FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"TOPICAL PHARMACEUTICAL COMPOSITIONS COMPRISING
MINOXIDIL"
2. APPLICANT:
(a) NAME: CIPLA LIMITED
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: Mumbai Central, Mumbai - 400 008, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be formed.

FIELD OF INVENTION:
The present invention relates to topical pharmaceutical compositions of minoxidil, methods for making the compositions, and methods for inducing and/or stimulating hair growth and/or reducing hair loss using the compositions.
BACKGROUND AND PRIOR ART:
Androgenic alopecia (AGA) is characterised by hereditary thinning of the hair induced by androgens in genetically susceptible men and women. This condition is also known as male pattern hair loss or common baldness in men and as female pattern hair loss in women. Thinning usually begins between the age of 12 and 40 years in both sexes, and at least 50% of the men by the age of 50 and 50% of women by the age of 60 are most affected. It is more common in men. The pattern of inheritance is polygenetic. Male pattern hair loss results from a combination of hereditary, acquired factors and hormones. Few references describe the interdependence of androgens, genetic factors and age which influences scalp hair growth. Androgens are important in regulating hair growth at puberty as they increase the size of follicles in beard, chest and limbs and decrease the size of follicle in bitemporal regions which reshapes the hair line in men and women. In susceptible hair follicle of the scalp dihydrotestosterone (DHT) binds to androgen receptor and this hormone receptor complex then activates the genes responsible for gradual transformation of large terminal follicle to miniaturized follicle. AGA susceptibility is largely determined by genetics, though the environment may also play a minor role. Androgen receptor polymorphisms probably make the key determination for androgen responsiveness, but 5a reductase, aromatase, and sex hormone binding globulin (SHBG) genes may also contribute along with other hormone metabolism associated genes.
Drug therapies specifically approved for treating AGA are limited to minoxidil and finasteride as major category products. Several other drugs are also used off label and a plethora of treatments with unsubstantiated hair growth claims can be obtained, however, looking at the number of treatment options currently available to patients with AGA, though the clinical data supporting their use is often very limited.

Minoxidil (i.e., 2,4-diamino-6-piperidinylpyrimidine-3-oxide) is the active ingredient of the brand Rogaine® (in USA and Canada) and Regaine®(in Europe and Asia Pacific) as a treatment and prevention for androgenic alopecia (male and female pattern baldness) available as 5% minoxidil solution designed for men and 2% solutions designed for women. The preparation of minoxidil is described in U.S. Pat. No. 3,461,461. Methods and topical preparations for using the compound to grow hair and to treat male and female pattern baldness are described and claimed in U.S. Pat. Nos. 4,139,619 and 4,596,812.
Pharmaceutical compositions for topical application may take a variety of forms including, for example, solutions, gels, suspensions, and the like. Generally speaking, improved absorption may be achieved when the topical compositions are in the form of a solution or gel, i.e., where the active ingredient, for example, minoxidil, is dissolved in the carrier solution, in contrast to topical compositions which are in the form of suspensions, i.e., where the active ingredient is merely suspended in the composition.
Topical solutions have not been entirely satisfactory for use in treating the scalp, as these solutions do not remain on the scalp long enough for adequate amounts of the drug to be absorbed. Formulations in the form of jellies and ointments have also been proposed but, these compositions may not be pharmaceutically elegant, and also may not be suitable for use as treatments for stimulating the growth of hair, especially from a cosmetic point of view. Attempts to provide pharmaceutically appropriate thickened formulations containing higher concentrations of solubilized minoxidil are hampered, by various processing difficulties. For example, minoxidil is poorly soluble, and may precipitate out of solution by the addition of additional ingredients, such as thickening agents. Accordingly, high percentages of solvents (about 30 -50% or even more), such as propylene glycol and lower alcohols (for e.g. ethanol) may be required. Due to the viscosity and tack of propylene glycol, large amounts of propylene glycol are not pharmaceutically or cosmetically elegant which may further lead to local irritation and hypersensitivity where applied to the skin. Further, solvents such as propylene glycol have been reported to contribute to various allergic reactions and lower alcohol (e.g. ethanol) presence causes dryness of scalp resulting in itching, flakes, dandruff, light sensitivity and inflammation. It has also been observed that after application of the topical

