DESC:BACKGROUND
Androgenetic alopecia also known as androgenic alopecia is a male or female- pattern baldness. In male, hair loss occurs either a receding front hairline, loss of hair on the crown (vertex) of the scalp, or a combination of both wherein in female’s hair loss occurs as diffuse thinning of the hair across the entire scalp. FPHL is 5 characterized as a non-scarring diffuse alopecia that evolves from the progressive miniaturization of hair follicles and subsequent reduction in the number of hairs, especially in the central, frontal, and parietal scalp regions [Olsen E.A. Female pattern hair loss. J Am Acad Dermatol. 2002; 45:S70–S80].
The baldness is common in both male and female however hair loss in women have 10 greater psychological and social impact than men as it is less socially acceptable for them leading to anxiety and depression. Therefore, early diagnosis and treatment are necessary to stop the progression of heavy hair loss. The pathogenesis of androgenetic alopecia (AGA) is a complex interplay of genetic, hormonal, and environmental factors. In scalp follicles of susceptible individuals, androgens 15 promote miniaturization of hair and shorten hair growth in the anagen stage, ultimately leading to AGA. The role of androgens is not clearly explained in females and only one-third of women with FAGA show abnormal androgen levels. There are several treatment options available such as topical, oral and hair transplant. Hair transplant is more effective than oral and topical treatment however the procedure 20 is very costly and required multiple sittings. Therefore, oral and topical method is mostly preferred by the patients.
FDA have approved topical minoxidil (Rogaine) which can be used by men and women, oral finasteride (Propecia)which is only prescribed for men and Low Level Laser Light therapy (LLLT) for both men and women. There are other variety of 25 options available for treating AGA like nutraceuticals, Platelet-rich plasma, micro-
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needling and other several invasive techniques such as transplantation. Although there are several options available, the treatment of AGA is more challenging in females as exact pathogenesis of the condition is not well understood, non-uniformity of response to the treatment, limited FDA approved treatment and expensive cosmetic procedure. Thus there remain a need in art in formulating an 5 effective dosage form taking consideration of individual’s age, lifestyle, preference, availability of treatment, extend of hair loss and economic condition of patient.
Minoxidil was first prescribed for hypertension and it was reported that oral Minoxidil have a side effect of hypertrichosis (hair growth stimulant) causing increased hair growth eventually leading to preparation of topical solution for the 10 treatment of hair loss. Minoxidil is available as topical solution 2% and 5% marketed as ROGAINE® for hair loss and hair regrowth and thinning of hair.
Minoxidil is converted to its metabolite minoxidil sulftate and enzyme which is responsible for this conversion is sulfotransferase, which is located in hair follicles and prolong the anagen phase of hair follicle therefore promote hair growth. 15 However, it was studies that sulfotransferase enzyme varies from human to human and is controlled genetically therefore patient with higher enzyme activity respond better than patient with lower enzyme activity. [Buhl, AE; Baker, CA Dietz; AJ.; Minoxidil sulfotransferase activity influences the efficacy of Rogaine topical solution (TS): enzyme studies using scalp and platelets, J Invest Dermatol, 1994; 102:534]. 20 Minoxidil should be continuously used to continued benefit however prolong use of Minoxidil may have adverse side effects.
Thus there is need of additional active agents which provide alternative and complementary mechanism to overcome the variable efficacy of minoxidil in patients and provide a synergistic effect by acting on different targets with fewer 25 side-effects.
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The inventors of present invention have surprisingly found that combining Cetirizine with Minoxidil have a synergistic effect on the hair growth in patients suffering from androgenetic alopecia than using alone.
Cetirizine is anti-histamine with anti-inflammatory action which reduces both the inflammatory cell infiltrate and high level of prostaglandin D2 (PGD2), hormone 5 which inhibits the hair growth and increases the level of prostaglandin E2 (PGE2) which stimulates the hair follicle growth. [NCT04481412]. Thus Cetirizine overcome the limitation associated with the variable efficacy of minoxidil.
It is therefore an object of the present invention to provide an effective composition comprising synergistic combination of Cetirizine and Minoxidil or pharmaceutically 10 salts thereof wherein cetirizine overcome the limitation associated with the variable efficacy of minoxidil and have less side effects than existing marketed products and effectively deliver the active agents directly to the hair follicle or hair shaft to promote hair growth in patients with androgenetic alopecia.
