New topical pharmaceutical compositions for the prevention and treatment of alopecia

Abstract

The present invention relates to a synergistic topical pharmaceutical formulation comprising levocetirizine and bimatoprost, and pharmaceutically acceptable excipients, for the treatment of androgenic alopecia. The synergistic topical formulation aims to provide a synergistic clinical efficacy in the treatment of androgenic alopecia by acting on multiple pathways involved in the hair physiology processes. Preferred topical pharmaceutical formulations include topical solutions, topical solutions for spray, topical gels, topical creams and topical foams.

Description

Technical Field

[0001] This invention relates to a synergistic topical hair growth formulation comprising levocetirizine and bimatoprost for promoting hair growth and treating androgenetic alopecia. Background Technology

[0002] Androgenetic alopecia (AGA) is a hereditary disease influenced by androgens and affected by a variety of genetic and environmental factors. AGA is the most common type of hair loss, with a chronic course. Its main symptoms are progressive hair loss and follicular atrophy, which may be accompanied by oily scalp, dandruff, and itching. Because hair loss directly affects a patient's appearance, it often significantly impacts their social activities and mental health, potentially leading to a decline in quality of life, exacerbating social barriers, and triggering depression in severe cases (Yamazaki M et al., J Dermatol 2011;38:773-7). With the socioeconomic development in recent years, more and more patients are seeking more proactive treatment outcomes; therefore, the role of AGA treatment is receiving increasing attention.

[0003] The etiology and mechanism of androgenetic alopecia (AGA) are not fully understood. Follicle atrophy, miniaturization, shortened anagen phase, prolonged telogen phase, follicle involvement, and abnormal growth cycle may be key aspects of its pathogenesis. It is generally believed that the occurrence and development of AGA are closely related to endocrine disorders, especially abnormal androgen metabolism in scalp hair follicles (Urysiak-Czubatka I et al., Postepy Dermatol Alergol 2014;31:207-15.). Medications for treating AGA include hormone regulators, vasodilators, and immunomodulators; however, very few drugs are currently effective in promoting hair growth. Finasteride and minoxidil are still commonly used drugs for treating AGA; however, finasteride has been reported to cause sexual dysfunction side effects such as decreased libido and impotence, while minoxidil use has been associated with irritant dermatitis, allergic contact dermatitis, headache, and hypotension (Zhang Y., Second Military Medical University, 2016). Although many new methods for treating AGA have been developed, including autologous hair transplantation, follicular reconstruction, and low-energy laser therapy (Ghanaat M. South Med J 2010;103:917-21), these methods are expensive and invasive, and therefore cannot be widely used.

[0004] Given the above, it is clear that there is a need to improve the methods for promoting hair regeneration.

[0005] Mounting evidence suggests that the prostaglandin pathway (especially the PGDS / PGD pathway) is involved in the pathogenesis of androgenetic alopecia (AGA) (Arias-Santiago S et al., J Am Acad Dermatol 2012;66:401-8). Prostaglandins (PGs) are a class of enzymatically metabolized unsaturated fatty acids. They are widely distributed in various tissues and body fluids and can mediate a variety of physiological functions and inflammatory responses, such as cell proliferation, differentiation, and apoptosis. Cyclooxygenase (COX) promotes the conversion of prostaglandins from arachidonic acid to unstable prostaglandin H2, which is then further processed by corresponding prostaglandin synthases into various biologically active prostaglandins (e.g., prostacyclin, PGD2, PGE2, PGF2a, and PGI2). Comparative studies on the effects of different prostaglandin subtypes on hair growth have shown that PGE2 and PGF2α can promote hair growth, while PGD2 inhibits hair growth and exacerbates hair follicle miniaturization (Heilmann S et al., Br J Dermatol 2013;169:222-4). Jeong et al. (JeongKH, Jung JH, Kim JE et al., NJ Mol. Sci. 2018, 19(2), 556) found that PGD2 leads to the activation of androgen receptors by regulating the DP2 and AKT / GSK3β signaling pathways on human hair follicle stem cells (hDPCs).

[0006] Levocetirizine is a safe, highly selective, and potent next-generation histamine H1 receptor antagonist that has been widely used to treat skin, respiratory, and ocular allergies. As the R-enantiomer of cetirizine, levocetirizine exhibits higher bioavailability and lower hepatic clearance, with a plasma binding rate of up to 95%. It is characterized by low tissue affinity, low cardiotoxicity, and mild sedative effects (Sijian We et al., Ann Palliat Med 2020;9(2):308-3). XYZAL ® Levocetirizine hydrochloride is a product approved by the U.S. Food and Drug Administration (FDA) for the relief of symptoms associated with allergic rhinitis (seasonal and perennial) in adults and children aged 6 years and older. Additionally, it is indicated for the treatment of simple cutaneous manifestations of chronic idiopathic urticaria in adults and children aged 6 years and older.