products comprising either high percentages of solvents such as propylene glycol or ethanol tend to undergo recrystallization of the drug/active ingredient on the scalp thereby leading to poor patient compliance.
US2003/0157046 discloses a minoxidil-containing composition which can be prevented from coloring for a long period of time.
U. S. Pat. No. 6,946,120 discloses a pharmaceutical composition for topical administration including piperidinopyrimidine derivative or salt thereof, an acid and a solvent composition with atJeast two solvents selected from water, ethanol and co-solvent which inturn includes propylene glycol.
US2005/0163811 discloses a method for achieving a novel solution comprising a high percentage of a piperidinopyrimidine derivative, more particularly minoxidil by way of specific processing.
Various of such topical therapies (e.g. such as gel based formulations) require an increased contact time which in turn leads to increase in local drug concentration because of: i) an effect where in ethanol evaporates quickly and the residue of the drug remains on the skin or ii) penetration enhancement affects wherein ethanol alters the physical integrity of stratum corneum barrier resulting in an increase in the ability of drug to penetrate the skin.
Hence, considering the conventional problems associated with use of potential solvents as discussed above, and keeping into consideration the contact time which in turn leads to increase in local drug concentration for specific formulations requiring presence of such potential solvents, there is a need to develop a suitable topical compositions which helps in inducing and/or stimulating hair growth and/or reducing hair loss without compromising on the aforementioned aspects that need be taken into consideration as well as which overcomes the drawbacks of the prior art compositions.

OBJECT OF THE INVENTION:
The object of the present invention is to provide a topical pharmaceutical composition comprising a solution of minoxidil with pharmaceutically suitable excipients which exhibits reduced or no irritation on application.
Another object of the present invention is to provide a topical pharmaceutical composition comprising a solution of minoxidil with pharmaceutically suitable excipients which does not form flakes or crystals on application.
Another object of the present invention is to provide a topical pharmaceutical composition comprising a solution of minoxidil with pharmaceutically suitable excipients wherein the said composition is devoid of higher amounts of propylene glycol and/ or lower alcohols.
Yet another object of the present invention is to provide a process for preparing a topical pharmaceutical composition comprising a solution of minoxidil with pharmaceutically suitable excipients.
Still another object of the present invention is to provide a method of inducing and/or stimulating hair growth by applying a topical pharmaceutical composition comprising a solution of minoxidil with pharmaceutically suitable excipients wherein the said composition is devoid of higher amounts of propylene glycol and/ or lower alcohols.
Still another object of the present invention is to provide a method of reducing hair loss by applying a topical pharmaceutical composition comprising a solution of minoxidil with pharmaceutically suitable excipients wherein the said composition is devoid of higher amounts of propylene glycol and/ or lower alcohols.
Another object of the present invention to provide a topical pharmaceutical composition comprising a solution of minoxidil with pharmaceutically suitable excipients for use in the treatment of androgenic alopecia.

SUMMARY OF THE INVENTION:
According to one aspect of the present invention, there is provided a topical pharmaceutical composition comprising minoxidil and at least one or more pharmaceutically acceptable excipients.
Preferably, the composition is suitable for topical administration. Preferably, the composition is an aqueous based solution. Preferably, the composition is an aqueous based solution comprising water.
Preferably, the composition is devoid of higher amounts of propylene glycol and/ or lower alcohols.
Preferably, the composition is free of propylene glycol. Preferably, the composition is free of lower alcohols.
According to another aspect of the invention, there is provided a composition of the invention for use in medicine. Preferably, the use comprises inducing and/or stimulating hair growth, reducing hair loss, and/or treating androgenic alopecia.
According to another aspect of the invention, there is provided the use of a topical pharmaceutical composition according to the invention in the manufacture of a medicament for inducing and/or stimulating hair growth, reducing hair loss, and/or treating androgenic alopecia.
According to another aspect of the invention, there is provided a method of inducing and/or stimulating hair growth, reducing hair loss, and/or treating androgenic alopecia, wherein the method comprises applying the composition of the invention to a patient in need thereof.
According to another aspect of the invention, there is provided a process for preparing a topical pharmaceutical composition of the present invention, wherein the process comprises blending minoxidil, with at least one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION OF THE INVENTION:
The existing therapies for the treatment of androgenic alopecia require an increased contact time to attain increased drug concentration at the site of application. These therapies incorporate higher amounts of potential solvents like propylene glycol and/ or lower alcohols to not only assist in solubilising the active ingredient but also promote the requisite activity.
The inventors of the present invention have observed that by avoiding use of higher amounts of the aforementioned potential solvents like propylene glycol or completely excluding propylene glycol and/ or lower alcohols, and by adjusting the acid concentration of the composition, the solubility of the active ingredient (minoxidil) significantly increases and wherein the composition may be proposed in the form of an aqueous solution which also exhibits a reduced contact time at the site of application.
The present invention provides a topical pharmaceutical composition comprising minoxidil with atleast one or more pharmaceutically suitable excipients.
The term "Minoxidil" or "active ingredient" or "active/s" or "active agent" is used in broad sense to include not only "Minoxidil" per se but also its pharmaceutically acceptable derivatives thereof. Suitable derivatives include pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable anhydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable isomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers, pharmaceutically acceptable complexes etc.
The term "topical pharmaceutical composition" may include liquid dosage forms (liquids, liquid dispersions, suspensions, solutions, emulsions, sprays, spot-on, pour-on), gels, foams, aerosols (propellant based or non-propellant based), ointments, creams, mousse, however, other dosage forms such as powders, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, (multi-unit pellet systems) MUPS, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, (multi-unit pellet

