Alcohol free foamable pharmaceutical composition ot Minoxidil and
combination thereof
Field of the Invention
Present invention relates to a thermostable, alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil and one or more pharmaceutically acceptable excipients comprising atleast one C4-C6 glycol and one or more pharmaceutically acceptable surfactant. Present invention also relates to process of preparation of pharmaceutical composition and a foam forming dispensing system suitable for said pharmaceutical compositions according to present invention.
Background of the Invention
Minoxidil is chemically 6-amino-l,2-dihydro-l-hydroxy-2-imino-4-piperidinopyrimidine, a growth stimulant which is approved for treatment of alopecia. Several topical preparations of Minoxidil are marketed currently, mostly solutions and aerosols.
US 4139619 discloses topical compositions of Minoxidil used for purpose of hair growth. US 4596812 discloses method of treating humans for alopecia by topical application to human scalp of an effective amount of minoxidil solution containing a solvent, preferably dimethylacetamide, ethyl alcohol and propylene glycol.
US 6946120 discloses a homogeneous aerosol formulation of minoxidil comprising an acid to solubilize minoxidil, a solvent system of water and lower alcohol and a co-solvent namely propylene glycol.
US 20080317679 discloses foamable compositions with effective concentration of active agent selected from a channel agent, a cholinergic agent and a nitric oxide donor and a foamable carrier composition comprising solvent, secondary solvent, surface-active agent, polymeric agent and liquefied or compressed gas propellant.

While none of the above mentioned patents or applications disclose the simultaneous use of minoxidil and aminexil, Kucerova et al., (Current therapies of female androgenetic alopecia and use offluridil, a novel topical antiandrogen, Scripta Medica (BRNO) - 79 (I), February 2006, 35-48) demonstrates use of minoxidil and its analogues, such as aminexil to cause hair growth and prevent further hair loss respectively in case of androgenetic alopecia. WO 2009101497 demonstrates that the addition of aminexil to topical solution containing ethanol or silicone oils comprising minoxidil would lead to a synergistic effect on the hair growth response.
Topical compositions like cream, ointment and lotion are not pharmaceutically elegant and are also not suitable for use as treatments for stimulating the growth of hair, especially from a cosmetic point of view. Alternative forms such as topical solutions have not been entirely satisfactory for use in treating the scalp, as they tend not to remain in place long enough for satisfactory amounts of the drug to be absorbed.
Aerosols or foams are better form of composition for topical application as it provides better patient compliance, especially when to be applied on larger surface area. There are many alternatives available in prior art to prepare alcohol based foamable composition of Minoxidil but in most of the compositions, very high percentage of propylene glycol is required in order to improve the solubility of minoxidil owing to its low solubility in ethanol and due to the viscosity and tack of propylene glycol, large amounts of propylene glycol in a composition are not pharmaceutically or cosmetically elegant and may be unacceptable to the consumer. In addition, high concentrations of propylene glycol may cause local irritation and hypersensitivity upon application to the scalp. Further, ethanol being used as a solvent in foamable compositions evaporates upon topical application leading to precipitation of minoxidil over the applied surface and hence, is not absorbed in desired amount. Use of ethanol in foam also leads to quick breaking foam, which further decreases the duration of drug absorption from the scalp, especially at higher temperatures. Also, alcohols in general, extract stratum

