FORM 2

THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION.
(See section10]
Title of the invention A PROCESS FOR THE PREPARATION OF
NOVEL TOPICAL MICROBICIDAL COMPOSITION'
M/S. J.B.CHEMICALS & PHARMACEUTICALS LTD., an Indian Company, having its Registered Office at Neelam Centre, B' Wing, 4th floor, Hind Cycle Road, Worli, Mumbai 400 025, Maharashta, India.
GRANTED
The following specifications particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.


A PROCESS FOR THE PREPARATION OF NOVEL TOPICAL MICROBICIDAL COMPOSITIONS
Abstract
A process for the preparation of pharmaceutical composition suitable for the treatment of microbial and mycotic infections caused by aerobic and anaerobic microorganisms is provided and involves administering topically to the patients in need thereof a composition comprising metronidazole and Povidone-Iodine, in effective amounts in various pharmaceutical dosage forms.
Description
Field of invention
The present invention relates to process for preparation of the pharmaceutical composition for topical application suitable for the treatment of various topical infections. The present inventor has discovered a process for preparation of composition comprising of an iodophor and a alkyl imidazole which has a wide antimicrobial activity against aerobic as well as anaerobic bacteria.
The present process for preparation of composition provides the method for the prophylactic or curative treatment to individuals affected with various skin infections such as: ♦ Pre-operative and post operative antisepsis

♦ Wounds: Contaminated lacerations, accidental wounds,
Traumatic wounds, abrasions, thermal wounds (Burns of lot,
2nd, 3rd degree), animal and human bites.
Skin infections like:
♦ Diabetic ulcers
♦ Lapromatous ulcers ♦ Decubitus ulcers
♦ Cellulitis
♦ Other skin infection showing presence of both aerobic as well as anaerobic microorganisms
♦ Mycotic infections such as Pyoderma, Otitis externa, tinea
pedis, tinea cruris, tinea corporis, tinea versicolor,
cutaneous candidiasis.
* Topical treatment of monialliasis, trichomoniasis and non¬specific vaginitis
* Bladder irrigation during catheterisation and before cathetor removal.
As Disinfectant :
♦ in small surgical procedures
♦ in catheter (peritoneal/ dialysis) exit site wounds. These indications are given solely as examples for the purpose of illustration and not construed as limitations of the present invention as many variations thereof are possible without departing from the spirit and scope.
Background of the invention
Anaerobic infections of the skin
Anaerobic bacteria are frequently found in infections of the skin, soft tissue, bones and in bacteremia. Injury to skin, bone or soft tissue by trauma, ischemia or surgery creates a

suitable environment for anaerobic infections. Because the sites that are colonized by anaerobic bacteria contain many species of bacteria, disruption of anatomic barriers allows penetration of many organisms, resulting in mixed infections involving multiple species of anaerobes, combined with facultative or microaerophilic organisms. Two-thirds of clinically significant anaerobic infections involve following five anaerobes Bacteroides fragilis group, Bacteroides melaninogenicus groups, Fusobacterium nucleatum, Clostridium perfringens and anaerobic cocci.
Certain types of infections as stated below commonly involve
anaerobic bacteria including lower extremity infections in
diabetics or in-patients with severe peripheral vascular
disease.
Skin and soft tissue Incidence of anaerobic
infections involvement (%)
Diabetic foot ulcers 95
Infected diabetic gangrene 85
Non-clostridial crepitant cellulitis 75
Decubitus ulcer with bacteremia 63
Cutaneous abscesses 62
Soft tissue abscesses 60
Topical infection of head and neck 48
Topical infection of trunk 36
Topical infection of hand 31
Topical infection of buttock 33
Therefore, there are many conditions such as diabetic ulcers, decubitusulcers, cellulitis, pyoderma etc.,which have aerobic

