DESC:TECHNICAL FIELD:
The present invention relates to the field of pharmaceutical sciences. Particularly, the present invention provides a combination of Octenidine or its pharmaceutically acceptable salt or analog and Metronidazole or its pharmaceutically acceptable salt or analog for an antiseptic and antimicrobial activity. More particularly, the present invention provides a pharmaceutical composition/formulation comprising Octenidine or its pharmaceutically acceptable salt or analog and Metronidazole or its pharmaceutically acceptable salt or analog for an antiseptic and antimicrobial activity. Furthermore, the present invention provides a preparation process for the said pharmaceutical composition/formulation.

BACKGROUND OF THE INVENTION:
Octenidine belongs to a class of cationic antiseptics having a bispyridine moiety. It is very effective against both Gram-positive and Gram-negative bacteria. It has better anti-bacterial properties than Chlorhexidine gluconate against strains of Staphylococcus and Streptococcus bacteria. Chlorhexidine (CHX) as a gold standard appears to be the most effective antimicrobial agent in Oral hygiene compositions for reduction of both plaque and gingivitis. Its effectiveness can be attributed to its bactericidal and bacteriostatic effects and its substantivity within the oral cavity. However, the adverse-effects of CHX limit the long-term use of this antiseptic agent and include taste alteration, excess formation of supragingival calculus, soft-tissue lesions in patients, allergic responses, and staining of teeth and soft tissues. This kind of discoloration especially in the interproximal areas, and tongue are often caused by a precipitation reaction between tooth-bound Chlorhexidine and chromogens from food or beverages. Hence, considering the limitations/ side effects associated with Chlorhexidine gluconate such as staining of teeth and other oral surfaces, bitter taste perception and less effective antimicrobial activity, Chlorhexidine gluconate is often replaced by Octenidine in oral compositions for managing Oral health and hygiene and is marketed in the form of Mouthwashes and gargles viz. Octenoxa®. Apart from oral compositions, Octenidine dihydrochloride is also widely used to treat various skin infections. It promotes wound healing and reduces itching. Octenidine dihydrochloride is commonly marketed as topical compositions viz. Octenilin® wound gel, Octedin® among others.
Metronidazole belongs to a class of nitroimidazole antimicrobials and is well known for its activity against the anaerobic bacteria. It is widely used to treat skin infections, rosacea and mouth infections, including infected gums and dental abscesses. It is also used in the management of conditions like bacterial vaginosis and pelvic inflammatory diseases. Metronidazole Benzoate is often substituted for Metronidazole when preparing oral dosage forms because of its bland taste as compared with very bitter taste of Metronidazole free base. Commonly available marketed formulations include Metrogyl Gel® for treatment of acne and some skin infections, Rexidin®-M Forte Gel for treatment of mouth ulcers, Crema-AnoTM Rectal Cream and many others.
Gingivitis is one of the most common ailments of the oral cavity with a prevalence of 85–90%. Plaque biofilms are bio-aggregation of various bacterial colonies together on teeth, and it is the prime requisite to initiate gingivitis which if left unchecked can lead to periodontitis that is the loss of alveolar bone. All this finally results in tooth mobility and tooth loss due to loss of surrounding soft and hard tissues. Thus, the foremost aim becomes to control the plaque buildup on teeth (anti-plaque effect) and control the soft tissue inflammation (anti-inflammatory).
Traditional therapies for Gingival disease include mechanical debridement to disrupt the subgingival flora (Scaling and root planning- SRP). The rationale for the use of antiplaque agents as adjuncts to mechanical cleaning methods is based on two factors. First, plaque is the major etiological factor in gingivitis. Second, the prevalence of gingivitis and evidence from studies suggest that mechanical cleaning methods are inadequate.
It appears that the effects of mechanical therapy might be augmented using antimicrobial agents which further suppress the remaining pathogens. In this context, it is evident that antimicrobial agents are of great interest and may be valuable as adjuncts to mechanical therapy. More recently local delivery of the drug into periodontal pockets has been found to have advantage over systemic administrations. The local route of drug delivery can attain 100-fold higher concentration of antimicrobial agent compared with systemic drug. Clinical studies have demonstrated that Combination gel (Chlorhexidine-Metronidazole) group showed a significant reduction in plaque index, Gingival index and microbial counts when compared to the Chlorhexidine (CHX) and Metronidazole (MTZ) gel groups, indicating that the combination gel demonstrates an additive effect of both components. However, the common side effects associated with Chlorhexidine gluconate are: 1) an increase in staining of teeth and other oral surfaces; 2) an increase in calculus formation; and 3) an alteration in taste perception/ bitter taste. Stain will be more pronounced in patients who have heavier accumulations of unremoved plaque. Hence, there is a need for an agent which has broad antimicrobial spectrum, should be well tolerated on skin, mucosa and wounds, and does not induce bacterial resistance. In addition to efficacy, it should not cause staining of tooth surface or oral mucosa as well. Octenidine dihydrochloride (OCT) is a most preferred alternative to chlorhexidine and successfully tested in vitro and in vivo. It is comparable or superior to chlorhexidine in terms of microbial efficacy and inhibiting plaque growth. Thus, topical gel containing antimicrobial agents like Octenidine and Metronidazole can be more effective when used as an adjunct to scaling and root planning to promote faster healing/ improved clinical outcome compared to scaling and root planning alone. Some of the prior arts disclosing oral compositions have been listed below.
WO2002002128A2 discloses topical oral compositions comprising a safe and effective amount of an antimicrobial agent in admixture with a pharmaceutically acceptable carrier, said compositions being effective in controlling bacterial-mediated diseases and conditions present in the oral cavity and in inhibiting the spread into the bloodstream of pathogenic oral bacteria, associated bacterial toxins and endotoxins, and resultant inflammatory cytokines and mediators.
US20090068122A1 discloses an oral composition for treating or preventing dry mouth with following benefits: antibacterial/anti-fungal efficacy, low irritancy, and moisture retention. The compositions can be a toothpaste, a mouth rinse or a spray and include one or more non-ionic surfactants, as foaming agents, one or more broad spectrum anti-microbial ingredient, such as chlorhexidine and cetylpyridinium chloride, and one or more oral surface adhesive polysaccharides that can encage cationic actives to help the deposition and retention of the agents onto oral surfaces and thus provide antimicrobial efficacy.
WO2019145546A1 discloses a method of producing a composition in powder form comprising the following steps (a) to (c): (a) providing highly dispersed silica particles, hydrophobic silica particles, and a cationic surfactant; (b) forming primary hydrophobic silica particles carrying the cationic surfactant on their surface and/or agglomerates of these primary particles; and (c) mixing the highly dispersed silica particles with the product obtained in step (b), thereby obtaining the composition in powder form; and a composition in powder form obtainable by the method.
WO2021148066A1 discloses a biodegradable dental preparation comprising at least one water-soluble fiber from hyaluronic acid or a physiologically acceptable salt thereof and at least one fiber from a non-polar derivative of hyaluronic acid. In a preferred embodiment, the dental composition comprises an antimicrobial agent. The dental preparation is intended for use, in particular, in the treatment of periodontal disease or in the treatment of injuries in the periodontium and oral mucosa.
Pharmaceutical compositions of present invention comprising combination of Octenidine or its pharmaceutically acceptable salts or analogs and Metronidazole or its pharmaceutically acceptable salts or analogs have improved taste/ palatability, broad antibacterial spectrum of activity, overcoming the disadvantages of teeth staining and thereby improving patient compliance.

OBJECT OF THE INVENTION:
It is an object of the present invention to develop a stable pharmaceutical composition comprising Octenidine or its pharmaceutically acceptable salts or analogs and Metronidazole or its pharmaceutically acceptable salts or analogs and one or more pharmaceutically acceptable excipients.
It is another object of the present invention to administer said pharmaceutical composition topically or in the mucosal cavity.
It is another object of the present invention to provide the composition in a form selected from solution, suspension, elixir, emulsion, gel, emulgel, lotion, cream, ointment, paste, mouthwash, spray, gargle, throat paints, transdermal patches, and drops.
It is a further object of the present invention to provide the composition as an oro-mucosal gel.
It is another object of the present invention to provide the composition where Octenidine dihydrochloride and Metronidazole benzoate are present in a ratio of 1:5 to 1:25.
It is another object of the present invention to provide the composition where the Octenidine dihydrochloride is in an amount of 0.01 to 10 wt.% of total composition, and the Metronidazole benzoate is in an amount of 0.1 to 10 wt.% of total composition.
It is another object of the present invention to provide the composition where the pharmaceutically acceptable excipient is in an amount of 80 to 99.89 wt.% of total composition.
It is another object of the present invention to provide the composition where the particle size distribution of Metronidazole benzoate used in the said pharmaceutical composition has X90 in the range between 1 to 150 µm.
It is another object of the present invention to provide the composition where the one or more pharmaceutically acceptable excipient is selected from a group comprising: solvent/vehicle/vehicle base, thickening or gelling agent, emollient, humectant, pH modifier, preservative, chelating agent, surfactant, solubilizer, penetration enhancer, antioxidant, colorant, sweetener and flavoring agent.
It is another object of the present invention to provide the composition where the solvent/vehicle/vehicle base is present in an amount of 40 to 90 wt. %, thickening or gelling agent is present in an amount of 0.1 to 10 wt. %, solubilizer is present in an amount 5 to 40 wt. %, emollient is present in an amount of 1 to 30 wt. %, humectant is present in an amount of 5 to 25 wt. %, preservative is present in an amount of 0.1 to 1 wt %, pH modifier is present in an amount of 0.05 to 5 wt%, chelating agent is present in an amount of 0.01 to 1 wt. %, surfactant/emulsifier is present in an amount of 0.5 to 20 wt. %, penetration enhancer is present in an amount of 3 to 20 wt. %, antioxidant is present in an amount of 0.01 to 5 wt. %, sweetener is present in an amount of 0.01 to 5 wt. % and flavourant is present in an amount of 0.01 to 2 wt. % of the total composition.
It is another object of the present invention to provide the composition where the solvent/vehicle/vehicle base is selected from a group comprising: ethanol, isopropanol, butyl alcohol, dimethyl isosorbide, propylene glycol, glycerin, ethylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, petrolatum jelly and purified water.
It is another object of the present invention to provide the composition where the thickening or gelling agent is selected from a group comprising: cellulose derivatives, carbomer, carbomer copolymers, gelatin, aluminum monostearate, dextrin, sodium alginate, alginic acid, pectin, acacia, carrageenan, xanthan gum, tragacanth, magnesium aluminum silicate, bentonite, poloxamers, polyvinyl alcohol, or a combination thereof, and wherein the cellulose derivative is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxy methylcellulose (HMC), sodium carboxymethyl cellulose and methylcellulose (MC) and a combination thereof.
It is another object of the present invention to provide the composition where the surfactant/emulsifier is selected from a group comprising: cationic surfactants, anionic surfactants, non-ionic surfactants, and amphoteric surfactants, wherein the cationic surfactant includes quaternary ammonium compounds, behentrimonium chloride, benzalkonium chloride, wherein the anionic surfactants include ammonium lauryl sulfate, sodium laureth sulfate, sodium lauryl sarcosinate, sodium myreth sulfate, sodium pareth sulfate, sodium stearte, sodium lauryl sulfate, a-olefin sulfonate, and ammonium laureth sulfate, wherein the non-ionic surfactants include cetomacrogol 1000, cetostearyl alcohol, cetyl alcohol, glyceryl monostearate (GMS), tween 80, sorbitans, polysorbates, poloxamers, isoceteth-20, sucrose ester, sorbitan ester, soybean phospholipid, monoglyceride laurate, propylene glycol fatty acid ester, polyethylene glycol hydrogenated castor oil, and wherein the amphoteric surfactants include alkylamidopropylamine N-oxide, alkyldimethylamine N-oxide, alkylbetaine, and alkylamidopropylbetaine, Cocamidopropyl betaine, cocoamphoacetate, cocoamphodiacetate and a combination thereof.
It is another object of the present invention to provide the composition where the solubilizer is selected from a group comprising: water, propylene glycol, glycerin, sorbitol, mineral oil, polyethylene glycol and vegetable oil.
It is another object of the present invention to provide the composition where the preservative is selected from a group comprising: methyl paraben, propyl paraben, methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, sodium benzoate, benzoic acid and a combination thereof.
It is another object of the present invention to provide the composition where the antioxidant is selected from a group comprising: epicatechin, epicatechin gallate, butylated hydroxy toluene, butylated hydroxy anisole, Propyl Gallate (PG), Tert-Butyl Hydroquinone (TBHQ) and a combination thereof.
It is another object of the present invention to provide the composition where the pH modifier is selected from a group comprising: acidic pH modifiers and basic pH modifiers including citric acid, lactic acid sodium citrate tromethamine, triethanolamine, sodium hydroxide, potassium hydroxide, phosphoric acid, sulfuric acid, hydrochloric acid and a combination thereof.
It is another object of the present invention to provide the composition where the emollient is selected from a group comprising: petroleum jelly, mineral oil, lanolin and liquid paraffin, natural oils like vegetable oils viz. coconut oil, almond oil, corn oil, jojoba oil, argan oil, sesame oil, palm oil and others, dimethicone, glycerin, propylene glycol, polyethylene glycol and a combination thereof.
It is another object of the present invention to provide the composition where the humectant is selected from a group comprising: glycerin, hyaluronic acid, propylene glycol, honey, urea and a combination thereof.
It is another object of the present invention to provide the composition where the chelating agent is selected from a group comprising: disodium edetate, tetrahydroxypropyl ethylenediamine and a combination thereof.
It is another object of the present invention to provide the composition where the penetration enhancer is selected from a group comprising: sulphoxides, azones, pyrrolidone, alcohols, alkanols, glycols and a combination thereof.
It is another object of the present invention to provide the composition where the sweetener is selected from a group comprising: sodium saccharin, sodium cyclamate, sucrose, lactose, maltose, fructose, aspartame, sucralose, neotame, advantame, saccharin, sorbitol and a combination thereof.
It is another object of the present invention to provide the composition where the flavoring agent/ flavourant is selected from a group comprising: volatile oil, aldehyde, ginger oil, double mint, peppermint oil, menthol, lemongrass oil, fruit, citrus, cherry and a combination thereof.
It is another object of the present invention to provide a stable pharmaceutical gel composition where the composition comprises:
a. Octenidine or its pharmaceutically acceptable salt in an amount ranging from 0.01 to 10% by weight of the composition.
b. Metronidazole or its pharmaceutically acceptable salt in an amount ranging from 0.1 to 10% by weight of the composition.
c. Solubilizer in an amount ranging from 5 to 40 % by weight of the composition.
d. Surfactant/emulsifier in an amount ranging from 0.5 to 20 % by weight of the composition.
e. Gelling agent in an amount ranging from 0.1 to 10 % by weight of the composition.
f. Sweetener in an amount ranging from 0.01 to 5 % by weight of the composition.
g. Antioxidant in an amount ranging from 0.01 to 5 % by weight of the composition.
h. Flavourant in an amount ranging from 0.01 to 2 % by weight of the composition.
i. pH modifier in an amount ranging from 0.05 to 5 % by weight of the composition.
j. Vehicle in an amount ranging from 40 to 90 % by weight of the composition.
It is another object of the present invention to provide the stable pharmaceutical gel composition, wherein the composition comprises:
a. Octenidine Dihydrochloride in an amount ranging from 0.01 to 10% by weight of the composition.
b. Metronidazole Benzoate in an amount ranging from 0.1 to 10% by weight of the composition.
c. Propylene glycol in an amount ranging from 5 to 20 % by weight of the composition.
d. Glycerin in an amount ranging from 5 to 20 % by weight of the composition.
e. Polyoxyl 40 Hydrogenated Castor Oil in an amount ranging from 0.5 to 20 % by weight of the composition.
f. Sorbitol solution 70% in an amount ranging from 5 to 20 % by weight of the composition.
g. Hydroxyethyl cellulose in an amount ranging from 0.5 to 10 % by weight of the composition.
h. Carbomer in an amount ranging from 0.5 to 10 % by weight of the composition.
i. Sucralose in an amount ranging from 0.01 to 5 % by weight of the composition.
j. Butylated Hydroxytoluene in an amount ranging from 0.05 to 5 % by weight of the composition.
k. Flavourant in an amount ranging from 0.01 to 2 % by weight of the composition.
l. Triethanolamine in an amount ranging from 0.05 to 5 % by weight of the composition.
m. Purified water in an amount ranging from 40 to 90 % by weight of the composition.
It is another object of the present invention to provide a process for the preparation of a pharmaceutical composition comprising Octenidine dihydrochloride and Metronidazole benzoate and stable pharmaceutical composition forming excipients.
It is another object of the present invention to provide a process for preparing a pharmaceutical composition, said process comprising:
a. providing Octenidine, or its pharmaceutically acceptable salts thereof;
b. providing Metronidazole, or its pharmaceutically acceptable salts thereof; and
c. combining Octenidine, or its pharmaceutically acceptable salts, Metronidazole, or its pharmaceutically acceptable salts with one or more pharmaceutically acceptable excipients.
It is another object of the present invention to provide process for preparing a pharmaceutical composition in a gel form, the process comprises:
a. preparing a clear solution of sweetener and surfactant/emulsifier;
b. preparing a clear solution of Octenidine dihydrochloride;
c. preparing a dispersion of Metronidazole benzoate;
d. dissolving an antioxidant in a suitable solubilizer;
e. adding the clear solution of Octenidine dihydrochloride to the clear solution of step (a);
f. adding the dispersion of Metronidazole benzoate to the clear solution of step (e) to obtain uniform dispersion;
g. adding the clear solution of antioxidant to dispersion obtained in step (f);
h. adding a gelling agent to the dispersion of step (g) to obtain the gel;
i. adding a flavourant to the gel obtained in step (h);
j. adding a pH modifier to step (i) to obtain a pH in the range 4 to 7; and
k. making up the weight by adding vehicle to step (j) to obtain the final composition.