corneum and sebum lipids that naturally moisturize the skin and therefore may cause skin to become dry and cracked.
Alternative to alcohol based foamable compositions, some oil based formulations have been proposed in prior art but incorporation of oils, particularly silicones and their derivatives in higher quantities, into topical products is difficult without destroying gel viscosity or foaming effect of the formulation. Further incorporation of oily substance in the topical compositions results in oily and sticky skin and thus reduces patient comfort.
Thus, there is a need for an improved alcohol free foamable pharmaceutical composition which overcomes all the mentioned problems with desired therapeutic effect.
The present invention provides a stable and therapeutically equivalent thermostable alcohol free foamable pharmaceutical composition of minoxidil in combination with aminexil and one or more pharmaceutically acceptable excipients, delivered through foam forming dispensing system which resolves all the mentioned issues.
Summary of the Invention
One aspect of the present invention is to provide a thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil and one or more pharmaceutically acceptable excipients.
Another aspect of the present invention is to provide a thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil and one or more pharmaceutically acceptable excipients, wherein said composition is in foam forming dispensing system lined with epoxy coating.
Another aspect of the present invention is to provide a thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil; atleast one suitable C4-C6 glycol and one or more pharmaceutically acceptable surfactant.

Another aspect of the present invention is to provide a thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil; atleast one suitable C4-C6 glycol and one or more pharmaceutically acceptable surfactant, wherein C4-C6 glycol and at least one pharmaceutically acceptable surfactant are in ratio of 4:1 to 12.5:1.
Another aspect of the present invention is to provide a thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil and more than 20% C4-C6 glycol.
Another aspect of the present invention is to provide a thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil and mixture of cetyl alcohol and stearyl alcohol, wherein cetyl alcohol and stearyl alcohol are present in ratio of 2:1 to 5:1.
Another aspect of the present invention is to provide a foam forming dispensing system with an epoxy coating for the thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil and one or more pharmaceutically acceptable excipients.
Another aspect of the present invention is to provide a process for preparation of the thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil and one or more pharmaceutically acceptable excipients.
Figures
Fig la: Physical appearance of foam prepared according to Example 1
Fig lb: Microscopic view of foam prepared according to Example 1
Fig 2: Physical appearance of container with clear epoxy phenolic coating
Fig 3: Comparative in-vitro permeation study at 32°C of minoxidil foam prepared according to Example 1
Fig 4: Comparative in-vitro permeation study at 32°C of minoxidil foam prepared according to Example 3

Fig 5: Comparative in-vitro permeation study at 32°C of minoxidil foam prepared according to Example 4
Fig 6a: Physical appearance of foam prepared according to Example 3
Fig 6b: Microscopic view of foam prepared according to Example 3
Detailed Description of the Invention
Present invention provides a thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil.
The use of the terms "a" and "an" and "the" and similar references in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
The term "alcohol free" as used herein means a composition which is substantially free of lower aliphatic alcohols selected from group consisting of methyl, ethyl, isopropyl and butyl alcohol.
The term "thermostable" as used herein means a pharmaceutical composition capable of being subjected to a temperature of 30°C to 40°C without loss of its physical or chemical characteristic properties including foam bubble structure and avoidance of drug re-precipitation.
The term "foamable" as used herein includes a pharmaceutical composition capable of forming foam upon delivery.
The term "minoxidil" as used herein includes minoxidil or pharmaceutically acceptable derivatives thereof. Suitable derivatives include pharmaceutically acceptable salts, solvates, hydrates, anhydrates, enantiomers, esters, isomers, polymorphs, prodrugs, tautomers, complexes etc.
The term "aminexil" as used herein includes aminexil or pharmaceutically acceptable derivatives thereof. Suitable derivatives include pharmaceutically