systems) MUPS, granules, and microspheres, multiparticulates) and sprinkles may also be envisaged under the ambit of the present invention.
According to the present invention, there is provided a topical pharmaceutical composition comprising minoxidil along with at least one or more pharmaceutically suitable excipients wherein the said composition is devoid of higher amounts of propylene glycol and/ or lower alcohols.
Preferably, the composition comprises less than 40% w/v of propylene glycol. More preferably, the composition comprises less than 30 % w/v of propylene glycol. More preferably, the composition comprises less than 20 % w/v of propylene glycol. More preferably, the composition comprises less than 10 % w/v of propylene glycol. Most preferably, the composition is free of propylene glycol.
Preferably, the composition is free of lower alcohols. The term "lower alcohol" would be understood by the skilled person in the broadest sense to mean an alcohol with 10 carbon atoms or less. Preferably, the composition of the invention is free of lower alcohols with 3 carbon atoms or less. Preferably, the composition is free of monohydric lower alcohols with 3 carbon atoms or less. Preferably, the composition is free of aliphatic monohydric lower alcohols with 3 carbon atoms or less. Preferably, the composition is free of methanol, ethanol and propanol. Preferably, the composition comprises less than 40% w/v of aliphatic monohydric alcohols with 3 carbon atoms or less. More preferably, the composition comprises less than 30% w/v of aliphatic monohydric alcohols with 3 carbon atoms or less. More preferably, the composition comprises less than 20% w/v of aliphatic monohydric alcohols with 3 carbon atoms or less. More preferably, the composition comprises less than 10% w/v of aliphatic monohydric alcohols with 3 carbon atoms or less. Most preferably, the composition is free of aliphatic monohydric alcohols with 3 carbon atoms or less.
Preferably, the composition comprises less than 40% w/v of propylene glycol and less than 40% w/v of monohydric alcohols with 3 carbon atoms or less. More preferably, the composition comprises less than 30% w/v of propylene glycol and less than 30% w/v of monohydric alcohols with 3 carbon atoms or less. Even more preferably, the composition

comprises less than 20% w/v of propylene glycol and less than 20% w/v of monohydric alcohols with 3 carbon atoms or less. Even more preferably, the composition comprises less than 10% w/v of propylene glycol and less than 10% w/v of monohydric alcohols with 3 carbon atoms or less. Most preferably, the composition is free of propylene glycol and monohydric alcohols with 3 carbon atoms or less.
Alternatively, there is provided a topical pharmaceutical composition comprising minoxidil along with at least one or more pharmaceutically suitable excipients wherein the said composition may totally exclude propylene glycol and/ or lower alcohols.
The inventors of the present invention have also further observed that the solubility properties of minoxidil improved by nanosizing.
Nanonization of hydrophobic or poorly water-soluble drugs or drug-excipient premix generally involves the production of drug nanocrystals through either chemical precipitation (bottom-up technology) or disintegration (top-down technology). Different methods may be utilized to reduce the particle size of the hydrophobic or poorly water soluble drugs. [Huabing Chen et al, discusses the various methods to develop nanoformulations in "Nanonization strategies for poorly water-soluble drugs," Drug Discovery Today, Volume 16, Numbers 7/8, April 2011],
The term "nanosize" as used herein refers to drug particles having an average particle size of less than or equal to about 2000 nm, preferably less than or equal to about 1000 nm.
Mostly all particles have a particle size of less than or equal to about 2000 nm, preferably less than or equal to about 1000 nm.
The term "particles" as used herein refers to individual particles of a drug or particles of drug or drug granules and/or mixtures thereof.
The nanosize particles of the present invention can be obtained by any of the process such as but not limited to milling, precipitation, homogenization, high pressure homogenization, spray-freeze drying, supercritical fluid technology, double