SUMMARY OF THE INVENTION:
The present invention discloses a stable pharmaceutical composition comprising a combination of Octenidine or its pharmaceutically acceptable salts or analogs thereof and Metronidazole or its pharmaceutically acceptable salts or analogs thereof.
In an embodiment, the present invention provides a stable pharmaceutical composition, comprising:
a) an antiseptic agent selected from Octenidine, or its pharmaceutically acceptable salts thereof;
b) an antimicrobial agent selected from Metronidazole, or its pharmaceutically acceptable salts thereof; and
c) one or more pharmaceutically acceptable excipients.

In another embodiment of the present invention, the composition is in a form selected from solution, suspension, elixir, emulsion, gel, emulgel, lotion, cream, ointment, paste, mouthwash, spray, gargle, throat paints, transdermal patches, and drops.
In another embodiment of the present invention, the composition is an oromucosal gel.
In another embodiment of the present invention, the Octenidine dihydrochloride and Metronidazole benzoate are present in a ratio of 1:5 to 1:25.
In another embodiment of the present invention, wherein the Octenidine dihydrochloride is in an amount of 0.01 to 10% of total composition, and the Metronidazole benzoate is in an amount of 0.1 to 10% of total composition.
In another embodiment of the present invention, the pharmaceutically acceptable excipient is in an amount of 80 to 99.89 wt.% of total composition.
In another embodiment of the present invention, the particle size distribution of Metronidazole benzoate used in the said pharmaceutical composition has X90 in the range between 1 to 150 µm.
In another embodiment of the present invention, the pharmaceutically acceptable excipient is selected from a group comprising: solvent/vehicle/vehicle base, thickening or gelling agent, emollient, humectant, pH modifier, preservative, chelating agent, surfactant/emulsifier, solubilizer, penetration enhancer, antioxidant, colorant, sweetener and flavoring agent.
In another embodiment of the present invention, the solvent/vehicle/vehicle base is selected from a group comprising: ethanol, isopropanol, butyl alcohol, ethyl acetate, dimethyl isosorbide, propylene glycol, glycerin, ethylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, water, petrolatum jelly and other non-limiting examples.
In another embodiment of the present invention, the solvent /vehicle/vehicle base is present in an amount of 40 to 90 wt. %, thickening or gelling agent is present in an amount of 0.1 to 10 wt. %, emollient is present in an amount of 1 to 30 wt. %, humectant is present in an amount of 5 to 25 wt. %, solubilizer is present in an amount of 5 to 40 wt. %, preservative is present in an amount of 0.1 to 1 wt %, pH modifier is present in an amount of 0.05 to 5 wt%, chelating agent is present in an amount of 0.01 to 1 wt. %, surfactant/emulsifier is present in an amount of 0.5 to 20 wt. %, penetration enhancer is present in an amount of 3 to 20 wt. %, antioxidant is present in an amount of 0.01 to 5 wt. % , sweetener is present in an amount of 0.01 to 5 wt. % and flavourant is present in an amount of 0.01 to 2 wt. % of the total composition.
In another embodiment of the present invention, the thickening or gelling agent is selected from a group comprising: cellulose derivatives, carbomer, carbomer copolymers, gelatin, aluminum monostearate, dextrin, sodium alginate, alginic acid, pectin, acacia, carrageenan, xanthan gum, tragacanth, magnesium aluminum silicate, bentonite, poloxamers, polyvinyl alcohol, or a combination thereof, and wherein the cellulose derivative is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxy methylcellulose (HMC), sodium carboxymethyl cellulose and methylcellulose (MC) and a combination thereof.
In another embodiment of the present invention, the surfactant/emulsifier is selected from a group comprising: quaternary ammonium compounds, behentrimonium chloride, benzalkonium chloride, ammonium lauryl sulfate, sodium laureth sulfate, sodium lauryl sarcosinate, sodium myreth sulfate, sodium pareth sulfate, sodium stearate, sodium lauryl sulfate, a-olefin sulfonate, ammonium laureth sulfate, cetomacrogol 1000, cetostearyl alcohol, cetyl alcohol, glyceryl monostearate, tween 80, sorbitans, polysorbates, poloxamers, isoceteth-20, sucrose ester, sorbitan ester, soybean phospholipid, monoglyceride laurate, propylene glycol fatty acid ester, polyethylene glycol hydrogenated castor oil, alkylamidopropylamine N-oxide, alkyldimethylamine N-oxide, alkylbetaine, and alkylamidopropylbetaine, Cocamidopropyl betaine, cocoamphoacetate, cocoamphodiacetate and a combination thereof.
In another embodiment of the present invention, the solubilizer is selected from a group comprising: water, propylene glycol, glycerin, sorbitol, mineral oil, polyethylene glycol and vegetable oils.
In another embodiment of the present invention, the preservative is selected from a group comprising: methyl paraben, propyl paraben, methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, sodium benzoate, benzoic acid and a combination thereof.
In another embodiment of the present invention, the antioxidant is selected from a group comprising: epicatechin, epicatechin gallate, butylated hydroxy toluene, butylated hydroxy anisole, Propyl Gallate (PG), Tert-Butyl Hydroquinone (TBHQ) and a combination thereof.
In another embodiment of the present invention, the pH modifier is selected from a group comprising: acidic pH modifiers and basic pH modifiers including citric acid, lactic acid sodium citrate tromethamine, triethanolamine, sodium hydroxide, potassium hydroxide, phosphoric acid, sulfuric acid, hydrochloric acid and a combination thereof.
In another embodiment of the present invention, the emollient is selected from a group comprising petroleum jelly, mineral oil, lanolin and liquid paraffin, natural oils like vegetable oils viz. coconut oil, almond oil, corn oil, jojoba oil, argan oil, sesame oil, palm oil and others, dimethicone, glycerin, propylene glycol, polyethylene glycol and a combination thereof.
In another embodiment of the present invention, the humectant is selected from a group comprising: glycerin, hyaluronic acid, propylene glycol, honey, urea and a combination thereof.
In another embodiment of the present invention, the chelating agent is selected from a group comprising: tetrasodium EDTA, tetrahydroxypropyl ethylenediamine and a combination thereof.
In another embodiment of the present invention, the penetration enhancer is selected from a group comprising: sulphoxides, azones, pyrrolidone, alcohols, alkanols, glycols and a combination thereof.
In another embodiment of the present invention, the sweetener is selected from a group comprising: sodium saccharin, sodium cyclamate, sucrose, lactose, maltose, fructose, aspartame, sucralose, neotame, advantame, saccharin, sorbitol and a combination thereof.
In another embodiment of the present invention, the flavourant is selected from a group comprising: volatile oil, aldehyde, ginger oil, peppermint oil, menthol, lemongrass oil, fruit, citrus, cherry and a combination thereof.
In another embodiment of the present invention, the composition is used topically or in the mucosal cavity.
In another embodiment, the present invention provides a stable pharmaceutical gel composition, wherein the composition comprises:
a. Octenidine or its pharmaceutically acceptable salt in an amount ranging from 0.01 to 10% by weight of the composition;
b. Metronidazole or its pharmaceutically acceptable salt in an amount ranging from 0.1 to 10% by weight of the composition;
c. Solubilizer in an amount ranging from 5 to 40 % by weight of the composition;
d. Surfactant/emulsifier in an amount ranging from 0.5 to 20 % by weight of the composition;
e. Gelling agent in an amount ranging from 0.1 to 10 % by weight of the composition;
f. Sweetener in an amount ranging from 0.01 to 5 % by weight of the composition;
g. Antioxidant in an amount ranging from 0.01 to 5 % by weight of the composition;
h. Flavourant in an amount ranging from 0.01 to 2 % by weight of the composition;
i. pH modifier in an amount ranging from 0.05 to 5 % by weight of the composition; and
j. Vehicle in an amount ranging from 40 to 90 % by weight of the composition.
In another embodiment of the present invention, the stable pharmaceutical gel composition comprises:
a. Octenidine Dihydrochloride in an amount ranging from 0.01 to 10% by weight of the composition;
b. Metronidazole Benzoate in an amount ranging from 0.1 to 10% by weight of the composition;
c. Propylene glycol in an amount ranging from 5 to 20 % by weight of the composition;
d. Glycerin in an amount ranging from 5 to 20 % by weight of the composition;
e. Polyoxyl 40 Hydrogenated Castor Oil in an amount ranging from 0.5 to 20 % by weight of the composition;
f. Sorbitol solution 70% in an amount ranging from 5 to 20 % by weight of the composition;
g. Hydroxyethyl cellulose in an amount ranging from 0.5 to 10 % by weight of the composition;
h. Carbomer in an amount ranging from 0.5 to 10 % by weight of the composition;
i. Sucralose in an amount ranging from 0.01 to 5 % by weight of the composition;
j. Butylated Hydroxytoluene in an amount ranging from 0.05 to 5 % by weight of the composition;
k. Flavourant in an amount ranging from 0.01 to 2 % by weight of the composition;
l. Triethanolamine in an amount ranging from 0.05 to 5 % by weight of the composition; and
m. Purified water in an amount ranging from 40 to 90 % by weight of the composition.
In another embodiment, the present invention provides a process for preparing a pharmaceutical composition, said process comprising:
a. providing Octenidine, or its pharmaceutically acceptable salts thereof;
b. providing Metronidazole, or its pharmaceutically acceptable salts thereof; and
c. combining Octenidine, or its pharmaceutically acceptable salts, Metronidazole, or its pharmaceutically acceptable salts with one or more pharmaceutically acceptable excipients.
In another embodiment of the present invention, the process for preparing a pharmaceutical composition, wherein the composition is in a gel form, comprises:
a. preparing a clear solution of sucralose;
b. preparing a clear solution of Octenidine dihydrochloride;
c. preparing a dispersion of Metronidazole benzoate;
d. dissolving an antioxidant in a suitable solubilizer;
e. adding the clear solution of Octenidine dihydrochloride to the clear solution of step (a);
f. adding the dispersion of Metronidazole benzoate to the clear solution of step (e) to obtain uniform dispersion;
g. adding the clear solution of antioxidant to dispersion obtained in step (f);
h. adding a Carbomer homopolymer to the dispersion of step (g); and
i. adding hydroxyethylcellulose to a suitable solvent to obtain a slurry followed by addition of the slurry to dispersion of step (h) to obtain the gel.
In another embodiment of the present invention, the stable pharmaceutical composition can be used for the treatment of topical infections/disorders and oral healthcare/hygiene.
In another embodiment of the present invention, the stable pharmaceutical composition can be used for maintenance of oral hygiene, for the treatment of periodontal diseases such as mouth ulcers, gingivitis, an adjunct to scaling and root planning procedures to promote gum healing after surgery, for topical treatment of wounds, inflammatory lesions, acute skin lesions such as cuts, grazes, slight burns, sunburn and itching.
In another embodiment of the present invention, Octenidine or pharmaceutically acceptable salts or analogs are used in the concentration about 0.01 to 10% by weight based on the total weight of the composition.
In another embodiment of the present invention, Metronidazole or pharmaceutically acceptable salts or analogs are used in the concentration about 0.1 to 10% by weight based on the total weight of the composition.
In another embodiment of the present invention, the composition comprises other pharmaceutically acceptable excipients.
An embodiment of the present invention provides a process for the preparation of a pharmaceutical composition comprising Octenidine or pharmaceutically acceptable salts or analogs and Metronidazole or pharmaceutically acceptable salts or analogs and stable pharmaceutical composition forming excipients

