DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

COMPOSITION OF CLOTRIMAZOLE VAGINAL FILM AND PROCESS FOR PREPARATION THEREOF

We, HETERO HEALTHCARE LIMITED.,
a company incorporated under the company’s Act, 1956 having address at
Sy.No:83/1, Plot Nos. 16/A/1 & 16/A/2, 19th& 20th Floor,
Hetero Tower, Commerzone, Silpa Gram Craft Village,
Madhapur, Shaikpet, Hyderabad, Telangana State, India- 500081

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition of Clotrimazole.
The present invention specifically relates to a pharmaceutical composition of Clotrimazole vaginal film.
The present invention specifically relates to the pharmaceutical composition of Clotrimazole vaginal film comprising Clotrimazole and pharmaceutically acceptable excipients.
The present invention more specifically relates to the pharmaceutical composition of Clotrimazole vaginal film comprising Clotrimazole and pharmaceutically acceptable excipients selected from film-forming agents, solubilizing agents, plasticizers, Opacifiers and solvents.
The present invention also relates to the process for the preparation of Clotrimazole vaginal film.

BACKGROUND OF THE INVENTION
Candidiasis is an infection caused by a yeast (a type of fungus) called Candida. Candida normally lives on skin and inside the body such as in the mouth, throat, gut, and vagina, without causing any problems. Candida can cause an infection if conditions change inside the vagina to encourage its growth. Things like hormones, medicines, or changes in the immune system can make infection more likely. The common term for candidiasis in the vagina is a vaginal yeast infection. Other names for this infection are vaginal candidiasis, vulvovaginal candidiasis, or candidal vaginitis.
The most common symptom is vaginal itching, which may be severe. Other symptoms include burning with urination, a thick, white vaginal discharge that typically does not smell bad, pain during sex, and redness around the vagina. Symptoms often worsen just before a woman's period.
Vaginal yeast infections are due to excessive growth of Candida. These yeasts are normally present in the vagina in small numbers. Vaginal yeast infections are typically caused by the yeast species Candida albicans. Candida albicans is a common fungus often harbored in the mouth, digestive tract, or vagina without causing adverse symptoms.
Clotrimazole is a broad-spectrum antifungal agent that inhibits the growth of pathogenic yeasts by changing the permeability of cell membranes. The action of clotrimazole is fungistatic at concentrations of drug up to 20 mcg/mL and may be fungicidal in vitro against Candida albicans and other species of the genus Candida at higher concentrations Label. Unfortunately, resistance to clotrimazole, which was rare in the past, is now common in various patient populations. Clotrimazole is generally considered to be a fungistatic, and not a fungicidal drug, although this contrast is not absolute, as clotrimazole shows fungicidal properties at higher concentrations.
Clotrimazole acts primarily by damaging the permeability barrier in the cell membrane of fungi. Clotrimazole causes inhibition of ergosterol biosynthesis, an essential constituent of fungal cell membranes. If ergosterol synthesis is either completely or partially inhibited, the cell is no longer able to construct an intact and functional cell membrane. Because ergosterol directly promotes the growth of fungal cells in a hormone-like fashion, rapid onset of the above events leads to dose-dependent inhibition of fungal growth.
Clotrimazole, a synthetic antifungal agent having the chemical name {1-(o-Chloro-a,a-diphenylbenzyl) imidazole}; the molecular formula C22H17ClN2; a molecular weight of 344.84; and the structural formula:

US 3,705,172 A discloses Clotrimazole product.
US 5,529,782 A discloses a device adapted for local administration of an agent material in an internal body area such as the vagina, rectum, oral cavity, nasal passages and the like, comprises a dissolvable element and an agent material carried in said dissolvable element, wherein said dissolvable element is made of dissolvable polymer material, particularly, a mixture of polyvinyl alcohol, polyethylene oxide, and/or complex carbohydrate material, which are selected such that the dissolvable element remains in solid form before use, and dissolves due to human body temperatures and moisture during use to release said agent material for local administration in the internal body area.
US 7,939,098 B2 discloses a transmucosal composition for delivery of an active pharmaceutically acceptable agent through nasal, buccal or vaginal mucosa, said composition consisting essentially of about 0.01 to about 60%, preferably from about 5 to about 20%, of ethoxydiglycol or another non-ionizable glycol, said composition formulated as a solution, suspension, emulsion, gel, lotion, spray, tablet, dissolvable tablet for buccal use, ointment or foam for administration thereof alone or incorporated into a device for insertion into nasal, buccal or vaginal cavity.
WO 2005/013906 A2 discloses a pH-responsive film comprising: (a) a biocompatible, hydrophilic polymer that is positively charged at a first pH and in electronically neutral form at a higher pH; and (b) an alkylene oxide polymer or copolymer. This application discloses clotrimazole.
WO 2009/043588 A2 discloses antibacterial films that may regulate pH and control bacterial growth in the oral or vaginal environment and methods of use thereof. The films may include Lactic acid as pH adjusting ingredient, eucalyptus oil, menthol, peppermint oil, crisp mint oil, spearmint oil, Pelargonium sidoides root extract as antimicrobial essential oil, and polyvinyl alcohol, polyethylene glycol, and rice starch as polymer. The polymer may include polyvinyl alcohol, polyethylene glycol, and rice starch. The vaginal films and methods of use may treat infections in the vagina.
Bhat R. Sudeendra et al., Acta Pharmaceutica Sciencia 52: 417-426 (2010) discloses bioadhesive vaginal films of clotrimazole, formulated by solvent casting technique using bioadhesive polymers such as chitosan, HPMC and sodium CMC. Glycerine and PEG-400 were used as plasticizer for treatment against vaginal candidiasis.
Najmeh Nematpour et al.,Materials science & Engineering 110 (2020) discloses physicochemical comparison is made between clotrimazole loaded film and nanofiber fabricated with the new hybrid mucoadhesive formulation of dextran and alginate.
However, chitosan causes cytotoxicity and further chitosan is not soluble in the water. To solubilize the chitosan organic solvents such as acetic acid (1%) have to be used. The use of acetic acid increases the manufacturing cost of the product. To avoid the cytotoxicity and solubility issue of chitosan in water, and to reduce the overall manufacturing cost of Clotrimazole vaginal films of the present invention avoids usage of chitosan as film former.
None of the prior-art disclosed the Clotrimazole vaginal film composition of the present application. The inventors of present invention have developed specific Clotrimazole vaginal film composition. The present invention has developed using combination of two mucoadhesive film formers such as Hypromellose and Poly vinyl alcohol and Polyvinyl pyrrolidone (k 90) and Poloxamer as dissolution enhancer/solubilizing agent. The inventors of present invention have also developed specific process for the preparation of Clotrimazole vaginal film.
The Clotrimazole vaginal film of the present invention is stable, safe and effective finished dosage form and it is developed based on the use of novel vaginal film technology.

OBJECTIVE OF INVENTION
The main objective of the present invention is to provide a pharmaceutical composition of Clotrimazole.
Another objective of the present invention is to provide a pharmaceutical composition of Clotrimazole vaginal film.

