WO2025069091A1

WO2025069091A1 - Novel topical pharmaceutical composition for prevention and treatment of hair loss

Info

Publication number: WO2025069091A1
Application number: PCT/IN2024/051888
Authority: WO
Inventors: Fredrik Enqvist; Desomayanandam PRABAKARAN; Kamalanathan SRINIVASAN; Mandapati Ravindhar REDDY; Ananya De BHOWMICK
Original assignee: Pdfe Pharma Innovations Fzco; Sterin Labs Private Ltd
Current assignee: Pdfe Pharma Innovations Fzco; Sterin Labs Private Ltd
Priority date: 2023-09-29
Filing date: 2024-09-28
Publication date: 2025-04-03
Anticipated expiration: 2026-03-29

Abstract

The present invention relates to a Novel Synergistic Topical Pharmaceutical Compositions comprising of Levocetirizine and Bimatoprost with pharmaceutically acceptable excipients for treatment of androgenic alopecia. The synergistic topical compositions intend to provide a synergistic clinical efficacy in androgenic alopecia by targeting multiple pathways involved in hair growth physiology. The preferable topical pharmaceutical compositions include topical solutions, topical solutions for spray, topical gels, topical creams and topical foams.

Description

Title of The Invention

Novel Topical Pharmaceutical Composition for Prevention and Treatment of Hair

Loss

Technical Field of Invention

The present invention relates to a synergistic topical hair growth formulation comprising Levocetirizine and Bimatoprost for promoting hair growth and treating Androgenic Alopecia.

Background of Invention

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.

The etiology and mechanism of AGA are not fully understood. 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). Although 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.

In view of the foregoing, it is clear that improved methods for restoring hair regrowth are needed.

More evidence has suggested that the prostaglandin pathways (especially the PGDS/PGD pathway) are involved in the pathogenesis of AGA (Ari as -Santiago S et al., J Am Acad Dermatol 2012;66:401-8). Prostaglandins (PG) 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 (COX) 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. Comparisons of the effects of different PG subtypes on hair growth have demonstrated that 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. As the R-enantiomer of Cetirizine, Levocetirizine has higher bioavailability and lower hepatic clearance, and its plasma binding rate can reach 95%. It is characterized by low tissue affinity, low cardiotoxicity, and low sedation effect (Sijian We et al., Ann Palliat Med 2020;9(2):308-3). 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.

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 hair dermal papilla cells (DPCs) and explored its effects on hair growth along with the related molecular mechanisms. Their experiments demonstrated that Levocetirizine could promote the growth and proliferation of hDPCs and significantly inhibit the expressions of relevant factors including COX- 2, PTGDS, PGD2, PGD2R, and GPR44 in the PGD2-GPR44 pathway. These findings provide an experimental and theoretical basis for the treatment of AGA with Levocetirizine.

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. Anagen varies from several years in large terminal scalp follicles forming long hairs, to only a few weeks for short finger hairs (Saitoh M et al., J. Invest. Dermatol. 1970, 54, 65-81) Karzan G. Khidhir et al., (FASEB J. 2013 Feb; 27(2): 557-567) assessed whether Bimatoprost could also stimulate non-eyelash follicles in vivo, particularly when supplied through the skin, the effects of topical Bimatoprost on rodent pelage hair growth. Thus, 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. This highlights a new follicular signalling system and confirms that Bimatoprost offers a novel, low-risk therapeutic approach for scalp alopecia. 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).

Considering all the rationale provided above, there are evidence available and indicating the use of Levocetirizine or Bimatoprost individually for hair regrowth potential. However, there is a need still existing for potential combination therapy which balances anagen, catagen and telogen phases of hair growth cycle. In a first attempt, 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. Also, Levocetirizine protects the hair follicle from micro inflammation which is thought to be the cause of irreversible damage in androgenic alopecia (AGA). 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.

Brief Summary of the Invention

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. Also, the topical pharmaceutical composition comprises suitable pharmaceutically acceptable excipients. In one embodiment, 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.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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.

According to a further embodiment, 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.

According to yet another embodiment, the present invention relates to the use of the compositions described herein for the preparation of a medicament for the treatment of androgenic alopecia. Detailed Description of the Invention

Recent studies on the pathogenesis of androgenetic alopecia (AGA) conclude a skewed prostaglandin (PG) balance in affected areas of the scalp, ultimately leading to hair follicle miniaturization and loss of hair. 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.