DETAILED DESCRIPTION OF THE INVENTION:
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are delineated here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have the meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below. The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. The term “about” is used to refer to a range of values that encompasses minor variations from the specified value, typically within ±10% unless otherwise specified. The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”. The term "at least one" is used to mean one or more and thus includes individual components as well as mixtures/combinations. Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps. The term “including” is used to mean “including but not limited to”. “including” and “including but not limited to” are used interchangeably.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods and materials are now described.
The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products, compositions, and methods are clearly within the scope of the disclosure, as described herein.
Pharmaceutical excipients are substances other than the active pharmaceutical ingredients used in a dosage form. They do not have any active role in therapeutics, but they can be used to support the process to produce an effective product. Commonly used excipients in a topical/ oro-mucosal preparation are solvents, cosolvents, thickening or gelling agents, carrier, emollients, humectants, pH modifiers, preservatives, chelating agents, oils, water repelling agents, anti-foaming agents, surfactant/emulsifiers, solubilizers, wetting agents, penetration enhancers, antioxidants, pigment dispersant, colorants, sweeteners and flavoring agents.
Solvent/vehicle/vehicle base are a heterogeneous group of structurally diverse chemicals that can be used to dilute, dissolve, or disperse other compounds. The ability of a solvents/vehicle/vehicle base to dissolve another molecule is dependent on molecular structure and physical properties of both the solvent and the solute. Solvent/ vehicle can be categorized as organic or inorganic, and in terms of chemical polarity.
Sweeteners are the additives that are used or intended to be used either to impart a sweet taste to food or any pharmaceutical preparations. Sweeteners are also used to decrease bitter taste of drugs/excipients or improve taste of formulation.
Flavoring agents are additives that give a pharmaceutical dosage form an additional taste or flavor. They help in masking unpleasant tastes (e.g., bitter or pungent taste) of drugs/excipients and instead improve the quality of their taste.
Surfactant/emulsifiers are substances that create self-assembled molecular clusters called micelles in a solution and adsorb to the interface between a solution and a different phase (gases/solids). Typically, surfactants can act as solubilizers and emulsifiers, based on concentration and system in which it is used. The terms ‘surfactant’ and ‘emulsifier’ are interchangeably used herein.
Solubilizers are substances that increase the solubility of the actives in the solvent. They also act as solubilization enhancers or co-solvents.
Gelling agent or thickening agents are the gel-forming agents which when dissolved in a liquid phase as a colloidal mixture forms a weakly cohesive internal structure. They are organic hydrocolloids or hydrophilic inorganic substances. In semisolid dosage forms, different gelling agents are used.
Humectants are hygroscopic substances that promote moisture retention in topical formulations.
Chelating agent is a substance that remove or control metal ions in formulations promoting product stability.
Penetration enhancers are incorporated into a formulation to improve the penetration of drugs through the topical surface.
Emollients are agents that provides softening effect on the topical surface after application and also improve the consistency and texture of topical formulations.
Antioxidants are substances that prevent or delay the oxidative degradation of a formulation. Antioxidants work by either preventing the formation of free-radicals or neutralize those that are formed or repair the damage done by free-radicals thereby preventing the oxidation of the product throughout shelf life.
The pH modifiers are substances that can alter the pH of a formulation. They have the effect of producing and maintaining a product at a specific pH throughout the shelf life of the product.
The present invention discloses a pharmaceutical composition comprising combination of Octenidine or pharmaceutically acceptable salts thereof and Metronidazole or pharmaceutically acceptable salts thereof.
In one embodiment of the present invention, the composition comprises pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients can be selected from solvents, cosolvents, thickening or gelling agents, carrier, emollients, humectants, pH modifiers, preservatives, chelating agents, oils, water repelling agents, anti-foaming agents, surfactant/emulsifiers, solubilizers, wetting agents, penetration enhancers, antioxidants, pigment dispersant, colorants, sweeteners and flavoring agents.
In one embodiment of the present invention, the solvent/vehicle/vehicle base is selected from a group comprising: ethanol, isopropanol, butyl alcohol, dimethyl isosorbide, propylene glycol, glycerin, ethylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, water, paraffin, petrolatum jelly and other non-limiting examples. In a preferred embodiment of the present invention, the solvent/vehicle/vehicle base is selected from purified water, glycerin, propylene glycol, polyethylene glycol, paraffin, petrolatum jelly and combinations thereof.
In another embodiment of the present invention, the gelling agent is selected from the group comprising tragacanth, pectin, starch, carbomer, carbomer copolymers sodium alginate, gelatin, cellulose derivatives, polyvinyl alcohol clays, sodium carboxymethyl cellulose, alginic acid, pectin, acacia, carrageenan, xanthan gum, magnesium aluminum silicate, bentonite, poloxamers, polyvinyl alcohol, or a combination thereof, and wherein the cellulose derivative is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxy methylcellulose (HMC), sodium carboxy methyl cellulose and methylcellulose (MC) and the like or any combination thereof. In a preferred embodiment of the present invention, the gelling agent is selected from xanthan gum, hydroxyethyl cellulose (HEC), carbomer, carbomer copolymers and combinations thereof.
In another embodiment of the present invention, solubilizer is selected from a group comprising: water, propylene glycol, glycerin, sorbitol, mineral oil, polyethylene glycol and vegetable oils and other non-limiting examples.
In another embodiment, the surfactant/emulsifier is selected from a group comprising: cationic surfactants, anionic surfactants, non-ionic surfactants, and amphoteric surfactants, wherein the cationic surfactants include quaternary ammonium compounds, behentrimonium chloride, benzalkonium chloride, wherein the anionic surfactants include ammonium lauryl sulfate, sodium laureth sulfate, sodium lauryl sarcosinate, sodium myreth sulfate, sodium pareth sulfate, sodium stearate, sodium lauryl sulfate, a-olefin sulfonate, and ammonium laureth sulfate, wherein the non-ionic surfactants include cetomacrogol, cetostearyl alcohol, cetyl alcohol, glyceryl monostearate, tween 80, sorbitans, polysorbates, poloxamers, isoceteth-20, sucrose ester, sorbitan ester, soybean phospholipid, monoglyceride laurate, propylene glycol fatty acid ester, polyethylene glycol hydrogenated castor oil, and wherein the amphoteric surfactants include alkylamidopropylamine N-oxide, alkyldimethylamine N-oxide, alkylbetaine, and alkylamidopropylbetaine, Cocamidopropyl betaine, cocoamphoacetate, cocoamphodiacetate and a combination thereof.
In a preferred embodiment of the present invention, the surfactant is selected from Cocamidopropyl betaine, polyethylene glycol hydrogenated castor oil, poloxamers, glyceryl monostearate, cetomacrogol, cetostearyl alcohol, cetyl alcohol, tween 80 and combinations thereof.
In a further embodiment, the surfactant/emulsifier is selected from a group comprising: quaternary ammonium compounds, behentrimonium chloride, benzalkonium chloride, ammonium lauryl sulfate, sodium laureth sulfate, sodium lauryl sarcosinate, sodium myreth sulfate, sodium pareth sulfate, sodium stearte, sodium lauryl sulfate, a-olefin sulfonate, ammonium laureth sulfate, cetomacrogol 1000, cetostearyl alcohol, cetyl alcohol, glyceryl monostearate, tween 80, sorbitans, polysorbates, poloxamers, isoceteth-20, sucrose ester, sorbitan ester, soybean phospholipid, monoglyceride laurate, propylene glycol fatty acid ester, polyethylene glycol hydrogenated castor oil, alkylamidopropylamine N-oxide, alkyldimethylamine N-oxide, alkylbetaine, alkylamidopropylbetaine, Cocamidopropyl betaine, cocoamphoacetate, cocoamphodiacetate and a combination thereof.
In another embodiment of the present invention, the preservative is selected from the group comprising of methyl paraben, propyl paraben, methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, sodium benzoate, benzoic acid, and the like.
In another embodiment of the present invention, the antioxidant is selected from the group comprising of epicatechin, epicatechin gallate, butylated hydroxy toluene, butylated hydroxy anisole, Propyl Gallate (PG) and Tert-Butyl Hydroquinone (TBHQ), and the like. In a preferred embodiment of the present invention, the antioxidant is butylated hydroxy toluene.
In another embodiment of the present invention, the pH modifier is selected from the group comprising of acidic pH modifiers and/or basic pH modifiers viz. citric acid, lactic acid sodium citrate tromethamine, triethanolamine, sodium hydroxide, potassium hydroxide, phosphoric acid, sulfuric acid, hydrochloric acid, and the like. In a preferred embodiment of the present invention, the pH modifier is selected from triethanolamine, citric acid monohydrate, sodium citrate or any combination thereof.
In another embodiment of the present invention, the emollient is selected from the group comprising of petroleum jelly, mineral oil, lanolin and liquid paraffin, natural oils like vegetable oils viz. coconut oil, almond oil, corn oil, jojoba oil, argan oil, sesame oil, palm oil and others, dimethicone, glycerin, propylene glycol, polyethylene glycol and a combination thereof. In a preferred embodiment of the present invention, the emollient is selected from mineral oil, petroleum jelly and combinations thereof.
In another embodiment of the present invention, the humectant is selected from a group comprising: glycerin, hyaluronic acid, propylene glycol, sorbitol, honey, urea and a combination thereof. In a preferred embodiment of the present invention, the humectant is selected from glycerin, propylene glycol, sorbitol, urea and combinations thereof.
In another embodiment of the present invention, the chelating agent is selected from the group comprising of disodium edetate and tetrahydroxypropyl ethylenediamine.
In another embodiment of the present invention, the penetration enhancer is selected from the group comprising of sulphoxides (such as dimethylsulphoxide, DMSO), azones (e.g.laurocapram), pyrrolidones (for example 2-pyrrolidone, 2P), alcohols and alkanols (ethanol, or decanol) and glycols (for example propylene glycol).
In another embodiment of the present invention, the sweetener is selected from a group comprising: sodium saccharin, sodium cyclamate, sucrose, lactose, maltose, fructose, aspartame, sucralose, neotame, advantame, saccharin, sorbitol and a combination thereof. In a preferred embodiment of the present invention, the sweetener is selected from sodium saccharin, sucralose, sorbitol and combination thereof.
In another embodiment of the present invention, the flavoring agent is selected from a group comprising: volatile oil, double mint, mint, aldehyde, ginger oil, peppermint oil, menthol, lemongrass oil, fruit, citrus, cherry and a combination thereof. In a preferred embodiment of the present invention, the flavoring agent is selected from mint, peppermint oil, citrus and combination thereof.
In one embodiment, the present invention provides a stable pharmaceutical composition comprising:
a) an antiseptic agent selected from Octenidine, or its pharmaceutically acceptable salts thereof;
b) an antimicrobial agent selected from Metronidazole, or its pharmaceutically acceptable salts thereof; and
c) one or more pharmaceutically acceptable excipients.
In another embodiment of the present invention, the composition is used topically or in the mucosal cavity.
In another embodiment of the present invention, the composition is in a form selected from solution, suspension, elixir, emulsion, gel, emulgel, lotion, cream, ointment, paste, mouthwash, spray, gargle, throat paints, transdermal patches, and drops.
In another embodiment of the present invention, the composition is an oromucosal gel.
In another embodiment of the present invention, the Octenidine dihydrochloride and Metronidazole benzoate are present in a ratio of 1:5 to 1:25.
In another embodiment of the present invention, the Octenidine dihydrochloride is in an amount of 0.01 to 10% of total composition, and the Metronidazole benzoate is in an amount of 0.1 to 10% of total composition.
In another embodiment of the present invention, the pharmaceutically acceptable excipient is in an amount of 80 to 99.89 wt.% of total composition.
In another embodiment of the present invention, the solvent/vehicle/vehicle base is present in an amount of 40 to 90 wt. %, preferably in an amount 50 to 90 wt. % thickening or gelling agent is present in an amount of 0.1 to 10 wt. %, preferably in an amount 0.2 to5 wt. %, solubilizer is present in an amount 5 to 40 wt. %, preferably in an amount 10 to 35 wt. %, emollient is present in an amount of 1 to 30 wt. %, humectant is present in an amount of 5 to 25 wt. %, preferably in an amount 5 to 20 wt. %, preservative is present in an amount of 0.1 to 1 wt %, preferably in an amount to wt. %, pH modifier is present in an amount of 0.05 to 5 wt%, chelating agent is present in an amount of 0.01 to 1 wt. %, surfactant/emulsifier is present in an amount of 0.5 to 20 wt. %, penetration enhancer is present in an amount of 3 to 20 wt. %, antioxidant is present in an amount of 0.01to 5 wt. %, sweetener is present in an amount of 0.01 to 5 wt. % and flavourant is present in an amount of 0.01 to 2 wt. % of the total composition.
In another embodiment of the present invention, the solvent/vehicle/vehicle base is selected from a group comprising: ethanol, isopropanol, butyl alcohol, dimethyl isosorbide, propylene glycol, glycerol, ethylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, purified water, mineral oil and petrolatum jelly.
In another aspect, the present invention provides a stable pharmaceutical gel composition, wherein the composition comprises:
a. Octenidine or its pharmaceutically acceptable salt in an amount ranging from 0.01 to 10% by weight of the composition;
b. Metronidazole or its pharmaceutically acceptable salt in an amount ranging from 0.1 to 10% by weight of the composition;
c. Solubilizer in an amount ranging from 5 to 40 % by weight of the composition;
d. Surfactant/emulsifier in an amount ranging from 0.5 to 20 % by weight of the composition;
e. Gelling agent in an amount ranging from 0.1 to 10 % by weight of the composition;
f. Sweetener in an amount ranging from 0.01 to 5 % by weight of the composition;
g. Antioxidant in an amount ranging from 0.01 to 5 % by weight of the composition;
h. Flavourant in an amount ranging from 0.01 to 2 % by weight of the composition;
i. pH modifier in an amount ranging from 0.05 to 5 % by weight of the composition; and
j. Vehicle in an amount ranging from 40 to 90 % by weight of the composition.
In another embodiment of the present invention, the stable pharmaceutical gel composition comprises:
a. Octenidine Dihydrochloride in an amount ranging from 0.01 to 10% by weight of the composition;
b. Metronidazole Benzoate in an amount ranging from 0.1 to 10% by weight of the composition;
c. Propylene glycol in an amount ranging from 5 to 20 % by weight of the composition;
d. Glycerin in an amount ranging from 5 to 20 % by weight of the composition;
e. Polyoxyl 40 Hydrogenated Castor Oil in an amount ranging from 0.5 to 20 % by weight of the composition;
f. Sorbitol solution 70% in an amount ranging from 5 to 20 % by weight of the composition;
g. Hydroxyethyl cellulose in an amount ranging from 0.5 to 10 % by weight of the composition;
h. Carbomer in an amount ranging from 0.5 to 10 % by weight of the composition;
i. Sucralose in an amount ranging from 0.01 to 5 % by weight of the composition;
j. Butylated Hydroxytoluene in an amount ranging from 0.05 to 5 % by weight of the composition;
k. Flavourant in an amount ranging from 0.01 to 2 % by weight of the composition;
l. Triethanolamine in an amount ranging from 0.05 to 5 % by weight of the composition; and
m. Purified water in an amount ranging from 40 to 90 % by weight of the composition.
In another embodiment of the present invention, the particle size distribution of Metronidazole benzoate used in the said pharmaceutical composition has X90 in the range between 1 to 150 µm.
In another aspect, the present invention provides a process for preparing a pharmaceutical composition, said process comprising:
a. providing Octenidine, or its pharmaceutically acceptable salts thereof;
b. providing Metronidazole, or its pharmaceutically acceptable salts thereof; and
c. combining Octenidine, or its pharmaceutically acceptable salts, Metronidazole, or its pharmaceutically acceptable salts with one or more pharmaceutically acceptable excipients.
In an embodiment of the present invention, the process for preparing a pharmaceutical composition, wherein the composition is in a gel form, comprises:
a. preparing a clear solution of sucralose;
b. preparing a clear solution of Octenidine dihydrochloride;
c. preparing a dispersion of Metronidazole benzoate;
d. dissolving an antioxidant in a suitable solubilizer;
e. adding the clear solution of Octenidine dihydrochloride to the clear solution of step (a);
f. adding the dispersion of Metronidazole benzoate to the clear solution of step (e) to obtain uniform dispersion;
g. adding the clear solution of antioxidant to dispersion obtained in step (f);
h. adding a Carbomer homopolymer to the dispersion of step (g); and
i. adding hydroxyethylcellulose to a suitable solvent to obtain a slurry followed by addition of the slurry to dispersion of step (h) to obtain the gel.
In a preferred embodiment of the present invention, the process for preparing a pharmaceutical composition, wherein the composition is in a gel form, comprises:
a. preparing a clear solution of sucralose by adding sucralose in water under stirring followed by addition of Polyoxyl 40 Hydrogenated castor oil with continuous stirring till clear solution is obtained;
b. preparing a clear solution of Octenidine dihydrochloride in purified water;
c. preparing a dispersion of Metronidazole benzoate by rinsing with glycerin;
d. dissolving antioxidant butylated hydroxytoluene (BHT) in propylene glycol under heating and stirring to form a clear solution followed by cooling down to room temperature;
e. adding the clear solution of Octenidine dihydrochloride to the clear solution of step (a);
f. adding the clear solution of Metronidazole Benzoate to the clear solution of step (e) followed by rinsing with glycerin and sorbitol solution and stirring to obtain uniform dispersion;
g. adding the clear solution of butylated hydroxytoluene (BHT) prepared in step (d) to dispersion obtained in step (f) followed by rinsing with propylene glycol and stirring to obtain a uniform dispersion;
h. adding Carbomer under stirring to the dispersion of step (g) to obtain a uniform dispersion; and
i. adding hydroxyethyl cellulose to propylene glycol under stirring for 7 to 10 minutes to obtain a slurry followed by addition of the slurry to dispersion of step (h) under stirring and rinsing with propylene glycol to obtain the gel.
In a preferred embodiment the present invention, the process for preparing a pharmaceutical composition, wherein the composition is in a toothpaste form, comprises:
a. providing a clear solution of sucralose, sodium benzoate, sodium saccharin and disodium edetate;
b. preparing a clear solution of Octenidine dihydrochloride;
c. preparing a dispersion of Metronidazole benzoate;
d. adding the clear solution of Octenidine dihydrochloride to the clear solution obtained in step (a);
e. adding the dispersion of Metronidazole benzoate to clear solution of step (d) to obtain a homogeneous dispersion;