acceptable salts, solvates, hydrates, anhydrates, enantiomers, esters, isomers, polymorphs, prodrugs, tautomers, complexes etc.
The term "foam forming dispensing system" as used herein includes an assembly of container and aerosol valve capable of delivering foamable composition.
The percentage "%" of the component as used herein means percent by weight of the total composition; whereas the % of propellant or propellant system as used herein means percent by weight of propellant in addition to %w/w of the total composition.
Alcohol based marketed foams consisting of minoxidil and other pharmaceutically acceptable excipients are quick breaking foams wherein alcohol is responsible for the quick breaking effect. Such marketed formulations are temperature sensitive and melt in warm conditions. Hence effective dispensing at temperature above 30°C is difficult due to its watery appearance which reduces ease of handling and application. Consequently it is essential for the patient to ensure cool conditions before dispensing the foam. Surprisingly, it was found by inventors that the alcohol free, thermostable, quick breaking foam with synergistic therapeutic effect comprising minoxidil in combination with aminexil remains stable for more than 5 minutes upon dispensing at temperature above 30°C. The foam so dispensed breaks upon applying shear force during its application.
Thus, the first embodiment of present invention provides a thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil and one or more pharmaceutically acceptable excipients.
Also alcoholic preparations containing minoxidil and propylene glycol as solvent are liable to rapid evaporation of solvent which leads to precipitation of drug on scalp and hence are less effective, with undesirable effects. Surprisingly it was found by inventors that a foamable pharmaceutical composition which is free of alcohol and propylene glycol and having an optimum ratio of C4-C6 glycols to atleast one pharmaceutically acceptable surfactant can resolve the problem of drug

re-precipitation and achieve pleasant skin feeling upon application along with providing a physically stable composition.
Thus, another embodiment of the present invention provides a thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil; atleast one suitable C4-C6 glycol and one or more pharmaceutically acceptable surfactant, wherein C4-C6 glycol and at least one pharmaceutical^ acceptable surfactant are in ratio of 4:1 to 12.5:1, preferably 6.25:1.
A preferred embodiment of the present invention provides a thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil; hexylene glycol and ceteareth-20, wherein hexylene glycol and ceteareth-20 are in ratio of 4:1 to 12.5:1, preferably in ratio of 6.25:1.
Another embodiment of the present invention provides a thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil and more than 20% C4-C6 glycols, preferably about 25% hexylene glycol (2-methyl-2,4-pentanediol).
Another aspect of the present invention is to provide a thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil, wherein said composition has pH between 4.0 to 5.0.
Minoxidil is effective in promoting hair growth after it reaches the hair follicle; the clinical efficacy of topical application is limited by low water solubility and by the fact that the outer layers of skin are an effective barrier to penetration of polar molecules such as Minoxidil. Concurrently minoxidil is associated with certain systemic side effects including fluid retention, tachycardia, dyspnoea, gynaeco- mastia, fatigue, nausea, cardiotoxicity and the like. It is consequently important to control the percutaneous permeation of minoxidil to achieve an optimum therapeutic effect. Surprisingly it was found by the inventors that an alcohol free foamable pharmaceutical composition with an optimum ratio of

mixture of fatty alcohols has marked influence on cumulative permeation of minoxidil.
Another embodiment of the present invention is to provide a thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil and mixture of fatty alcohols.
A preferred embodiment of the present invention provides a thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil and mixture of cetyl alcohol and stearyl alcohol, wherein cetyl alcohol and stearyl alcohol are present in ratio of 2:1 to 5:1, preferably in ratio of 2.85:1.
Surprisingly, it was found by the inventors that concentration of stearyl alcohol used according to present invention also influences the foam bubble structure, foam density, stability of foam and foam breaking time of the thermostable alcohol free foamable pharmaceutical composition according to present invention.
Another preferred embodiment of the present invention provides a thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil and 0.15 to 0.25 % of stearyl alcohol.
Another embodiment of present invention provides a thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil and one or more pharmaceutically acceptable excipients, wherein said composition is in foam forming dispensing system lined with epoxy coating.
Another embodiment of the present invention provides a foam forming dispensing system with a epoxy coating for the thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil and one or more pharmaceutically acceptable excipients.
Another embodiment of present invention provides a pharmaceutical product comprising pharmaceutical composition according to present invention and a