SUMMARY OF THE INVENTION 15
The present invention provides a novel drug delivery comprising synergistic combination of vasodilator and antihistamine as active agents for effective management of androgenetic alopecia in male and female.
In an another aspect the present invention provides a novel drug delivery composition comprising synergistic combination of vasodilator and antihistamine 20 wherein vasodilator is Minoxidil and antihistamine is Cetirizine or pharmaceutical acceptable salts thereof.
In an another embodiment the present invention provides a topical composition comprising Minoxidil and Cetirizine wherein cetirizine is anti-histamine with anti-inflammatory action which reduces high level of prostaglandin D2 (PGD2), hormone 25
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which inhibits the hair growth and increases the level of prostaglandin E2 (PGE2) which stimulates the hair follicle growth. Thus Cetirizine overcome the limitation associated with the variable efficacy of Minoxidil.
Therefore, the present invention provides a novel drug delivery system comprises synergistic combination of Minoxidil and Cetirizine or pharmaceutical acceptable 5 salts therefore for the treatment of androgenetic wherein the synergistic combination is formulated as topical dosage form.
DETAILED DESCRIPTION OF THE INVENTION:
Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be 10 understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such compositions, components of the composition, referred to or indicated in this specification, individually or collectively and all combinations of any or more of such components or composition.
Definitions 15
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have their meanings recognized and known to those of skill in the art, however, for convenience and completeness, 20 particular terms and their meanings are set forth below.
The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be 25 construed as “consists of only”.
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Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps. 5
The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to 10 those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described. All publications mentioned herein are incorporated herein by reference.
The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. 15 Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein.
The term “pharmaceutical composition” refers to delivery system in which active agents are delivered to the patients. This could be in the form of tablet, capsule, injection, liquid etc. 20
The term “pharmaceutically acceptable excipient” refers to inert substances other than active ingredients which are used in the preparation of pharmaceutical products.
The term “excipients” or “carrier” or “vehicles” as used herein means a component of a pharmaceutical product that is not an active ingredient. The excipients that are 25 useful in preparing a pharmaceutical composition are generally safe and non-toxic
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and does not interact with other components of the composition in a deleterious matter.
The terms "effective amount" or a "therapeutically effective amount" of a pharmacologically active agent is meant a non-toxic but sufficient amount of the drug or agent to provide the desired effect. 5
The terms "active agent" or "active pharmaceutical ingredient" or "drug" are used interchangeably herein to refer to a chemical material or compound that induces a desired pharmacological, physiological effect, and include agents that are therapeutically effective, prophylactically effective, or cosmeceutically effective.
The terms "topical" conventionally mean delivery of a drug or pharmacologically 10 active agent to the skin (including hair and scalp) or mucosa.
The present invention provides a novel drug delivery system comprising synergistic combination of vasodilator and antihistamine wherein vasodilator is Minoxidil and antihistamine is Cetirizine or pharmaceutical acceptable salts thereof.
In an another embodiment the novel drug delivery system is administered in form of 15 oral, topical and parenteral form wherein topical form is being preferred.
In a preferred embodiment the present invention provides a topical composition comprising therapeutically effective amount of Minoxidil and Cetirizine or pharmaceutical acceptable salts thereof. The compositions encompassed by this invention include formulations adapted for topical application to the human scalp. 20 Conventional pharmaceutical preparations for this purpose include ointments, lotions, solution, emulsion pastes, jellies, gels, mousses, sprays, foams, aerosols, and the like.
The hair growth stimulant composition of the present invention thus obtained can be used as a suitable topical preparation; however, one of ordinary skill in the art 25
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will readily use Applicants' inventive method to prepare lotions, ointments, aerosols, tonics, creams, solution, gels, and the like.
In a preferred embodiment the present invention provides topical solution comprising therapeutically effective amount of Minoxidil and Cetirizine or pharmaceutical acceptable salts thereof and pharmaceutically acceptable excipients. 5
In an another embodiment the topical formulation further comprises one or more pharmaceutically acceptable excipients selected from solubilizers, buffering agents, stabilizer antioxidants, solvents and pH modifier, fragrance.
In embodiments of the invention solubilizers are selected from the group consisting of glyceryl oleate, isopropyl myristate, methyl laurate, N-lauroyl sarcosine, oleic acid 10 (octadecenoic acid), sodium lauryl sulfoacetate, sodium octyl sulfate, tromethamine, propylene glycol (PG), propylene glycol dipelargonate (PGDP), transcutol, fatty alcohols, such as oleyl alcohol, caprylic alcohol, decyl alcohol, lauryl alcohol, 2-lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, linoleyl alcohol and linolenyl alcohol. Preferably, the solubilizer used in the preferred composition is 15 selected from tromethamine or combinations thereof.