f. dissolving an antioxidant in a suitable solubilizer;
g. adding the clear solution of step (b) to the homogeneous dispersion of step (e) to form a uniform dispersion;
h. preparing a xanthan gum and sodium carboxymethyl cellulose base in glycerin followed by addition of the said base to the uniform dispersion of step (g) to obtain a final dispersion: and
i. preparing a clear solution of a surfactant/emulsifier and adding the same to final dispersion of step (h) to form a toothpaste.
In a preferred embodiment of the present invention, the process for preparing a pharmaceutical composition, wherein the composition is in a toothpaste form, comprises:
a. adding sucralose, sodium benzoate, sodium saccharin and disodium edetate in about 60% total quantity of purified water under stirring till a clear solution is obtained;
b. preparing a clear solution of Octenidine dihydrochloride by adding Octenidine dihydrochloride in about 30% total quantity of purified water under stirring;
c. preparing a dispersion of Metronidazole benzoate by adding Metronidazole benzoate to about 70% total quantity of Glycerin under stirring to obtain a uniform dispersion;
d. adding the clear solution of Octenidine dihydrochloride to the clear solution obtained in step (a);
e. adding the dispersion of Metronidazole benzoate to clear solution of step (d) to obtain a homogeneous dispersion;
f. dissolving Butylated hydroxytoluene (BHT) in propylene glycol under heating and stirring to form a clear solution followed by cooling the solution to room temperature;
g. adding the clear solution of step (b) to the homogeneous dispersion of step (e) to form a uniform dispersion;
h. preparing a xanthan gum and sodium carboxymethyl cellulose base by dispersing xanthan gum and sodium carboxymethyl cellulose in glycerin under to form a uniform dispersion followed by addition of the said base to the uniform dispersion of step (g) under stirring to obtain a final dispersion: and
i. preparing a clear solution of sodium lauryl sulphate in purified water followed by adding the same alongwith cocamidopropyl betaine to final dispersion of step (h) under stirring to form a toothpaste.
In another embodiment of the present invention, the process for preparing a pharmaceutical composition, wherein the composition is in a mouthwash or spray form, comprises:
a. preparing a clear solution of excipients including sweetener, preservative, chelating agent and surfactant/emulsifier;
b. preparing Octenidine dihydrochloride;
c. preparing Metronidazole benzoate dispersion;
d. adding Octenidine dihydrochloride clear solution to clear solution of step (a) to obtain a final clear solution;
e. adding Metronidazole benzoate dispersion to the final clear solution of step (d) to obtain a uniform dispersion;
f. dissolving an antioxidant in a suitable solubilizer followed by addition of a gelling agent to obtain a uniform dispersion;
g. adding the uniform dispersion obtained in step (f) to the uniform dispersion obtained in step (e) to form a final dispersion; and
h. preparing a clear solution of Poloxamer and adding the poloxamer solution to final dispersion of step (g) to form a clear solution.
In a preferred embodiment of the present invention, the process for preparing a pharmaceutical composition, wherein the composition is in a mouthwash form, comprises:
a. adding sucralose, sodium saccharin, sodium benzoate, disodium edetate and copovidone) to 60% total quantity of purified water under stirring followed by addition of Polyoxyl 40 hydrogenated castor oil to obtain a clear solution;
b. preparing Octenidine dihydrochloride clear solution by adding Octenidine dihydrochloride to 30% total quantity of purified water;
c. preparing Metronidazole benzoate dispersion by adding Metronidazole benzoate to 90% total quantity of glycerin;
d. adding Octenidine dihydrochloride clear solution to clear solution of step (a) under stirring to obtain a final clear solution;
e. adding Metronidazole benzoate dispersion to the final clear solution of step (d) under stirring to obtain a uniform dispersion;
f. adding BHT to 95% total quantity of Propylene Glycol under heating and stirring at a clear solution followed by cooling to room temperature and further adding Hydroxyethyl cellulose in the obtained clear solution to obtain a uniform dispersion;
g. adding the uniform dispersion obtained in step (f) to the uniform dispersion obtained in step (e) to form a final dispersion; and
h. preparing a clear solution of Poloxamer by adding Poloxamer in purified water followed by adding the poloxamer solution to final dispersion of step (g) to form a clear solution.
In another embodiment of the present invention, the process for preparing a pharmaceutical composition, wherein the composition is in an ointment form, comprises: preparing a dispersion of Octenidine dihydrochloride and Metronidazole benzoate in oil and adding to an ointment base.
In a preferred embodiment of the present invention, the process for preparing a pharmaceutical composition, wherein the composition is in an ointment form, comprises:
a. heating white soft paraffin to 65°C to 75°C followed by its cooling to temperature between 40°C to 50°C;
b. preparing a uniform dispersion of Octenidine dihydrochloride in mineral oil fooled by addition of Metronidazole benzoate; and
c. adding API dispersion of step (b) to cooled white soft paraffin at temperature between 40°C to 50°C followed by cooling to room temperature to obtain ointment.
In a preferred embodiment of the present invention, the process for preparing a pharmaceutical composition, wherein the composition is in an ointment form, comprises:
a. heating Polyethylene glycol to 65°C to 75°C followed by its cooling to temperature between 40°C to 50°C;
b. preparing a uniform dispersion of Octenidine dihydrochloride in mineral oil fooled by addition of Metronidazole benzoate; and
c. adding API dispersion of step (b) to cooled polyethylene glycol at temperature between 40°C to 50°C followed by cooling to room temperature to obtain ointment.
In another embodiment of the present invention, the process for preparing a pharmaceutical composition, wherein the composition is in a cream form, comprises:
a. preparing a clear solution of excipients including chelating agent and preservatives;
b. dispersing a gelling agent in the clear solution of step (a) to form a uniform dispersion;
c. heating a mixture of excipients including surfactant/emulsifier, antioxidant and emollient to form clear solution;
d. mixing uniform dispersion of step (b) and clear solution of step (c) to obtain a uniform emulsion;
e. preparing a clear solution of Octenidine dihydrochloride;
f. preparing a dispersion of Metronidazole benzoate in a suitable solvent/vehicle/vehicle base/solubilizer; and
g. adding Octenidine dihydrochloride clear solution and Metronidazole benzoate dispersion to the emulsion to obtain the cream.
In a preferred embodiment of the present invention, the process for preparing a pharmaceutical composition, wherein the composition is in a cream form, comprises:
a. preparing a clear solution of Disodium edetate and Sodium benzoate;
b. dispersing Xanthan Gum in the clear solution of step (a) followed by heating to form a uniform dispersion;
c. heating a mixture of Propylene Glycol, Butylated Hydroxytoluene, Fractionated coconut oil, Cetomacrogol 1000, Cetostearyl Alcohol and Glyceryl Monostearate (GMS) to form clear solution;
d. mixing uniform dispersion of step (b) and clear solution of step (c) to obtain a uniform emulsion followed by cooling to below 35°C to 50°C;
e. preparing a clear solution of Octenidine dihydrochloride;
f. preparing a dispersion of Metronidazole benzoate in glycerin; and
g. adding Octenidine dihydrochloride clear solution and Metronidazole benzoate dispersion to the emulsion followed by cooling to room temperature to obtain the cream.
In another embodiment of the present invention, the process for preparing a pharmaceutical composition, wherein the composition is in a lotion form, comprises:
a. preparing a clear solution of a chelating agent followed by addition of a gelling agent to obtain a dispersion;
b. heating a mixture of excipients including surfactant/emulsifiers, antioxidants, preservatives and emollients to obtain a clear solution;
c. adding the clear solutions of step (a) and (b) to obtain a uniform emulsion;
d. preparing a clear solution of Octenidine dihydrochloride;
e. preparing a dispersion of Metronidazole Benzoate in a suitable solvent/vehicle/vehicle base/solubilizer; and
f. mixing clear solution of Octenidine dihydrochloride and dispersion of Metronidazole benzoate to the emulsion to obtain the lotion.
In a preferred embodiment of the present invention, the process for preparing a pharmaceutical composition, wherein the composition is in a lotion form, comprises:
a. preparing a clear solution of Disodium edetate followed by addition of Xanthan Gum to obtain dispersion and heating until a clear solution is obtained;
b. heating a mixture of Propylene Glycol, Butylated Hydroxytoluene, Mineral oil, Methylparaben, Propylparaben, Cetyl Alcohol, Polysorbate 80, Stearic acid and Glyceryl Monostearate (GMS) to obtain a clear solution;
c. adding the clear solutions of step (a) and (b) to obtain a uniform emulsion and cooling to below 35°C to 50°C;
d. preparing a clear solution of Octenidine dihydrochloride;
e. preparing a dispersion of Metronidazole Benzoate in glycerin; and
f. mixing clear solution of Octenidine dihydrochloride and dispersion of Metronidazole benzoate to the emulsion and cooling to room temperature to obtain the lotion.
In another embodiment of the present invention, Octenidine or its pharmaceutically acceptable salts are used in the concentration about 0.01 to 10% by weight, preferably 0.02 to 5% by weight, more preferably 0.05 to 1% by weight, more preferably 0.075 to 0.5% by weight, most preferably 0.1 to 0.2% by weight based on the total weight of the composition. In a preferred embodiment of the present invention, Octenidine or its pharmaceutically acceptable salt is used in the concentration of about 0.1% by weight based on the total weight of the composition.
In another embodiment of the present invention, Metronidazole or its pharmaceutically acceptable salts are used in the concentration about 0.1 to 10% by weight preferably 0.2 to 7.5% by weight, more preferably 0.5 to 5% by weight, more preferably 0.75 to 2.5% by weight, most preferably 1 to 2% by weight based on the total weight of the composition. In a preferred embodiment of the present invention, Metronidazole is used in the concentration of about 1% by weight based on the total weight of the composition or equivalent weight of any pharmaceutically acceptable salt of Metronidazole.
In another embodiment of the present invention, the composition can be in the form selected from solution, suspension, elixir, emulsion, gel, emulgel, lotion, cream, ointment, paste, mouthwash/rinse, spray, gargle, throat paints, transdermal patches, drops and the like.
In another embodiment, the present invention provides a composition that can be used topically or in oro-mucosal cavity that can be used for the treatment of topical infections/disorders and oral healthcare/hygiene. Preferably the compositions of present inventions can be used for the treatment of disorders related to oral hygiene and promote oral health. More preferably the compositions of the present invention can be used for the treatment of Gingivitis and an adjunct to scaling and root planning procedures to promote gum healing after surgery.
In another embodiment, the present invention provides a composition in the form of oro-mucosal gel or toothpaste or mouthwash or mouth spray for the treatment of Gingivitis and an adjunct to scaling and root planning procedures to promote gum healing after surgery.
In an embodiment, Carbomer and Hydroxyethyl cellulose (HEC) polymer are used as thickening agents which increase the viscosity of the gel and provide better mucoadhesion / retention of the gel in oral area. Glycerin and Propylene Glycol are used as solvents and solubilizers to maintain moisture and help to dissolve other ingredients in the formulation. Polyoxyl 40 Hydrogenated Castor oil is used as surfactant/emulsifier in the formulation which acts as a surface wetting agent which permits the active ingredient to diffuse and keep Metronidazole uniformly dispersed in the gel. Sorbitol solution 70% and Sucralose act as sweetening agent to decrease bitter taste of drugs/excipients or improve taste of formulation. Butylated Hydroxytoluene (BHT) acts as antioxidant to prevent the oxidative degradation of the product throughout shelf life. Doublemint act as Flavoring agent which improve the taste and the consumer acceptance of product. Triethanolamine/trolamine acts as pH modifier to adjust the desired pH of the product. Hence, the selection of excipient is critical to make stable product.
The qualitative and quantitative composition of the product and the manufacturing process according to the present invention allows to obtain a stable formulation during shelf life and with good properties for application in Oro-mucosal area and with excellent taste and palatability properties.
In an embodiment, the present invention provides a composition/formulation comprising combination of Octenidine Dihydrochloride and Metronidazole oro-mucosal Gel 0.1% and 1% w/w to treat the Gingivitis and an adjunct to scaling and root planning procedures to promote gum healing after surgery.
In another embodiment of the present invention, Sweetener like Sucralose and Sodium saccharin are used.
In another embodiment of the present invention, propylene glycol and polyethylene glycol are used as solvent/vehicle /vehicle base/solubilizer.
In another embodiment of the present invention, Double mint flavor is used as flavoring agent to increase the palatability of the product.
In another embodiment of the present invention, glycerin is used as solvent/vehicle /vehicle base/solubilizer to disperse the Metronidazole Benzoate under stirring to form uniform lump free dispersion of API.
In another embodiment of the present invention, BHT was dissolved in Propylene glycol at temperature of 65°C to 70°C under stirring to form clear solution.
In another embodiment of the present invention, Polyoxyl 40 Hydrogenated castor oil is used as surfactant/emulsifier in the present formulation to make formulation stabilized during shelf life.
In another embodiment of the present invention, it has been found that a pharmaceutical composition comprising Metronidazole Benzoate with a particle size distribution of X90 in the range between 1µm to 150µm, provided a stable composition with no aggregation/ settlement of API in the composition over 6 months in accelerated stability studies. In a preferred embodiment of the present invention, Metronidazole Benzoate with a particle size distribution of X90 was selected in the range between 2.5µm to 100µm. In a more preferred embodiment, Metronidazole Benzoate with a particle size distribution of X90 was selected in the range between 5µm to 50µm. In another preferred embodiment, Metronidazole Benzoate with a particle size distribution of X90 was selected in the range between 10µm to 25µm. In the most preferred embodiment, Metronidazole Benzoate with a particle size distribution of X90 = 15µm provided a stable composition with no aggregation / settlement of API in the composition over 6 months in accelerated stability studies which also provided a smooth application of the composition without any feeling of grittiness or discomfort, was selected for development of the composition/formulation.
In another embodiment of the present invention, the Octenidine Dihydrochloride and Metronidazole Benzoate Phase were added in the main bulk below 30°C temperature to avoid temperature exposure.
EXAMPLES:
The disclosure will now be illustrated with non-limiting working examples, which are intended to illustrate the working of disclosure and not intended to take restrictively to imply any limitations on the scope of the present disclosure.
Example 1: Manufacturing of gel formulation.
(a) Compositions of Gel
Table 1: Octenidine Dihydrochloride and Metronidazole benzoate Gel formulations (Oral)
Sr. No Ingredients Formulation A Formulation B Formulation C
Quantity %w/w
1 Octenidine Dihydrochloride 0.10 0.10 0.10
2 *Metronidazole Benzoate 1.608 1.608 1.608
3 Propylene glycol 10.00 10.00 10.00
4 Hydroxyethyl cellulose 1.50 -- 1.50
5 Carbomer -- 1.00 0.20
6 Sorbitol solution 70% (Non-crystallizing) 7.00 7.00 7.00
7 Butylated Hydroxytoluene 0.05 0.05 0.05
8 Glycerin 10.00 10.00 10.00
9 Polyoxyl 40 Hydrogenated castor oil 1.00 1.00 1.00
10 Sucralose 0.20 0.20 0.20
11 Double mint flavor 0.30 0.30 0.30
12 Triethanolamine -- 0.85 0.085
13 Purified water q.s. to 100 q.s. to 100 q.s. to 100
* Metronidazole Benzoate IP 1.608% w/w is equivalent to Metronidazole l% w/w
(b) Manufacturing process of gel formulation:
Step 1: Bulk Preparation: To One portion of purified water in manufacturing vessel, add dispensed qty. of sucralose under stirring. Then stir the bulk for about 10 to20 minutes to form a clear solution.
Step 2: Addition of Poloxamer: To bulk of step 1 add Poloxamer under stirring. Container rinsed with purified water. Then continue stirring for about 40 to 50 minutes to form a clear solution.
Step 3: Preparation of Octenidine Dihydrochloride Phase: To second portion of purified water in separate Stainless Steel (SS) vessel, Octenidine Dihydrochloride was added slowly under stirring. The polybag of Octenidine Dihydrochloride was rinsed with Fourth portion of purified water and rinsate was transferred to bulk. Stirring was continued for about 45 to 50 minutes to form a clear solution.
Step 4: Preparation of Metronidazole Benzoate phase: To glycerin in a SS container, Metronidazole Benzoate API was added slowly under stirring. Polybag of Metronidazole Benzoate was rinsed with glycerin and rinsate was added to SS container. Stirring was continued for about 40 to50 minutes to form uniform lump free dispersion.
Step 5: Preparation of Antioxidant phase: To Propylene Glycol in SS container, batch qty. of Butylated Hydroxy Toluene was added. Heated the phase to 60°C to 70 ? under stirring to form clear solution. After formation of clear solution, kept cool down the bulk under stirring to below 25°C to 35°C temperature.
Step 6: Addition of Octenidine Dihydrochloride phase: Octenidine Dihydrochloride phase prepared in step 3 added to bulk of step 2. Drug phase container was rinsed with Part E of purified water and rinsate was added to bulk. This phase was kept under stirring for 15 to25 minutes and ensured to form clear solution.
Step 7: Addition of Metronidazole Benzoate phase: Metronidazole Benzoate phase prepared in step 4 added to bulk of step 6. Drug phase container was rinsed with remaining qty. of glycerin and then sorbitol solution added the rinsate to bulk. Bulk kept on stirring for about 25 to 35 minutes and ensured to form uniform dispersion.
Step 8: Addition of Antioxidant phase: Antioxidant phase prepared in step 5 added to bulk of step 7. This container was rinsed with propylene glycol. Rinsate was added to bulk and stirring continued for about 10 to 20 minutes and ensured to form uniform dispersion.
Step 9: Addition of Carbomer: To bulk of step 8, added carbomer under stirring. homogenization at a speed of 2500 to 3000 rpm. Polybag rinsed with purified water and rinsate added to bulk. This phase was homogenized for about 45 to 55 minutes and ensured to form uniform dispersion.
Step 10: Hydroxyethyl Cellulose Preparation & Addition: To propylene glycol in SS vessel, Hydroxyethyl Cellulose was added under stirring. Stirring was continued for about 5 to 10 minutes to ensure the formation of lump free slurry. After this, Hydroxyethyl Cellulose phase added to bulk of step 9 under homogenization at 2500 to 3000 rpm and stirring for time 55 to 65 minutes was continued. The container was rinsed with propylene glycol and this rinsate was transferred to bulk and ensured to form lump free gel.
Step 11: Addition of Flavor: To bulk of step 10 flavor was added, and bulk was allowed to stir for about 25 to 35 minutes. Container was rinsed with water and rinsate added to bulk.
Step 12: Addition of Triethanolamine: To bulk of step 11, triethanolamine was added under stirring and bulk was allowed to stir for about 10 to 20 minutes. The container was rinsed with Part F of purified water and rinsate was added to bulk. Then the remaining quantity of purified water was added to the bulk and allowed to stir for about 10 to 15 minutes [Target pH (4.00 to 7.00)].
Step 13: Final Mixing: Final mixing performed for about 25 to 35 minutes under stirring to obtain white to off-white gel pH: 4.0 to 7.0 [Target pH (4.00 to 7.00)].