foam forming dispensing system, wherein said container is capable of delivering foamable composition.
A preferred embodiment of the present invention provides thermostable; alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil and one or more pharmaceutically acceptable excipients; wherein minoxidil is present in range of 1 to 10% w/w, preferably about 5.0%w/w of the total composition and aminexil is present in range of 1 to 2% w/w, preferably about 1.5% w/w of the total composition. The pharmaceutically acceptable excipients comprise C4-C6 glycols, in range of 5.0 to 50% w/w, preferably hexylene glycol (2-methyl-2,4-pentanediol) about 25.0% w/w of the total composition, one or more pharmaceutically acceptable surfactant, in range of 0.10 to 20% w/w, preferably ceteareth-20 about 4.0% w/w and polysorbate 60 about 0.42% w/w of the total composition and mixture of pharmaceutically acceptable foam adjuvants in range of 0.10 to 30% w/w, preferably stearyl alcohol about 0.175% w/w and cetyl alcohol about 0.50% w/w of the total composition. The pharmaceutically acceptable excipients may further comprise a humectant, a solubilizer, an antioxidant, a pH modifier. The said pharmaceutical composition further comprises a vehicle and a propellant system. The foamable composition is preferably dispensed through foam forming dispensing system lined with epoxy coating.
The present invention provides a process for preparation of thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil and one or more pharmaceutically acceptable excipients.
Another embodiment of the present invention provides a process of preparation of the said pharmaceutical composition comprising following steps:
(a) Dissolving minoxidil and aminexil in suitable vehicle and optionally one or more pharmaceutically acceptable excipients.

(b) Preparing a solvent phase by dissolving fatty alcohols, one or more
pharmaceutically acceptable surfactant in atleast one suitable C4-C6 glycol and
optionally one or more pharmaceutically acceptable excipients.
(c) Mixing the solution of step (b) with solution of step (a) resulting in a solution and
optionally adding pH modifier or one or more pharmaceutically acceptable
excipients.
(d) Filling the solution of step (c) into epoxy coated container and crimping aerosol valve onto the container.
(e) Adding foam generator in the prepared solution.
A preferred embodiment of the present invention provides a process of preparation of the said pharmaceutical composition comprising following steps:
(a) Dissolving minoxidil, aminexil, lactic acid and glycerin into water, forming an aqueous phase.
(b) Preparing a solvent phase by dissolving stearyl alcohol, cetyl alcohol, butylatedhydroxy toluene, polysorbate 60 and ceteareth-20 in hexylene glycol.
(c) Mixing the solution of step (b) with aqueous phase of step (a) at 35°C to 45°C with continuous mechanical stirring resulting in a solution.
(d) Adjusting the pH of solution of previous step in range of 4.0 to 5.0 with potassium hydroxide.
(e) Filling the solution of step (d) into epoxy coated aluminium container and crimping aerosol valve onto the container and filling of propellant, preferably propane, butane and isobutane.
A pharmaceutically acceptable excipient according to present invention can be any excipients required for formulating composition according to present invention such as surfactant, foam stabilizer/ foam adjuvant, humectant,

solubilizer, antioxidant, pH modifiers or permeation enhancers. Any of such excipients may be used alone or in combination of same/other excipients.
A solvent is also used for the preparation of alcohol free foam of the present invention comprising minoxidil in combination with aminexil. Solvents such as C4-C6 glycols are preferred, where in atleast one C4-C6 glycol is present in amount from 5.0% to 50% by weight of the said pharmaceutical composition.
Additionally, a vehicle is used for the preparation of alcohol free foam of the present invention. An aqueous vehicle such as water is preferred, where in water phase is present in amount from 40% to 95% by weight of the said pharmaceutical composition.
An alcohol free composition of the present invention comprises a foam generator, such as propellant or propellant system. A propellant is selected from chlorofluorocarbons, hydrocarbons (propane, butane, isobutane or mixtures thereof), compressed gas and hydrofluoroalkanes (HFAs) or hydroflurorocarbon (HFCs) and mixtures thereof. The range of propellant concentration used according to present invention is from 1 to 70%, preferably, 6-10% w/w in addition to %w/w of the total composition.
A surfactant for use in compositions of the present invention include, but are not limited to, fatty acid ethoxylates, fatty alcohol ethoxylates, polysorbates, glycerol ester ethoxylates and polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate and polyoxyethylene fatty acid ester. Examples of these include Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, Ceteareth-20, Ceteareth-40, Ceteareth-60, Steareth-20, Ceteth-2, Ceteth-20, Laureth-4, Laureth-23, POE(15) glycerol monolaurate and the like and mixtures thereof. Pharmaceutical composition comprises surfactant/s in the range of 0.1 to 20% w/w of the total composition. Preferred surfactants used are ceteareth-20, preferably in range of 1 to 4% w/w of the total composition and polysorbate 60, preferably in range of 0.4 to 0.5% w/w of the total composition.