emulsion/solvent evaporation, PRINT (Particle replication in non-wetting templates), thermal condensation, ultrasonication, spray drying or the like. Such nanoparticles obtained by any of these processes may further be formulated into desired dosage forms.
Suitably, the topical pharmaceutical composition, according to the present invention, is presented in a liquid dosage form, conveniently packaged in single or multiple units, which may further comprise one or more pharmaceutically acceptable excipients. The liquid dosage form as envisaged under the present invention may be aqueous-based, alcohol-based or hydro-alcohol based composition wherein the said alcohol refers to class of lower alcohols. Alternatively, the topical pharmaceutical composition, according to the present invention, may include suitable excipients which may increase the viscosity of the composition to provide range of viscous liquid to semisolid consistency based composition.
Preferably, the topical pharmaceutical composition, according to the present invention, is aqueous based composition with minimum amount of alcohols (e.g. lower alcohols) or totally devoid of alcohols (e.g. lower alcohols). Alternatively, the topical pharmaceutical composition may be alcohol or hydro-alcohol based composition which may comprise pharmaceutically suitable amount of alcohol ranging from 0% to 10% with one or more pharmaceutically acceptable excipients.
Preferably, the topical pharmaceutical composition, according to the present invention, is an aqueous based composition which may comprise minoxidil with one or more of pharmaceutically acceptable excipients wherein the said composition i) is totally devoid of excipients like propylene glycol and/ or lower alcohols, or, ii) may comprise less than 10% of excipients like propylene glycol and/ or lower alcohols.
As envisaged under the present invention, one or more pharmaceutically acceptable excipients may be used for formulating the topical pharmaceutical composition according to the present invention.
Suitable excipients may comprise one or more of surfactants/wetting agents, acidifying agents, solubilizers, penetration enhancers, preservatives, humectants, moisturizers, anti-

oxidants, de-tackifying agents, conditioning agents, proteins, fragrances and mixtures thereof.
According to the present invention, surfactants/wetting agents may be suitably selected from but not limited to anionic, cationic, nonionic, zwitterionic, amphoteric and ampholytic surfactants, as well as mixtures of these surfactants and suitable non-limiting examples may comprise one or more, but not limited to polyethoxylated fatty acids, fatty acid diesters, polyethylene glycol glycerol fatty acid esters, alcohol-oil transesterification products, polyglycerized fatty acids, sterol and sterol derivatives, polyethylene glycol sorbitan fatty acid esters/ Polysorbates; polyethylene glycol alkyl ethers, sugar esters, polyethylene glycol alkyl phenols, polyoxyethylene- polyoxypropylene block copolymers, sorbitan fatty acid esters and lower alcohol fatty acid esters; polyoxyethylene (POE) fatty acid esters, such as Myrj®; polyoxyethylene alkylyl ethers, such as poly oxyethylene cetyl ether, polyoxyethylene palmityl ether, polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether, Brij®; Sodium dodecyl sulfate (sodium lauryl sulfate), Lauryl dimethyl amine oxide, Docusate sodium, Cetyl trimethyl ammonium bromide (CTAB); Octoxynol; N, N-dimethyldodecylamine-N-oxide; Hexadecyltrimethylamrnonium bromide; Polyoxyl 10 lauryl ether; Bile salts (sodium deoxycholate, sodium cholate); Methicones; Polyoxyl' castor oil; Nonylphenol ethoxylated Cyclodextrins; Lecithins; Methylbenzethonium chloride; Glycol esters of fatty acids, Carboxylic amides, Monoalkanolamine condensates, Polyoxyethylene fatty acid amides, Quaternary ammonium salts, Polyoxyethylene alkyl and alicyclic amines or mixtures thereof. The topical pharmaceutical composition, according to the present invention may comprise one or more surfactants/wetting agents in an amount ranging from about 1% w/v to about 10% w/v.
Suitable solubilizers, according to the present invention, may comprise one or more of glycerols; glycols such as polyethylene glycols of various grades; aliphatic alcohols/ aromatic alcohols; Polyoxyl n castor oil (synonyms - ethoxylated castor oil, polyethylene glycol castor oil and wherein "n" is the number of oxyethylene units in the compound); Polyoxyl n hydrogenated castor oil or mixtures thereof. The topical pharmaceutical composition, according to the present invention may comprise one or more solubilizers in an amount ranging from about 1 % w/v to about 50% w/v.

