FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
TITLE OF THE INVENTION:
Alcohol-free Foamable Composition of Clindamycin
APPLICANT(S):
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh Hall, Ahmedabad 380
009, Gujarat, India
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the Invention
Present invention relates to a non-emulsified, alcohol free foamable composition comprising clindamycin or pharmaceutically acceptable salt thereof, at least one permeation enhancer and one or more pharmaceutically acceptable carriers. The non-emulsified alcohol free foamable composition of present invention remains stable at least for 15 minutes after dispensing and is quick breaking on applying shear force.
Background of the Invention:
Clindamycin phosphate is a water-soluble ester of the semi-synthetic antibiotic produced by a 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent antibiotic, lincomycin. It is approved as hydrochloride or phosphate salt. The chemical name for clindamycin phosphate is methyl 7-ch!oro-6,7,8-trideoxy-6-(l-methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)-l-thio-L-threo-a-D-galacto-octopyranoside 2-(dihydrogen phosphate).
Clindamycin is commonly used to treat infections with anaerobic bacteria, including topical treatment for Acne vulgaris. Acne vulgaris is a pleomorphic skin disease characterized by blackheads, whiteheads, papules, pustules, and cysts. The lesions are often contaminated with bacteria, which can lead to secondary infections. The appearance of acne ranges from slight skin irritation to pitting. In extreme cases, acne leads to the development of disfiguring scars. Acne vulgaris affects the areas of skin with the densest population of sebaceous follicles; these areas include the face, the upper part of the chest, and the back.
Clindamycin is approved in various forms for topical application such as topical gel, solution, swab, lotion or foam. The foam has advantage among all available

forms as desired quantity of the composition can be applied at desired site without extensive rubbing and it spreads effectively because of its good flow properties. The approved foamable composition of clindamycin phosphate (Evoclin) is thermolabile and quick breaking aerosol composition, which comprises 58% ethanol.
US7141237 discloses an alcohol based composition of clindamycin for the treatment of acne vulgaris which comprises foaming agent, such as fatty alcohols, surfactants, humectants, pH controlling agents, water, dehydrated alcohol and propellant. Patent mentions that the alcohol such as ethanol has been used to facilitate quick breaking of foam. Patent provides temperature sensitive quick breaking foam which breaks at body temperature.
An alcohol based composition has disadvantage that quick evaporation of alcohol leaves the skin dry and cracky. Thus, at the smooth body surfaces such as face and back, it is not desirable to apply an alcohol based composition. Also, precipitation of fatty alcohols such as cetyl alcohol and stearyl alcohol at the affected site, due to quick evaporation of ethanol, may resist to permeation of clindamycin through skin membrane.
US7700076 and WO2011119585 disclose alcohol free foamable compositions which are prepared as emulsion by using aqueous and oily phase. Emulsion based formulation are not patient compliant for acne because it leaves an oily residue after application of composition. Moreover, preparation of an emulsion based foamable composition involves tedious process and more risk factors.
Thus, there is a need for an improved foamable pharmaceutical composition which overcomes all the mentioned problems with desired therapeutic effect.

Therefore, present invention provides a single phase non-emulsified alcohol free foamable composition comprising clindamycin or pharmaceutically acceptable salt thereof, at least one permeation enhancer and one or more pharmaceutically acceptable carriers, wherein the composition remains stable at least for 15 minutes after dispensing and is quick breaking on applying shear force.
Summary of the Invention:
One aspect of the present invention is to provide a non-emulsified alcohol-free foamable pharmaceutical composition comprising clindamycin or pharmaceutically acceptable salt thereof, at least one permeation enhancer and one or more pharmaceutically acceptable carriers.
Another aspect of the present invention is to provide a non-emulsified alcohol free foamable pharmaceutical composition comprising clindamycin or pharmaceutically acceptable salt thereof, at least one permeation enhancer and one or more pharmaceutically acceptable carriers, wherein the composition remains stable at least for 15 minutes after dispensing.
Another aspect of present invention provides process of preparation of a single phase alcohol-free foamable pharmaceutical composition comprising clindamycin or pharmaceutically acceptable salt thereof at least one permeation enhancer and one or more pharmaceutically acceptable carriers.
Another aspect of the present invention is to provide a single phase alcohol-free foamable pharmaceutical composition comprising clindamycin or pharmaceutically acceptable salt thereof, at least one permeation enhancer and one or more pharmaceutically acceptable carriers, wherein the composition remains stable at least for 15 minutes after dispensing.