A foam adjuvant includes fatty alcohols having 15 or more carbon atoms in their carbon chain. The foam adjuvant is selected from cetyl alcohol, stearyl alcohol, arachidyl alcohol, behenyl alcohol, 1-triacontanol or mixtures thereof. Pharmaceutical composition comprises foam adjuvants in the range of 0.10 to 30%; Preferred foam adjuvant/s used are cetyl alcohol, preferably in range of 0.2 to 0.5% w/w of the total composition, most preferably 0.5% w/w of the total composition and stearyl alcohol, preferably in range of 0.10 to 0.25% w/w of the total composition, most preferably in range of 0.150 to 0.175% w/w of the total composition.
A humectant is selected from glycerol (glycerin), cetyl palmitate, PPG-15 stearyl ether, lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate, octyl stearate, mineral oil, isocetyl stearate, myristyl myristate, octyl dodecanol, 2-ethylhexyl palmitate (octyl palmitate), dimethicone, phenyl trimethicone, cyclomethicone, C12-C15 alkyl benzoates, dimethiconol, propylene glycol, hexylene glycol, theobroma grandiflorum seed butter, ceramides (e.g., ceramide 2 or ceramide 3), hydroxypropyl bispalmitamide MEA, hydroxypropyl bislauramide MEA, hydroxypropyl bisisostearamide MEA, 1,3-bis(N-2-(hydroxyethyl)stearoylamino)-2-hydroxy propane, bis-hydroxyethyl tocopherylsuccinoylamido hydroxypropane, urea, aloe, allantoin, glycyrrhetinic acid, and dicaprylate/dicaprate. Pharmaceutical composition comprises humectants/s in range of 1 to 50% w/w of the total composition, preferably in range of 5 to 10% w/w of the total composition.
A solubilizer is selected from short or long chain organic acids and/or non organic acids. Short chain organic acids such as citric and lactic acid are preferred. Longer chain acids such as stearic acid are needed in higher concentrations to achieve foamable formulations. Non organic acids such as hydrochloric acid, phosphoric acid and sulfuric acid may also be selected. Pharmaceutical composition comprises solubilizer/s in range of 0.01 to 8% w/w of the total composition, preferably in range of 3 to 4% w/w of the total composition.

An antioxidant is selected from butylatedhydroxy toluene and butyl hydroxy anisole, tocopherol succinate, propyl gallate or mixtures thereof. Pharmaceutical composition comprises antioxidant/s in range of 0.0075 to 0.1% w/w of the total composition, preferably 0.1% w/w of the total composition.
A pH modifier is selected from bicarbonates, carbonates, and hydroxides such as alkali or alkaline earth metal hydroxide as well as transition metal hydroxides such as sodium hydroxide, potassium hydroxide and the like. Alternatively, the pH adjusting agent can also be an acid, an acid salt, or mixtures thereof. Further, the pH adjusting agent can also be a buffer. Suitable buffers include citrate/citric acid buffers, acetate/acetic acid buffers, phosphate/phosphoric acid buffers, formate/formic acid buffers, propionate/propionic acid buffers, lactate/lactic acid buffers, carbonate/carbonic acid buffers, ammonium/ammonia buffers, and the like. Pharmaceutical composition comprises pH modifier/s in range of 0.1 to 14% w/w of the total composition, preferably in range of 0.4 to 0.5% w/w of the total composition.
A permeation enhancer is selected from diethylene glycol monoethyl ether or transcutol. Pharmaceutical composition comprises permeation enhancer in range of 0.05 to 2% w/w of the total composition.
A foam forming dispensing system according to the present invention comprises a pressurized container and an aerosol valve. The pressurized container is any conventional container used for dispensing foams. Preferably a one-piece aluminum container in which the inner surface is lined with a chemically inert lining such as epoxy coating, opaque vinyl coating, polyamide-imide coating and the like. A preferred inner surface lining is epoxy coating. Typically, the container is fitted with an upright or inverted valve without diptube and a conventional foam spout actuator.
Epoxy coating as used herein comprises coatings derived/of epoxy resins which contain epoxide groups. Epoxy resins may be reacted (cross-linked) either with