Suitable penetration enhancers, according to the present invention, may comprise one or more of glycol ether solvents such as Ethylene glycol monomethyl ether, Ethylene glycol monoethyl ether, Ethylene glycol monopropyl ether, Ethylene glycol monoisopropyl ether, Ethylene glycol monobutyl ether, Ethylene glycol monophenyl ether, Ethylene glycol monobenzyl ether, Diethylene glycol monomethyl ether, Diethylene glycol monoethyl ether, Diethylene glycol mono-n-butyl ether; dialkyl ethers and dialkyl ether esters such as ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, and ethylene glycol methyl ether acetate, ethylene glycol monoethyl ether acetate, ethylene glycol monobutyl ether acetate or mixtures thereof. The topical pharmaceutical composition, according to the present invention may comprise one or more penetration enhancers in an amount ranging from about 1% w/v to about 20% w/v.
Suitable acidifying agents, according to the present invention, may comprise one or more of acetic acid, hydrochloric acid, salicylic acid, boric acid, sulfuric acid, lactic acid, and citric acid or mixtures thereof. The topical pharmaceutical composition, according to the present invention may comprise one or more acidifying agents in an amount ranging from about 0.5% w/v to about 10% w/v.
Suitable preservatives, according to the present invention, may comprise one or more of aliphatic or aromatic alcohols; glycols; parahydroxybenzoic acid derivatives (e.g. parabens); Vitamin E or its derivatives which may include, but are not limited to, ethyl alcohol, benzyl alcohol, propylene glycol, glycerin, benzoic acid/sodium benzoate, sorbic acid, methylparaben, propylparaben, benzalkonium chloride or mixtures thereof. The topical pharmaceutical composition, according to the present invention may comprise one or more preservatives in an amount ranging from about 0.1% w/v to about 10% w/v.
Suitable de-tackifying agents, according to the present invention, may comprise one or more of silanes; methicones; alkyl/aryl lactates or mixtures thereof. The topical pharmaceutical composition, according to the present invention may comprise one or more de-tackifying agents in an amount ranging from 0.1% w/v.to about 15% w/v.

The topical pharmaceutical composition may comprise one or more surfactants, one or more solubilisers, one or more penetration enhancers, one or more acidifying agents, one or more preservatives and one or more detackifying agents.
The topical pharmaceutical composition, according to the present invention, may further comprise at least one additional active ingredient effectively acting as hair re-growth agent such as, but not limited to, finasteride, dutasteride, ketoconazole, and in case of female androgenic alopecia, other drugs that may be used include, but are not limited to, spironolactone, alfatradiol or flutamide.
Additionally, for the purposes of hair re-growth and maintenance, the topical pharmaceutical composition may comprise one or more vitamins (water soluble or fat soluble or both) eg. Biotin, D-panthenol, niacinamide; herbal extracts and dietary supplements eg. saw palmetto (Serenoa repens), stinging nettle (Urtica dioica), turmeric (Curcubita pepo), and Pygeum africanum. Other herbs include black cohosh (Actaea racemosa), dong quai (Angelica sinensis), false unicorn (Chamaelirium luteum), chasteberry (Vitex agnus-castus), red clover (Trifolium pratense), L-arginine, Boswellia serrata, L-Carnitine, curcumin, ginger, grape seed extract, Grateloupia ettiptica, green tea, lycopene, pumpkin seed oil (Curcurbitae pepo), and resveratrol. It will be well acknowledged by a person skilled in the art that each of these additional active ingredients may be in the form of nano-size particles and may be processed by any of the aforementioned techniques.
Alternatively, it will be well acknowledged to the person skilled in the art that the above additional drugs may be presented in combination with the topical pharmaceutical composition as envisaged under the invention as a fixed and single presentation or as separate kit presentation either solely in the form of topical route or in the form of combination of topical route and other than topical route (which may include but is not limited to oral route) presentations.
According to another embodiment of the present invention, there is provided a process for preparing the topical pharmaceutical composition, which comprises blending minoxidil