Figures:
Fig la: Physical appearance of foam
Fig lb: Microscopic view of foam
Fig 2a: Comparative cumulative release of clindamycin foam prepared according to •
Example 1
Fig 2b: Comparative in-vitro flux study of clindamycin foam prepared according to
Example 1
Fig 3: In-vitro flux study of clindamycin foam prepared according to Example 2 at
initial time point, 3 months at 40°C/75% RH and 3 months at 30°C/75% RH
Detailed description of the Invention:
The following paragraphs detail various embodiments of the invention. For the avoidance of doubt, it is specifically intended that any particular feature(s) described individually in any one of these paragraphs (or part thereof) may be combined with one or more other features described in one or more of the remaining paragraphs (or part thereof). In other words, it is explicitly intended that the features described below individually in each paragraph (or part thereof) represent important aspects of the invention that may be taken in isolation and combined with other important aspects of the invention described elsewhere within this specification as a whole, and including the examples and figures. The skilled person will appreciate that the invention extends to such combinations of features and that these have not been recited in detail here in the interests of brevity.
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, such as C1-C6 alcohol including methyl, ethyl, isopropyl and butyl alcohol. The total content of alcohol in said composition is less than 5%, preferably less than 3%, most preferably, less than 1%.
The term "clindamycin" as used herein includes clindamycin or its pharmaceutically acceptable salt, preferably phosphate or hydrochloride salt.
The term "single phase" or " non-emulsified" as used herein means the composition in prepared by mixing solution of either hydrophilic in nature or hydrophobic in nature and it does not form emulsion by mixing of hydrophilic and hydrophobic phase.
The term "permeation enhancer" as used herein means any agent which increases the permeability of clindamycin or pharmaceutically acceptable salt thereof through a membrane.
The percentage "%" of the component as used herein means percent by weight of the total composition.
The term "temperature sensitive" as used herein means foam which breaks at body temperature without applying shear force.
Present invention provides a single phase, alcohol free foamable pharmaceutical composition comprising clindamycin or pharmaceutically acceptable salt thereof and at least one permeation enhancer. Marketed foam of clindamycin phosphate is an alcohol based composition wherein alcohol provides quick breaking of foam. Surprisingly, it was found by inventors of present invention that the quick breaking

foam can be prepared without using alcohol with improved flux of clindamycin. Also, present invention solves the problem associated with prior art such as irritation after application, dry skin after alcohol evaporation on application of alcohol based composition or oily residue left on application of emulsion based compositions.
Thus, one embodiment of the present invention provides a non-emulsified alcohol-free foamable pharmaceutical composition comprising clindamycin or pharmaceutically acceptable salt thereof, at least one permeation enhancer and one or more pharmaceutically acceptable carriers.
Another embodiment of the present invention provides a single phase alcohol free foamable pharmaceutical composition comprising clindamycin or pharmaceutically acceptable salt thereof, at least one permeation enhancer and one or more pharmaceutically acceptable carriers.
For easy application of foam over the affected area, it is required to dole out the foam on palm or in a saucer. Since marketed formulation is temperature sensitive foam, it was observed that foam starts breaking itself immediately after dispensing, thus patient need to apply such foam immediately after doling it out of container. Further such foams may not be suitable for patients who have large infected area. Therefore, it is required to have a foamable composition which overcomes the mentioned problems. Inventors of present invention have developed a foamable composition which remains stable for at least for 15 minutes after dispensing it out from the container, even at palm, and breaks only after applying shear force during its application.
Thus, another embodiment of the present invention provides a non-emulsified alcohol free foamable pharmaceutical composition comprising clindamycin or