[0007] Sijian Wen et al. (Ann Palliat Med 2020;9(2):308-3) investigated the effects of levocetirizine on the growth, proliferation, and expression of PG-related signaling factors in human follicular papillary cells (DPCs), and explored its role in hair growth and related molecular mechanisms. Their experiments showed that levocetirizine can promote the growth and proliferation of hDPCs and significantly inhibit the expression of related factors in the PGD2-GPR44 pathway, including COX-2, PTGDS, PGD2, PGD2R, and GPR44. These findings provide experimental and theoretical basis for the use of levocetirizine in the treatment of AGA.

[0008] Bimatoprost is a synthetic prostaglandin F2a analog (PGF2a). LATISSE ® This is an FDA-approved 0.03% bimatoprost ophthalmic solution (Allergan, Irvine, California) used to treat sparse eyelashes by promoting eyelash growth, including length, thickness, and color. While its exact mechanism of action is not fully understood, eyelash growth is thought to occur by increasing the proportion of hairs in the anagen (growth) phase and its duration.

[0009] Eyelashes are highly specialized short hairs that have evolved to protect the eyes from foreign objects. They differ significantly from hair in that their follicles lack the usual arrector pili muscles. Nevertheless, eyelashes are still produced by follicles and, like other hairs, are periodically replaced through the follicle cycle (Karzan G. Khidhir et al., FASEB J. 2013 Feb; 27(2): 557–567). The difference between producing long and short hair depends primarily on the variation in the length of the anagen phase (the growth phase in the hair growth cycle) rather than the rate of hair growth, which is relatively constant in the body. The anagen phase can last for years in the large terminal hair follicles that form long hairs, while it lasts only a few weeks in short finger hairs (Saitoh M et al., J. Invest. Dermatol. 1970, 54, 65–81).

[0010] Karzan G. Khidhir et al. (FASEB J. 2013 Feb; 27(2): 557–567) evaluated whether bimatoprost could also stimulate non-eyelash follicles in vivo, particularly when administered via the skin, and the effects of topical bimatoprost on rodent hair growth. Thus, bimatoprost can stimulate human scalp follicles in vitro and rodent hair follicles in vivo, acting similarly to eyelash behavior, and scalp follicles contain bimatoprost-sensitive prostaglandin receptors in vivo. This highlights a novel follicle signaling system and confirms that bimatoprost offers a novel, low-risk treatment for scalp alopecia. Bimatoprost is an effective alternative for treating scalp alopecia as part of a novel treatment strategy that stimulates follicles by acting directly on prostaglandin F2α receptors in dermal papilla cells within the hair follicle (L Subedi et al., 2022, Drug Delivery).

[0011] Based on the above theoretical foundations, existing evidence suggests that levocetirizine or bimatoprost, used alone, has potential hair regrowth effects. However, a combination therapy that can balance the anagen, catagen, and telogen phases of the hair growth cycle still needs to be developed. This invention is the first to attempt to provide a synergistic combination, using levocetirizine and bimatoprost together. Levocetirizine has the potential to counteract prostaglandin D2 (PGD2)-mediated hair follicle inhibition, while bimatoprost has the potential to promote prostaglandin E2 / prostaglandin F2α (PGE2 / PGF2α)-mediated hair growth enhancement. Furthermore, levocetirizine can protect hair follicles from microinflammatory damage, which is considered a cause of irreversible damage in androgenic alopecia (AGA). This invention expands the pharmacological treatment options for hair loss. Furthermore, there is an urgent need for a topical formulation comprising a synergistic combination of levocetirizine and bimatoprost to improve the treatment efficacy of androgenetic alopecia. This invention provides a solution to the need for long-term effective treatment of androgenetic alopecia. Summary of the Invention

[0012] This invention relates to a topical pharmaceutical formulation containing a synergistic combination of levocetirizine and bimatoprost to prevent hair loss and improve hair growth parameters by acting on a mechanism that regulates the balance of anagen, catagen, and telogen phases. This invention makes a significant contribution to pharmaceutical treatments for hair loss.

[0013] The combination contains levocetirizine, which provides anti-inflammatory and anti-allergic effects, targeting inflammatory infiltrations prominently present in bald areas, while simultaneously inhibiting PGD2 on DP2 receptors, thereby neutralizing the inhibitory effect of PGD2 on hair follicles. Bimatoprost (a prostaglandin PGF2α analog) in the combination acts directly on prostaglandin F2α receptors (FP) in the dermal papilla and outer root sheath of the hair follicle to promote hair growth.