and anaerobic microflora. Thus, it is rational to use an agent having action on both types of organisms.
Metronidazole
Metronidazole ie.1-(B-hydroxyethyl)-2-methyl-5-nitroimidazole belongs to the class of alkyl imidazole derivatives and are useful as antimicrobial agents. The term Metronidazole as used in this specification and claims, includes not only 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, but also those analogs and derivatives of metronidazole (salts, esters etc) which are soluble in the pharmaceutical compositions described herein and which exhibit therapeutic activity when applied as taught by the present invention.
The mechanism of action of Metronidazole is thought to involve interference with DNA by a metabolite in which a nitro group of metronidazole has been reduced by bacterial nitroreductases to an unstable intermediate, which interacts with DNA, effectively preventing further replication.
Metronidazole is a anaerobicidal. It has activity against the facultative anaerobes Gardnerella vaginalis, Helicobacter pyroli and effective against some spirochetes. Moreover several protozoa and anaerobic bacteria including Bacteroides and Clostridium Spp. are sensitive to Metronidazole. Efficacy of metronidazole against obligate anaerobic bacteria in vitro including the gram-negative organisms Bacteroides fragilisr Fusobacterium Spp., Peptococcus spp, Peptostreptccoccus spp. and Villanelle spp. is well established.

Metronidazole 1% solution is reported to be effective in treating various ulcers, which included pressure sores in elderly and chronically ill patients, diabetic ulcers, venous ulcers. The solution was also used as irrigation or packs in the management of ischiorectal abscess, large abscesses in other areas, undermining subcutaneous cavitation complicating simple sacral pressure sores. Metronidazole topical therapy is also recommended for anaerobic decubitus ulcers (Grade III & IV), marginal cellulitis and sacral ulcers.
Povidone-1odine
Iodine has long been accepted as a uniquely effective antiseptic and used widely both for the prevention and treatment of infection. It has a broad antimicrobial spectrum: bacteria, viruses, bacterial endospores, fungi, and protozoas are destroyed, however, been limited by a number of undesirable factors. It was discovered that Povidone-Iodine [iodine complexed with the inert polymer, polyvinyl pyrrolidone (povidone)] ceases to irritate, sensitize or stain and yet retains its unique microbicidal activity as iodine is continually delivered. Biochemical research has indicated that this high degree of microbiocidal activity is the result of the interruption of vital metabolic pathways. This is accomplished by the iodination of the amino acid sequence of the microorganisms' proteins.
Specific examples of iodophors useful in this invention include polyvinylpyrrolidone-iodine, polyvinyl alcohol-iodine, polyvinyl oxazolidone-iodine, polyvinyl imidazole-iodine, polyvinyl morpholone-iodine, polyvinyl caprolactam-

iodine, soluble starch-iodine, betacyclodextrin-iodine, polyoxyethylenepolyOxypropylene condensate-iodine, and ethoxylated linear alcohol-iodine, with polyvinyl pyrrolidone-iodine being the most preferred.
Povidone-Iodine is effective against variety of strains such as Staphylococcus aureus, Proteus mirabilus, Proteus vulgaris, Escherichia coli, Enterobacter areogenes, Enterobacter spp., Streptococcus faecalis, Streptococcus pyogenes, Streptococcus hemolyticus, Salmonella typhimurium, Salmonella typhosa, Salmonella type C1, Salmonella spp., Serratia marcescens, Serratia spp., Shigella sonni, Pseudomonas aeruginosa, Klebsiella pneumoniae, Diplococcus pneumoniae, Mycobacterium tuberculosis, Bacillus subtillis, Clostridium septicum, Clostridium tetani, Bacillus subtillis spores, Trichophyton rubrum, Candida albicans, pichomonas vaginalis, Aspergillus flavus, Aspergillus niger. Povidone-iodine^ is used for the treatment of burns and of different skin lesions (decubitus and leg ulcers, etc.). In special preparations it is available for the therapy of inflammations in the mouth and pharynx and for vaginitis. Povidone-Iodine is used in the treatment of skin disinfection in the prevention of nosocomial infections, especially, prior to invasive procedures such as the insertion of peripheral catheters, treatment of exit site infection and bacteremia in haemodyletic patients. It is also used as surgical scrub as an effective method for avoiding intra as well as post¬surgical infection. Povidone-iodine cream effectively limits bacterial infection in-patients with traumatic lacerations requiring sutures.