themselves or with a wide range of co-reactants including polyfunctional amines, acids (and acid anhydrides), phenols, alcohols and thiols. Epoxy coating as used herein is preferably epoxy phenolic coating.
A foamable pharmaceutical composition according to present invention is used topically for androgenetic alopecia.
The invention will be further illustrated by the following examples, however, without restricting its scope to these embodiments. Example 1:

S.No Ingredients % w/w
1 Minoxidil 5.0
2 Aminexil 1.5
3 Butylated hydroxytoluene 0.10
4 Citric acid anhydrous 0.10
5 Glycerin 10.00
6 Lactic acid 3.40
7 Cetearth-20 4.00
8 Transcutol P 2.00
9 Polysorbate 60 0.42
10 Hexylene glycol (2-methyl-2,4-pentanediol) 25.00
11 Purified water 48.48
12 20% Potassium Hydroxide q.s
13 Propane, butane and Iso-butane 10.0
(a) Minoxidil, aminexil, anhydrous citric acid, lactic acid and glycerin were dissolved into water, forming an aqueous phase.
(b) Solvent phase was prepared by dissolving butylated hydroxytoluene in hexylene glycol and mixing transcutol P.

(c) Surfactant phase was prepared by dissolving polysorbate 60 and ceteareth-20 in purified water.
(d) Surfactant phase of step (c) was added at 45°C to the solvent phase of step (b).
(e) Solution of step (d) was mixed with aqueous phase of step (a) at 45°C with continuous mechanical stirring resulting in a solution.
(f) pH of solution of previous step was adjusted to 5.0 with 20% potassium hydroxide.
(g) Solution of step (f) was filled into clear phenolic epoxy coated aluminium container and aerosol valve was crimped onto the container.
(h) Assembly of step (g) was cooled at 25°C followed by filling of propellant, preferably propane, butane and isobutane.
Physical appearance and microscopic view of Example 1 foam is given in Fig la and lb.
Table 1 below illustrates stability of Example 1 with clear epoxy phenolic coated container:

Example 1
Condition Container with clear epoxy coating
Tests 1M (40°C/75% RH)
Description (Foam) White Color Foam
pH (Foam) 4.72
Assay
(Foam) Minoxidil
(with propellant) 91.00%
Fig 2 illustrates the container with clear epoxy phenolic coating In-vitro permeation study: Method:

About 5gm (n=6 set) of each foam was dispensed in 100ml scott duran screw bottle. The bottle was kept at 40°C in an incubator for sufficient time to break the foam. The base solution so formed was used for in vitro test.
In-vitro test was conducted by using standard procedures as known to skilled person using following assembly and parameters. Analytical evaluation was performed using HPLC.
Table 2: Experimental Parameters to check in-vitro permeation