[0014] The synergistic combination of the present invention restores a proper balance between the anagen (growth) and telogen (resting) phases, contributing to healthy hair. The topical pharmaceutical formulation proposed in this invention comprises levocetirizine and bimatoprost. Furthermore, the topical pharmaceutical formulation also includes suitable pharmaceutically acceptable excipients.

[0015] In one embodiment, the present invention provides a topical pharmaceutical preparation comprising levocetirizine and bimatoprost for promoting healthy hair growth in cases of androgenetic alopecia, which is harmless to the human body.

[0016] In another embodiment, the present invention provides a topical pharmaceutical preparation comprising levocetirizine and bimatoprost, wherein the topical pharmaceutical preparation of the present invention is a topical solution or a spray-on topical solution.

[0017] In another embodiment, the present invention provides a topical pharmaceutical composition comprising levocetirizine and bimatoprost, wherein the topical pharmaceutical composition of the present invention is a topical gel, a topical cream, or a topical foam.

[0018] In another embodiment, the present invention provides a topical pharmaceutical composition comprising levocetirizine and bimatoprost, wherein the content of levocetirizine ranges from about 0.001% to 10% (w / w), the content of bimatoprost ranges from about 0.0001% to 10% (w / w), and contains pharmaceutically acceptable excipients.

[0019] According to a further embodiment, the present invention provides a method for treating androgenetic alopecia, comprising applying an effective amount of the composition of the present invention to human skin in need of such treatment.

[0020] According to another embodiment, the present invention relates to the use of the compositions described herein in the preparation of a medicament for treating androgenetic alopecia. Detailed Implementation

[0021] Recent studies on the pathogenesis of androgenetic alopecia (AGA) have shown that an imbalance of prostaglandins (PGs) in the affected scalp areas ultimately leads to hair follicle shrinkage and hair loss. The synergistic topical composition of this invention comprises levocetirizine (an "H1 receptor antagonist"), which activates the Wnt / β-catenin pathway (increasing PGE2 activity and decreasing PGD2 activity), thereby driving the anagen phase (active phase) of the hair follicle; and bimatoprost (a "prostaglandin analog"), which inhibits the bone morphogenetic protein pathway (increasing PGF2α activity), which drives the catagen phase (passive phase) of the hair follicle, while also protecting the hair follicle from microinflammation.

[0022] According to the present invention, it has been surprisingly found that topical application of a topical pharmaceutical composition of levocetirizine and bimatoprost with pharmaceutically acceptable excipients can promote hair growth in androgenetic alopecia and produce synergistic therapeutic effects on androgenetic alopecia through multiple pathways.

[0023] As used herein, the term “H1 receptor antagonist” is intended to include cetirizine, levocetirizine, cetirizine, levocetirizine, olopatadine, desloratadine, azalstatin, rupatadine, misolastine, ebastine, and meclozar hydrochloride, as well as their salts, isomers, polymorphs, solvates, and hydrates.

[0024] As used herein, the term “prostaglandin analogues” is intended to include bimatoprost, latanoprost, carboprost, treprost, and tavprost, as well as their salts, isomers, polymorphs, solvates, and hydrates.

[0025] In describing this invention, the following definitions apply throughout the document.

[0026] "Topical application" refers to application to surfaces such as the skin.

[0027] "Topically active" refers to a composition or drug intended for topical application, which exerts its therapeutic effect primarily on the application surface.

[0028] As used in this article, the term "topical pharmaceutical composition" includes creams, ointments, lotions, liniments, gels, solutions, foams, sprays, etc.

[0029] "Transdermal penetration" or "transdermal availability" means that when the composition is applied topically, the drug is absorbed through the skin. Typically, although not always, the drug is subsequently distributed throughout the body, resulting in a systemic effect, rather than just local activity.

[0030] "Penetration enhancer" refers to a component used to increase the rate at which a drug penetrates the skin, preferably by temporarily reducing the skin's impermeability. Penetration enhancers are also known as "accelerators" and "adsorption enhancers."

[0031] The local composition of the present invention contains about 0.001%-10% (w / w) of levocetirizine and about 0.0001%-10% (w / w) of bimatoprost, preferably about 0.1%-5% (w / w) of levocetirizine and about 0.01%-5% (w / w) of bimatoprost, more preferably about 0.1%-3% (w / w) of levocetirizine and about 0.01%-3% (w / w) of bimatoprost, and contains pharmaceutically acceptable excipients.