Patients admitted in ICU, trauma ward, emergency wards, burn wards, unconscious patients, patients with neurological/ spinal disorders and patients undergoing urinary tract surgery are often catheterized. Bladder irrigation with Povidone-Iodine is effective in prevention of urinary tract infection after single or intermittent catheterization.
The objective of the invention
Taking into consideration the limitations associated with the conventional topical composition with individual active agents stated -above, the inventor has come out with a process for preparation of unique pharmaceutical composition comprising Metronidazole and Povidone-Iodine. Povidone-Iodine acts against aerobic and metronidazole acts against anaerobic organisms.
It is a object of this invention to provide a process for the preparation of pharmaceutical formulation comprising a combination of metronidazole and Povidone-Iodine in the form of topical pharmaceutical composition having the effect on aerobic and anaerobic bacteria. Thus this invention describes a process for preparation of the combination which has been found to be therapeutically advanced over either metronidazole or Povidone-Iodine individually with improved patient compliance.
The combination offers following advantages:
1) Easy application schedule i.e. single application takes care of both the types i.e. aerobic and anaerobic organisms.

2) Reduced number of applications.
3) Broad spectrum of anhi microbial activity
4) Rapid control of infection.
The present invention relates to a process for the preparation of pharmaceutical composition comprising metronidazole and Povidone-Iodine. The mechanism of action of combination of metronidazole and Povidone-Iodine of the present composition is as follows: -
This formulation when applied on the affected part, flows and fills out the wounded area after application and thereafter comes into contact with the damaged tissue with microbial infection. Metronidazole exerts its aerobicidal activity and Povidone-Iodine reacts with amino acids of microbial cell wall of anaerobic bacteria present thereby killing the microbes. Thus, the combination comprising Metronidazole and Povidone-Iodione is therapeutically better over either metronidazole or Povidone-Iodine individually. The combination has a topical microbicidal activity against bacteria including spores, fungi, yeast, protozoa and viruses, even in presence of blood, serum, pus and necrotic tissue.
Detailed description of Preferred embodiments
The present invention relates to a process for the preparation of pharmaceutical composition for topical application having enhanced antimicrobial action comprising therapeutically active amounts of Metronidazole and Povidone-

Iodine for treating various types of wounds, infections caused by aerobic and anaerobic microorganisms.
The term " a process for the preparation of pharmaceutical composition for topical application", as used herein, means the processes for the preparation of various compatible dosage forms which are suitable for topical administration to a human or veterinary application.
Suitably, a process for the preparation of pharmaceutical compositions adapted for topical administration include processes for the preparation of for instance, ointments, solutions, creams or lotions, powder, topical patches, aerosols and the dosage forms used in the form of scrub, irrigating solution, paint and wound dressings. A process for the preparation of pharmaceutical compositions of the present invention involves preparation of the compositions which may also contain appropriate conventional additives such as preservatives, chelating agents, solvents to assist drug penetration and emollients, hydrocarbon waxes, oleaginous substances, fatty acids and fatty alcohol in ointments and creams. Ingredients present in the topical carrier of the present invention are suitable for administration to different infected sites.
Such a process for the preparation of pharmaceutical compositions is most preferably describes manufacturing processes for the above stated compositions administered in the form of ointment and solution although the other dosage forms are also advantageously envisioned. Advantages of

administering the composition as an ointment and solution include convenience and ease of manufacturing, ease of application and handling, increased patient compliance and safety.
Preferred process for the preparation of pharmaceutical compositions for topical application according to the present invention describes a process of manufacturing the composition comprising metronidazole or a pharmaceutically acceptable salt or ester thereof from 0.01 to 10%, preferably from 0.05 to 5 % and most preferably 1 % by weight of the composition.
Preferred process for the preparation of pharmaceutical compositions for topical application according to the present invention describes a process of manufacturing the composition comprising Povidone-Iodione from 1 to 20%, preferably from 3 to 10% and most preferably 5% by weight of the composition.
The process for the preparation of pharmaceutical composition in the form of ointment describes a process of manufacturing the composition comprising Metronidazole and Povidone-Iodine impregnated in a suitable water-soluble base. The compositions of water soluble ointment bases are known to those skilled in the art. A water-soluble base lowers surface tension of the composition aiding uniform distribution of the composition.