pharmaceutically acceptable salt thereof, at least one permeation enhancer and one or more pharmaceutically acceptable carriers, wherein the composition remains stable at least for 15 minutes after dispensing.
Another embodiment of the present invention provides a non-emulsified alcohol free foamable pharmaceutical composition comprising clindamycin or pharmaceutically acceptable salt thereof, at least one permeation enhancer and one or more pharmaceutically acceptable carriers, wherein the composition remains stable at least for 15 minutes at 37°C after dispensing.
Another embodiment of the present invention provides an alcohol-free single phase aqueous system comprising clindamycin or pharmaceutically acceptable salt thereof and at least one permeation enhancer wherein the composition is not temperature sensitive.
Another embodiment of the present invention provides an alcohol-free single phase aqueous system comprising clindamycin or pharmaceutically acceptable salt thereof and at least one permeation enhancer, one or more surfactant and a foam generator, wherein the composition remains stable at least for 15 minutes after dispensing.
Another embodiment of the present invention provides a non-emulsified alcohol-free foamable pharmaceutical composition comprising clindamycin or pharmaceutically acceptable salt thereof, at least one permeation enhancer, one or more surfactant and one or more humectant.
A preferred embodiment of the present invention provides a non-emulsified alcohol-free foamable pharmaceutical composition comprising clindamycin or pharmaceutically acceptable salt thereof, 0.1 to 2% of at least one permeation enhancer, 0.5 to 5% of one or more surfactant and 1-6% of one or more humectant.

Another preferred embodiment of the present invention provides a non-emulsified alcohol-free foamable pharmaceutical composition comprising clindamycin or pharmaceutically acceptable salt thereof, 0.1 to 2% of at least one permeation enhancer, 0.5 to 5% of one or more surfactant, 1-6% of one or more humectant and 80-95% of aqueous solvent optionally with one or more viscosity modifier, antimicrobial agent, buffering agent, chelating agent or pH modifier.
Another embodiment of the present invention provides a non-emulsified alcohol-free foamable pharmaceutical composition comprising of 0.05% to 2% clindamycin phosphate, 0.1% to 2% of permeation enhancer, 1% to 6% of humectant, 0.5% to 5% of surfactant, 0.1% to 1.5% of antimicrobial agent, 0.01% to 0.3% of pH modifier, 0.01% to 0.3% of chelating agent, 0.01% to 0.3% of viscosity modifier, 0.1% to 0.5% of buffering agent, 0.01% to 0.3% of foam adjuvant and 50% to 95% of solvent.
Another embodiment of the present invention provides a non-emulsified alcohol-free foamable pharmaceutical composition consisting of 0.05% to 2% clindamycin phosphate, 0.1% to 2% of permeation enhancer, 1% to 6% of humectant, 0.5% to 5% of surfactant, 0.1% to 1.5% of antimicrobial agent, 0.01% to 0.3% of pH modifier, 0.01% to 0.3% of chelating agent, 0.01% to 0.3% of viscosity modifier, 0.1% to 0.5% of buffering agent, 0.01% to 0.3% of foam adjuvant, 50% to 95% of solvent and propellant.
A preferred embodiment of the present invention provides a non-emulsified alcohol-free foamable pharmaceutical composition consisting of 0.05% to 2% clindamycin phosphate, 0.1% to 2% of transcutol, 1% to 6% of hexylene glycol, 0.5% to 5% of polysorbate-60, and polyoxyl 20 cetostearyl ether, 0.1% to 1.5% of phenoxyethanol, 0.01% to 0.3% of sodium hydroxide, 0.01% to 0.3% of disodium