Example 2: Optimization of the excipients in gel formulation.
Example 2a: Optimisation of the gelling agent.
The viscosity of the product is of utmost importance in this development determining product stability, uniform distribution of the actives as well as extrudability of the product from the pack. A combination of Hydroxyethyl cellulose and Carbomer is selected based on the experiments and used further for development. In order to finalize the concentration of Carbomer and Hydroxyethyl cellulose in combination, further development trials taken and evaluated for physicochemical analysis.
Table 2: Optimization of the gelling agents in Octenidine Dihydrochloride and Metronidazole benzoate Gel formulation (Oral)
Sr. No. Ingredients Formulation D
Formulation E Formulation F Formulation G
Quantity %w/w
1 Octenidine Dihydrochloride 0.10 0.10 0.10 0.10
2 *Metronidazole Benzoate 1.608 1.608 1.608 1.608
3 Propylene glycol 10.00 10.00 10.00 10.00
4 Hydroxyethyl cellulose 1.50 1.50 1.40 1.60
5 Carbomer 0.15 0.25 0.20 0.20
6 Sorbitol solution 70% (Non-crystallizing) 7.00 7.00 7.00 7.00
7 Butylated Hydroxytoluene 0.05 0.05 0.05 0.05
8 Glycerin 10.00 10.00 10.00 10.00
9 Polyoxyl 40 Hydrogenated castor oil 1.00 1.00 1.00 1.00
10 Sucralose 0.20 0.20 0.20 0.20
11 Double mint flavor 0.30 0.30 0.30 0.30
12 Triethanolamine 0.112 0.14 0.14 0.14
13 Purified water q.s. to 100 q.s. to 100 q.s. to 100 q.s. to 100

