysorbates prepared from lauric, palmitic, stearic, and oleic acids; dioctyl sodium sulfosuccinate (DOSS); docusate sodium; sodium lauryl sulfate; Span® 20 and 80; macrogol ethers such as cetomacrogol 1000; polyoxyethylene castor oil derivatives; polyoxyethylene sorbitan fatty acid esters such as Tween®; polyoxyethylene stearates; poloxamers such as Pluronic® F-68 and Pluronic® F.108; macrogolglycerol esters such as Cremophor® EL or Kolliphor ® EL; glycerides esters such as lauroyl polyoxyl-32 glycerides (Gelucire®); soy
  • co-surfactants/co-solvents include, but are not limited to, short chain mono-, di-, and polyhydric alcohols, such as ethanol, benzyl alcohol, glycerol, propylene glycol, propylene carbonate, polyethylene glycol with an average molecular weight of about 200 to about 10,000, polyethylene glycol esters such as Labrafil® M1944CS, polyglyceryl-3 dioleate, diethylene glycol monoethyl ether such as Transcutol ® HP, and mixtures thereof.
  • short chain mono-, di-, and polyhydric alcohols such as ethanol, benzyl alcohol, glycerol, propylene glycol, propylene carbonate
  • polyethylene glycol with an average molecular weight of about 200 to about 10,000 polyethylene glycol esters such as Labrafil® M1944CS, polyglyceryl-3 dioleate, diethylene glycol monoethyl ether such as Transcutol ® HP, and mixtures thereof.
  • the topical gel, cream and foam compositions according to the present invention can include emollients.
  • the emollient can be selected from the group consisting of petrolatum, isopropyl palmitate, vegetable oils whether or not hydrogenated, silicone oils, any liquid polymerized siloxane such as dimethicone, cyclomethicone, cyclopentasiloxane, dimethiconol and amodimethicone, mineral oil, waxes such as parrafin, paraffinum liquidum, and petrolatum, aloe vera, fatty alcohols such as arachidyl alcohol, batyl alcohol, behenyl alcohol, C12-13 alcohols, cetearyl alcohol, cetyl alcohol, coconut alcohol, isocetyl alcohol, octyl dodecanol and palm alcohol, fatty acids and esters of fatty acids such as batyl stearate, cetearyl behenate, cetearyl isononanoate, cetyl est
  • the topical gel, cream and foam compositions can include humectants selected from the group consisting of pyrrolidone carboxylic acid (PCA) and derivatives (arginine PCA, chitosan PCA, copper PCA, ethylhexyl PCA, lauryl PCA, magnesium PCA, sodium PCA, zinc PCA) butylene glycol, calcium gluconate, fructose, glucose, isomalt, lactose, maltitol, mannitol, polydextrose, sorbitol, sucrose, xylitol, glycerol, glycyrrhizic acid and derivatives, histidine, hyaluronic acid and its salts (sodium hyaluronate), hydrolysates of silk, keratin or soya, PEG (-7, -8, -10, -12, -14), phytantriol, propylene glycol, silk (serica), urea
  • the topical gel, cream and foam compositions can include a rheology modifier in an amount form about 0.5% to about 5% by w/w of the topical composition.
  • the rheology modifier may be selected form the list consisting of cetyl alcohol, stearyl alcohol, carnauba wax, and stearic acid, vegetable gums (hydroxyethylcellulose, guar gum, locust bean gum, xanthan gum), and gelatin, silica, bentonite, and magnesium aluminum silicate, carbomers (polyacrylic acids) and mixtures thereof.
  • the topical compositions of present invention can include a preservatives include ammonium Benzoate, Butyl Benzoate, Calcium Benzoate, Ethyl Benzoate, Isobutyl Benzoate, Isopropyl Benzoate, Magnesium Benzoate, Mea-Benzoate, Methyl Benzoate, Phenyl Benzoate, Potassium Benzoate, Propyl Benzoate, Benzoic Acid, Sodium Benzoate, Propionic Acid, Ammonium Propionate, Calcium Propionate, Magnesium Propionate, Potassium Propionate, Sodium Propionate, Salicylic Acid, Calcium Salicylate, Magnesium Salicylate, Mea-Salicylate, Sodium Salicylate, Potassium Salicylate, Tea-Salicylate, Sorbic Acid, Calcium Sorbate, Sodium Sorbate, Potassium Sorbate and like.
  • the topical pharmaceutical composition can include a preservative in an amount form about 0.1% to about 5% by w/w/ of the topical composition.
  • the topical composition of the present invention also contains one or more antioxidants.
  • antioxidants include, but are not limited to, water-soluble antioxidants such as sulfhydryl compounds and their derivatives (e.g., sodium metabisulfite and N-acetylcysteine), lipoic acid and dihydrolipoic acid, resveratrol, lactoferrin, ascorbic acid, and ascorbic acid derivatives (e.g., ascorbyl palmitate and ascorbyl polypeptide).
  • Oil-soluble antioxidants suitable for use in the compositions of this invention include, but are not limited to, butylated hydroxytoluene, tocopherols (e.g., tocopheryl acetate), tocotrienols, and ubiquinone.
  • the topical pharmaceutical composition can include a anti-oxidant in an amount form about 0.01% to about 5% by w/w of the topical composition.
  • Example 2 Topical Solution Composition
  • Example 3 Topical Solution for Spray Composition
  • Example 4 Topical Solution for Spray Composition
  • the topical solution compositions are generally prepared by mixing the ingredients with stirring, without liquefied propellant, at a temperature of from 0° C. to 100° C. and at ambient pressure. If propellant is to be added, the resulting mixture is then charged with the liquefied propellant into an aerosol dispenser to achieve the final composition. Mixing is preferably carried out at a temperature of from 10° C. to 25° C.
  • the mixed composition is placed in a pump dispenser, for example, a metered dose pump, which dispenses the composition typically without liquefied propellant since a pressurized atmosphere is not required.
  • Propellant which is liquid at room temperature may, however, be included in a pump dispenser composition as part of the aqueous vehicle. The composition so prepared is sprayed from the dispenser onto a topical site.
  • topical solution compositions of the present invention are quick drying, nonocclusive formulations which cause marked enhancement of the skin permeation of the drug both in vitro and in vivo. They offer the advantages of lower skin irritation, greater ease of use, increased dosage flexibility and a simpler method of manufacture.
  • the preferable procedure for preparation of the gel is as follows: The Part 1 ingredients are mixed by homogenization at lower speed until the carbomer is dispersed. Part 2 ingredients are mixed first and then added to Part 1 and further homogenized at moderate speed homogenization. Part 3 ingredients except drugs are mixed and heated at 60°C until uniform mixing, allowed to cool, and then Levocetirizine and Bimatoprost is dispersed well. Part 3 and Part 1 & 2 mix are thoroughly mixed further using homogenizer at low speed, finally, with this Part 4 ingredients are mixed to obtain homogeneous gel formulation. The final pH of the gel formulation is 5.8.
  • Example 6 Topical Cream Composition
  • preparation of cream composition involves the following steps: i) Warm oil phase excipients and water separately, ii) oil phase excipients and water were mixed together and homogenized for about 10 minutes and followed by iii) addition of preservative, Levocetirizine and Bimatoprost stirring is continued & cooled up to room temperature.
  • the viscosity of cream formulation found to be 0.40 to 0.90 poise (observed: 0.60 poise) measured by Brookfield CAP Viscometer. pH of the white cream formulation was 4.6.
  • compositions disclosed herein that are in the form of emulsions (including foams) and which therefore comprise an aqueous phase in addition to the oil phase, it may be useful to incorporate an antimicrobial preservative.
  • an antimicrobial preservative if the composition is intended for a multidose product presentation, it is preferred that it comprises a preservative, or a combination of preservatives.
  • any antimicrobial preservative can be used in the preparation of the pharmaceutical composition disclosed herein, as long as it does not interfere with the pharmacokinetic and pharmacodynamic properties of the compositions.
  • the preferable procedure for preparation of the gel is as follows: Mix the Part 1 ingredients and heat to get uniform mix. Mix Part 2 ingredients separately. Add propylene glycol and ethanol with Part 2 to obtain uniform mixture under homogenization, mixture allowed to cool and then Levocetirizine and Bimatoprost in ethanol is added, stirred to obtain uniform foam formulation, which is finally neutralized with triethanolamine in water to obtain final pH 6.0-7.0. The final foam formulation filled in cans and charged with Trichloromonofluoromethane (PH). Hair Growth Efficacy Study in Mouse Model
  • the topical composition of the present invention was tested in an animal study for improved hair growth in androgenic alopecia based on methods reported by Laxman Subedi et al., Drug Delivery 2022, VOL. 29, NO. 1, 328-341. Androgenic alopecia was induced in C57/BL6 mice by once-daily intra-peritoneal administration of dihydrotestosterone (0.5 mg/kg) for five days, and the dorsal hair of mice were removed using wax and tape stripping. Then, the mice were randomly divided into the following 5 groups (8 mice/ group) for topical treatment:

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Abstract

La présente invention concerne de nouvelles compositions pharmaceutiques topiques synergiques comprenant de la lévocétirizine et du bimatoprost avec des excipients pharmaceutiquement acceptables pour le traitement de l'alopécie androgénique. Les compositions topiques synergiques visent à assurer une efficacité clinique synergique dans l'alopécie androgénique en ciblant de multiples voies impliquées dans la physiologie de la croissance des cheveux. Les compositions pharmaceutiques topiques préférables comprennent des solutions topiques, des solutions topiques pour pulvérisation, des gels topiques, des crèmes topiques et des mousses topiques.
PCT/IN2024/051888 2023-09-29 2024-09-28 Nouvelle composition pharmaceutique topique pour la prévention et le traitement de la chute des cheveux Pending WO2025069091A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2017202667B2 (en) * 2011-01-31 2019-02-21 Allergan, Inc. Method of enhancing hair growth
US20210093646A1 (en) * 2009-11-09 2021-04-01 Allergan, Inc. Topical compositions comprising bimatoprost and methods for stimulating hair growth therewith

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210093646A1 (en) * 2009-11-09 2021-04-01 Allergan, Inc. Topical compositions comprising bimatoprost and methods for stimulating hair growth therewith
AU2017202667B2 (en) * 2011-01-31 2019-02-21 Allergan, Inc. Method of enhancing hair growth

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WEN SIJIAN, WEI JUMEI, BAO JIAJUAN, GUO TING, ZHENG WENJUN, ZHUANG XIAOSHENG, LIN YOUKUN: "Effect of levocetirizine hydrochloride on the growth of human dermal papilla cells: a preliminary study", ANNALS OF PALLIATIVE MEDICINE, vol. 9, no. 2, 1 March 2020 (2020-03-01), pages 308 - 317, XP093301995, ISSN: 2224-5820, DOI: 10.21037/apm.2020.01.15 *

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