Water soluble bases are prepared from mixtures of high and low molecular weight polythylene glycols, which have general formula HOCH2[CH2OCH2]nCH2OH. Suitable derivatives include ethers and esters of the poly (substituted or unsubstituted alkylene) glycols, such as macrogol ethers and esters e.g. cetomacrogol; glycofurol; block copolymers including poly (substituted or unsubstituted alkylene) glycols such as block copolymers of polyethylene glycol and polypropylene glycol and cross-linked polyethylene glycols.
Various grades of poly (substituted or unsubstituted alkylene) glycols and derivatives thereof may be used in combination to achieve the desired physical properties of the formulation. Preferably the formulation comprises polyethylene glycol or a derivative thereof which are commercially available in a variety of chain lengths and with a variety of consistencies. Suitable polyethylene glycols include PEG 300 and PEG 400 (liquids); PEG 1000 (semi¬solids); and PEG 4000 and PEG 6000 (hard solids).
These may be used singly or admixed in suitable proportions to achieve the desired consistency of formulation. A preferred process for preparation of the above stated composition in the form of ointment describes a process of manufacturing the vehicle base comprising PEG 4000 and PEG 400, suitably in a ratio of from 0.5:1 to 1:5, preferably from 1:1 to 1:3; most preferably about 1:2.
Typically, A preferred process for preparation of the above stated composition in the form of ointment describes a

process of manufacturing the "vehicle base comprising of at least 70%, preferably at least 80%, most preferably at least 90% by weight of a pharmaceutically acceptable poly (substituted or unsubstituted alkylene) glycol or a derivative thereof.
Where the a process for preparation of the pharmaceutical composition describes the method of manufacturing composition in the form of solution, the active ingredients are combined with following ingredients:
1. Surface active agent
2. Co-solvent
3. Buffering agent
The expression "Surface active agent" as used in this specification refers to anioinic surfactant. Such a surfactant provides better surface contact of the composition with infected area.
Specific preferred anionic surfactants include, but are not limited to, lauryl sulfates, octyl sulfates, 2-ethylhexyl sulfates, decyl sulfates, tridecyl sulfates, cocoates, lauroyl sarcosinates, lauryl sulfosuccinates, diphenyl oxide disulfonates, lauryl sulfosuccinates, myristyl sulfates, oleates, stearates, tallates, ricinoleates, cetyl sulfates, and similar surfactants.
A preferred process for preparation describes a process of manufacturing where sodium lauryl sulphate is the most preferred surface active agent in the solution composition of

the present invention and is present in an amount of 0.1% to about 5.0% by wt. and more preferably, in an amount of about 0.5% by wt. based on the total wt. of the composition.
The expression "co-solvent" as used in this specification refers to used in combination to increase the solubility of the solutes. Examples of preferred class are ethanol, sorbitol, glycerin, propylene glycol and members of polyethylene glycol polymer series. A preferred process for preparation describes a process of manufacturing where Polyethylene glycol 400 is the most preferred cosolvent in the solution composition of the present invention and is present in an amount of 2.5% to about 10.0% by wt. and more preferably, in an amount of about 5.0% by wt. based on the total wt. of the composition.
The expression buffering agent' as used in this specification refers to combination of basic pH adjuster and acidic pH adjuster.
Examples of preferred classes of basic pH adjusters are ammonia; mono-, di-, and tri-alkyl amines; mono-, di-, and tri-alkanolamines; alkali metal and alkaline earth metal hydroxides; alkaline phosphates and mixtures thereof. However, the identity of the basic pH adjuster is not limited, and any basic pH adjuster known in the art can be used. A preferred process for preparation describes a process of manufacturing where Dibasic sodium phosphate is the most preferred basic pH adjuster in the solution composition of the present invention and is present in an amount of 2.5 to