[0032] The preferred formulations of this invention are topical solutions, spray topical solutions, gels, creams, foams, ointments, liniments, and lotions. The most preferred formulations of this invention are topical solutions, spray topical solutions, gels, creams, and foams.

[0033] The topical pharmaceutical composition of the present invention may further contain pharmaceutically acceptable excipients selected from the group consisting of solvents, penetration enhancers, surfactants, plasticizers, film-forming agents, preservatives, humectants, stabilizers, defoamers, antioxidants, pressure-sensitive adhesives, gelling agents, softeners, astringents, propellants, buffers, and opacifiers.

[0034] The present invention comprises a topical solution or topical spray solution composition containing levocetirizine and bimaprost, dissolved or dispersed in one or more carriers, wherein the carrier constitutes up to 95% of the composition (e.g., from 1% to about 95%). The composition may also contain a penetration enhancer, a humectant, a surfactant, an antioxidant, a film-forming agent, a preservative, a buffer, and optionally a propellant.

[0035] The composition may contain one or more additives, wherein the carrier content is from 1% to about 95%, the humectant content is from 1% to about 80%, the transdermal enhancer content is from 1% to about 30%, the surfactant content is from 1% to about 10%, the preservative content is from 1% to about 5%, the film-forming agent content is from 0.5% to about 10%, and may optionally contain a propellant at a content of from 5% to about 25% (w / w) of the total composition. The composition of the present invention can be topically applied or sprayed onto specific areas to exert a localized effect on the surface or for transdermal absorption. The composition can be dispensed using any dispenser, preferably a dispenser capable of dispensing the composition in a spray form.

[0036] The carrier used can be water or a non-aqueous solvent. Preferred non-aqueous carriers include water, ethanol, acetone, isopropanol, dichloromethane, methyl ethyl ketone, ethyl acetate, trichlorofluoromethane (P11), methylene dimethyl ether, or combinations of two or more of the above. The aqueous or non-aqueous carrier may also additionally contain up to 80% (by weight / carrier weight) one or more humectants. Preferred humectants include polyols and polyvinylpyrrolidone. Preferred polyols are propylene glycol, butylene glycol, polyethylene glycol, glycerin, and sorbitol.

[0037] The penetration enhancer is preferably a lipophilic solvent, such as dimethyl sulfoxide, dimethylformamide, or isopropyl myristate; a surfactant, such as Tween or sodium lauryl sulfate; menthol; oleic acid, octyl dimethyl para-aminobenzoic acid (Padimate O); a mixed ester of octanoic acid and decanoic acid; or a fatty acid ester; or a polyol, such as propylene glycol or diethylene glycol monoethyl ether EP (Transcutol). ® P); has the general formula C4H9O3 (C n H 2n+1 (where n is 1-4) diethylene glycol monoalkyl ethers; or any combination of two or more of the above.

[0038] Film-forming agents preferably comprise acrylic polymers or copolymers, including methacrylic polymers and copolymers. Preferred film-forming agents include nonionic copolymers of methyl methacrylate and methyl butyl acrylate (Plastoid B). ® ), a copolymer of dimethylaminoethyl acrylate and neutral acrylate (Eudragit E100) ® Eudragit RS (a type of ammonium acrylate copolymer) ® USP / NF), methyl methacrylate copolymer of type A (Eudragit RL) ® USP / NF), type A acrylic copolymer (Eudragit L100) ® USP / NF), type B acrylic copolymer (Eudragit S100) ® USP / NF), polyvinyl acetate, cellulose acetate, polyvinyl alcohol, povidone, vinyl acetate-povidone copolymer, hydroxypropyl methylcellulose, hydroxyethylcellulose, methylcellulose and ethylcellulose.

[0039] The composition can be dispensed using a pump dispenser or an aerosol dispenser. In the latter case, the composition also includes about 5% to 90% of a propellant to provide appropriate pressure within the aerosol dispenser. Typically, compositions dispensed via a pump dispenser do not require a propellant. However, if desired, such compositions may also contain about 5% to 90% of a propellant that is liquid at room temperature, such as trichlorofluoromethane (P11).

[0040] The present invention also provides a method for preparing a pump dispenser comprising the spray composition of the present invention, the method comprising mixing the components of the composition with or without a liquid propellant, and placing the mixed components in the pump dispenser.

[0041] Furthermore, the present invention provides a method for preparing an aerosol sprayer containing the spray composition of the present invention, the method comprising mixing the components of the composition without adding a propellant, and filling the mixture together with a propellant into an aerosol sprayer. The composition is preferably sprayed from a selected sprayer at a metered dose.