Example 2b: Optimization of the antioxidant.
Oxidation may manifest as products with an unpleasant odor, taste, appearance, precipitation, discoloration or even a slight loss of activity. In order to avoid the oxidative degradation of product, BHT added as antioxidant in the formulation. To finalize the concentration of BHT few development trials were executed and. further development trials taken and evaluated for physicochemical analysis.
Table 3: Optimization of antioxidant in Octenidine Dihydrochloride and Metronidazole benzoate Gel formulation (Oral)
Sr.No. Ingredients Formulation H Formulation I
Quantity %w/w
1 Octenidine Dihydrochloride 0.10 0.10
2 *Metronidazole Benzoate 1.608 1.608
3 Propylene glycol 10.00 10.00
4 Hydroxyethyl cellulose 1.50 1.50
5 Carbomer 0.20 0.20
6 Sorbitol solution 70% (Non-crystallizing) 7.00 7.00
7 Butylated Hydroxytoluene 0.0475 0.0525
8 Glycerin 10.00 10.00
9 Polyoxyl 40 Hydrogenated castor oil 1.00 1.00
10 Sucralose 0.20 0.20
11 Double mint flavor 0.30 0.30
12 Triethanolamine 0.112 0.112
13 Purified water q.s. to 100 q.s. to 100

Example 2c: Optimisation of the pH Modifier.
The pH is important in aqueous, drug-product formulation, especially since it involves drug solubility, activity, absorption, stability, sorption and patient comfort. The pH is also related to certain physical characteristics, such as the viscosity of some polymers used as gel-forming agents. The pH of the formulation is also a critical aspect to stabilize it throughout the shelf life. Based on literature, pH range between 4.0 to 7.0 is found to be optimum pH range for stability of formulation. Based on prior experience, trials with different concentrations of Triethanolamine were executed and further development trials taken and evaluated for physicochemical analysis.
Based on the trials, concentration of Triethanolamine is finalized for getting desired pH range between 4.0 to 7.0.

Table 4: Optimization of pH Modifier in Octenidine Dihydrochloride and Metronidazole benzoate Gel formulation (Oral)
Sr. No. Ingredients Formulation J Formulation K
Quantity %w/w
1 Octenidine Dihydrochloride 0.10 0.10
2 *Metronidazole Benzoate 1.608 1.608
3 Propylene glycol 10.00 10.00
4 Hydroxyethyl cellulose 1.50 1.50
5 Carbomer 0.20 0.20
6 Sorbitol solution 70% (Non-crystallizing) 7.00 7.00
7 Butylated Hydroxytoluene 0.05 0.05
8 Glycerin 10.00 10.00
9 Polyoxyl 40 Hydrogenated castor oil 1.00 1.00
10 Sucralose 0.20 0.20
11 Double mint flavor 0.30 0.30
12 Triethanolamine 0.1064 0.1176
13 Purified water q.s. to 100 q.s. to 100