Another objective of the present invention is to provide a pharmaceutical composition of Clotrimazole vaginal film comprising Clotrimazole and pharmaceutically acceptable excipients.
Another objective of the present invention is to provide a pharmaceutical composition of Clotrimazole vaginal film comprising Clotrimazole and pharmaceutically acceptable excipients selected from film-forming agents, solubilizing agents, plasticizers, Opacifier and solvents.
Yet another objective of the present invention is to provide a process for the preparation of Clotrimazole vaginal film.
SUMMARY OF INVENTION
Accordingly, the present invention provides a pharmaceutical composition of Clotrimazole.
In one embodiment, the present invention provides a pharmaceutical composition of Clotrimazole vaginal film.
In one embodiment, the present invention provides a pharmaceutical composition of Clotrimazole vaginal film comprising Clotrimazole and pharmaceutically acceptable excipients.
In one embodiment, the present invention provides a pharmaceutical composition of Clotrimazole vaginal film comprising Clotrimazole and pharmaceutically acceptable excipients, wherein said composition is devoid of Chitosan, dextran and alginate
In one embodiment, the present invention provides a pharmaceutical composition of Clotrimazole vaginal film comprising Clotrimazole and pharmaceutically acceptable excipients selected from film-forming agents, solubilizing agents, plasticizers, opacifiers and solvents.
In another embodiment, the present invention provides process for the preparation of Clotrimazole vaginal film.

In yet another embodiment, the present invention is to provide a pharmaceutical composition of Clotrimazole vaginal film comprising:
a) 1 to 30 % w/w of Active ingredient,
b) 1 to 80 % w/w of film forming agents,
c) 1 to 30 % w/w of solubilizing agents,
d) 1 to 30 % w/w of plasticizers, and
e) solvents qs.
In yet another embodiment, the present invention is to provide a pharmaceutical composition of Clotrimazole vaginal film comprising:
a) 1 to 30 % w/w of Active ingredient,
b) 1 to 80 % w/w of film forming agents,
c) 1 to 30 % w/w of solubilizing agents,
d) 1 to 30 % w/w of plasticizers,
e) 0.1 to 5 % w/w of Opacifiers , and
f) solvents qs.
Yet another embodiment of the present invention provides a pharmaceutical composition of Clotrimazole vaginal film comprising:
a) 1 to 30 % w/w of Clotrimazole,
b) 1 to 80 % w/w of film forming agents selected from hydroxypropylmethylcellulose, polyvinyl alcohol or combinations thereof,
c) 1 to 30 % w/w of solubilizing agents selected from polyvinyl pyrrolidone, polyoxyl 40 hydrogenated castor oil / macrogolglycerol hydroxy stearate and poloxamer,
d) 1 to 30 % w/w of plasticizers selected from glycerine, propylene glycol and triethyl citrate and
e) solvents in qs.
Yet another embodiment of the present invention provides a pharmaceutical composition of Clotrimazole vaginal film comprising:
a) 1 to 30 % w/w of Clotrimazole,
b) 1 to 20 % w/w of polyvinyl pyrrolidone,
c) 1 to 10% w/w of poloxamer,
d) 1 to 40 % w/w of hydroxypropylmethylcellulose,
e) 1 to 40 % w/w of polyvinyl alcohol,
f) 1 to 10 % w/w of glycerine,
g) 1 to 20 % w/w of propylene glycol,
h) 0.1 to 5 % w/w of titanium dioxide, and
i) solvents in qs.
Yet another embodiment of the present invention provides a process for the preparation of Clotrimazole vaginal film.
Yet another embodiment of the present invention provides a process for the preparation of Clotrimazole vaginal film, wherein the process comprising steps of:
a) adding film forming agents to solvent under stirring get clear solution,
b) adding plasticizers to solvent and mixing to get the clear solution,
c) adding Clotrimazole to step (b) solution and mixing to get clear solution,
d) adding dispersion of step (c) to step (d) solution and mixing the final polymeric dispersion,
e) deaerating polymeric drug dispersion prepared in step (d) by applying vacuum,
f) coating the polymeric drug dispersion obtained in step (e) and drying in hot air oven, and
g) cutting the film role into desired size using slitter and packing the films into suitable pouches.
Yet another embodiment of the present invention provides a process for the preparation of Clotrimazole vaginal film, wherein the process comprising steps of:
a) adding film forming agents to solvent under stirring get clear solution,
b) adding plasticizers to solvent and mixing to get the clear solution,
c) adding Clotrimazole to step (b) solution and mixing to get clear solution,
d) adding Opacifiers in solvent and mixing to get uniform dispersion,
e) adding dispersion of step (d) to step (e) solution and mixing the final polymeric dispersion,
f) deaerating polymeric drug dispersion prepared in step (e) by applying vacuum,
g) coating the polymeric drug dispersion obtained in step (f) and drying in hot air oven, and
h) cutting the film role into desired size using slitter and packing the films into suitable pouches.
Yet another embodiment of the present invention provides a process for the preparation of Clotrimazole vaginal film, wherein the process comprising steps of:
a) adding polyvinyl alcohol under stirring, polyvinyl pyrrolidone in purifies water and mixing to get clear solution,
b) heating the dispersion to get uniform viscous dispersion,
c) adding propylene glycol and glycerine to acetone and mixing to get the clear solution,
d) adding Poloxamer to step (c) and mixing to get the clear solution,
e) adding Clotrimazole to step (d) solution and mixing to get clear solution,
f) adding hydroxypropylmethylcellulose to water and mixing up to form uniform viscous blend,
g) adding titanium dioxide in purified water and mixing to get uniform dispersion and adding this dispersion to step (f) viscous blend,
h) adding dispersion of step (a) to step (g) solution and mixing the final polymeric dispersion,
i) deaerating Polymeric drug dispersion prepared in step (h) by applying vacuum,
j) coating the polymeric drug dispersion obtained in step (i) and drying in hot air oven, and
k) cutting the film role into desired size using slitter and packing the films into suitable pouches.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure. 1 : Resolution of signs and symptoms (Clinical cure) at the end of day 7 of test group
Figure. 2 : Resolution of signs and symptoms (Clinical cure) at the end of day 7 of reference group
Figure. 3 : Proportion of patients with mycological cure at the end of day 7 of test group
Figure. 4 : Proportion of patients with mycological cure at the end of day 7 of reference group
Figure. 5 : Therapeutic cure (clinical cure along with mycological cure) at the end of day 7, test group.
Figure. 6 : Therapeutic cure (clinical cure along with mycological cure) at the end of day 7, reference group.

DETAILED DESCRIPTION OF THE INVENTION
The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.
Accordingly, the present invention provides a pharmaceutical composition of Clotrimazole.
In one embodiment, the present invention provides a pharmaceutical composition of Clotrimazole vaginal film.
In one embodiment, the present invention provides a pharmaceutical composition of Clotrimazole vaginal film comprising Clotrimazole and pharmaceutically acceptable excipients.

In one embodiment, the present invention provides a pharmaceutical composition of Clotrimazole vaginal film comprising Clotrimazole and pharmaceutically acceptable excipients selected from film-forming agents, solubilizing agents, plasticizers, Opacifiers and solvents.
In another embodiment, the present invention provides a process for the preparation of Clotrimazole vaginal film.
The vaginal films pharmaceutical form consists of a thin and small sheet of polymeric hydrophilic substances that disperse or dissolve in contact with vaginal fluids to release the active substance. Vaginal films are pharmaceutical forms that are convenient, discrete, they do not require the use of an applicator to be administered and, as they disperse in vaginal fluids, they have low risk of increasing fluids volume and leak out, therefore improving comfort of use and efficacy after administration. Other advantages of vaginal films include their portability and low cost per unit. Since they are solid pharmaceutical forms, films can vehicle drugs that are susceptible to hydrolytic degradation, guaranteeing their stability. They can be formulated for immediate or sustained drug release.
The term “vaginal film” of the present invention can be interchangeably used with “vaginal device”.
The term “active ingredient” of the present invention is used to treats wide variety of dermatophyte infections and candidiasis. Topical formulations are used for Tinea pedis, tinea cruris, and tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Candidiasis due to Candida albicans, Tinea versicolor due to Malassezia furfur, Diaper rash infected by Candida albicans.
Preferably used active ingredient is Clotrimazole. The concentration of Clotrimazole used in the vaginal film is from 1 to 30 % w/w in total weight of the composition.