[0042] When the composition is released in the form of an aerosol or spray, the carrier portion contains a propellant comprising approximately 5% to 90% (by weight) of the total composition. The propellant can be any pharmaceutically acceptable propellant capable of providing suitable pressure within the aerosol dispenser, preferably in the range of approximately 20 psig to approximately 130 psig. Preferred propellants include hydrocarbons such as propane, butane, isobutane, or dimethyl ether; hydrofluorocarbons and chlorofluorocarbons such as dichlorodifluoromethane (P12), trichlorofluoromethane (P11), dichlorofluoroethane, dichlorodifluoromethane (P22), dichlorotetrafluoroethane (P114), difluoroethane (P152a), tetrafluoroethane (P134a), heptafluoropropane (P227b); or compressed gases such as nitrogen or carbon dioxide.

[0043] This invention relates to topical gels, creams, or foams containing levocetirizine and bimatoprost, wherein the dissolved or dispersed substances may include an oil phase, such as paraffin oil, perylene, perhydrosqualene, microcrystalline wax, petrolatum, mineral oil (liquid paraffin), polyolefins, ceresin, polyethylene, perhydrosqualene, stearic acid, palmitic acid, oleic acid, palmitoleic acid, cetyl alcohol or oleyl alcohol, polyalphaolefins, hydrogenated polyisobutylene, beeswax, and mixtures thereof; saturated esters, such as isopropyl palmitate, alkyl myristate esters (e.g., isopropyl myristate, butyl myristate, and cetyl myristate), hexadecyl stearate, ethyl palmitate, caprylic and caprylic triglycerides, and cetyl ricinoleate, sodium formate, tocopheryl acetate, butyl acetate, ethyl acetate, methoxyisopropyl acetate, glyceryl laurate, PEG-30 Glyceryl laurate, potassium laurate, glyceryl myristate, isopropyl myristate, potassium myristate, propylene glycol myristate, zinc myristate, ascorbyl palmitate, cetyl palmitate, isopropyl palmitate, potassium palmitate, retinyl palmitate, acetylated ethylene glycol stearate, ethylhexyl stearate, glyceryl isostearate, glyceryl stearate, glyceryl stearate SE, ethylene glycol distearate, magnesium stearate, PEG-150 distearate, PEG-3 distearate, PEG-30 glyceryl stearate, PEG-32 stearate, PEG-6 stearate, polyglycerol-2 diisostearate, polyglycerol-3 Distearate, potassium stearate, unsaturated esters (potassium sorbate, glyceryl oleate, ethyl linoleate, glyceryl linoleate, tocopheryl linoleate); silicone oils, such as dimethyl polysiloxane, methylphenyl polysiloxane, and ethylene glycol polymers; vegetable oils containing triglycerides of linoleic acid, such as coconut oil (Cocos Nucifera), palm oil (Elaeis Guineensis Oil), peanut oil (Arachis Hypogaea), and argan oil (Arachis... Hypogaea, sweet almond oil, avocado oil, tamanu oil, lanolin, castor oil, olive oil, wheat germ oil, corn germ oil, soybean oil, sunflower seed oil, cottonseed oil, alfalfa oil, poppy oil, chestnut oil, sesame oil, rapeseed oil, evening primrose oil, millet oil, barley oil, quinoa oil, rye oil, safflower oil, tamarisk oil, passion fruit oil, grapeseed oil, rapeseed oil, tall seed oil, flaxseed oil, peanut oil, sea buckthorn oil, blackcurrant seed oil, Siberian pine nut oil, evening primrose oil, soybean oil, hazelnut oil (Corylus Avellana), walnut oil (Juglans Regia), grape oil (Vitis Vinifera).

[0044] The oil phase of the topical gel, cream, or foam composition comprises about 5% to about 40% by weight, or about 10% to about 30%, or about 10% to about 20% of the topical pharmaceutical composition.

[0045] The aqueous phase of the topical gel, cream, or foam pharmaceutical composition comprises about 30% to about 95% by weight, or about 50% to about 90%, or about 60% to about 90% of the topical pharmaceutical composition. In the topical pharmaceutical composition, the preferred ratio of the oil phase to the aqueous phase is about 1:1 to 1:9.