EDTA, 0.01% to 0.3% of xanthan gum, 0.1% to 0.5%of sodium phosphate monobasic, 0.01% to 0.3% of cetyl alcohol, 50% to 95% of water and propellant.
A preferred embodiment of the present invention provides a non-emulsified alcohol-free foamable pharmaceutical composition consisting of 1.25% clindamycin phosphate, 0.5% of transcutol, 3% of hexylene glycol, 1% of polysorbate-60, 2% of polyoxyl 20 cetostearyl ether, 0.3% of phenoxyethanol, 0.1% of sodium hydroxide, 0.1% of disodium EDTA, 0.4% of xanthan gum, 0.3% of sodium phosphate monobasic, 0.2% of cetyl alcohol, 90.85%) of water and propellant.
Another preferred embodiment of the present invention provides non-emulsified alcohol-free foamable pharmaceutical composition consisting of 1.25% clindamycin phosphate, 0.5% of transcutol, 3% of hexylene glycol, 1% of polysorbate-60, 2% of polyoxyl 20 cetostearyl ether, 0.5% of phenoxyethanol, 0.1% of sodium hydroxide, 0.1% of disodium EDTA, 0.2% of xanthan gum, 0.3% of sodium phosphate monobasic, 0.2% of cetyl alcohol, 90.85% of water and propellant.
The alcohol-free single phase aqueous system of present invention does not provide a greasy or oily residue after its application on affected area. Moreover, present composition can be prepared without involving complex steps of preparing emulsion. Other advantages of present invention over emulsion based formulation include quick onset of action as partitioning from aqueous phase to skin lipid is faster, storage temperature can be flexible, cost effective and more stability.
Another embodiment of the present invention provides a process of preparation of the foamable pharmaceutical composition according to present invention comprises steps:

(a) Preparing aqueous solution of clindamycin optionally with one or more pharmaceutically acceptable carriers.
(b) Preparing solution of permeation enhancer optionally with one or more pharmaceutically acceptable carriers.
(c) Mixing solution of (a) and (b) and optionally adding pH modifier or one or more pharmaceutically acceptable carriers.
(d) Adding foam generator in the prepared solution.
A preferred embodiment of the present invention provides a process of preparation of the foamable pharmaceutical composition according to present invention comprises steps:
(a) Preparing aqueous solution of clindamycin optionally with one or more pharmaceutically acceptable carriers.
(b) Preparing solution of permeation enhancer, surfactant and humectant optionally with one or more pharmaceutically acceptable carriers.
(c) Mixing solution of (a) and (b) and optionally adding pH modifier or one or more pharmaceutically acceptable carriers.
(d) Adding foam generator in the prepared solution.
Preferably, the composition is prepared in foam dispenser, wherein the solution of step (a) and (b) are mixed together in foam dispenser and foam generator is added to the solution. Alternatively solution of step (a) and (b) are mixed together and then filled in foam dispenser followed by addition of foam generator.
Clindamycin or its pharmaceutically acceptable salt is present in the composition prepared according to present invention in the range of 0.05% to 2%, preferably 1% to 2% most preferably 1.25%.

Permeation enhancer according to present invention includes diethylene glycol monoethyl ether or transcutol. The permeation enhancer is present in the composition in the range of 0.05 to 2%, preferably 0.1 to 2%, most preferably 0.1 to 1%.
A pharmaceutical I y acceptable carrier according to present invention can be any excipients required for formulating composition according to present invention such as humectant, surfactant, antimicrobial agent, pH modifier, chelating agent, viscosity modifier, buffering agent or foam adjuvant. Any of such excipients may be used alone or in combination of same/other excipients.
Additionally, a solvent is used for the preparation of alcohol free foam of the present invention. Preferably, solvent is aqueous solvent such as water, where in water phase is present in amount from 50% to 95% by weight of aqueous phase or the total composition.
An alcohol-free composition of the present invention comprises a foam generator, such as propellant. A propellant is selected from chlorofluorocarbons , hydrocarbons (propane, butane, isobutane or mixture), compressed gas and hydrofluoroalkanes (HFAs) or hydroflurorocarbon (HFCs) and mixture thereof. The range of propellant concentration used according to present invention is from 4 to 15%, preferably, 4-10%.
A buffering agent is selected from phosphates such as sodium phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate, disodium hydrogen phosphate dodecahydrate, potassium phosphate, potassium dihydrogen phosphate and dipotassium hydrogen phosphate; boric acid and borates such as, sodium borate and potassium borate; citric acid and citrates such as sodium citrate and disodium citrate; acetates such as sodium acetate