Clotrimazole is a broad-spectrum antifungal agent that inhibits the growth of pathogenic yeasts by changing the permeability of cell membranes. The action of clotrimazole is fungistatic at concentrations of drug up to 20 mcg/mL and may be fungicidal in vitro against Candida albicans and other species of the genus Candida at higher concentrations Label. Unfortunately, resistance to clotrimazole, which was rare in the past, is now common in various patient populations. Clotrimazole is generally considered to be a fungistatic, and not a fungicidal drug, although this contrast is not absolute, as clotrimazole shows fungicidal properties at higher concentrations.
The term “film forming agents” as used herein includes but not limited to hydroxyethyl cellulose, carrageen, eudragit EPO, hydroxypropyl cellulose, hydroxypropylmethylcellulose, gums, starch, polymerized rosin, pullulan, pectin, gelatine, maltodextrins, polyvinyl alcohol, sodium carboxy methyl cellulose, copovidone.
The concentration of film forming agents used in the composition of the present invention is from 1 to 80 % w/w of the total weight of the composition.
The solubilizing agent can be selected from polyvinylpyrrolidones, polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer, polyoxyl 40 hydrogenated castor oil / macrogolglycerol hydroxy stearate, fatty acids, castor oil, cyclodextrins, polyethyleneglycol, glyceryl distearate, monoglycerides, diglycerides, triglycerides, propylene glycol monostearate, Labrafils (e.g., oleoyl macrogol-6 glycerides, oleoyl polyoxyl-6-glycerides, linoleoyl macrogol-6 glycerides, linoleoyl polyoxyl-6 glycerides, lauroyl macrogol-6 glycerides, lauroyl polyoxyl-6 glycerides), Labrasols (e.g., caprylocaproyl macrogol-8 glycerides, caprylocaproyl polyoxyl-8 glycerides), Solutols (e.g., poly-oxyethylene esters of 12-hydroxystearic acid), Soluplus (e.g., polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer), sodium lauryl sulphate, sodium dioctyl sulphosuccinate, glycerol monostearate, glyceryl monooleate, glyceryl monobutyrate, block copolymers of ethylene oxide and propylene oxide, polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol, Poloxamer, Poloxamer 124, Poloxamer 188, Poloxamer 237, Poloxamer 388, Poloxamer 407, sorbitan mono laurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan stearate, sorbitan monolaurate, polyoxyethylene (20) sorbitan, polyoxyethylene sorbitan monooleate (Tween), PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate, hydrogenated castor oil and polyoxyethylene castor oil derivates, e.g. polyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oil (Cremophor® EL; BASF Corp.); or polyoxyethyleneglycerol oxystearate such as polyethylenglycol 40 hydrogenated castor oil (Cremophor RH® 40) or polyethylenglycol 60 hydrogenated castor oil (Cremophor RH® 60), sucrose stearate, sucrose oleate, sucrose palmitate, sucrose laurate, and sucrose acetate butyrate, vitamin E-TPGS® (d-alpha-tocopheryl polyethylene glycol 1000 succinate), glycerophospholipids (lecithins, kephalins, phosphatidyl serine), glyceroglycolipids (galactopyransoide), sphingophospholipids (sphingomyelin), and sphingoglycolipids (ceramides, gangliosides), DSS (docusate sodium), docusate calcium, docusate potassium, SDS (sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidic acid, sodium caprylate, cetyl-trimethylammonium bromide, cetylpyridinium chloride,
The concentration of solubilizing agent used in the composition of the present invention is from 1 to 30 % w/w of the total weight of the composition.
Plasticizers are low molecular weight compounds that can be added to the formulation to increase the plasticity, soften the polymer carrier, and enhance the flexibility of the final product. The addition of plasticizers to the formulation can improve the manufacturing conditions or the physiochemical properties of the film.
Plasticizers used in the composition of the present invention include but not limited to triacetin, low molecular weight polyethylene glycols, triethyl citrate, glycerine, propylene glycol and vitamin E TPGS.
Propylene glycol and glycerin were used as plasticizer and hygroscopic material to prevent moisture loss.
The concentration of plasticizers used in the composition of the present invention is from 1 to 30% w/w of the total weight of the composition.
Opacifiers used in the composition of the present invention include but not limited to titanium dioxide, calcium carbonate, kaolin, magnesium trisilicate, magnesium aluminum silicate, zinc carbonate, bentonite and barium sulfate.
The concentration of Opacifiers used in the composition of the present invention is from 0.1 to 5 % w/w of the total weight of the composition.
Colorants used in the composition of the present invention include but not limited to titanium dioxide, FD&C, D&C, lakes and any approved colour/colorants.
The concentration of colorants used in the composition of the present invention is from 0.1 to 5 % w/w of the total weight of the composition.
The solvents used in the present invention are water, a polar organic solvent including, but not limited to, ethanol, isopropanol, acetone, methylene chloride, or any combination thereof.
The present invention is illustrated in detail but not limiting to, the following examples. It will be apparent to those skilled in the art that many modifications may be practiced without departing from the scope of the invention.

EXAMPLE 1
S. No Name of the Material Quantity per film
mg %w/w
1 Clotrimazole IP 50.00* 17.42
2 Polyvinyl Pyrrolidone (Bovidoen K 90) IP 30.00 10.45
3 Poloxamer 407 (Lutrol F127) IP 5.00 1.74
4 Glycerine IP 10.00 3.48
5 Hydroxypropyl Methylcellulose 15 CPS IP 75.00** 26.13
6 Polyvinyl Alcohol Cold WS (160000 MW) IP 75.00 26.13
7 Propylene Glycol IP 40.00 13.94
8 Titanium Dioxide IP 2.00 0.70
9 Acetone IH 300.00** --
10 Purified Water IP 650.00** --
Total Weight 287.00 100
** Acetone and purified water evaporated during the drying process and did not appear in finished product except in traces.