Example 3: Optimisation of manufacturing process parameters.
Manufacturing process of the formulation involved different steps like preparation of aqueous phase, preparation and addition of antioxidant phase, preparation and addition of drug phase, preparation and addition of gelling agents, addition of other excipients like triethanolamine, flavoring agent etc.
Example 3a: Optimisation of Homogenization Speed.
Carbomer and Hydroxyethyl cellulose act as gelling agent. So, it is important to make uniform lump free dispersion after addition of it in the bulk to obtain the optimum viscosity of the product. So, development trials were executed to optimize the homogenization speed after addition of Carbomer and after addition of Hydroxyethyl cellulose in the bulk and further development trials taken and evaluated for physicochemical analysis.
Example 3a: Optimisation of the final mixing time.
Metronidazole benzoate is dispersed in the formulation. So uniform distribution of it in the main bulk is important. Hence final mixing is a critical step during the manufacturing process. Development trials were executed to fix the final mixing time of the formulation.
Example 4: Manufacturing of toothpaste.
(a) Composition of toothpaste.
Table 5: Octenidine Dihydrochloride and Metronidazole benzoate Toothpaste (Oral)
Sr. No Ingredients Quantity (%w/w)
1 Octenidine dihydrochloride 0.10
2 *Metronidazole benzoate 1.608
3 Propylene glycol 5.00
4 Glycerin 15.00
5 Sorbitol solution 70% (Non-crystalline) 5.00
6 Sodium Carboxymethyl Cellulose 1.50
7 Xanthan Gum 3.00
8 Cocamidopropyl Betaine 2.00
9 Sodium Lauryl Sulphate 1.50
10 Butylated Hydroxytoluene 0.05
11 Sodium Saccharin 0.20
12 Sucralose 0.20
13 Sodium Benzoate 0.20
14 Disodium Edetate 0.05
15 Peppermint flavor 0.20
16 Triethanolamine q.s. to pH
17 Citric Acid Monohydrate q.s. to pH
18 Purified Water q.s. to 100
* Metronidazole Benzoate 1.608% w/w is equivalent to Metronidazole l% w/w
(b) Manufacturing Process of toothpaste.
Step 1: Bulk Preparation: In One portion of Purified water add dispensed qty. of Sucralose, Sodium Benzoate, Sodium Saccharin and Disodium Edetate under stirring to form clear solution.
Step 2: Preparation of Octenidine Dihydrochloride Phase: In Second portion of Purified water in separate SS vessel, added Octenidine Dihydrochloride slowly under stirring. Polybag of Octenidine Dihydrochloride rinsed with Purified water and rinsate transferred to bulk. Continue stirring to form a clear solution.
Step 3: Preparation of Metronidazole Benzoate phase: In One portion of Glycerin (about 70% total quantity of Glycerin) in a separate SS container, add Metronidazole Benzoate API slowly under stirring. Rinse polybag of Metronidazole Benzoate with Glycerin (about 1% total quantity of Glycerin) and add rinsate to bulk. Continue stirring to form uniform lump free dispersion.
Step 4: Addition of Octenidine Dihydrochloride phase: Octenidine Dihydrochloride phase prepared in step 2 added to bulk of step 1. Drug phase container rinsed with Fourth portion of Purified water (about 1% total quantity of purified water) and rinsate added to bulk. This phase kept under stirring to form a clear solution.
Step 5: Addition of Metronidazole Benzoate phase: Metronidazole Benzoate phase prepared in step 3 added to bulk of step 4. Drug phase container rinsed with Part E of purified water and bulk kept on stirring under homogenization to form uniform, white colour lump free dispersion.
Step 6: Preparation of Antioxidant phase: To batch quantity of Propylene Glycol in SS container, add batch qty. of BHT. Heated the phase to 60°C to 70°C under stirring to form clear solution. After formation of clear solution, cool down the bulk under stirring to below 25°C to 35°C temperature.
Step 7: Addition of Antioxidant phase: Antioxidant phase prepared in step 6 added to bulk of step 5 under homogenization to form uniform dispersion.
Step 8: Preparation of Xanthan Gum and Sodium Carboxymethyl Cellulose base: Dispersed Batch quantity of Xanthan Gum and Sodium Carboxymethyl Cellulose in Glycerin (remaining quantity of Glycerin) in a separate SS container. Stir to form uniform lump free dispersion.
Step 9: Addition of Xanthan Gum and Sodium Carboxymethyl Cellulose base: Add Step 8 to main bulk of step 7 under stirring to form uniform lump free bulk.
Step 10: Preparation of Sodium Lauryl Sulphate (SLS) Phase: Dissolved batch quantity of SLS in remaining quantity of purified water under stirring to form clear solution.
Step 11: Addition of Sodium Lauryl Sulphate (SLS) phase and Cocamidopropyl Betain: Add Step 10 and Cocamidopropyl Betain to main bulk of step 9 under slow stirring to form uniform bulk.
Step 12: Addition of Flavor: To bulk of step 9 added flavoring agent (Peppermint Flavor) and stir the bulk to form uniform lump free paste.
Step 13: Check the pH of the paste: [Target pH (4.00 to 7.00)] If pH observed outside of target pH range, then adjusted it with Triethanolamine / Citric acid monohydrate as per requirement.
Step 14: Final Mixing: Check the weight of the bulk. Adjusted it with remaining quantity of Purified water and final mixing performed under stirring and vacuum.
Example 5: Manufacturing of Mouthwash / Spray.
(a) Composition of Mouthwash / Spray.
Table 6: Octenidine Dihydrochloride and Metronidazole benzoate Mouthwash (Oral) and Octenidine Dihydrochloride and Metronidazole Spray (Oral) in a suitable packaging device
Sr. No Ingredients Quantity (%w/w)
1 Octenidine dihydrochloride 0.10
2 *Metronidazole benzoate 1.608
3 Propylene glycol 8.00
4 Hydroxyethyl cellulose 0.40
5 Poloxamer 1.00
6 Copovidone 0.50
7 Polyoxyl 40 hydrogenated Castor Oil 1.00
8 Glycerin 10.00
9 Sorbitol solution 70% (Non-crystalline) 20.00
10 Butylated Hydroxytoluene 0.05
11 Sodium Saccharin 0.05
12 Sucralose 0.10
13 Disodium Edetate 0.05
14 Doublemint flavor 0.20
15 Triethanolamine q.s. to pH
16 Citric Acid Monohydrate q.s. to pH
17 Purified Water q.s. to 100
* Metronidazole Benzoate 1.608% w/w is equivalent to Metronidazole l% w/w
(b). Manufacturing Process of Mouthwash/spray:
Step 1: Bulk Preparation: In One portion of Purified water add dispensed qty. of Sucralose, Sodium Saccharin, Sodium Benzoate, Disodium Edetate and copovidone under stirring to form clear solution. Then add Polyoxyl 40 hydrogenated castor oil in it under stirring and homogenization to form clear solution.
Step 2: Preparation of Octenidine Dihydrochloride Phase: In Second portion of Purified water in separate SS vessel, added Octenidine Dihydrochloride slowly under stirring. Polybag of Octenidine Dihydrochloride rinsed with Purified water and rinsate transferred to bulk. Continue stirring to form a clear solution.
Step 3: Preparation of Metronidazole Benzoate phase: In One portion of Glycerin in a separate SS container, add Metronidazole Benzoate API slowly under stirring. Rinse polybag of Metronidazole Benzoate with Glycerin (remaining quantity of Glycerin) and add rinsate to SS container. Continue stirring to form uniform lump free dispersion.
Step 4: Addition of Octenidine Dihydrochloride phase: Octenidine Dihydrochloride phase prepared in step 2 added to bulk of step 1. Drug phase container rinsed with Fourth portion of Purified water and rinsate added to bulk. This phase kept under stirring to form a clear solution.
Step 5: Addition of Metronidazole Benzoate phase: Metronidazole Benzoate phase prepared in step 3 added to bulk of step 4. Drug phase container rinsed with Part E of purified water and bulk kept on stirring and homogenization to form uniform lump free dispersion.
Step 6: Preparation of Antioxidant phase and Hydroxyethyl cellulose Phase: To about 95% total quantity of Propylene Glycol in SS container, add batch qty. of BHT. Heated the phase to 60°C to 70°C under stirring to form clear solution. After formation of clear solution, kept cool down the bulk under stirring to below 25°C to 35°C temperature. To this, add Hydroxyethyl cellulose in it under stirring to form uniform lump free dispersion.
Step 7: Addition of Antioxidant and Hydroxyethyl cellulose Phase: Add Step 6 into bulk of step 5 under stirring and homogenization. This container rinsed with remaining quantity propylene glycol and then with batch quantity of Sorbitol solution 70%. Rinsate added to bulk followed by stirring for about 25 to 35 minutes. to form uniform dispersion.
Step 8: Addition of Doublemint Flavor: To bulk of step 7 added flavoring agent (Doublemint Flavor) under stirring and homogenization for about 10 to 15 minutes.
Step 9: Preparation and Addition of Poloxamer Phase: in remaining quantity of Purified water in SS container, add batch qty. of Poloxamer under stirring to form clear solution. Add this Poloxamer solution to Step 8 under stirring for 10 to 15 minutes.
Check the pH of the bulk. [Target pH (4.00 to 7.00)]. If pH observed is outside of target pH range, then adjusted it with Triethanolamine / Citric acid monohydrate as per requirement.
Step 10: Final Mixing: Check the weight of the bulk. Adjusted it with remaining quantity of Purified water and final mixing performed under stirring and vacuum.
Step 11: Packaging in spray device: For oral spray formulation, the final product obtained in Step 10 can be filled in suitable spray device.
Example 6: Manufacturing of Ointment formulation.
(a) Composition of ointment.
Table 7: Octenidine Dihydrochloride and Metronidazole benzoate Ointment (Topical)
Sr. No Ingredients Quantity (%w/w)
1 Octenidine dihydrochloride 0.10
2 *Metronidazole benzoate 1.608
3 Mineral Oil Part A 9.00
4 Mineral Oil Part B 3.00
5 White Soft Paraffin– (White Petroleum Jelly) 86.29
* Metronidazole Benzoate 1.608% w/w is equivalent to Metronidazole l% w/w
(b) Manufacturing Process of ointment:
Step 1: Preparation of Ointment Base: Dispensed batch quantity of White soft paraffin in main manufacturing vessel. Heat the bulk to 65°C to 75°C under stirring to form clear solution.
Step 2: Start cooling in Step 1 under stirring to drop the temperature between 40°C to 50°C.
Step 3: Preparation of API Phase: In Part A of Mineral Oil in separate SS vessel, added Octenidine Dihydrochloride slowly under stirring and under homogenization for about 40 to 50 minutes to form uniform dispersion. Then add Metronidazole Benzoate in it while stirring and under homogenization for about 55 to 60 minutes to form uniform lump free dispersion.
Step 4: Addition of API Phase: Add API phase of Step 3 to main bulk of Step 2 (Temperature of main bulk is between 40°C to 50°C during addition of API) under homogenization and stirring. Rinse the API container with Part B of Mineral oil and the rinsate to bulk. Mix the bulk for about 40 to50 minutes under stirring and homogenization.
Step 5: Cooling of API: Further cool down the bulk under stirring to temperature below 25°C to 35°C.
Step 6: Final Mixing: At the temperature below 25°C to 35°C, final mixing of the bulk done for 25 to 35 minutes.
Example 7: Manufacturing of Ointment formulation.
(a) Composition of ointment formulation.
Table 8: Octenidine Dihydrochloride and Metronidazole benzoate Ointment (Topical)
Sr. No Ingredients Quantity (%w/w)
1 Octenidine dihydrochloride 0.10
2 *Metronidazole benzoate 1.608
3 Polyethylene Glycol 200/300/400/600/800 (Part A) 15.00
4 Polyethylene Glycol 200/300/400/600/800 (Part B) 5.00
5 Polyethylene Glycol 3350/4000/6000 q.s. to 100
* Metronidazole Benzoate 1.608% w/w is equivalent to Metronidazole l% w/w
(b) Manufacturing Process of ointment:
Step 1: Preparation of Ointment Base: Dispensed batch quantity of Polyethylene Glycol 3350/4000/6000 in main manufacturing vessel. Heat the bulk to 70°C to 75°C under stirring to form clear solution.
Step 2: Start cooling in Step 1 under stirring to drop the temperature between 40°C to 50°C.
Step 3: Preparation of API Phase: In Part A of Polyethylene Glycol 200/300/400/600/800 in separate SS vessel, added Octenidine Dihydrochloride slowly under stirring and under homogenization for about 40 to 50 minutes to form uniform dispersion. Then add Metronidazole Benzoate in it while stirring and under homogenization for about 55 to 60 minutes to form uniform lump free dispersion.
Step 4: Addition of API Phase: Add API phase of Step 3 to main bulk of Step 2 (Temperature of main bulk is between 40°C to 50°C during addition of API) under homogenization and stirring. Rinse the API container with Part B of Polyethylene Glycol 200/300/400/600/800 and add the rinsate to bulk. Mix the bulk for about 55 to 60 minutes under stirring and homogenization.
Step 5: Cooling of API: Further cool down the bulk under stirring to temperature below 25°C to 35°C.
Step 6: Final Mixing: At the temperature below 25°C to 35°C, final mixing of the bulk done for 25 to 30 minutes.
Example 8: Manufacturing of cream.
(a) Composition of cream.
Table 9: Octenidine Dihydrochloride and Metronidazole benzoate
Cream (Topical)
Sr. No Ingredients Quantity (%w/w)
1 Octenidine dihydrochloride 0.100
2 *Metronidazole benzoate 1.608
3 Xanthan Gum 0.200
4 Propylene glycol 5.000
5 Fractionated coconut oil 3.000
6 Glycerin 10.000
7 Butylated Hydroxytoluene 0.050
8 Sodium Benzoate 0.500
9 Disodium Edetate 0.050
10 Cetomacrogol 1000 5.000
11 Glyceryl Monostearate (GMS) 3.000
12 Cetostearyl Alcohol 7.000
13 Triethanolamine q.s to pH
14 Citric Acid Monohydrate q.s to pH
15 Purified Water q.s to 100
* Metronidazole Benzoate 1.608% w/w is equivalent to Metronidazole l% w/w
(b) Manufacturing Process of cream:
Step 1: Aqueous Phase Preparation: In One portion of purified water, add dispensed qty. of Disodium edetate and Sodium Benzoate under stirring to form clear solution. Then dispersed Xanthan Gum in it under stirring to form uniform lump free dispersion. Heat the aqueous phase to 70°C to 80°C under stirring.
Step 2: Oil Phase Preparation: Propylene Glycol, Butylated Hydroxytoluene, Fractionated coconut oil, Cetomacrogol 1000, Cetostearyl Alcohol and Glyceryl Monostearate (GMS) in another SS container. Heat the bulk to 70°C to 80°C under stirring to melt the phase completely and to form clear solution.
Step 3: Emulsification: Add Step 2 to Step 1 (Temperature of both phases is between 70°C to 80°C) under homogenization and under stirring for about 35 to 45 minutes to form uniform emulsion.
Step 4: Cooling: Cool down the temperature of the bulk in Step 3 to below 40 to 45°C under stirring.
Step 5: Preparation of Octenidine Dihydrochloride Phase: In Second portion of Purified water add Octenidine Dihydrochloride slowly under stirring. Continue stirring till to form a clear solution.
Step 6: Preparation of Metronidazole Benzoate phase: In approx. about 90% total quantity of Glycerin in a separate SS container, add Metronidazole Benzoate API slowly under stirring. Continue stirring till to form uniform lump free dispersion.
Step 7: Addition of Octenidine Dihydrochloride phase: Add Step 5 to main bulk of Step 4 under stirring and homogenization. Continue mixing for about 10 to15 minutes to form uniform lump free bulk.
Step 8: Addition of Metronidazole Benzoate phase: Add Step 6 (Metronidazole Benzoate phase) to main bulk of Step 7. Rinse the API container with the remaining quantity of Glycerin and add the rinsate to the bulk. Continue mixing done under stirring and homogenization for about 25 to 30 minutes to form uniform lump free bulk.
Step 8: Cooling: Further Cool down the temperature of the bulk in Step 7 to below 25 to 30°C under stirring.
Step 9: Check the pH of the bulk. [Target pH (4.00 to 7.00)]. If pH observed outside of target pH range, then adjusted it with Triethanolamine / Citric acid monohydrate as per requirement.
Step 10: Final Mixing: Check the weight of the bulk. Adjusted it with remaining quantity of Purified water and final mixing performed under stirring and vacuum.
Example 9: Manufacturing of lotion.
(a) Composition of lotion.
Table 10: Octenidine and Metronidazole benzoate Lotion (Topical)
Sr. No Ingredients Quantity (%w/w)
1 Octenidine dihydrochloride 0.100
2 *Metronidazole benzoate 1.608
3 Xanthan Gum 0.500
4 Propylene glycol 3.000
5 Mineral Oil 4.000
6 Glycerin 10.000
7 Butylated Hydroxytoluene 0.050
8 Methylparaben 0.200
8 Propylparaben 0.020
9 Disodium Edetate 0.050
10 Polysorbate 80 2.000
11 Glyceryl Monostearate (GMS) 3.000
12 Cetyl Alcohol 3.000
12 Stearic acid 2.000
13 Triethanolamine q.s to pH
14 Citric Acid Monohydrate q.s to pH
15 Purified Water q.s. to 100
* Metronidazole Benzoate 1.608% w/w is equivalent to Metronidazole l% w/w
(b) Manufacturing Process of lotion:
Step 1: Aqueous Phase Preparation: In Purified water add dispensed qty. of Disodium edetate under stirring to form clear solution. Then dispersed Xanthan Gum in it under stirring to form uniform lump free dispersion. Heat the aqueous phase to 70°C to 75°C under stirring.
Step 2: Oil Phase Preparation: Add Propylene Glycol, Butylated Hydroxytoluene, Mineral oil, Methylparaben, Propylparaben, Cetyl Alcohol, Polysorbate 80, Stearic acid and Glyceryl Monostearate (GMS) in another SS container. Heat the bulk to 70°C to 75°C under stirring to melt the phase completely and to form clear solution.
Step 3: Emulsification: Add Step 2 to Step 1 (Temperature of both phases is between 70°C to 75°C) under homogenization and under stirring for about 25 to 35 minutes to form uniform emulsion.
Step 4: Cooling: Cool down the temperature of the bulk in Step 3 to below 45°C under stirring.
Step 5: Preparation of Octenidine Dihydrochloride Phase: In Second portion of Purified water add Octenidine Dihydrochloride slowly under stirring. Continue stirring till to form a clear solution.
Step 6: Preparation of Metronidazole Benzoate phase: In approx. about 90% total quantity of Glycerin in a separate SS container, add Metronidazole Benzoate API slowly under stirring. Continue stirring till to form uniform lump free dispersion.
Step 7: Addition of Octenidine Dihydrochloride phase: Add Step 5 to main bulk of Step 4 under stirring and homogenization. Continue mixing for about 10 to 20 minutes to form uniform lump free bulk.
Step 8: Addition of Metronidazole Benzoate phase: Add Step 6 (Metronidazole Benzoate phase) to main bulk of Step 7. Rinse the API container with the remaining quantity of Glycerin and add the rinsate to the bulk. Continue mixing done under stirring and homogenization for about 25 to 35 minutes to form uniform lump free bulk.
Step 9: Cooling: Further Cool down the temperature of the bulk in Step 8 to below 30°C under stirring.
Step 10: Check the pH of the bulk. [Target pH (4.00 to 7.00)]. If pH observed outside of target pH range, then adjusted it with Triethanolamine / Citric acid monohydrate as per requirement.
Step 11: Final Mixing: Check the weight of the bulk. Adjusted it with remaining quantity of Purified water and final mixing performed under stirring and vacuum.
Stability details of the gel formulation (Example 1):
Formal batches manufactured as per the above manufacturing formula and process and charged for stability at long term condition, intermediate condition and accelerated condition. Stability data for all experiments was found satisfactory and within specification limit.
Octenidine-Metronidazole Gel Stability studies
Formal batches were manufactured as per the manufacturing formula and process of Example 1 and charged for stability at long term condition, intermediate condition and accelerated condition. Parameters such as product description, pH, viscosity, assay, related substance and microbial limit test were evaluated throughout the studies. Below Table provides an overview of the Stability conditions and time period for Example 1 according to the International Conference for Harmonization (ICH) guidelines for Stability Testing.
Table 11: Stability conditions and time period for Example 1
Condition Time Period
40°C/75%RH 6 M
30°C/65%RH 24 M
25°C/60%RH 24 M
30°C/75%RH 24 M