and potassium acetate and carbonates such as sodium carbonate and sodium hydrogen carbonate. A buffering agent is used in the range of 0.1 to 0.5%, preferably 0.3%.
A humectant is selected from cetyl palmitate, glycerol (glycerin), 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-(hydroxyethyI)stearoylamino)-2-hydroxy propane, bis-hydroxyethyl tocopherylsuccinoylamido hydroxypropane, urea, aloe, allantoin, glycyrrhetinic acid, and dicaprylate/dicaprate. A humectant is used in the range of 1 to 6%, preferably 3%.
An antimicrobial agent is selected from imidazolidinyl urea, diazolidinyl urea; phenoxyethanol; sodium methyl paraben, methylparaben, ethylparaben, and propylparaben; potassium sorbate; sodium benzoate; sorbic acid; benzoic acid; formaldehyde; citric acid; sodium citrate; chlorine dioxide; quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride; mercurial agents such as phenylmercuric nitrate, phenylmercuric acetate, and thimerosal; piroctone olamine; vitis vinifera seed oil; and alcoholic agents, for example, chlorobutanol, dichlorobenzyl alcohol, phenylethyl alcohol and benzyl alcohol . An antimicrobial agent is used in the range of 0.1 to 1.5%, preferably 0.3%.

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 and potassium hydroxide. 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. A pH modifier is used in the range of 0.01 to 0.3%, preferably 0.1%.
A chelating agent is selected from EDTA (e.g., disodium EDTA), citric acid, and sodium citrate. A chelating agent is used in the range of 0.01 to 0.3%, preferably 0.1%.
A surfactant is selected from sodium lauryl sulfate, sodium taurocholate, lecithin, lyso-lecithin, phosphatidyl glycerol, polyethylene glycol-phosphatidyl ethanolamine, cetyl trimethyl ammonium bromide, lauryl betaine, sucrose esters, polysorbates, sorbitan fatty acid esters, polyethylene glycosylated glycerides, PEGylated glycerides and combinations thereof. The non-ionic surfactant may include mixtures of monoglycerides, diglycerides, and triglycerides and monoesters and diesters of polyethylene glycol, polyethylene glycosylated almond glycerides, polyethylene glycosylated corn glycerides, polyethylene glycosylated caprylic/capric triglyceride, polysorbate 20, polysorbate 60, polysorbate 80, polyoxyl 20 cetostearyl ether, polyoxyl 10 oleyl ether and combinations thereof. Surfactants are used in the range of 0.5 to 5%; preferably 0.5 to 3%.
A viscosity modifier is selected from naturally-occurring polymeric materials such as, locust bean gum, sodium alginate, sodium caseinate, egg albumin, gelatin