In an another embodiment the present invention the stabilizer used are selected from but not limited to ammonium hydroxide, arginine, 2-amino-2-methyl-1-propanol, dimethanolamine, dibutanolamine, diisobutanolamine, tributanolamine, triisobutanolamine, tripropylamine, ethanolamine, diethanolamine, 20 triethanolamine, diisopropanolamine, methylethanolamine, diisopropylamine, dipropylenetriamine, tromethamine, isopropylamine ethylene diamine, triisopropanolamine, tetrahydroxypropyl ethylenediamine, trimethamine, 2-aminobutanol, aminoethyl propanediol, aminomethyl propanediol, aminomethyl propanol, sodium hydroxide, and potassium hydroxide. 25
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In an embodiment the preferred stabilizer is arginine present in an amount ranging from 0.5 to 10% w/v more preferably 1.50% w/v.
In embodiments of the invention, buffering agents are selected from the group consisting of diethanolamine, triethanolamine, sodium hydroxide, hydrochloric acid, sodium citrate dihydrate, citric acid and mono basic sodium phosphate. 5
In embodiments of the invention antioxidants are selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, beta-carotene, alpha-tocopherol, propyl gallate, gentisic acid sodium ascorbate, sodium bisulfite, sodium metabisulfite, monothioglycerol, cysteine, thioglycolate sodium, acetone sodium bisulfite, ascorbate (sodium/acid), bisulfite 10 sodium, cystein/cysteinate HCl, dithionite sodium (Na hydrosulfite, Na sulfoxylate), gentisic acid, gentisic acid ethanolamine, glutamate monosodium, formaldehyde sulfoxylate sodium, metabisulfite potassium, metabisulfite sodium, monothioglycerol (thioglycerol), propyl gallate, sulfite sodium, tocopherol alpha, thioglycolate sodium, EDTA in calcium and sodium compounds (disodium EDTA) or 15 the mixtures thereof.
In an embodiment the composition may comprises optionally one or more polymer.
In an another embodiment pH modifier is selected from but not limited to acetic acid, hydrochloric acid, salicylic acid, boric acid, sulphuric acid, lactic acid, citric acid, or any combination thereof. 20
In a preferred embodiment pH modifier is lactic acid present in an amount ranging from 0.1 % w/v to 10 % w/v more preferably 1.00% w/v.
In an another embodiment the composition further comprises one or more solvent selected from but not limited to ethanol, propanol, butanol, propylene glycol,
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dipropylene glycol, hexylene glycol, 1,3-butylene glycol, PEG-200, PEG-400, glycerol or combinations thereof.
In a preferred embodiment the solvent is Propylene glycol present in an amount ranging from 50 to 90% w/v more preferably 75% w/v.
The present invention provides a topical composition synergistic combinations of 5 Minoxidil and Cetirizine or pharmaceutical acceptable salts. The stimulatory actions of both compounds can promote each other's effectively, i.e., synergism, Minoxidil can promote hair growth by prolonging the anagen phase and Cetirizine with anti-inflammatory action reduces high level of prostaglandin D2 (PGD2), hormone which inhibits the hair growth and increases the level of prostaglandin E2 (PGE2) which 10 stimulates the hair follicle growth and overcome the limitation associated with the variable efficacy of minoxidil.
In an embodiment the present invention provides method of stimulating the growth of hair or prevent hair loss in both men and women preferably more in women, the solution of the current invention is topically applied to the scalp to increase terminal 15 hair density and hair shaft diameter, promotes vellus hair density, prevent hair loss and promotes hair growth in patient suffering from androgenic alopecia.
In an another embodiment the topical composition preferably comprises:
a. Cetirizine hydrochloride in the range about 0.5-5% weight by volume of the total volume of composition and; 20
b. Minoxidil in the range about 1-10% weight by volume of the total composition
In an embodiment the topical composition comprises:
a. Cetirizine hydrochloride present in an amount of about 1.00 % w/v of total volume of composition and; 25
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b. Minoxidil present in an amount of about 5.00% w/v of total volume of composition
In a further embodiment the present invention provides a topical solution comprising:
a) Cetirizine hydrochloride present in the range about 0.5-5% weight by volume 5 of the total volume of composition and;
b) Minoxidil present in the range about 1-10% weight by volume of the total composition
In an another embodiment the pH of topical solution is between 4.5 to 6.5.