Manufacturing Process

Preparation of Polymeric Solution
Transferred 82% of batch quantity of purified water to SS vessel and heat up to reach temperature 80 ± 50C. Added batch quantity of polyvinyl alcohol under stirring and added batch quantity of polyvinyl pyrrolidone K-90 and mixed up to get clear solution free from lumps. Then cool down polymeric solution to 20 to 250C.
Preparation of Clotrimazole Dispersion
Transferred 20% of batch quantity of Acetone to another SS vessel. Added batch quantity of propylene glycol and mixed for 5 min using stirrer. Added batch quantity of glycerine and mixed for 5 min using stirrer. Added 80% of batch quantity of Acetone solution and mixed up to get clear solution. Added batch quantity of Poloxamer P 407 and mixed up to get clear solution. Added batch quantity of Clotrimazole and mixed for 5 min and apply heat 400C ± 20C until clear solution was formed. Added batch quantity of Hydroxypropyl methylcellulose and mixed for 5 min. Add 12% of batch quantity of Purified water and mix for 10 min to form viscous blend. 2% of Purified water taken in another beaker and to this added titanium dioxide and mixed for 5 min (Or) until uniform dispersion obtained. Added this dispersion to main polymeric solution and mixed for 10 min. Rinsed the SS vessel with 4% batch quantity of purified water and added the rinses to main manufacturing vessel. Then cool down polymeric dispersion to 20 to 250C.
De-aeration:
Polymeric drug dispersion prepared was subjected to de-aeration by applying vacuum.
Coating & drying:
The polymeric drug dispersion was coated on polyester and dried in hot air oven chambers at 800c.
Slitting:
Dried mother roll is cut into a desired size using slitter.
Packing
Packed the film into suitable pouches.

Example 2
S. No Name of the Material Quantity per film
mg %w/w
1 Clotrimazole IP 50.00* 17.54
2 Polyvinyl Pyrrolidone (Bovidoen K 90) IP 30.00 10.53
3 Poloxamer 407 (Lutrol F127) IP 5.00 1.75
4 Glycerine IP 10.00 3.51
5 Hydroxypropyl Methylcellulose 15 CPS IP 75.00* 26.32
6 Polyvinyl Alcohol Cold WS (160000 MW) IP 75.00 26.32
7 Propylene Glycol IP 40.00 14.04
9 Acetone IH 300.00** --
10 Purified Water IP 650.00** --
Total Weight 285.00 100
**Acetone and purified water evaporated during the drying process and did not appear in finished product except in traces.

Manufacturing Process
Preparation of Polymeric Solution
Transferred 82% of batch quantity of purified water to SS vessel and heat up to reach temperature 80 ± 50C. Added batch quantity of polyvinyl alcohol under stirring and added batch quantity of polyvinyl pyrrolidone K-90 and mixed up to get clear solution free from lumps. Then cool down polymeric solution to 20 to 250C.
Preparation of Clotrimazole Dispersion
Transferred 20% of batch quantity of Acetone to another SS vessel. Added batch quantity of propylene glycol and mixed for 5 min using stirrer. Added batch quantity of glycerine and mixed for 5 min using stirrer. Added 80% of batch quantity of Acetone solution and mixed up to get clear solution. Added batch quantity of Poloxamer P 407 and mixed up to get clear solution. Added batch quantity of Clotrimazole and mixed for 5 min and apply heat 400C ± 20C until clear solution was formed. Added batch quantity of Hydroxypropyl methylcellulose and mixed for 5 min. Add 12% of batch quantity of Purified water and mix for 10 min to form viscous blend. 2% of Purified water taken in another beaker and mixed for 5 min (Or) until uniform dispersion obtained. Added this dispersion to main polymeric solution and mixed for 10 min. Rinsed the SS vessel with 4% batch quantity of purified water and added the rinses to main manufacturing vessel. Then cool down polymeric dispersion to 20 to 250C.
De-aeration:
Polymeric drug dispersion prepared was subjected to de-aeration by applying vacuum.
Coating & drying:
The polymeric drug dispersion was coated on polyester and dried in hot air oven chambers at 800c.
Slitting:
Dried mother roll is cut into a desired size using slitter.
Packing
Packed the film into suitable pouches.

Example 3
S. No Name of the Material Quantity per film
mg %w/w
1 Clotrimazole IP 50.00* 17.42
2 Polyoxyl 40 Hydrogenated Castor Oil / Macrogolglycerol Hydroxy stearate 30.00 10.45
3 Poloxamer 407 (Lutrol F127) IP 5.00 1.74
4 Glycerine IP 10.00 3.48
5 Hydroxypropyl Methylcellulose 15 CPS IP 75.00** 26.13
6 Polyvinyl Alcohol Cold WS (160000 MW) IP 75.00 26.13
7 Propylene Glycol IP 40.00 13.94
8 Titanium Dioxide IP 2.00 0.70
9 Acetone IH Q.S** --
10 Purified Water IP Q.S** --
Total Weight 287.00 100
**Acetone and purified water evaporated during the drying process and did not appear in finished product except in traces.

Manufacturing Process
Preparation of Polymeric Solution
Transferred 82% of batch quantity of purified water to SS vessel and heat up to reach temperature 80 ± 50C. Added batch quantity of polyvinyl alcohol under stirring and added batch quantity of Polyoxyl 40 Hydrogenated Castor Oil / Macrogolglycerol Hydroxy stearate and mixed up to get clear solution free from lumps. Then cool down polymeric solution to 20 to 250C.
Preparation of Clotrimazole Dispersion
Transferred 20% of batch quantity of Acetone to another SS vessel. Added batch quantity of propylene glycol and mixed for 5 min using stirrer. Added batch quantity of glycerine and mixed for 5 min using stirrer. Added 80% of batch quantity of Acetone solution and mixed up to get clear solution. Added batch quantity of Poloxamer P 407 and mixed up to get clear solution. Added batch quantity of Clotrimazole and mixed for 5 min and apply heat 400C ± 20C until clear solution was formed. Added batch quantity of Hydroxypropyl methylcellulose and mixed for 5 min. Add 12% of batch quantity of Purified water and mix for 10 min to form viscous blend. 2% of Purified water taken in another beaker and to this added titanium dioxide and mixed for 5 min (Or) until uniform dispersion obtained. Added this dispersion to main polymeric solution and mixed for 10 min. Rinsed the SS vessel with 4% batch quantity of purified water and added the rinses to main manufacturing vessel. Then cool down polymeric dispersion to 20 to 250C.
De-aeration:
Polymeric drug dispersion prepared was subjected to de-aeration by applying vacuum.
Coating & drying:
The polymeric drug dispersion was coated on polyester and dried in hot air oven chambers at 800c.
Slitting:
Dried mother roll is cut into a desired size using slitter.
Packing
Packed the film into suitable pouches.

Example 4:
S. No Name of the Material Quantity per film
mg %w/w
1 Clotrimazole IP 50.00* 17.42
2 Polyoxyl 40 Hydrogenated Castor Oil / Macrogolglycerol Hydroxystearate 20.00 8.97
3 Polyvinyl Pyrrolidone K 90 IP 10.00 3.48
4 Poloxamer 407 (Lutrol F127) IP 5.00 1.74
5 Glycerine IP 10.00 3.48
6 Hydroxypropyl Methylcellulose 15 CPS IP 75.00** 26.13
7 Polyvinyl Alcohol Cold WS (160000 MW) IP 75.00 26.13
8 Propylene Glycol IP 40.00 13.94
9 Titanium Dioxide IP 2.00 0.70
10 Acetone IH Q.S** --
11 Purified Water IP Q.S** --
Total Weight 287.00 100
**Acetone and purified water evaporated during the drying process and did not appear in finished product except in traces.