agar, carrageenin gum sodium alginate, xanthan gum, quince seed extract, tragacanth gum, starch, chemically modified starches and the like; semi-synthetic polymeric materials such as cellulose ethers (e.g. hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxy propylmethyl cellulose), polyvinylpyrrolidone, polyvinylalcohol, guar gum, hydroxypropyl guar gum, soluble starch, cationic celluloses, cationic guars and the like and synthetic polymeric materials such as carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol polyacrylic acid polymers, polymethacrylic acid polymers, polyvinyl acetate polymers, polyvinyl chloride polymers, polyvinylidene chloride polymers and the like. Optionally, mixtures of the above compounds are contemplated. A viscosity modifier is used in the range of 0.01 to 0.3%, preferably 0.1%.
A foam adjuvant is selected fromcetyl alcohol, stearyl alcohol or mixture thereof. A foam adjuvant is used in the range of 0.01 to 0.3%, preferably 0.2%.
A foamable composition according to present invention can be filled in a suitable dispenser, fitted with suitable delivery device such as actuator for application of foam on the affected area. Actuator of dispenser can be modified as per affected area for which foam is to be delivered.
A foamable pharmaceutical composition according to present invention is useful for the treatment of conditions arises due to bacterial infection, such as skin infections including acne vulgaris or vaginal infection such as vaginosis, or vaginitis.
A foamable pharmaceutical composition according to present invention can be administered topically over the affected area. Also, the composition can be administered into the body cavity including vaginal cavities.

The invention will be further illustrated by the following examples, however, without restricting its scope to these embodiments.
Examples-1:

Sr. no Ingredients % w/w
1 Clindamycin Phosphate 1.25
2 Xanthan Gum 0.6
3 Polyoxyl 20 cetosteryl ether 2.0
4 Polysorbate-60 1
5 Hexylene glycol 3
6 Transcutol 0.5
7 Phenoxyethanol 0.3
8 Sodium phosphate monobasic 0.3
9 Disodium EDTA 0.1
10 Sodium Hydroxide (10% solution) 0.1
11 Water 90.85
Total 100
12 Propellant(Propane/Butane/Isobutane) 10
Step 1: 90 % of water was taken in clean SS beaker and Sodium phosphate monobasic and Disodium EDTA was dissolved in it at room temperature. Clindamycin phosphate was dissolved in prepared solution followed by addition of xanthan gum. Solution was mixed till the transparent viscous solution is obtained. Step 2: In a separate SS beaker Hexylene glycol, Polyoxyl 20 cetosteryl ether, Polysorbate-60, Transcutol and Phenoxyethanol were added and were mixed at 40°C till clear solution is obtained.
Step 3: Solutions of step 1 and 2 were mixed for 30 minutes and pH of the solution was adjusted to 5.0 using sodium hydroxide solution. Remaining amount of water was added to the prepared mixture to make 100% weight and was mixed for 10 minutes.

Step 4: 30 g of solution step 3 was filled in a container or dispenser at room temperature and valve was closed with deep tube and crimp. 3 gm of propellant was filled in the container or dispenser and was fitted with actuator. Physical appearance and microscopic view of foam is given in fig la and 1 b.
In vitro flux, study (Microgram/cm2/h) and cumulative release (Microgram/cm )of clindamycin from the foam prepared according to example 1 and Evoclin was carried out using regenerated cellulose memberane in 0.05 M phosphate buffer at pH 7.4. Results are given in Fig 2a and 2b. Specific gravity (relative to water) was measured as per European Pharcopoeia.
Chemical and physical characteristics of foam prepared according to example 1: Table 1

Test/Parameter Result
Description White coloured foam
Foam breaking time at 33°C Not break up to 30 minutes
Foam breaking time at 40°C Stable upto 15 mins, breaks on low shear which ensures ease of application
Specific Gravity/Foam Density 0.04
pH 4.9
Flux (μg/cm2/hr) 1277.1
Packing detail
Can 35 x 85 mm; 1" opening
Actuator + cap V05.967 + V20.60 - upright use
Valve NKPM1.847/R