In an another embodiment the present invention provides topical solution 10 comprises:
a) Cetirizine hydrochloride present in the range about 0.5-5% weight by volume of the total volume of composition and;
b) Minoxidil present in the range about 1-10% weight by volume of the total composition and; 15
c) One or more stabilizer presents in an amount ranging from 0.5 to 10% w/v and;
d) One or more pH modifier presents in an amount ranging from 0.1 % w/v to 10 % w/v
In an another embodiment the present invention provides a topical composition 20 comprises:
a) Cetirizine hydrochloride present in the amount of about 0.5-5% weight by volume of the total volume of composition and;
b) Minoxidil present in the amount of about 1-10% weight by volume of the total composition and; 25
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c) Arginine present in amount of about 1.5% weight by volume of the total composition as stabilizer and;
d) Lactic acid present in an amount of about 1.0% weight by volume of the total composition as pH Modifier
The invention further provides method of preparing topical solution of the present 5 invention:
i. Preparing propylene glycol phase by heating up to 60°C ± 5°C and;
ii. Add arginine into propylene glycol with continuous stirring until a clear solution was obtained and;
iii. Add Minoxidil to above solution obtained from step-ii with continuous 10 stirring until a clear solution was obtained and;
iv. Add cetirizine hydrochloride to above solution obtained from step-iii with continuous stirring until a clear solution was obtained and;
v. Addition of fragrance to the solution obtained from step-iv with continuous stirring and; 15
vi. Adjust the pH of the solution by using lactic acid between 4.5 to 6.5
EXAMPLES
The present invention will be described in more detail by the following examples, which should not be construed as limiting the present invention.
Example-1 20
Ingredients
% w/v
Role
Minoxidil
5.0
Active agent
Cetirizine Hydrochloride
1.0
Active agent
L-Arginine
1.50
Stabilizer
Lactic acid
1.00
pH Modifier
13
Denim perfume
0.50
Fragrance
Propylene Glycol
75.0
Solvent
Purified water
QS to 100
Example-2: The topical solution prepared by example-1 was subjected to stability study under various temperature: a) When solution stored at 50°C for 7 days 5 Test Acceptance criteria Results Description Clear colourless liquid filled in HDPE bottle Clear colourless liquid filled in HDPE bottle Related substance (by HPLC) As below As below Cetirizine
As below
As below Cetirizine impurity A Not more than 0.5 % Not detected Single maximum impurity Not more than 0.5 % Not detected Total impurities Not more than 2.0 % Not detected Minoxidil
As below
As below Single maximum impurity Not more than 0.2 % 0.150 % Total impurities Not more than 2.0 % 0.190 % Assay: (by HPLC) Each ml contains: Shelf life limit
Cetirizine Hydrochloride I.P. Eq. to cetirizine 1.0% w/v Not less than 0.90% w/v & not more than 1.10 % w/v 0.996 % w/v 99.60 %
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(not less than 90.00% & not more than 110.00% of label claim) Minoxidil I.P. 5.0% w/v Not less than 4.50 % w/v & not more than 5.50 % w/v (not less than 90.00% & not more than 110.00% of label claim) 5.24 % w/v 104.80 %
The topical solution of present invention was found to be stable when stored at 50°C for 7 days. b) When stored at room temperature for 7 days Test Acceptance criteria Results Description Clear colourless liquid filled in HDPE bottle Clear colourless liquid filled in HDPE bottle Related substance (by HPLC) As below As below Cetirizine
As below
As below Cetirizine impurity A Not more than 0.5 % Not detected Single maximum impurity Not more than 0.5 % Not detected Total impurities Not more than 2.0 % Not detected Minoxidil
As below
As below Single maximum impurity Not more than 0.2 % 0.150 % Total impurities Not more than 2.0 % 0.180 % Assay: (by HPLC) Each ml contains: Shelf life limit
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Cetirizine Hydrochloride I.P. Eq. to cetirizine 1.0% w/v Not less than 0.90% w/v & not more than 1.10 % w/v (not less than 90.00% & not more than 110.00% of label claim) 0.996 % w/v 99.60 % Minoxidil I.P. 5.0% w/v Not less than 4.50 % w/v & not more than 5.50 % w/v (not less than 90.00% & not more than 110.00% of label claim) 5.23 % w/v 104.60 %
The topical solution of present invention prepared by example-1 was found to be stable at room temperature when stored for 7 days. c) When stored at room temperature for 14 days Test Acceptance criteria Results Description Clear colourless liquid filled in HDPE bottle Clear colourless liquid filled in HDPE bottle Related substance (by HPLC) As below As below Cetirizine
As below
As below Cetirizine impurity A Not more than 0.5 % Not detected Single maximum impurity Not more than 0.5 % Not detected Total impurities Not more than 2.0 % Not detected Minoxidil
As below
As below Single maximum Not more than 0.2 % 0.150 %
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impurity Total impurities Not more than 2.0 % 0.180 % Assay: (by HPLC) Each ml contains: Shelf life limit
Cetirizine Hydrochloride I.P. Eq. to cetirizine 1.0% w/v Not less than 0.90% w/v & not more than 1.10 % w/v (not less than 90.00% & not more than 110.00% of label claim) 0.996 % w/v 99.60 % Minoxidil I.P. 5.0% w/v Not less than 4.50 % w/v & not more than 5.50 % w/v (not less than 90.00% & not more than 110.00% of label claim) 5.23 % w/v 104.60 %
The solution was found to be stable when stored at room temperature when stored for 14 days.