Manufacturing Process
Preparation of Polymeric Solution
Transferred 82% of batch quantity of purified water to SS vessel and heat up to reach temperature 80 ± 50C. Added batch quantity of polyvinyl alcohol under stirring and added batch quantity of Polyoxyl 40 Hydrogenated Castor Oil / Macrogolglycerol Hydroxy stearate under stirring, added batch quantity of Polyvinyl Pyrrolidone K 90 and mixed up to get clear solution free from lumps. Then cool down polymeric solution to 20 to 250C.
Preparation of Clotrimazole Dispersion
Transferred 20% of batch quantity of Acetone to another SS vessel. Added batch quantity of propylene glycol and mixed for 5 min using stirrer. Added batch quantity of glycerine and mixed for 5 min using stirrer. Added 80% of batch quantity of Acetone solution and mixed up to get clear solution. Added batch quantity of Poloxamer P 407 and mixed up to get clear solution. Added batch quantity of Clotrimazole and mixed for 5 min and apply heat 400C ± 20C until clear solution was formed. Added batch quantity of Hydroxypropyl methylcellulose and mixed for 5 min. Add 12% of batch quantity of Purified water and mix for 10 min to form viscous blend. 2% of Purified water taken in another beaker and to this added titanium dioxide and mixed for 5 min (Or) until uniform dispersion obtained. Added this dispersion to main polymeric solution and mixed for 10 min. Rinsed the SS vessel with 4% batch quantity of purified water and added the rinses to main manufacturing vessel. Then cool down polymeric dispersion to 20 to 250C.
De-aeration:
Polymeric drug dispersion prepared was subjected to de-aeration by applying vacuum.
Coating & drying:
The polymeric drug dispersion was coated on polyester and dried in hot air oven chambers at 800c.
Slitting:
Dried mother roll is cut into a desired size using slitter.
Packing
Packed the film into suitable pouches.

Example 5:

S. No Name of the Material Quantity per film
mg %w/w
1 Clotrimazole IP 50.00* 17.42
2 Polyvinyl Pyrrolidone K 90 IP 30.00 10.45
3 Poloxamer 407 (Lutrol F127) IP 5.00 1.74
4 Glycerine IP 10.00 3.48
5 Hydroxypropyl Methylcellulose 15 CPS IP 75.00** 26.13
6 Polyvinyl Alcohol Cold WS (160000 MW) IP 75.00 26.13
7 Triethyl citrate 5.00 1.74
8 Propylene Glycol IP 35.00 12.20
9 Titanium Dioxide IP 2.00 0.70
10 Acetone IH Q.S** --
11 Purified Water IP Q.S** --
Total Weight 287.00 100
**Acetone and purified water evaporated during the drying process and did not appear in finished product except in traces.

Manufacturing Process
Preparation of Polymeric Solution
Transferred 82% of batch quantity of purified water to SS vessel and heat up to reach temperature 80 ± 50C. Added batch quantity of polyvinyl alcohol under stirring and added batch quantity of polyvinyl pyrrolidone K-90 and mixed up to get clear solution free from lumps. Then cool down polymeric solution to 20 to 250C.
Preparation of Clotrimazole Dispersion
Transferred 20% of batch quantity of Acetone to another SS vessel. Added batch quantity of propylene glycol and mixed for 5 min using stirrer. Added batch quantity of glycerine and mixed for 5 min using stirrer. Added batch quantity of Triethyl citrate and mixed for 5 min using stirrer Added 80% of batch quantity of Acetone solution and mixed up to get clear solution. Added batch quantity of Poloxamer P 407 and mixed up to get clear solution. Added batch quantity of Clotrimazole and mixed for 5 min and apply heat 400C ± 20C until clear solution was formed. Added batch quantity of Hydroxypropyl methylcellulose and mixed for 5 min. Add 12% of batch quantity of Purified water and mix for 10 min to form viscous blend. 2% of Purified water taken in another beaker and to this added titanium dioxide and mixed for 5 min (Or) until uniform dispersion obtained. Added this dispersion to main polymeric solution and mixed for 10 min. Rinsed the SS vessel with 4% batch quantity of purified water and added the rinses to main manufacturing vessel. Then cool down polymeric dispersion to 20 to 250C.
De-aeration:
Polymeric drug dispersion prepared was subjected to de-aeration by applying vacuum.
Coating & drying:
The polymeric drug dispersion was coated on polyester and dried in hot air oven chambers at 800c.
Slitting:
Dried mother roll is cut into a desired size using slitter.

Example 6:
S. No Name of the Material Quantity per film
mg %w/w
1 Clotrimazole IP 50.00* 18.05
2 Polyvinyl Pyrrolidone K 90 30.00 10.83
3 Poloxamer 407 (Lutrol F127) IP 5.00 1.81
4 Polyvinyl Alcohol Cold WS (160000 MW) IP 150.00 54.15
5 Propylene Glycol IP 40.00 14.44
6 Titanium Dioxide IP 2.00 0.72
7 Acetone IH Q.S** --
8 Purified Water IP Q.S** --
Total Weight 277.00 100
**Acetone and purified water evaporated during the drying process and did not appear in finished product except in traces.

Manufacturing Process
Preparation of Polymeric Solution
Transferred 82% of batch quantity of purified water to SS vessel and heat up to reach temperature 80 ± 50C. Added batch quantity of polyvinyl alcohol under stirring and added batch quantity of Polyvinyl Pyrrolidone K 90 and mixed up to get clear solution free from lumps. Then cool down polymeric solution to 20 to 250C.
Preparation of Clotrimazole Dispersion
Transferred 20% of batch quantity of Acetone to another SS vessel. Added batch quantity of Propylene glycol and mixed for 5 min using stirrer. Added 80% of batch quantity of Acetone solution and mixed up to get clear solution. Added batch quantity of Poloxamer P 407 and mixed up to get clear solution. Added batch quantity of Clotrimazole and mixed for 5 min and apply heat 400C ± 20C until clear solution was formed. Add 12% of batch quantity of Purified water and mix for 10 min to form viscous blend. 2% of Purified water taken in another beaker and to this added titanium dioxide and mixed for 5 min (Or) until uniform dispersion obtained. Added this dispersion to main polymeric solution and mixed for 10 min. Rinsed the SS vessel with 4% batch quantity of purified water and added the rinses to main manufacturing vessel. Then cool down polymeric dispersion to 20 to 250C.
De-aeration:
Polymeric drug dispersion prepared was subjected to de-aeration by applying vacuum.
Coating & drying:
The polymeric drug dispersion was coated on polyester and dried in hot air oven chambers at 800c.
Slitting:
Dried mother roll is cut into a desired size using slitter.
Packing
Packed the film into suitable pouches.

Example 7:
S. No Name of the Material Quantity per film
mg %w/w
1 Clotrimazole IP 50.00* 18.05
2 Polyvinyl Pyrrolidone K 90 30.00 10.83
3 Poloxamer 407 (Lutrol F127) IP 5.00 1.81
4 Hydroxypropyl Methylcellulose 15 CPS IP 150.00 54.15
5 Propylene Glycol IP 40.00 14.44
6 Titanium Dioxide IP 2.00 0.72
7 Acetone IH Q.S** --
8 Purified Water IP Q.S** --
Total Weight 277.00 100.00
**Acetone and purified water evaporated during the drying process and did not appear in finished product except in traces.