Example -2

Sr. no Ingredients % w/w
1 Clindamycin Phosphate 1.25
2 Xanthan Gum 0.4
3 Polyoxyl 20 cetosteryl ether 2.0
4 Cetyl Alcohol 0.2
5 Polysorbate-60 1
6 Hexylene glycol 3
7 Transcutol 0.5
8 Phenoxyethanol 0.3
9 Sodium phosphate monobasic 0.3
10 Disodium EDTA 0.1
11 Sodium Hydroxide (10% solution) 0.1
12 Water 90.85
Total 100
13 Propellant(Propane/Butane/Isobutane) 10
Step 1: 90 % of water was taken in clean SS beaker and Sodium phosphate monobasic and Disodium EDTA was dissolved in it at room temperature. Clindamycin phosphate was dissolved in prepared solution followed by addition of xanthan gum. Solution was mixed till the transparent viscous solution is obtained. Step 2: In a separate SS beaker Hexylene glycol, Polyoxyl 20 cetosteryl ether, Polysorbate-60, Transcutol, cetyl alcohol and Phenoxyethanol were added and were mixed at 40°C till clear solution is obtained.
Step 3: Solutions of step 1 and 2 were mixed for 30 minutes and pH of the solution was adjusted to 5.0 using sodium hydroxide solution. Remaining amount of water was added to the prepared mixture to make 100% weight and was mixed for 10 minutes.
Step 4: 30 g of solution step 3 was filled in a container or dispenser at room temperature and valve was closed with deep tube and crimp. 3 gm of propellant was filled in the container or dispenser and was fitted with actuator.

Composition of Example 2 was kept for 3 months under the conditions 30°C ± 2°C/75 ± 5% RH and 40°C ± 2°C/75 ± 5% RH. in-vitro flux study (Microgram/cm2/h) of clindamycin from the foam was carried out using regenerated cellulose membrane in 0.05 M phosphate buffer at pH 7.4 at a) initial time point and b) after 3 months. Results are given in Fig 3.
Also, stability of the composition was assessed after 3 months, when kept at 40°C ± 2°C/75 ± 5% RH. Results are summarized in table 2.
Table 2: Stability data of compositions of example 2

s. Test Initial 40°C±2°C/75±5%RH
No

1 Month 2 Month 3 Month
1 Description White colour foam White colour foam White colour foam White colour foam
2 PH 5.01 5.06 4.93 4.98
3 Assay 99.90% 95.10% 99.10% 99.90%
Example -3

Sr. no Ingredients %w/w
1 Clindamycin Phosphate 1.25
2 Xanthan Gum 0.2
3 Polyoxyl 20 cetosteryl ether 2.0
4 Cetyl Alcohol 0.2
5 Polysorbate-60 1
6 Hexylene glycol 3
7 Transcutol 0.5
8 Phenoxyethanol 0.5
9 Sodium phosphate monobasic 0.3
10 Disodium EDTA 0.1
11 Sodium Hydroxide (10% solution) 0.1
12 Water 90.85
Total 100
13 Propellant(Propane/Butane/Isobutane) 10

Step 1: 90 % of water was taken in clean SS beaker and clindamycin phosphate was dissolved in it at room temperature. Sodium phosphate monobasic and Disodium EDTA was dissolved in prepared solution followed by the addition of xanthan gum. Solution was mixed till the transparent viscous solution is obtained at 35°C.
Step 2: In a separate SS beaker Hexylene glycol, Polyoxyl 20 cetosteryl ether, Polysorbate-60, Transcutol, cetyl alcohol and Phenoxyethanol were added and mixed at 45°C till clear solution is obtained. Solution was cooled to 35°C.
Step 3: Solutions of step 1 and 2 were mixed for 30 minutes and pH of the solution was adjusted to 5.0 using sodium hydroxide solution. Remaining amount of water was added to the prepared mixture to make 100% weight and was mixed for 10 minutes.
Step 4: 30 g of solution step 3 was filled in a container or dispenser at room temperature and valve was closed with deep tube and crimp. 3 gm of propellant was filled in the container or dispenser and was fitted with actuator.