about 5.0% by wt. and more preferably, in an amount of about 3.83% by wt. based on the total wt. of the composition.
The preferred classes of acidic pH adjusters are the mineral acids and polycarboxylic acids. Examples of mineral acids are hydrochloric acid, nitric acid, phosphoric acid, and sulfuric acid. Nonlimiting examples of polycarboxylic acids are citric acid, glycolic acid, and lactic acid. The identity of the acidic pH adjuster is not limited and any acidic pH adjuster known in the art, alone or in combination can be used. A preferred process for preparation describes a process of manufacturing where Citric acid is the most preferred basic pH adjuster in the solution composition of the present invention and is present in an amount of 0.5% to about 2.0% by wt. and more preferably, in an amount of about 1.63% by wt. based on the total wt. of the composition.
A preferred process for preparation describes a process of manufacturing the composition of the present invention, which has a pH of below 7, most preferably between 5 to 6.5.
Method of preparation
The process of pharmaceutical composition of the invention in the form of ointment comprises of following steps:
Step 1 : Metronidazole is dissolved in a mixture of PEG 400 and water under stirring.
Step 2 : Povidone-Iodine is added to above solution and dissolved under stirring.

Step 3 : PEG 4000 is melted by heating to 60-65°C and then added to the above viscous solution under stirring.
Step 4 : The mixture is allowed to cool to room temperature to form uniform viscous ointment.
The process of pharmaceutical composition of the invention in the form of solution comprises of following steps:
Step 1 : The buffer is prepared by dissolving dibasic sodium phosphate and citric acid in water.
Step 2 : Povidone-Iodine is dissolved in buffer under stirring.
Step 3 : Metronidazole is dissolved in PEG 400 under stirring and added to the above solution containing Povidone-Iodine with mixing.
Step 4 : Sodium lauryl sulphate is dissolved in water and added to the bulk solution under stirring.
Step 5 : The volume is adjusted with water to get the specified concentration.
Clinical trials
To investigate the effectiveness of the composition described in the present invention in various types of wounds, controlled clinical trials were carried out all over India.

This study is not disclosed to the public and the trials are done in confidence. The results of clinical study in India are given below.
A. 40 patients having lacerated wound were included in the
study to evaluate the efficacy and safety of
Metronidazole and Povidone-Iodine ointment as described
in present invention and its comparison with Povidone -
Iodine ointment 5%. Patients were divided in to two
groups of twenty each. Group one received treatment with
Povidone - Iodine ointment 5% where as group two
received treatment with Metronidazole and Povidone-
Iodine ointment as described in present invention.
General and wound parameters such as pain, tenderness,
edema, discharge, stages of healing, final healing, type
and strength of scar were recorded. Treatment was given
twice a day in each group. In group one healing took
place in 8 weeks where as in group 2 it took 5 weeks.
The improvement in pain, tenderness, edema and discharge
improved much faster in Metronidazole and Povidone-
Iodine ointment group as described in present invention
group compared to Povidone-Iodine 5% group. Similarly
scar formation was much faster in Metronidazole and
Povidone-Iodine ointment as described in present
invention group than Povidone - Iodine 5% ointment.
B. 50 patients suffering from Bacterial and mycotic skin
infections were included in the trial. They were divided
in to two groups 25 each. Group 1 received treatment
with Povidone - Iodine ointment 5% and group 2 received

Metronidazole and Povidone-Iodine ointment as described in present invention ointment. Both the ointments applied twice a day. The time for recovery, signs of inflammation and response of the lesions were monitors. All patients completed study without any side effect. The healing of lesions in Povidone - Iodine ointment 5% group occurred in 9 days while in Metronidazole and Povidone-Iodine ointment as described in present invention ointment group healing occurred in 6 days. Inflammatory parameters showed faster remission in Metronidazole and Povidone-Iodine ointment as described in present invention group than Povidone - Iodine ointment 5% group.
C. 50 patients undergoing gastro-intestinal surgery were included in the evaluation of Metronidazole and Povidone-Iodine solution as described in present invention 5% solution and its comparison with Povidone-Iodine 5% solution as pre operative and post- operative anti-sepsis. They were divided two groups of 25 each group 1 received treatment with Povidone - Iodine 5% solution as pre and post operative scrub and Povidone-Iodine 5% ointment post operatively applied twice a day on operation wound. Group 2 received Metronidazole and Povidone-Iodine solution as described in present invention 5% solution as pre and post-operative scrub and Metronidazole and Povidone-Iodine solution as described in present invention 5% ointment as application twice a day on surgical wound. There were no serious post operative wound infections in any of the