Manufacturing Process
Preparation of Polymeric Solution
Transferred 82% of batch quantity of purified water to SS vessel and heat up to reach temperature 80 ± 50C. Added batch quantity of Polyvinyl Pyrrolidone K 90 and mixed up to get clear solution free from lumps. Then cool down polymeric solution to 20 to 250C.
Preparation of Clotrimazole Dispersion
Transferred 20% of batch quantity of Acetone to another SS vessel. Added batch quantity of Propylene glycol and mixed for 5 min using stirrer. Added 80% of batch quantity of Acetone solution and mixed up to get clear solution. Added batch quantity of Poloxamer P 407 and mixed up to get clear solution. Added batch quantity of Clotrimazole and mixed for 5 min and apply heat 400C ± 20C until clear solution was formed. Added batch quantity of Hydroxypropyl methylcellulose and mixed for 5 min. Added 12% of batch quantity of Purified water and mix for 10 min to form viscous blend. 2% of Purified water taken in another beaker and to this added titanium dioxide and mixed for 5 min (Or) until uniform dispersion obtained. Added this dispersion to main polymeric solution and mixed for 10 min. Rinsed the SS vessel with 4% batch quantity of purified water and added the rinses to main manufacturing vessel. Then cool down polymeric dispersion to 20 to 250C.
De-aeration:
Polymeric drug dispersion prepared was subjected to de-aeration by applying vacuum.
Coating & drying:
The polymeric drug dispersion was coated on polyester and dried in hot air oven chambers at 800c.
Slitting:
Dried mother roll is cut into a desired size using slitter.
Packing
Packed the film into suitable pouches.

Example 8:
S. No Name of the Material Quantity per film
mg %w/w
1 Clotrimazole IP 50.00* 16.84
2 Polyvinyl Pyrrolidone K 90 30.00 10.10
3 Poloxamer 407 (Lutrol F127) IP 5.00 1.68
4 Polyvinyl Alcohol Cold WS (160000 MW) IP 150.00 50.51
5 Glycerol 60.00 20.20
6 Titanium Dioxide IP 2.00 0.67
7 Acetone IH Q.S** --
8 Purified Water IP Q.S** --
Total Weight 297.00 100
**Acetone and purified water evaporated during the drying process and did not appear in finished product except in traces.

Manufacturing Process
Preparation of Polymeric Solution
Transferred 82% of batch quantity of purified water to SS vessel and heat up to reach temperature 80 ± 50C. Added batch quantity of polyvinyl alcohol under stirring and added batch quantity of Polyvinyl Pyrrolidone K 90 and mixed up to get clear solution free from lumps. Then cool down polymeric solution to 20 to 250C.
Preparation of Clotrimazole Dispersion
Transferred 20% of batch quantity of Acetone to another SS vessel. Added batch quantity of Glycerine and mixed for 5 min using stirrer. Added 80% of batch quantity of Acetone solution and mixed up to get clear solution. Added batch quantity of Poloxamer P 407 and mixed up to get clear solution. Added batch quantity of Clotrimazole and mixed for 5 min and apply heat 400C ± 20C until clear solution was formed. Add 12% of batch quantity of Purified water and mix for 10 min to form viscous blend. 2% of Purified water taken in another beaker and to this added titanium dioxide and mixed for 5 min (Or) until uniform dispersion obtained. Added this dispersion to main polymeric solution and mixed for 10 min. Rinsed the SS vessel with 4% batch quantity of purified water and added the rinses to main manufacturing vessel. Then cool down polymeric dispersion to 20 to 250C.
De-aeration:
Polymeric drug dispersion prepared was subjected to de-aeration by applying vacuum.
Coating & drying:
The polymeric drug dispersion was coated on polyester and dried in hot air oven chambers at 800c.
Slitting:
Dried mother roll is cut into a desired size using slitter.
Packing
Packed the film into suitable pouches.

Example 9:
S. No Name of the Material Quantity per film
mg %w/w
1 Clotrimazole 50.00* 16.84
2 Polyvinyl Pyrrolidone K 90 30.00 10.10
3 Poloxamer 407 (Lutrol F127) 5.00 1.68
4 Hydroxypropyl Methylcellulose 15 CPS 150.00 50.51
5 Glycerine 60.00 20.20
6 Titanium Dioxide IP 2.00 0.67
7 Acetone IH Q.S** --
8 Purified Water IP Q.S** --
Total Weight 297.00 100.00
**Acetone and purified water evaporated during the drying process and did not appear in finished product except in traces.

Manufacturing Process
Preparation of Polymeric Solution
Transferred 82% of batch quantity of purified water to SS vessel and heat up to reach temperature 80 ± 50C. Added batch quantity of Polyvinyl Pyrrolidone K 90 and mixed up to get clear solution free from lumps. Then cool down polymeric solution to 20 to 250C.
Preparation of Clotrimazole Dispersion
Transferred 20% of batch quantity of Acetone to another SS vessel. Added batch quantity of Glycerine and mixed for 5 min using stirrer. Added 80% of batch quantity of Acetone solution and mixed up to get clear solution. Added batch quantity of Poloxamer P 407 and mixed up to get clear solution. Added batch quantity of Clotrimazole and mixed for 5 min and apply heat 400C ± 20C until clear solution was formed. Added batch quantity of Hydroxypropyl methylcellulose and mixed for 5 min. Added 12% of batch quantity of Purified water and mix for 10 min to form viscous blend. 2% of Purified water taken in another beaker and to this added titanium dioxide and mixed for 5 min (Or) until uniform dispersion obtained. Added this dispersion to main polymeric solution and mixed for 10 min. Rinsed the SS vessel with 4% batch quantity of purified water and added the rinses to main manufacturing vessel. Then cool down polymeric dispersion to 20 to 250C.
De-aeration:
Polymeric drug dispersion prepared was subjected to de-aeration by applying vacuum.
Coating & drying:
The polymeric drug dispersion was coated on polyester and dried in hot air oven chambers at 800c.
Slitting:
Dried mother roll is cut into a desired size using slitter.
Packing
Packed the film into suitable pouches.

Example 10:
S. No Name of the Material Quantity per film
mg %w/w
1 Clotrimazole IP 50.00* 17.42
2 Polyvinyl Pyrrolidone (Bovidoen K 90) IP 30.00 10.45
3 Poloxamer 407 (Lutrol F127) IP 5.00 1.74
4 Glycerine IP 10.00 3.48
5 Hydroxypropyl Methylcellulose 15 CPS IP 75.0 26.13
6 Polyvinyl Alcohol Cold WS (160000 MW) IP 75.00 26.13
7 Propylene Glycol IP 40.00 13.94
8 Calcium Carbonate 2.00 0.70
9 Acetone IH Q.S** --
10 Purified Water IP Q.S** --
Total Weight 287.00 100
**Acetone and purified water evaporated during the drying process and did not appear in finished product except in traces.

Manufacturing Process
Preparation of Polymeric Solution
Transferred 82% of batch quantity of purified water to SS vessel and heat up to reach temperature 80 ± 50C. Added batch quantity of polyvinyl alcohol under stirring and added batch quantity of polyvinyl pyrrolidone K-90 and mixed up to get clear solution free from lumps. Then cool down polymeric solution to 20 to 250C.
Preparation of Clotrimazole Dispersion
Transferred 20% of batch quantity of Acetone to another SS vessel. Added batch quantity of propylene glycol and mixed for 5 min using stirrer. Added batch quantity of glycerine and mixed for 5 min using stirrer. Added 80% of batch quantity of Acetone solution and mixed up to get clear solution. Added batch quantity of Poloxamer P 407 and mixed up to get clear solution. Added batch quantity of Clotrimazole and mixed for 5 min and apply heat 400C ± 20C until clear solution was formed. Added batch quantity of Hydroxypropyl methylcellulose and mixed for 5 min. Add 12% of batch quantity of Purified water and mix for 10 min to form viscous blend. 2% of Purified water taken in another beaker and to this added calcium carbonate and mixed for 5 min (Or) until uniform dispersion obtained. Added this dispersion to main polymeric solution and mixed for 10 min. Rinsed the SS vessel with 4% batch quantity of purified water and added the rinses to main manufacturing vessel. Then cool down polymeric dispersion to 20 to 250C.
De-aeration:
Polymeric drug dispersion prepared was subjected to de-aeration by applying vacuum.
Coating & drying:
The polymeric drug dispersion was coated on polyester and dried in hot air oven chambers at 800c.
Slitting:
Dried mother roll is cut into a desired size using slitter.