with at least one or more pharmaceutically suitable excipients wherein the said composition is devoid of higher amounts of propylene glycol and/ or lower alcohols.
Alternatively, according to another embodiment, there is provided a process for preparing topical pharmaceutical composition, as an aqueous based composition which comprises blending minoxidil with one or more of pharmaceutically acceptable excipients wherein the said composition i) is totally devoid of excipients like propylene glycol and/ or lower alcohols, or, ii) may comprise less than 30% of excipients like propylene glycol and/ or lower alcohols.
The process for preparing the topical pharmaceutical composition may comprise preparing a separate "active dispersion" comprising minoxidil with one or more active ingredients and optionally pharmaceutically acceptable excipients and a separate "excipient dispersion" comprising one or more pharmaceutically acceptable excipients and yielding batch-wise production of the topical solution as envisaged under the invention.
Preferably, there is provided a process for preparing the topical pharmaceutical composition which process comprises co-solvency technology or solvent blending. The term "Co-solvency" refers to a technique of using one or more co-solvents or a co-solvent system that may be used in liquid formulations to increase the solubility of poorly water soluble or sparingly water soluble active ingredients/ drugs. Accordingly, the topical pharmaceutical composition, according to the present invention may be prepared by solvent blending in order to solubilize the active ingredient minoxidil and prevent re-crystallization of minoxidil.
Alternatively, the process of preparing the topical pharmaceutical composition, comprises preparing a separate "active dispersion" comprising minoxidil with one or more active ingredients and optionally pharmaceutically acceptable excipients and separate a "excipient dispersion" comprising one or more pharmaceutically acceptable excipients wherein the said composition i) is totally devoid of excipients like propylene glycol and/ or lower alcohols, or, ii) may comprise less than 30% of excipients like propylene glycol and/ or lower alcohols.

There is also provided a method of inducing and/or stimulating hair growth by applying a topical pharmaceutical composition according to the invention comprising minoxidil with one or more pharmaceutically suitable excipients wherein the said composition is devoid of higher amounts of propylene glycol and/ or lower alcohols.
There is also provided a method of inducing and/or stimulating hair growth by applying a topical pharmaceutical composition comprising minoxidil with one or more pharmaceutically suitable excipients wherein the said composition i) is totally devoid of excipients like propylene glycol and/ or lower alcohols, or, ii) may comprise less than 30% of excipients like propylene glycol and/ or lower alcohols.
There is also provided a method of reducing hair loss by applying a topical pharmaceutical composition according to the present invention comprising minoxidil with pharmaceutically suitable excipients wherein the said composition is devoid of higher amounts of propylene glycol and/ or lower alcohols.
There is also provided a method of reducing hair loss by applying a topical pharmaceutical composition of the present invention comprising minoxidil with pharmaceutically suitable excipients wherein the said composition i) is totally devoid of excipients like propylene glycol and/ or lower alcohols, or, ii) may comprise less than 30% of excipients like propylene glycol and/ or lower alcohols.
There is also provided a topical pharmaceutical composition of the present invention comprising minoxidil with pharmaceutically suitable excipients for use in reducing hair loss or treatment of androgenic alopecia wherein the said composition is devoid of higher amounts of propylene glycol and/ or lower alcohols.
There is also provided a topical pharmaceutical composition comprising minoxidil with pharmaceutically suitable excipients for use in reducing hair loss or treatment of androgenic alopecia wherein the said composition i) is totally devoid of excipients like propylene glycol and/ or lower alcohols, or, ii) may comprise less than 30% of excipients like propylene glycol and/ or lower alcohols.