group. However, healing of the wound was much faster in
Metronidazole and Povidone-Iodine solution as described
in present invention group than Povidone - Iodine 5%
solution group.
Above clinical studies confirm the efficacy of the present pharmaceutical composition of this invention:-
From this trial it can be concluded that combination of Metronidazole and Povidone-Iodine as described in present invention is better than Povidone-Iodine alone in the management of bacterial and mycotic skin infections. This can be attributed to the unique combination comprising Metronidazole, an anerobicidal agent and Povidone-Iodine, an aerobicidal agent which offered significantly rapid reduction due to the synergistic effect.
The invention will now be illustrated by the following Examples:
Examples and method of manufacturing
Example 1
Metronidazole 1.00 %
Povidone-Iodine 5.00%
Polyethylene glycol 4000 30.00%
Polyethylene glycol 400 59.75 %
Purified Water 4.25 %
The ointment preparations of the invention can be prepared by dissolving Metronidazole in a mixture of PEG 400 and water

under stirring. Then adding Povidone-Iodine to above solution and dissolving under stirring. Then melting PEG 4000 by heating to 60-65°C and adding to the above viscous solution under stirring. Allowing to cool to room temperature to form uniform viscous ointment.
Example 2
Metronidazole 2.00 %
Povidone-Iodine 10.00%
Polyethylene glycol 4000 30.00%
Polyethylene glycol 400 59.75 %
Purified Water 4.25 %
The same procedure as used in example 1 was repeated only change is the concentration of the metronidazole and Povidone-Iodine are different to that of example 1.
Example 3
Metronidazole 1.00 %
Povidone-Iodine 5.00 %
Polyethylene glycol 400 5.00 %
Sodium lauryl sulphate 0.50 %
Dibasic Sodium phosphate 3.83 %
Citric acid 1.63 %
Purified Water 4.25 %
The solution preparation of this invention can be prepared by dissolving dibasic sodium phosphate and citric acid in water.

In this solution dissolving Povidone-Iodine under stirring. Then dissolving metronidazole in PEG 400 under stirring and adding this solution to the above solution containing Povidone-Iodine. Mixing well. Then dissolving sodium lauryl sulphate in water and adding this to the bulk solution under stirring. Mixing well and adjusting the volume with water to get the specified concentration.
Example 4

Metronidazole 2.00 %
Povidone-Iodine 10.00 %
o„
Polyethylene glycol 400 5.00
Sodium lauryl sulphate 0.50
Dibasic Sodium phosphate 3.83
Citric acid 1.63
Purified Water 4.25

The same procedure as used in example 3 was repeated only change is the concentration of the metronidazole and Povidone-Iodine are different to that of example 3. In addition the combination of Metronidazole and Povidone-Iodine may be applied or formulated contemporaneously with other topical agents to provide synergistic or amplified activity for management of wounds.
It is to be understood that the example and embodiments described hereinabove are for the purpose of providing a description of the present invention by way of example and are not to be viewed as limiting the present invention in any

We claim
1. A process for preparation of pharmaceutical, composition for topical application comprising therapeutically effective amounts of alkylimidazole derivative and iodophore as active ingredients wherein the composition is suitable for treatment of various types of microbial and mycotic infections caused by aerobic and anaerobic microorganisms.
2. A process for preparation of pharmaceutical composition for topical application suitable for treatment of various types of wounds as claimed in claim 1 wherein the alkyl imidazole derivative is preferably 5-nitroimidazole derivatives such as tinidazole, nimorazole, satranidazole ,ornidazole, metronidazole and benznidazole.
3. A process for preparation of pharmaceutical composition for topical application as claimed in claim 1 and 2 wherein the most preferred nitroimidazole useful in this invention is Metronidazole or a pharmaceutically acceptable salt or ester thereof.
4. A process for preparation of pharmaceutical composition for topical application suitable for treatment of various types of wounds as claimed in claim 1 wherein the iodophor is selected from the group consisting of