Assembly Franz-diffusion cell
Dissolution Medium 0.1M Citrate Buffer
Volume Of Medium ~ 25 ml*
Temperature 32°C ±0.5 °C
Membrane Regenerated Cellulose
Stirred Speed 500 RPM
Spiking Volume 700ul
Withdrawal volume 200ul
Sampling Interval 1,2,3,4,5 and 6 Hours
Measured parameters Cumulative permeation (mcg/cm2)
* Media volume is base on diffusion cell capacity.
In-vitro permeation study of Example 1 (alcohol free) was carried out in comparison with Men's Rogaine® and Tugain® (alcohol based) marketed foams as shown in Fig 3.
Example 2:

S.No Ingredients %w/w
1 Minoxidil 5.0
2 Aminexil* 1.71
3 Butylated Hydroxytoluene 0.1
4 Citric acid anhydrous 0.10

5 Glycerin 10.0
6 Lactic acid 3.4
7 Cetearth-20 4.0
8 Polysorbate 60 0.42
9 Hexylene glycol (2-methyl-2,4-pentanediol) 25.0
10 Purified water 50.27
11 20% Potassium hydroxide q.s
Total 100.00
Physical observation (base solution) Clear, colorless solution at room
temperature and 45°C, No
precipitation
*Aminexil concentration was adjusted with water concentration for potency correction
Composition of example 2 was prepared analogous to process applied for example 1.
Example 3:

S.No. Ingredients %w/w
1 Minoxidil 5.0
2 Aminexil* 1.71
3 Butylated Hydroxytoluene 0.1
4 Glycerin 10.0
5 Lactic acid 3.4
6 Cetyl alcohol 0.50
7 Stearyl alcohol 0.25
8 Cetearth-20 4.0
9 Polysorbate 60 0.42
10 Hexylene glycol (2-methyl-2,4- 25.0

pentanediol)
11 Purified water 49.83
12 20% Potassium hydroxide q.s
13 Propellant (Propane, butane and Iso-butane) 10.0
Total ( ?ase) 100.00
Physical observation (base solution) Clear, colorless solution at45°Cand hazy at RT
Time to break analysis at 40°C 8.58 min
*Aminexil concentration was adjusted with water concentration for potency correction
(a) Minoxidil, aminexil, lactic acid and glycerin were dissolved into water, forming an aqueous phase.
(b) Solvent phase was prepared by dissolving stearyl alcohol, cetyl alcohol, butylated hydroxy toluene, polysorbate 60 and ceteareth-20 in hexylene glycol.
(c) Solution of step (b) was mixed with aqueous phase of step (a) at 35°C with continuous mechanical stirring resulting in a solution.
(d) pH of solution of previous step was adjusted to 4.5 with required quantity of potassium hydroxide solution.
(e) Solution of step (d) was filled into clear epoxy phenolic coated aluminium container and aerosol valve was crimped onto the container, followed by filling of propellant, preferably propane, butane and isobutane.
In-vitro permeation study of Example 3 (alcohol free) was carried out in comparison with Tugain and Men's Rogaine® (alcohol based) marketed foams as shown in Fig 4.
Experimental parameters followed were same as disclosed in Table 2.

Composition prepared according to example 3 produces white colored foam with spherical bubble shape indicating stable foam.
Physical appearance and microscopic view of Example 3 foam is given in Fig 6a and 6b respectively.
Example 4:

S.No. Ingredients %w/w
1 Minoxidil 5.0
2 Aminexil 1.5
3 Butylated Hydroxytoluene 0.1
4 Glycerin 10.0
5 Lactic acid 3.4
6 Cetyl alcohol 0.50
7 Stearyl alcohol 0.175
8 Cetearth-20 4.0
9 Polysorbate 60 0.42
10 Hexylene glycol (2-methyl-2,4-pentanediol) 25.0
11 Purified water 49.50
12 Potassium hydroxide 0.40
13 Propellant (Propane, butane and Iso-butane) 8.0
Total ( ?ase) 100.00
Composition of example 4 was prepared analogous to process applied for example 3.
In-vitro permeation study of Example 4 (alcohol free) was carried out in comparison with Tugain® and Men's Rogaine® (alcohol based) marketed foams as shown in Fig 5.
Experimental parameters followed are as disclosed in Table 3 below.