In accordance with the present invention, it has surprisingly been found that the 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.

The term “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.

The term “prostaglandin analogs” as employed herein is intended to include Bimatoprost, Latanoprost, Carboprost, Travoprost and Tafluprost and their salts, isomers, polymorphs, solvates and hydrates.

In describing the invention, the following definitions are applicable throughout. “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.

The term “Topical pharmaceutical composition” as used herein 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.

The present invention includes topical solutions or topical solution for spray 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.

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, hydroxypropyl methyl cellulose, hydroxy ethyl cellulose, methyl cellulose and ethyl cellulose.

The composition may be dispensed from a pump dispenser or from an aerosol dispenser. In the latter case, the composition additionally comprises from about 5% to 90% of propellant in order to provide a suitable pressure within the aerosol dispenser. Generally, propellant is not required for compositions dispensed from a pump dispenser. However, if desired, 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.

In addition, 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.

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.

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 cetyl ricinoleate, Sodium Formate, Tocopheryl Acetate, Butyl Acetate, Ethyl Acetate, Methoxy isopropyl 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 Glycol Stearate, Ethylhexyl Stearate, Glyceryl Isostearate, Glyceryl Stearate, Glyceryl Stearate SE, Glycol Distearate, Magnesium Stearate, PEG-150 Distearate, PEG-3 Distearate, PEG-30 Glyceryl Stearate, PEG-32 Stearate, PEG-6 Stearate, Polyglyceryl-2 Diisostearate, Polyglyceryl-3 Distearate, Potassium Stearate, unsaturated esters Potassium Sorbate, Glyceryl Oleate, Ethyl Linoleate, Glyceryl Linoleate, Tocopheryl Linoleate; silicone oils such as dimethylpolysiloxane, methylphenylpolysiloxane and silicone-glycol polymer; vegetable oils comprising linoleic acid triglycerides such as Cocos Nucifera (coco oil), Elaeis Guineensis Oil (palm oil), Arachis Hypogaea (arachide oil), Argania Spinosa (argan oil) sweet almond oil, avocado oil, calophyllum oil, lanolin, castor oil, Olea Europaea olive oil, Triticum Vulgare wheat germ oil, maize germ oil, soybean oil, sunflower oil, cottonseed oil, Lucerne oil, poppy oil, red kuri oil, Sesamum Indicum sesame oil, rapeseed oil, evening primrose oil, millet oil, barley oil, quinoa oil, rye oil, safflower oil, candlenut oil, passionflower oil, grape seed oil, rapeseed oil, tall seed oil, flaxseed oil, peanut oil, buckthorn oil, blackcurrant seed oil, Siberian pine seed oil, primrose oil, Glycine Soja, Corylus Avellana (Hazel oil), Juglans Regia (nut oil), Vitis Vinifera (Grape oil).

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®); soya phosphatidylcholine, polyoxyethylene-polyoxypropylene copolymers (Pol oxamer 188, Pol oxamer 407), polyoxyethylene castor oil derivatives (Cremophor RH40), One or more surfactants selected from ethylene stearate (Myrj 52) and mixtures thereof.

The 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.

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 esters, coconut acid, ethyl linoleate, ethyl linolenate, ethyl olivate, ethylhexyl cocoate, ethylhexyl myristate, glyceryl caprylate, glyceryl laurate/oleate, glyceryl ricinoleate, isocetyl salicylate, isostearyl alcohol, linoleic acid, linolenic acid, oleic acid, palm kernel acid, palmitic acid and wheat germ acid, shea butter (Butyrospermum parkii butter), cocoa butter (Theobroma cacao butter), waxes, derivatives of glycerides such as capric/caprylic triglyceride, cocoglycerides, and palm glycerides, cholesterol, lanolin and derivatives, derivatives of PEGs, squalane, squalene, sucrose and derivatives, glycerol derivatives such as glycerol trioctanoate:tricaprylin, glycerol, tri stearate :tri stearin, and mixtures thereof. The emollient may be in the composition from about 1% to about 15% by w/w of the composition.

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 and mixtures thereof. At least one humectant can be in the composition in an amount from about 1% to about 15% by w/w of the composition.

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. In one embodiment, the topical composition of the present invention also contains one or more antioxidants. Examples of 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. The disclosure is further illustrated by the following examples, which are not to be construed as limiting the disclosure in scope or spirit to the specific procedures described in them.

Example 1 - Topical Solution 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.

Alternatively, 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.