polyvinyl pyrrolidone-iodine, polyvinyl alcohol-iodine, polyvinyl oxazolidone-iodine, polyvinyl imidazole-iodine, polyvinyl morpholone-iodine, and polyvinyl caprolactam iodine, nonylphenolethoxylate-iodine, soluble starch iodine, betacyclodextrin-iodine,polyoxyethylenepolyoxypro-pylene condensate-iodine, ethoxylated linear alcohol-iodine, and mixtures thereof.
A process for preparation of pharmaceutical composition for topical application as claimed in 1 and 4 wherein the most preferred iodophor useful in this invention is polyvinyl pyrrolidone-iodine.
A process for preparation of pharmaceutical composition for topical application as claimed in claim 1 to 5 wherein the composition comprises from 0.01 to 10% of metronidazole or a pharmaceutically acceptable salt or ester thereof by weight of the composition; and from 2 to 20% Povidone-Iodine by weight of the composition.
A process for preparation of pharmaceutical composition for topical application as claimed in claim 1 to 4 wherein the composition comprises from 0.05 to 5 % metronidazole or a pharmaceutically acceptable salt or ester thereof by weight of the composition; and from 5 to 15% Povidone-Iodine or a pharmaceutically acceptable salt thereof by weight of the composition.

A process for preparation of pharmaceutical composition as claimed in claim 1 wherein the composition comprises metronidazole,present in about 1% by weight of the composition and the Povidone-Iodine is present in about 5% (i.e. 0.5% as the available iodine) by weight of the composition.
A process for preparation of pharmaceutical composition for topical application as claimed in claim 1 wherein the composition is in the. form of ointment and contains a combination comprising of PEG 4000 and PEG 400, suitably in a ratio of from 0.5:1 to 1:5, preferably from 1:1 to 1:3; more preferably about 1:2.
A process for preparation of pharmaceutical composition for topical application as claimed in claim 1 wherein the composition is in the form of solution and contains inactive agents such as a surface-active agent, buffering agent and a cosolvent.
A process for preparation of pharmaceutical composition for topical application in the form of solution as claimed in claim 10 wherein composition comprises surface active agent which is selected from lauryl sulfates, octyl sulfates, 2-ethylhexyl sulfates, lauramine oxide, decyl sulfates, tridecyl sulfates, cocoates, lauroyl sarcosinates, lauryl sulfosuccinates, linear C.sub.10 diphenyl oxide disulfonates, lauryl sulfosuccinates, lauryl ether sulfates (1 and 2 moles ethylene oxide), myristyl sulfates, oleates, stearates,

tallates, ricinoleates, cetyl sulfates, and similar surfactants.
12. A process for preparation of pharmaceutical composition for topical application in the form of solution as claimed in claim 12 wherein the composition comprises sodium lauryl sulphate as the preferred surface active agent, present in an amount of 0.1% to about 5.0% by wt. and preferably, in an amount of about 5.0% by wt. based on the total wt. of the composition.
13. A process for preparation of pharmaceutical composition for topical application in the form of solution as claimed in claim 10 wherein the composition comprises buffering agent which is a combination of basic pH adjuster and acidic pH adjuster.
14. A process for preparation of pharmaceutical composition for topical application in the form of solution as claimed in claim 13 wherein the composition comprises dibasic sodium phosphate as basic pH adjuster in the solution composition of the present invention is present in an amount of 2.5% to about 5.0% by wt. and preferably, in an amount of about 3.83 % by wt. based on the total wt. of the composition. Citric acid is preferably used as acidic pH adjuster in the solution composition of the present invention in an amount of 0.5% to about 2.0% by wt. and preferably, in an amount of about 1.63 % by wt. based on the total wt. of the composition.

15. A process for preparation of pharmaceutical composition for topical application in the form of solution as claimed in claim 10 wherein the composition contains a co-solvent which is selected from ethanol, sorbitol, glycerin, propylene glycol and different grades of polyethylene glycol polymers.
16. A process for preparation of pharmaceutical composition for topical application in the form of solution as claimed in claim 15 the composition contains polyethylene glycol 400 as preferred co-solvent which may be present in an amount of 2.5% to about 10.0% by wt. and preferably, in an amount of about 5.0% by wt. based on the total wt. of the composition
Dated this 22nd day of May, 2001.
For J.B.CHEMICALS & PHARMACEUTICALS LIMITED
SHIRISH BHAGWANLAL MODY DIRECTOR