The product of present invention has evaluated for various physicochemical properties like water content, disintegration time, dissolution, assay, related substances and microbial limits.
The stability data at various stability conditions 40°C ± 2°C/75%± 5% RH, 30°C ± 2°C/75% ± 5% RH, 25°C ± 2°C/60% ± 5% RH. The data depicted below in the table
Stability Data: 40°C ± 2°C/75%± 5% RH
Duration Description Water
Content Dissolution (%) Related Substances (%) Assay
(%) Disintegration time
White colored opaque square shaped, vaginal film. NMT
10.0 %
w/w NLT 80 in 45 minutes Imp
A Imp B Imp D Imp E Imp
F Unknown Imp Total impurities
20 Min 45 Min NMT 0.2 NMT 0.2 NMT 0.2 NMT 0.2 NMT 0.1 NMT
0.1 NMT
1.0 NLT 90.0 & NMT 110.0 NMT 180
sec
Initial Same as above 5.20 99.9 101.2 0.04 0.01 BDL BDL 0.01 0.02 0.09 107.1 2 min 16 sec
1 Month Same as above 5.14 98.3 106.1 0.03 0.02 BDL BDL 0.02 0.06 0.16 102.9 2 min 25 sec
3 Month Same as above 5.07 96.5 105.4 0.03 0.02 BDL BDL 0.02 0.04 0.17 101.2 2 min 30 sec
6 Month Same as above 4.82 94.5 102.3 0.03 0.03 BDL BDL 0.02 0.05 0.18 100.5 2 min 32 sec

Stability Data: 30°C ± 2°C/75% ± 5% RH
Duration Description Water
Content Dissolution (%) Related Substances (%) Assay
(%) Disintegration time
White colored opaque square shaped, vaginal film. NMT
10.0 %
w/w NLT 80 in 45 minutes Imp
A Imp B Imp D Imp E Imp
F Unknown Imp Total impurities
20 Min 45 Min NMT 0.2 NMT 0.2 NMT
0.2 NMT
0.2 NMT
0.1 NMT
0.1 NMT
1.0 NLT 90.0 & NMT 110.0 NMT 180
sec
Initial Same as above 5.20 99.9 101.2 0.04 0.01 BDL BDL 0.01 0.02 0.09 107.1 2 min 16 sec
1 Month Same as above 5.10 98.7 103.2 0.03 0.01 BDL BDL 0.01 0.04 0.15 105.4 2 min 9 sec
3 Month Same as above 5.01 94.5 102.5 0.03 0.02 BDL BDL Not detected 0.04 0.17 102.6 2 min 12 sec
6 Month Same as above 4.95 93.5 100.4 0.04 0.02 BDL BDL Not detected 0.05 0.18 101.4 2 min 14 sec
9 Month Same as above 4.91 92.8 99.7 0.04 BDL BDL BDL Not detected 0.05 0.17 101.1 2 min 31 sec
12 Month Same as above 4.93 93.4 98.9 0.03 BDL BDL BDL Not detected 0.04 0.17 101.1 2 min 33 sec

Stability Data: 25°C ± 2°C/60% ± 5% RH
Duration Description Water
Content Dissolution (%) Related Substances (%) Assay
(%) Disintegration time
White colored opaque square shaped, vaginal film. NMT
10.0 %
w/w NLT 80 in 45 minutes Imp
A Imp B Imp D Imp E Imp
F Unknown Imp Total impurities
20 Min 45 Min NMT 0.2 NMT 0.2 NMT 0.2 NMT 0.2 NMT 0.1 NMT
0.1 NMT
1.0 NLT 90.0 & NMT 110.0 NMT 180
sec
Initial White colored opaque square shaped, vaginal film. 5.20 99.9 101.2 0.04 0.01 BDL BDL 0.01 0.02 0.09 107.1 2 min 16 sec
1 Month Same as above 5.15 97.8 100.8 0.04 0.01 BDL BDL 0.01 0.05 0.15 105.4 2 min 20 sec
3 Month Same as above 5.10 96.8 99.9 0.03 0.02 BDL BDL 0.02 0.04 0.15 103.1 2 min 15 sec
6 Month Same as above 4.90 95.8 98.7 0.04 0.02 BDL BDL Not detected 0.04 0.16 101.5 2 min 10 sec
9 Month Same as above 4.91 93.4 95.1 0.03 BDL BDL BDL BDL 0.02 0.06 101.6 2 min 30 sec
12 Month Same as above 4.95 95.5 98.4 0.03 BDL BDL BDL BDL 0.03 0.08 100.5 2 min 26 sec

As per the data provided in above tables, the composition of the present invention has passed all the physico chemical tests.
Comparative clinical evaluation of efficacy and safety of Clotrimazole vaginal film vs marketed Vaginal Tablet was done in the management of symptomatic vulvovaginal candidiasis in non-pregnant women - open label, randomized, comparative, parallel, prospective, multicentric study.
In this open label, randomized, comparative, parallel, prospective multicentric study, 300 patients with clinical and mycologically confirmed vulvovaginal candidiasis were enrolled and divided randomly into two groups. 150 patients received clotrimazole vaginal films (50mg x 2) and 150 patients received marketed vaginal tablet (100mg) for seven days. Follow up visits were done for all patients on day 7 for efficacy and safety and on day 14 for safety. Clinical and mycological outcomes were evaluated on day 7. Statistical analysis was performed based on Intention to treat.

107 patients (71.3%) in the clotrimazole vaginal film group and 95patients (63.3%) in the marketed vaginal tablet group were clinically cured by day 7. Similarly, the mycological cure was seen in 146 patients (97.3%) in the clotrimazole vaginal film group and 143 patients (95.3%) in the marketed vaginal table group. The therapeutic cure was seen in 106 patients (70.7%) and 95 patients (63.3%) in the clotrimazole vaginal film and marketed vaginal tablet groups respectively. Seven patients reported adverse events during the study period. The adverse events were of mild intensity and not related to the study medication and resolved at the safety evaluation visit on day 14. No patient was withdrawn from the study due to adverse events and the study medication was well tolerated. Clotrimazole vaginal film once daily for 7 days was safe and effective in achieving clinical and mycological cure as compared to marketed vaginal tablet in the management of patients with symptomatic vulvovaginal candidiasis.