The following example is for the purpose of illustration of the invention only and is not intended in any way to limit the scope of the present invention. Example I: Formula:

Sr. Ingredients Minoxidil Minoxidil Minoxidil Solution 10%
No. Solution 2% Solution 5% Quantity
Quantity (%w/v) Quantity
(%w/v) (%w/v)
1. Minoxidil 2.00 5.00 10.00
2. Polyethylene glycol 400 40.00 40.00 35.00
3. "Glycerin 5.00 5.00 5.00
4. Diethylene Glycol Monoethyl Ether (Transcutol P) 8.00 8.00 8.00
5. PEG 40 Hydrogenated Castor Oil (Cremophor RH 40) 1.00 1.00 1.00
6. Citric acid (Anhydrous) 0.50 0.50
7. Lactic acid 1.50 1.50 5.00
8. Benzyl Alcohol 2.00 2.00 2.00
9. Butylated Hydroxytoluene 0.01 0.01 0.01
10. PEG-12
Dimethicone (DC 193C) 3.00 3.00 3.00
11. (Bis-PEG-18 1.00 1.00 1.00

Methyl Bther Dimethyl Siiane) (DC 2501)
12. Hydrolyzed Keratin 1.00 1.00 1.00
13. Fragrance 0.05 0.05 0.05
14. Purified water q. s. to 100% (Approx. q. s. to 100% (Approx. q. s. to 100% (Approx. 28.94%)
34.94%) 31.94%)
Manufacturing process:
1. Batch quantity of citric acid and lactic acid were added and dissolved in part quantity of purified water.
2. Minoxidil, Glycerin, Polyethylene glycol 400, Transcutol P, and Cremophor RH40 were added and dispersed in the solution obtained in step (1) followed by heating under continuous stirring.
3. The solution obtained in step (2) was cooled.
4. Batch quantity of Butylated Hydroxytoluene in Benzyl alcohol was prepared and this solution was added to the solution obtained in step (3) under continuous stirring.
5. Suitable quantity of PEG-12 Dimethicone was added and dissolved in the solution obtained in step (4) under stirring followed by addition of Bis-PEG-18 Methyl Ether Dimethyl Siiane.
6. Batch quantity of Hydrolyzed keratin was prepared in remaining quantity of purified water, and was added to the solution obtained in step (5) under stirring.
7. Suitable fragrance was added to the solution obtained in step (6) under stirring, and the volume was made up with purified water.
The following studies have been conducted to compare the aqueous topical minoxidil composition of the present invention with a minoxidil composition comprising alcohol. Study 1.

Comparative In Vitro Diffusion of Minoxidil Solution 5%w/v (Aqueous) and Minoxidil Solution 5%w/v (Alcoholic)
In Vitro diffusion of two solutions viz. Minoxidil Solution 5%w/v (Aqueous) and Minoxidil Solution 5%w/v (Alcoholic) were compared using a dialysis membrane.

As can be seen from the graph, average drug diffused in 4 hours from aqueous solution
and alcoholic solution is 30.15% and 32.18% respectively. Similarly, average drug
diffused in 24 hours from aqueous solution and alcoholic solution is 82.3% and 81.8%
respectively. The average rate of drug diffusion over 24 hours was higher for the aqueous
composition of the invention than for the alcoholic minoxidil formulation.
Conclusion:
The average release rate of Minoxidil solution 5%w/v (aqueous) is nearly similar to
average release rate of Minoxidil Solution 5%w/v (alcoholic).
Study 2.
A further study compares the tendency of minoxidil solution to recrystallize. The aqueous
composition of the invention is compared to the commercially available product Regaine.

Comparative In vitro Recrystallization Study Data of Minoxidil Solution 5%w/v (Aqueous) with Minoxidil Solution 5%w/v (Alcoholic)

Conclusion:
Minoxidil 5%w/v Solution (Aqueous) did not show recrystallization for 8 hours whereas Minoxidil 5%w/v Solution (Alcoholic) showed recrystallization at 30 minutes. It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.
It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to a "preservative" includes a single preservative as well as two or more different preservatives; reference to a "cosolvent" refers to a single cosolvent or to combinations of two or more cosolvents, and the like.