[0046] The topical gel, cream, and foam compositions of the present invention may contain surfactants selected from the group consisting of: lecithin; sorbitan ester; polysorbate prepared from lauric acid, palmitic acid, stearic acid, and oleic acid; sodium dioctyl sulfosuccinate (DOSS); sodium docusate; sodium lauryl sulfate; and Span. ® 20 and 80; polyethylene glycol ethers such as cetearyl alcohol polyether 1000; polyoxyethylene castor oil derivatives; polyoxyethylene sorbitan fatty acid esters such as Tween ® Polyoxyethylene stearate; poloxamer, such as Pluronic ® F-68 and Pluronic ® F.108; Polyethylene glycol glycerol esters, such as Cremophor ® EL or Kolliphor ® EL; glycerides, such as lauroyl polyoxyethyl-32 glyceride (Gelucire) ® ); soybean phosphatidylcholine, polyethylene oxide-propylene oxide copolymers (Poloxamer 188, Poloxamer 407), polyoxyethylene castor oil derivatives (Cremophor RH40), and one or more surfactants selected from vinyl stearate (Myrj 52) and mixtures thereof.

[0047] The co-surfactant / co-solvent includes, but is not limited to, short-chain monohydric alcohols, diols, and polyols, such as ethanol, benzyl alcohol, glycerol, propylene glycol, propylene carbonate, polyethylene glycol with an average molecular weight of about 200 to about 10,000, and polyethylene glycol esters (such as Labrafil). ® M1944CS), polyglycerol-3 dioleate, diethylene glycol monoethyl ether (such as Transcutol) ® HP), and its mixtures.

[0048] According to the present invention, the topical gel, cream, and foam compositions may contain emollients. The emollients may be selected from the group consisting of: petrolatum, isopropyl palmitate, vegetable oils (whether hydrogenated or not), silicone oils, any liquid polymeric siloxanes (such as dimethyl silicone oil, cyclodimethylsiloxane, cyclopentasiloxane, dimethylsilanol, and amino-modified silicone oil), mineral oils, waxes (such as paraffin, liquid paraffin, and petrolatum), aloe vera, and fatty alcohols (such as arachidonic acid, cetyl alcohol, behenyl alcohol, C12-13 alcohol, cetearyl alcohol, cetyl alcohol, coconut alcohol, isocetyl alcohol, octyldodecyl alcohol, and palmitol). Fatty acids and their esters (such as cetearyl stearate, cetearyl behenate, cetearyl isononanoate, cetearyl, coconut acid, ethyl linoleate, ethyl linolenic acid, ethyl oleoyl oleate, ethylhexyl cocoate, ethylhexyl myristate, caprylic acid glyceride, lauric acid / oleic acid glyceride, castor oil glyceride, isocetyl salicylate, isostearyl alcohol, linoleic acid, linolenic acid, oleic acid, palmitic acid, palmitic acid and wheat germ acid), shea butter (Butyrospermum parkii), cocoa butter (Theobroma cacao), waxes, glyceryl ester derivatives (such as caprylic / capric triglyceride, coconut glyceride and palm glyceride), cholesterol, lanolin and its derivatives, PEG derivatives, squalane, squalene, sucrose and its derivatives, glyceryl derivatives (such as tricaprylic tricaprylate, tricaprylic tristearate) and mixtures thereof. The emollient in the composition is about 1% to about 15% (w / w).

[0049] The topical gel, cream, and foam compositions may further comprise a humectant selected from the group consisting of: pyrrolidone carboxylic acids (PCA) and their derivatives (such as arginine PCA, chitosan PCA, copper PCA, ethylhexyl PCA, lauryl PCA, magnesium PCA, sodium PCA, zinc PCA), butylene glycol, calcium gluconate, fructose, glucose, isomaltitol, lactose, maltitol, mannitol, polydextrose, sorbitol, sucrose, xylitol, glycerin, glycyrrhizic acid and its derivatives, histidine, hyaluronic acid and its salts (such as sodium hyaluronate), silk / keratin / soybean hydrolysate, PEG (-7, -8, -10, -12, -14), phytanetriol, propylene glycol, silk fibroin (Serica), urea, and mixtures thereof. The humectant is present in the composition at a concentration of approximately 1% to approximately 15% (w / w).

[0050] The localized gel, cream, and foam compositions may contain a rheology modifier at a concentration of about 0.5% to about 5% (w / w). The rheology modifier may be selected from the group consisting of: cetyl alcohol, stearyl alcohol, carnauba wax, stearic acid, plant gums (such as hydroxyethyl cellulose, guar gum, locust bean gum, xanthan gum), gelatin, silica, bentonite, magnesium aluminum silicate, carbomer (polyacrylic acid derivatives), and mixtures thereof.

[0051] The local composition of the present invention may further comprise a preservative, including ammonium benzoate, butyl benzoate, calcium benzoate, ethyl benzoate, isobutyl benzoate, isopropyl benzoate, magnesium benzoate, monoethanolamine 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, monoethanolamine salicylate (MEA-salicylate), sodium salicylate, potassium salicylate, triethanolamine salicylate (TEA-salicylate), sorbic acid, calcium sorbate, sodium sorbate, potassium sorbate, etc. The preservative content in the composition is from about 0.1% to about 5% (w / w).