The preferable procedure for preparation of solutions as follows: Mix Levocetirizine, Bimatoprost and Transcutol P and in 50% stock of ethanol, water propylene glycol mixture, and allow to dissolve, to make clear solution with rest of the stock, and adjust pH with sodium hydroxide solution.

The 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. Example 5 - Topical Gel Composition

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

More preferably, 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.

For all 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. In particular, if the composition is intended for a multidose product presentation, it is preferred that it comprises a preservative, or a combination of preservatives. A skilled artisan would appreciate that 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.

Example 7 - Topical Foam Composition

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:

Group 1 : Topical Solution Formulation provided in Example 1.

Group 2: Topical Solution of Levocetirizine 1% (Example 1 except Bimatoprost)

Group 3: Topical Solution of Bimatoprost 1% (Example 1 except Levocetirizine)

Group 4: 5% Minoxidil Solution

Group 5: Placebo Solution of Example 1 (solution without drugs)

1 mL of each formulation was uniformly applied to the dorsal skin of mice once per day for 14 days and mice were caged individually. Hair regrowth was examined in dorsal photographs taken 0, 3, 5, 7, 10, and 14 days after treatment and hair regrowth areas were measured.

Once-daily topical treatment with topical formulation of current invention (Levocetirizine 1% w/w and Bimatoprost 1%, w/w) and 5% (w/v) Minoxidil solution significantly promoted new hair growth in androgenic alopecia mice. When the mice were treated with once-daily topical formulation of current invention and other formulations mentioned above for 14 days and the topical formulation of current invention (Levocetirizine 1% w/w and Bimatoprost 1%, w/w) showed superior the hair regrowth area. Also, Once-daily application of topical formulation of current invention (Levocetirizine 1% w/w and Bimatoprost 1%, w/w), for 14 days significantly accelerated the next hair cycle, with significant new hair growth clearly visible on day 5 in mice and the rate of regrowth is faster than the other formulations.

Results of Hair Growth Efficacy Study in Mouse Model

Observations on Hair Growth Efficacy in Human

Two Indian males 46 years old and 43 years old with male pattern baldness due to androgenetic alopecia used Levocetirizine 1% w/w and Bimatoprost 1% w/w topical solution of Example 1, once daily before sleeping, in areas where baldness and low hair density observed. After 52 days of application, visibly noticeable hair growth was observed in applied areas in both males and continuous application was recommended to observe the hair growth area and hair quality after 120 days.

Claims

We Claim,

1. Synergistic pharmaceutical topical compositions comprises Bimatoprost and Levocetirizine for treatment of androgenic alopecia wherein Levocetirizine activate the Wnt/p-catenin pathway (increasing PGE2 and decreasing PGD2 activities) that drives the anagen (active) phase of the hair follicle and Bimatoprost deactivate the Bone morphogenetic protein (increasing PGF2a activity) pathway that drives the Catagen (passive) phase of the hair follicle, and the compositions protects the hair follicle from micro inflammation.

2. The pharmaceutical compositions as claimed in claim 1, wherein the topical dosage form is selected from the group consisting of solutions, solutions for sprays, creams, gels, foams, ointments, lotions and liniment.

3. The pharmaceutical compositions as claimed in claim 1, wherein the composition comprising Levocetirizine ranging from about 0.001%-10% (w/w) and Bimatoprost ranging from about 0.0001%-10% (w/w) of the total composition.

4. A synergistic topical pharmaceutical composition comprising:

0.001 - 10 percent by weight of Levocetirizine

0.0001 - 10 percent by weight of Bimatoprost

0.1-40 percent by weight of Permeation enhancer

1-25 percent by weight of surfactants l-20percent by weight of antioxidants Optionally 1-10 percent by weight of film-forming agent, 0.1-5 percent by weight of preservatives and propellants up to 95% of the composition, wherein the composition is solution or solution for spray dosage form.

5. A synergistic topical pharmaceutical composition comprising:

0.001 - 10 percent by weight of Levocetirizine

0.0001 - 10 percent by weight of Bimatoprost

5-70 percent by weight of oil phase

5-70 percent by weight of aqueous phase

1-15 percent by weight of surfactants

1-16 percent by weight of emollients

1-15 percent by weight of humectants

0.5-5 percent by weight of permeation enhancers

0.5-5 percent by weight of rheology modifier

0.1-5 percent by weight of preservative

0.1-5% percent by weight of antioxidants, wherein the composition is topical gel or cream or foam composition.