,CLAIMS:We claim:
1. A topical composition comprising:
a) a therapeutically effective amount of minoxidil or its pharmaceutically acceptable salts
b) a therapeutically effective amount of cetirizine or its 5 pharmaceutically acceptable salts and;
c) one or more pharmaceutically acceptable excipients.
2. A topical composition as claimed in claim 1 comprising:
a) Cetirizine hydrochloride in the range about 0.5-5% weight by volume of the total volume of composition and; 10
b) Minoxidil present in an amount ranging about 0.5-5% weight by volume of the total volume of composition
3. A topical composition as claimed in claim 2 comprising:
a) Cetirizine hydrochloride present in an amount of about 1.00 % w/v of total volume of composition and; 15
b) Minoxidil present in an amount of about 5.00% w/v of total volume of composition
4. A topical composition as claimed in claim 1 further comprises one more excipients selected from but not limited to solubilizers, buffering agents, stabilizer antioxidants, solvents and pH modifier, fragrance 20
5. A topical composition as claimed in claim 3 comprises:
a) Cetirizine hydrochloride present in the range about 0.5-5% weight by volume of the total volume of composition and;
b) Minoxidil present in the range about 1-10% weight by volume of the total composition and; 25
c) One or more stabilizer presents in an amount ranging from 0.5 to 10% w/v and;
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d) One or more pH modifier presents in an amount ranging from 0.1 % w/v to 10 % w/v
6. A topical composition as claimed in claim 1 wherein said composition is in the form of a solution, shampoo, ointment, cream, lotion, emulsion, dispersion, suspension or gel. 5
7. A topical composition as claimed in claim 6 is a solution comprising:
a) Cetirizine hydrochloride present in an amount of about 1.00 % w/v of total volume of composition and;
b) Minoxidil present in an amount of about 5.00% w/v of total volume of composition 10
8. A topical solution as claimed in claim 1-7 comprises:
a) Cetirizine hydrochloride present in an amount of about 1.00 % w/v of total volume of composition and;
b) Minoxidil present in an amount of about 5.00% w/v of total volume of composition and; 15
c) Arginine present in amount of about 1.5% weight by volume of the total composition as stabilizer and;
d) Lactic acid present in an amount of about 1.0% weight by volume of the total composition as pH Modifier
9. A topical solution as claimed in claim 8 further comprises propylene glycol as 20 solvent, fragrance and water.
10. A process of preparing a topical solution as claimed in claim 1-9 comprises following steps:
i. Preparing propylene glycol phase by heating up to 60°C ± 5°C and;
ii. Add arginine into propylene glycol with continuous stirring until a 25 clear solution was obtained and;
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iii. Add Minoxidil to above solution obtained from step-ii with continuous stirring until a clear solution was obtained and;
iv. Add cetirizine hydrochloride to above solution obtained from step-iii with continuous stirring until a clear solution was obtained and;
v. Addition of fragrance to the solution obtained from step-iv with 5 continuous stirring and;
vi. Adjust the pH of the solution by using lactic acid between 4.5 to 6.5
Dated this 26 June 2023

Siddhartha Dulakakhoria
DGM | IPR
Akums Drugs & Pharmaceuticals limited