[0052] In one embodiment, the topical composition of the present invention may further comprise one or more antioxidants. Examples of antioxidants include, but are not limited to, water-soluble antioxidants such as thiol compounds and their derivatives (e.g., sodium metabisulfite and N-acetylcysteine), lipoic acid and dihydrolipoic acid, resveratrol, lactoferrin, ascorbic acid and its derivatives (e.g., ascorbic acid palmitate and ascorbic acid polypeptides); and lipid-soluble antioxidants including, but not limited to, butylated hydroxytoluene, tocopherols (e.g., tocopherol acetate), tocotrienols, and ubiquinone. The antioxidant is present in the topical pharmaceutical composition at a concentration of about 0.01% to about 5% (w / w).

[0053] This disclosure is further illustrated by the following embodiments, but should not be construed as limiting the scope or spirit of this disclosure to the specific procedures described herein.

[0054] Example 1 – Composition of External Solution

[0055] Example 2 – Composition of External Solution

[0056] Example 3 – Topical solution for spray composition

[0057] Example 4 – Topical solution for spray composition

[0058] External liquid formulations are typically prepared by mixing the components with stirring at temperatures between 0°C and 100°C, under normal pressure, without the use of liquefied propellant. If propellant is required, the resulting mixture is dispensed into an aerosol dispenser containing liquefied propellant to obtain the final formulation. Mixing is preferably carried out at temperatures between 10°C and 25°C.

[0059] Alternatively, the mixed formulation can be placed in a pump dispenser, such as a metering pump, which typically dispenses the formulation without liquefying the propellant because a pressurized environment is not required. However, propellants that are liquid at room temperature can also be added to the pump dispenser formulation as part of an aqueous carrier. The formulation prepared in this way can then be sprayed from the dispenser onto the application site.

[0060] The preferred method for preparing the solution is as follows: Levocetirizine, bimatoprost, and Transcutol P are mixed in a 50% mixture of ethanol, water, and propylene glycol and dissolved. The solution is then mixed with the remaining stock solution to obtain a clear solution, and the pH is adjusted with sodium hydroxide solution.

[0061] The topical solution compositions of the present invention are fast-drying, non-occlusive formulations that significantly improve the skin permeability of drugs both in vitro and in vivo. They offer advantages such as lower skin irritation, greater ease of use, higher dosage flexibility, and simpler manufacturing methods.

[0062] Example 5 – Topical Gel Formulation

[0063] The preferred steps for preparing the gel are as follows: First, homogenize the components of the first part at a low speed until the carbomer is evenly dispersed. Then, mix the components of the second part first, add them to the first part, and further homogenize at a medium speed. Mix the components of the third part (excluding the drug) and heat to 60°C until homogeneous. After cooling, thoroughly disperse levocetirizine and bimaprost. Use a low-speed homogenizer to thoroughly mix the third part with the mixture of the first and second parts. Finally, mix the fourth part to obtain a homogeneous gel formulation. The final pH of the gel formulation is 5.8.

[0064] Example 6 – Composition of Topical Cream

[0065] More preferably, the preparation of the cream composition includes the following steps: i) heating the oil phase excipient and water separately; ii) homogenizing the oil phase excipient and water after mixing for approximately 10 minutes; and iii) adding the preservative, levocetirizine, and bimaprost, continuing stirring, and cooling to room temperature. The viscosity of the cream formulation is 0.40 to 0.90 poise (observed value: 0.60 poise), measured by a Brookfield CAP viscometer. The pH of the white cream formulation is 4.6.

[0066] For all the compositions disclosed herein that are in the form of emulsions (including foams), and therefore compositions that contain an aqueous phase in addition to an oil phase, the addition of an antimicrobial preservative may be useful. In particular, if the composition is intended for use in a multi-dose product presentation, it is preferable that it contains a preservative or a combination of preservatives. A person skilled in the art will understand that any antimicrobial preservative can be used to prepare the pharmaceutical compositions disclosed herein, provided it does not interfere with the pharmacokinetic and pharmacodynamic properties of the composition.

[0067] Example 7 – External Foaming Preparation

[0068] The preferred method for preparing the gel is as follows: The first component is mixed and heated until homogeneous. The second component is mixed separately. Propylene glycol and ethanol are added together with the second component, and a homogeneous mixture is obtained under homogenization. After the mixture is cooled, levocetirizine and bimaprost in ethanol are added, and the mixture is stirred to obtain a homogeneous foam formulation. Finally, the mixture is neutralized with triethanolamine in water to obtain a final pH of 6.0-7.0. The final foam formulation is filled into a container and filled with trichlorofluoromethane (P11).