WE CLAIMS,
1. A topical pharmaceutical composition comprising minoxidil and at least one or more pharmaceutically acceptable excipients.
2. A topical pharmaceutical composition according to claim 1, wherein minoxidil is in the form of a pharmaceutically acceptable derivative which optionally comprises pharmaceutically acceptable salts, solvates, hydrates, isomers, esters, tautomers, anhydrates, enantiomers, complexes, polymorphs or prodrugs.
3. A topical pharmaceutical composition according to any preceding claim, wherein the composition is an aqueous based solution.
4. A topical pharmaceutical composition according to any preceding claim, wherein the composition comprises less than 40% w/v of solvents.
5. A topical pharmaceutical composition according to any preceding claim, wherein the composition comprises less than 30% w/v of solvents.
6. A topical pharmaceutical composition according to any preceding claim, wherein the composition comprises less than 20 % w/v solvents.
7. A topical pharmaceutical composition according to any preceding claim, wherein the composition comprises less than 10 % w/v of solvents.
8. A topical pharmaceutical composition according to any preceding claim, wherein the composition is free of solvents.
9. A topical pharmaceutical composition according to claims 4 to 8, wherein the solvents comprise one or more of propylene glycol and monohydric alcohols with 3 carbon atoms or less.
10. A topical pharmaceutical composition according to any preceding claim, wherein the at least one or more pharmaceutically acceptable excipients comprise one or more surfactants/wetting agents present in an amount of from 1 % w/v to 10 % w/v.
11. A topical pharmaceutical composition according to any preceding claim, wherein the at least one or more pharmaceutically acceptable excipients comprise one or more solubilisers present in an amount of from 1 % w/v to 50 % w/v.
12. A topical pharmaceutical composition according to any preceding claim, wherein the at least one or more pharmaceutically acceptable excipients comprise one or more penetration enhancers present in an amount of from 1 % w/v to 20 % w/v.

13. A topical pharmaceutical composition according to any preceding claim, wherein the at least one or more pharmaceutically acceptable excipients comprise one or more acidifying agents present in an amount of from 0.5 % w/v to 10 % w/v.
14. A topical pharmaceutical composition according to claim 13, wherein the one or more acidifying agents comprise one or more of acetic acid, hydrochloric acid, salicylic acid, boric acid, sulphuric acid, lactic acid, citric acid, or any combination thereof.
15. A topical pharmaceutical composition according to any preceding claim, wherein the at least one or more pharmaceutically acceptable excipients comprise one or more preservatives present in an amount of from 0.1 % w/v to 10 % w/v.
16. A topical pharmaceutical composition according to any preceding claim, wherein the at least one or more pharmaceutically acceptable excipients comprise one or more de-tackifying agents present in an amount of from 0.1 % w/v to 15 % w/v.
17. A topical pharmaceutical composition according to any preceding claim wherein the at least one or more pharmaceutically acceptable excipients comprise one or more surfactants, one or more solubilisers, one or more penetration enhancers, one or more acidifying agents, one or more preservatives and one or more detackifying agents.
18. A topical pharmaceutical composition according to any preceding claim, wherein the composition is in the form of a liquid dosage form such as liquid dispersions, suspensions, solutions, emulsions, sprays, spot-on, pour-on, gels, foams, propellant based or non-propellant based aerosols, ointments, creams, mousse, or solid dosage forms such as powders, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, multi-unit pellet systems (MUPS), granules, microspheres, and multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, multi-unit pellet systems (MUPS), granules, microspheres, and multiparticulates) and sprinkles.
19. A topical pharmaceutical composition according to any preceding claim, wherein, the average particle size of minoxidil is less than or equal to 2000 nm, preferably less than or equal to 1000 nm.

20. A topical pharmaceutical composition according to any preceding claim, wherein the composition further comprises at least one additional active ingredient effectively acting as a hair re-growth agent.
21. A topical pharmaceutical composition according to any preceding claim, wherein the minoxidil is present in the composition in an amount of from 2% to 15% by weight of the composition.
22. A topical pharmaceutical composition according to any preceding claim for use in medicine.
23. A topical pharmaceutical composition according to claim 22, wherein the use comprises inducing and/or stimulating hair growth, reducing hair loss, and/or treating androgenic alopecia.
24. Use of a topical pharmaceutical composition according to any one of claims 1 to 21 in the manufacture of a medicament for inducing and/or stimulating hair growth, reducing hair loss, and/or treating androgenic alopecia.
25. A method of inducing and/or stimulating hair growth, reducing hair loss, and/or treating androgenic alopecia, wherein the method comprises applying the topical pharmaceutical composition according to any one claims 1 to 21 to a patient in need thereof.
26. A process for preparing a topical pharmaceutical composition according to any one of claims 1 to 21, wherein the process comprises blending minoxidil, with at least one or more pharmaceutically acceptable excipients.
27. A topical pharmaceutical composition substantially as described herein with reference to the description and examples.