Table 3: Experimental Parameters to check in-vitro permeation

Assembly Franz-diffusion cell (Hanson)
Dissolution Medium 0.1M Citrate Buffer
Volume Of Medium ~7ml*
Temperature 32°C ±0.5 °C
Membrane Strat-M Membrane
Stirred Speed 500 RPM
Spiking Volume 700ul
Withdrawal volume 1ml
Sampling Interval 1,2,3,4,5 and 6 Hours
Measured parameters Cumulative permeation (mcg/cm2)
* Media volume is base on diffusion cell capacity.
Table 4 given below shows comparative foam breaking time of Example 4 (alcohol free) and Men's Rogaine® (alcohol based) marketed foams:

S.No. Test Parameters Results

Men's Rogaine Example 4
foam 5%
1 Description (Foam) White colored foam White colored foam
2 Description (Base) Clear solution at Clear, colorless to Pale
35°C yellow color solution at 35°C
3 Foam Breaking At 40 °C: 18 sec At 40 °C: More than 5
time at 40°C minutes

We Claim:
1. A thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil, atleast one C4-C6 glycol and one or more pharmaceutically acceptable excipients selected from group comprising of surfactant and foam adjuvant.
2. The pharmaceutical composition according to claim 1, wherein C4-C6 glycol is hexylene glycol, surfactant is selected from ceteareth-20, polysorbate 60 and mixtures thereof and foam adjuvant is selected from cetyl alcohol, stearyl alcohol and mixtures thereof.
3. The pharmaceutical composition according to claim 2, wherein hexylene glycol is more than 20% w/w, preferably 25% w/w of the total composition.
4. The pharmaceutical composition according to claim 2, wherein hexylene glycol and ceteareth-20 are in ratio of 4:1 to 12.5:1, preferably 6.25:1.
5. The pharmaceutical composition according to claim 2, wherein stearyl alcohol is in range of 0.15 to 0.25 % w/w of the total composition.
6. The pharmaceutical composition according to claim 2, wherein cetyl alcohol and stearyl alcohol are in ratio of 2:1 to 5:1, preferably in ratio of 2.85:1.
7. A thermostable alcohol free foamable pharmaceutical composition comprising: Minoxidil in range of 1 to 10% w/w, aminexil in range of 1 to 2% w/w, atleast one C4-C6 glycol in range of 5.0 to 50% w/w, one or more pharmaceutically acceptable surfactant in range of 0.10 to 20% w/w, mixture

of pharmaceutically acceptable foam adjuvants in range of 0.10 to 30% w/w; of the total composition and one or more pharmaceutically acceptable excipients.
8. The thermostable alcohol free foamable pharmaceutical composition according to any of the preceding claims, wherein said composition is in a foam forming dispensing system lined with epoxy coating.
9. A process of preparation of a thermostable alcohol free foamable pharmaceutical composition comprising minoxidil in combination with aminexil and one or more pharmaceutically acceptable excipients comprising following steps:

a) Dissolving minoxidil and aminexil in suitable vehicle and optionally one or more pharmaceutically acceptable excipients
b) Preparing a solvent phase by dissolving fatty alcohols, one or more pharmaceutically acceptable surfactant in atleast one suitable C4-C6 glycol and optionally one or more pharmaceutically acceptable excipients
c) Mixing the solution of step (b) with solution of step (a) resulting in a solution and optionally adding pH modifier or one or more pharmaceutically acceptable excipients
d) Filling the solution of step (c) into epoxy coated container and crimping aerosol valve onto the container and
e) Adding a foam generator in the prepared solution.
10. A thermostable alcohol free foamable pharmaceutical composition
comprising minoxidil in combination with aminexil and one or more
pharmaceutically acceptable excipients and process of its preparation as herein
described with reference to the examples and drawings accompanying the
specification.