[0069] Study on hair growth efficacy in mouse models The topical composition of the present invention has been tested in an animal model to evaluate its effect on improving hair growth in androgenetic alopecia. This animal model was based on the method reported by Laxman Subedi et al. (Drug Delivery 2022, VOL. 29, NO. 1, 328–341). Androgenetic alopecia was induced in C57 / BL6 mice by intraperitoneal injection of dihydrotestosterone (0.5 mg / kg) once daily for five consecutive days, and the hair on the back of the mice was removed using a wax and tape stripping method. The mice were then randomly divided into five groups (n=8 per group) for topical treatment: Group 1: The topical medication solution provided in Example 1.

[0070] Group 2: 1% levocetirizine topical solution (Example 1, without bimatoprost).

[0071] Group 3: 1% bimatoprost topical solution (Example 1, without levocetirizine).

[0072] Group 4: 5% minoxidil solution.

[0073] Group 5: Placebo solution (drug-free solution) of Example 1.

[0074] One mL of each formulation was applied evenly to the skin on the back of mice once daily for 14 consecutive days. Mice were housed individually. Photographs of the backs were taken at 0, 3, 5, 7, 10, and 14 days after treatment to observe hair regeneration and measure the area of ​​hair regeneration.

[0075] Topical application of the present invention's formulation (1% w / w levocetirizine and 1% w / w bimatoprost) and 5% (w / v) minoxidil solution once daily significantly promoted new hair growth in mice with androgenetic alopecia. After 14 days of treatment with the present invention's formulation and the other formulations mentioned above, the hair regeneration area with the formulation (1% w / w levocetirizine and 1% w / w bimatoprost) was significantly superior to that with the other formulations. Furthermore, topical application of the present invention's formulation (1% w / w levocetirizine and 1% w / w bimatoprost) once daily for 14 days significantly accelerated the next hair growth cycle; noticeable new hair growth was observed in mice as early as day 5, and its regeneration rate was faster than with other formulations.

[0076] Results of a study on the efficacy of hair growth in a mouse model

[0077] Observations on the efficacy of human hair growth

[0078] Two Indian men, aged 46 and 43, with male pattern baldness due to androgenetic alopecia, used the 1% w / w levocetirizine and 1% w / w bimatoprost topical solution from Case 1, applied once nightly before bedtime to the bald and thinning hair areas. After 52 days of application, significant hair growth was observed in the application areas of both men, and continued use was recommended to observe the area of ​​hair growth and hair quality after 120 days.

Claims

1. A synergistic topical composition comprising bimatoprost and levocetirizine for the treatment of androgenetic alopecia. Wherein, Levocetirizine activates the Wnt / p-catenin pathway (increasing PGE2 activity and decreasing PGD2 activity), thereby driving the anagen phase (active phase) of hair follicles; bimatoprost inhibits the bone morphogenetic protein (increasing PGF2α activity) pathway, thereby driving the catagen phase (passive phase) of hair follicles. This composition can protect hair follicles from damage caused by microinflammation.

2. The pharmaceutical composition of claim 1, wherein the topical dosage form is selected from solutions, sprays, creams, gels, foams, ointments, lotions, and liniments.

3. The pharmaceutical composition of claim 1, wherein the composition comprises about 0.001% to 10% (w / w) of levocetirizine and about 0.0001% to 10% (w / w) of bimatoprost.

4. A synergistic topical pharmaceutical composition comprising: 0.001–10% by weight of levocetirizine 0.0001–10% by weight of bimatoprost 0.1–40% by weight of penetration enhancer 1-25% by weight of surfactant 1-20% by weight of antioxidants Optionally, it may contain 1 to 10% by weight of a film-forming agent, 0.1 to 5% by weight of a preservative, and a propellant, with the total weight percentage reaching up to 95% of the composition. The composition is a solution or a spray-type solution.

5. A synergistic topical pharmaceutical composition comprising: 0.001-10% by weight of levocetirizine 0.0001-10% by weight of bimatoprost 5-70% by weight of oil phase 5-70% aqueous phase 1-15% by weight of surfactant 1-16% by weight of emollient 1-15% by weight of moisturizer 0.5-5% by weight of penetration enhancer 0.5-5% by weight of rheology modifier 0.1-5% by weight of preservative 0.1-5% by weight of an antioxidant, wherein the composition is a topical gel, cream or foam.

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