Results:
107 patients (71.3%) in the test group and 95 patients (63.3%) in the reference group had complete resolution of signs and symptoms (Clinical cure) at the end of day 7. Further, 43 patients (28.7%) in the test group and 55 patients (36.7%) in the reference group had mild signs and symptoms score at the end of day 7 (Table 1, Figure 1 & 2).
Table 1
Clinical cure at the end of day 7
Test group (n=150) Reference group (n=150)
Number of patients Percentage (%) Number of patients Percentage (%)
Yes 107 71.3% 95 63.3%
No 43 28.7% 95 36.7%
Microscopic examination of wet mount from vaginal smear at screening and baseline (Day 0), showed filamentous hyphae in 54 patients, pseudo hyphae in 38 patients, budding in 25 patients, filamentous hyphae along with pseudo hyphae in 9 patients, filamentous hyphae along with budding in 3 patients, pseudo hyphae along with budding in 17 patients and filamentous hyphae along with pseudo hyphae and budding in 4 patients the test group. Similarly, in the reference group 54 patients had filamentous hyphae, 44 patients had pseudo hyphae, 22 patients had budding, 12 patients had filamentous hyphae along with pseudo hyphae, 2 patients had filamentous hyphae along with budding, 14 patients had pseudo hyphae along with budding and 2 patients had filamentous hyphae along with pseudo hyphae and budding.

Table 2 shows the proportion of patients with mycological cure at the end of day 7 in both the treatment groups. (Figure 3 & 4). Mycological cure was seen in 97.3% of patients in the test group and 95.3% of patients in the reference group.
Table 2
Clinical cure at the end of day 7
Test group (n=150) Reference group (n=150)
Number of patients Percentage (%) Number of patients Percentage (%)
Yes 146 97.3% 143 95.3%
No 4 2.7% 7 4.7%

Therapeutic cure (clinical cure along with mycological cure) was seen in 70.7% of the patients in the test group and 63.3% in the reference group at the end of day 7. (Table 3, Figure 5 & 6)
Table 3
Clinical cure at the end of day 7
Test group (n=150) Reference group (n=150)
Number of patients Percentage (%) Number of patients Percentage (%)
Yes 106 70.7% 95 63.3%
No 44 29.3% 55 36.7%

One hundred and forty-nine patients in the test group and 140 patients in the reference group reported comfort or convenience to use the study medication (Table 4). Similarly, 124 patients in the test group and 122 patients in the reference group reported the study medication was not messy to use (Table 5).
Table 4
Is it comfortable / convenient to use
Test group(n=150) Reference group(n=150)
Yes 149 140
No 1 10

Table 5
Is it Messy
Test group(n=150) Reference group(n=150)
Not messy 124 122
Slight messy 25 24
Very Messy 1 4

As per the data, the Clotrimazole vaginal film of the present application has shown better clinical cure and more convenient to patient when compared to marketed Clotrimazole vaginal tablet products.

,CLAIMS:WE CLAIM

1. A pharmaceutical composition of Clotrimazole vaginal film comprising Clotrimazole and pharmaceutically acceptable excipients, wherein the Clotrimazole is present in the range from 1 to 30 % w/w in total weight of the composition.
2. The composition as claimed in claim 1, wherein pharmaceutically acceptable excipients selected from film-forming agents, solubilizing agents, plasticizers, Opacifiers and solvents.
3. The composition as claimed in claim 2, wherein film forming agents are selected from hydroxyethyl cellulose, carrageen, eudragit EPO, hydroxypropyl cellulose, hydroxypropylmethylcellulose, gums, starch, polymerized rosin, pullulan, pectin, gelatine, maltodextrins, polyvinyl alcohol, sodium carboxy methyl cellulose, copovidone the concentration of film forming agents is from 1 to 80 % w/w of the total weight of the composition.
4. The composition as claimed in claim 2, wherein solubilizing agent selected from polyvinylpyrrolidones, polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer, polyoxyl 40 hydrogenated castor oil / macrogolglycerol hydroxy stearate, fatty acids, castor oil, cyclodextrins, polyethyleneglycol, glyceryl distearate, monoglycerides, diglycerides, triglycerides, propylene glycol monostearate, Labrafils (e.g., oleoyl macrogol-6 glycerides, oleoyl polyoxyl-6-glycerides, linoleoyl macrogol-6 glycerides, linoleoyl polyoxyl-6 glycerides, lauroyl macrogol-6 glycerides, lauroyl polyoxyl-6 glycerides), Labrasols (e.g., caprylocaproyl macrogol-8 glycerides, caprylocaproyl polyoxyl-8 glycerides), Solutols (e.g., poly-oxyethylene esters of 12-hydroxystearic acid), Soluplus (e.g., polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer), sodium lauryl sulphate, sodium dioctyl sulphosuccinate, glycerol monostearate, glyceryl monooleate, glyceryl monobutyrate, block copolymers of ethylene oxide and propylene oxide, polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol, Poloxamer, Poloxamer 124, Poloxamer 188, Poloxamer 237, Poloxamer 388, Poloxamer 407, sorbitan mono laurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan stearate, sorbitan monolaurate, polyoxyethylene (20) sorbitan, polyoxyethylene sorbitan monooleate (Tween), PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate, hydrogenated castor oil and polyoxyethylene castor oil derivates, e.g. polyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oil (Cremophor® EL; BASF Corp.); or polyoxyethyleneglycerol oxystearate such as polyethylenglycol 40 hydrogenated castor oil (Cremophor RH® 40) or polyethylenglycol 60 hydrogenated castor oil (Cremophor RH® 60), sucrose stearate, sucrose oleate, sucrose palmitate, sucrose laurate, and sucrose acetate butyrate, vitamin E-TPGS® (d-alpha-tocopheryl polyethylene glycol 1000 succinate), glycerophospholipids (lecithins, kephalins, phosphatidyl serine), glyceroglycolipids (galactopyransoide), sphingophospholipids (sphingomyelin), and sphingoglycolipids (ceramides, gangliosides), DSS (docusate sodium), docusate calcium, docusate potassium, SDS (sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidic acid, sodium caprylate, cetyl-trimethylammonium bromide, cetylpyridinium chloride, the concentration of solubilizing agent is from 1 to 30 % w/w of the total weight of the composition.
5. The composition as claimed in claim 2, wherein plasticizers are selected from triacetin, low molecular weight polyethylene glycols, triethyl citrate, glycerine, propylene glycol and vitamin E TPGS, the concentration of plasticizers is from 1 to 30% w/w of the total weight of the composition.
6. The composition as claimed in claim 2, wherein Opacifiers are selected from titanium dioxide, calcium carbonate, kaolin, magnesium trisilicate, magnesium aluminum silicate, zinc carbonate, bentonite and barium sulfate, wherein the concentration of Opacifiers is from 0.1 to 5 % w/w of the total weight of the composition.
7. The composition as claimed in claim 2, wherein the solvents are selected from ethanol, isopropanol, acetone, methylene chloride, or any combination thereof.

8. The composition as claimed in claim 1, the composition further comprising excipients selected from lubricants, disintegrating agents, preservatives and other conventionally using excipients.
9. The process for the preparation of Clotrimazole vaginal film as claimed in claim 1, wherein the process comprising steps of:
a) adding film forming agents to solvent under stirring get clear solution,
b) adding plasticizers to solvent and mixing to get the clear solution,
c) adding Clotrimazole to step (b) solution and mixing to get clear solution,
d) adding Opacifiers in solvent and mixing to get uniform dispersion,
e) adding dispersion of step (d) to step (e) solution and mixing the final polymeric dispersion,
f) deaerating polymeric drug dispersion prepared in step (e) by applying vacuum,
g) coating the polymeric drug dispersion obtained in step (f) and drying in hot air oven, and
h) cutting the film role into desired size using slitter and packing the films into suitable pouches.

Dated this Twenty Seventh (27th) day of March, 2025

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883