Chemical and physical characteristics of foam prepared according to example 3: Table 3

Test/Parameter Result
Description White colored foam
Foam breaking time at
37°C Stable up to 15 minutes
Foam breaking time at 40°C Stable upto 15 mins, breaks on low shear which ensures ease of application
Specific Gravity/Foam
density 0.05
pH 5.04
Flux (μg/cm2/hr) 1730
Packing detail
Can 35 x 85 mm; 1" opening
Actuator + cap V05.967 + V20.60 -uprightuse
Valve NKPM1.847/R

Claims
1. A non-emulsified alcohol-free foamable pharmaceutical composition comprising clindamycin or pharmaceutically acceptable salt thereof, at least one permeation enhancer and one or more pharmaceutically acceptable carrier.
2. The non-emulsified alcohol-free foamable pharmaceutical composition according to claim 1, wherein pharmaceutically acceptable carrier is selected from surfactant, humectant, aqueous solvent, antimicrobial agent, pH modifier, chelating agent, viscosity modifier, buffering agent, foam adjuvant and mixture thereof.
3. A non-emulsified alcohol-free foamable pharmaceutical composition comprising of 0.05% to 2% clindamycin phosphate, 0.1% to 2% of permeation enhancer, 1% to 6% of humectants, 0.5% to 5% of surfactant, 0.1% to 1.5% of antimicrobial agent, 0.01% to 0.3% of pH modifier, 0.01% to 0.3% of chelating agent, 0.01% to 0.3% of viscosity modifier, 0.1% to 0.5% of buffering agent, 0.01% to 0.3% of foam adjuvant and 50% to 95% of solvent.
4. The non-emulsified alcohol-free foamable pharmaceutical composition according to any of the preceding claims, wherein the composition further comprising of propellant selected from chlorofluorocarbons , hydrocarbons, compressed gas and hydrofluoroalkanes or hydroflurorocarbon and mixture thereof.
5. The non-emulsified alcohol-free foamable pharmaceutical composition according to claim 3, wherein the composition consisting of 0.05% to 2% clindamycin phosphate, 0.1% to 2% of transcutol, 1% to 6% of hexylene glycol, 0.5% to 5% of polysorbate-60, 0.5% to 5% of polyoxyl 20 cetostearyl ether, 0.1% to 1.5% of

phenoxyethanol, 0.01% to 0.3% of sodium hydroxide, 0.01% to 0.3% of disodium EDTA, 0.01% to 0.3% of xanthan gum, 0.1% to 0.5% of. sodium phosphate monobasic, 0.01% to 0.3% of cetyl alcohol, 50% to 95% of water and propellant.
6. The non-emulsified alcohol-free foamable pharmaceutical composition according to any of the preceding claims, wherein said composition remain stable at least for 15 minutes after dispensing.
7. The non-emulsified alcohol-free foamable pharmaceutical composition according to any of the preceding claims, wherein said composition is not temperature sensitive.
8. A process for the preparation of a non-emulsified alcohol-free foamable pharmaceutical composition of clindamycin or pharmaceutically acceptable salt thereof comprising steps of:

a) Preparing aqueous solution of clindamycin optionally with one or more pharmaceutically acceptable carriers.
b) Preparing solution of permeation enhancer optionally with one or more pharmaceutically acceptable carriers.
c) Mixing solution of (a) and (b) and optionally adding pH modifier or one or more pharmaceutically acceptable carriers.
d) Adding foam generator in the prepared solution.
9. The process for the preparation of a foamable pharmaceutical composition of
claim 8, wherein the process comprising steps of:
a) Preparing aqueous solution of clindamycin phosphate with sodium phosphate monobasic, disodium EDTA, xanthan gum and water

b) Preparing solution of transcutol, Polyoxyl 20 cetosteryl ether, Polysorbate-60 and Hexylene glycol, optionally with cetyl alcohol and phenoxyethanol,
c) Mixing solution of (a) and (b) and optionally adding sodium hydroxide or one or more pharmaceutically acceptable carriers.
d) Adding propellant in the prepared solution.
10. A non-emulsified alcohol-free foamable pharmaceutical composition of clindamycin and pharmaceutically acceptable salt thereof and process of its preparation as herein described with reference to the examples and drawings accompanying the specification.