Tables 12-15 provide Stability data of Octenidine-Metronidazole gel (Example 1) in different stability conditions.
Table 12: Stability Condition: 40°C/75%RH Climatic Zone: IVB
Tests Specification Initial 3 Months 6 Months
Description White to off-white colored gel. Complies Complies Complies
pH Between 4.00 to 7.00 5.89 5.44 5.27
Viscosity$ (cP) 90000- 600000 cps 357000 243900 246600
Assay (By HPLC)
Octenidine dihydrochloride Not less than 90.0% and Not more than 110.0% of the labelled amount. 102.5 101.7 99.7
Metronidazole Benzoate equivalent to Metronidazole Not less than 90.0% and Not more than 110.0% of the labelled amount. 102.5 100.5 102.0
Related Substance (By HPLC)
Metronidazole Benzoate Impurity A Not more than 2.5% 0.03 0.74 1.17
Metronidazole Benzoate Impurity B Not more than 0.5% BDL ND ND
Metronidazole Benzoate Impurity C Not more than 1.0% ND 0.17 0.29
Any maximum unknown impurity of Metronidazole Benzoate Not more than 0.2%. 0.05 0.05 0.08
4-Octyl Amino Pyridine Impurity
Not more than 1.0% BDL BDL BDL
Any maximum unknown impurity of Octenidine Dihydrochloride Not more than 0.5% ND BDL 0.12
Total impurities (Excluding known impurities) Not more than 2.0%. 0.05 0.08 0.26
Microbiology Limit Tests (MLT)
Total aerobic microbial count Not more than 200cfu/g <10 < 10 < 10
Total yeast and mould count Not more than 20cfu/g <10 < 10 < 10
Test for specified microorganisms
E. coli Should be absent per g Absent Absent Absent
Salmonella Should be absent per 10g Absent Absent Absent
P. aeruginosa Should be absent per g Absent Absent Absent
S. aureus Should be absent per g Absent Absent Absent

Table 13: Stability Condition: 30°C/65%RH Climatic Zone: Not Applicable
Tests Specification Initial 3 Month 6 Month 12 Months 24 Months
Description White to off-white colored gel. Complies Complies Complies Complies Complies
pH Between 4.00 to 7.00 5.89 5.74 5.64 5.25 5.49
Viscosity$ (cP) 90000- 600000 cps 357000 307800 348300 306300 314700
Assay (By HPLC)
Octenidine dihydrochloride
Not less than 90.0% and Not more than 110.0% of the labelled amount. 102.5 102.8 100.1 99.4 101.3
Metronidazole Benzoate equivalent to Metronidazole Not less than 90.0% and Not more than 110.0% of the labelled amount. 102.5 102.6 101.8 99.3 100.2
Related Substance (By HPLC)
Metronidazole Benzoate Impurity A Not more than 2.5% 0.03 0.20 0.32 0.50 0.76
Metronidazole Benzoate Impurity B Not more than 0.5% BDL ND ND ND ND
Metronidazole Benzoate Impurity C Not more than 1.0% ND BDL 0.06 0.09 0.18
Any maximum unknown impurity of Metronidazole Benzoate Not more than 0.2%. 0.05 0.03 0.03 0.03 0.05
4-Octyl Amino Pyridine Impurity
Not more than 1.0% BDL BDL BDL BDL BDL
Any maximum unknown impurity of Octenidine Dihydrochloride Not more than 0.5% ND BDL BDL BDL 0.08
Total impurities (Excluding known impurities) Not more than 2.0%. 0.05 0.03 0.03 0.07 0.16
Microbiology Limit Tests (MLT)
Total aerobic microbial count Not more than 200cfu/g < 10 < 10 < 10 < 10 < 10
Total yeast and mould count Not more than 20cfu/g < 10 < 10 < 10 < 10 < 10
Test for specified microorganisms
E. coli Should be absent per g Absent Absent Absent Absent Absent
Salmonella Should be absent per 10g Absent Absent Absent Absent Absent
P. aeruginosa Should be absent per g Absent Absent Absent Absent Absent
S. aureus Should be absent per g Absent Absent Absent Absent Absent

Table 14: Stability Condition: 25°C/60%RH Climatic Zone: Not Applicable
Tests Specification Initial 3 Month 6 Month 12 Months 24 Months
Description White to off-white colored gel. Complies Complies Complies Complies Complies
pH Between 4.00 to 7.00 5.89 5.82 5.75 5.56 5.71
Viscosity$ (cP) 90000- 600000 cps 357000 331500 366900 307500 336300
Assay (By HPLC)
Octenidine dihydrochloride
Not less than 90.0% and Not more than 110.0% of the labelled amount. 102.5 102.2 100.9 99.6 101.7
Metronidazole Benzoate equivalent to Metronidazole Not less than 90.0% and Not more than 110.0% of the labelled amount. 102.5 102.9 102.6 99.9 101.1
Related Substance (By HPLC)
Metronidazole Benzoate Impurity A Not more than 2.5% 0.03 0.11 0.17 0.27 0.42
Metronidazole Benzoate Impurity B Not more than 0.5% BDL ND ND ND ND
Metronidazole Benzoate Impurity C Not more than 1.0% ND BDL BDL BDL 0.09
Any maximum unknown impurity of Metronidazole Benzoate Not more than 0.2%. 0.05 0.03 0.03 0.03 0.03
4-Octyl Amino Pyridine Impurity
Not more than 1.0% BDL BDL BDL BDL BDL
Any maximum unknown impurity of Octenidine Dihydrochloride Not more than 0.5% ND BDL BDL BDL BDL
Total impurities (Excluding known impurities) Not more than 2.0%. 0.05 0.03 0.03 0.03 0.06
Microbiology Limit Tests (MLT)
Total aerobic microbial count Not more than 200cfu/g < 10 < 10 < 10 < 10 < 10
Total yeast and mould count Not more than 20cfu/g < 10 < 10 < 10 < 10 < 10
Test for specified microorganisms
E. coli Should be absent per g Absent Absent Absent Absent Absent
Salmonella Should be absent per 10g Absent Absent Absent Absent Absent
P. aeruginosa Should be absent per g Absent Absent Absent Absent Absent
S. aureus Should be absent per g Absent Absent Absent Absent Absent

Table 15: Stability Condition: 30°C/75%RH Climatic Zone: IVB
Tests Specification Initial 3 Month 6 Month 12 Months 24 Months
Description White to off-white colored gel. Complies Complies Complies Complies Complies
pH Between 4.00 to 7.00 5.89 5.74 5.59 5.31 5.49
Viscosity$ (cP) 90000- 600000 cps 357000 348600 294600 295500 290100
Assay (By HPLC)
Octenidine dihydrochloride
Not less than 90.0% and Not more than 110.0% of the labelled amount. 102.5 101.2 99.2 100.6 100.0
Metronidazole Benzoate equivalent to Metronidazole Not less than 90.0% and Not more than 110.0% of the labelled amount. 102.5 101.5 102.4 100.6 99.7
Related Substance (By HPLC)
Metronidazole Benzoate Impurity A Not more than 2.5% 0.03 0.21 0.34 0.53 0.83
Metronidazole Benzoate Impurity B Not more than 0.5% BDL ND ND ND ND
Metronidazole Benzoate Impurity C Not more than 1.0% ND BDL 0.07 0.10 0.20
Any maximum unknown impurity of Metronidazole Benzoate Not more than 0.2%. 0.05 0.03 0.03 0.04 0.05
4-Octyl Amino Pyridine Impurity
Not more than 1.0% BDL BDL BDL BDL BDL
Any maximum unknown impurity of Octenidine Dihydrochloride Not more than 0.5% ND BDL BDL BDL 0.08
Total impurities (Excluding known impurities) Not more than 2.0%. 0.05 0.03 0.06 0.07 0.16
Microbiology Limit Tests (MLT)
Total aerobic microbial count Not more than 200cfu/g < 10 < 10 < 10 < 10 < 10
Total yeast and mould count Not more than 20cfu/g < 10 < 10 < 10 < 10 < 10
Test for specified microorganisms
E. coli Should be absent per g Absent Absent Absent Absent Absent
Salmonella Should be absent per 10g Absent Absent Absent Absent Absent
P. aeruginosa Should be absent per g Absent Absent Absent Absent Absent
S. aureus Should be absent per g Absent Absent Absent Absent Absent
ND: Not Detected
BDL: Below disregard limit ,CLAIMS:1. A stable pharmaceutical composition comprising:
a) an antiseptic agent selected from Octenidine, or its pharmaceutically acceptable salts thereof;
b) an antimicrobial agent selected from Metronidazole, or its pharmaceutically acceptable salts thereof; and
c) one or more pharmaceutically acceptable excipients.

2. The composition as claimed in claim 1, wherein the composition is in a form selected from solution, suspension, elixir, emulsion, gel, emulgel, lotion, cream, ointment, paste, mouthwash, spray, gargle, throat paints, transdermal patches, and drops.

3. The composition as claimed in claim 2, wherein the composition is an oromucosal gel.

4. The composition as claimed in claim 1, wherein the Octenidine dihydrochloride and Metronidazole benzoate are present in a ratio of 1:5 to 1:25.

5. The composition as claimed in claim 1, wherein the Octenidine dihydrochloride is in an amount of 0.01 to 10 wt.% of total composition, and the Metronidazole benzoate is in an amount of 0.1 to 10 wt.% of total composition.

6. The composition as claimed in claim 1, wherein the pharmaceutically acceptable excipient is in an amount of 80 to 99.89 wt.% of total composition.

7. The composition as claimed in claim 1, wherein the particle size distribution of Metronidazole benzoate used in the said pharmaceutical composition has X90 in the range between 1 to 150 µm.

8. The composition as claimed in claim 1, wherein the one or more pharmaceutically acceptable excipient is selected from a group comprising: solvent/vehicle /vehicle base, solubilizer, thickening or gelling agents, emollients, humectants, pH modifiers, preservatives, chelating agents, surfactant/emulsifiers, penetration enhancers, antioxidants, colorants, sweeteners and flavoring agents.
9. The composition as claimed in claim 8, wherein the solvent/vehicle /vehicle base is present in an amount of 40 to 90 wt. %, thickening or gelling agent is present in an amount of 0.1 to 10 wt. %, solubilizer is present in an amount 5 to 40 wt. %, emollient is present in an amount of 1 to 30 wt. %, humectant is present in an amount of 5 to 25 wt. %, preservative is present in an amount of 0.1 to 1 wt %, pH modifier is present in an amount of 0.05 to 5 wt%, chelating agent is present in an amount of 0.01 to 1 wt. %, surfactant/emulsifier is present in an amount of 0.5 to 20 wt. %, penetration enhancer is present in an amount of 3 to 20 wt. %, antioxidant is present in an amount of 0.01 to 5 wt. %, sweetener is present in an amount of 0.01 to 5 wt. % and flavourant is present in an amount of 0.01 to 2 wt. % of the total composition.

10. The composition as claimed in claim 8, wherein the solvent/vehicle/vehicle base is selected from a group comprising: ethanol, isopropanol, butyl alcohol, dimethyl isosorbide, propylene glycol, glycerin, ethylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, petrolatum jelly and purified water.

11. The composition as claimed in claim 8, wherein the solubilizer is selected from a group comprising: water, propylene glycol, glycerin, sorbitol, mineral oil, polyethylene glycol and vegetable oils.

12. The composition as claimed in claim 8, wherein the thickening or gelling agent is selected from a group comprising: cellulose derivatives, carbomer, carbomer copolymers, gelatin, aluminum monostearate, dextrin, sodium alginate, alginic acid, pectin, acacia, carrageenan, xanthan gum, tragacanth, magnesium aluminum silicate, bentonite, poloxamers, polyvinyl alcohol, or a combination thereof, and wherein the cellulose derivative is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxy methylcellulose (HMC), sodium carboxymethyl cellulose and methylcellulose (MC) and a combination thereof.

13. The composition as claimed in claim 8, wherein the surfactant/emulsifier is selected from a group comprising: quaternary ammonium compounds, behentrimonium chloride, benzalkonium chloride, ammonium lauryl sulfate, sodium laureth sulfate, sodium lauryl sarcosinate, sodium myreth sulfate, sodium pareth sulfate, sodium stearte, sodium lauryl sulfate, a-olefin sulfonate, ammonium laureth sulfate, cetomacrogol 1000, cetostearyl alcohol, cetyl alcohol, glyceryl monostearate, tween 80, sorbitans, polysorbates, poloxamers, isoceteth-20, sucrose ester, sorbitan ester, soybean phospholipid, monoglyceride laurate, propylene glycol fatty acid ester, polyethylene glycol hydrogenated castor oil, alkylamidopropylamine N-oxide, alkyldimethylamine N-oxide, alkylbetaine, alkylamidopropylbetaine, Cocamidopropyl betaine, cocoamphoacetate, cocoamphodiacetate and a combination thereof.

14. The composition as claimed in claim 8, wherein the preservative is selected from a group comprising: methyl paraben, propyl paraben, methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, sodium benzoate, benzoic acid and a combination thereof.

15. The composition as claimed in claim 8, wherein the antioxidant is selected from a group comprising: epicatechin, epicatechin gallate, butylated hydroxy toluene, butylated hydroxy anisole, Propyl Gallate (PG), Tert-Butyl Hydroquinone (TBHQ) and a combination thereof.

16. The composition as claimed in claim 8, wherein the pH modifier is selected from a group comprising: acidic pH modifiers and basic pH modifiers including citric acid, lactic acid, sodium citrate, tromethamine, triethanolamine, sodium hydroxide, potassium hydroxide, phosphoric acid, sulfuric acid, hydrochloric acid and a combination thereof.

17. The composition as claimed in claim 8, wherein the emollient is selected from a group comprising: petroleum jelly, mineral oil, lanolin and liquid paraffin, natural oils like vegetable oils selected from a group comprising: coconut oil, almond oil, corn oil, jojoba oil, argan oil, sesame oil, palm oil, dimethicone, glycerin, propylene glycol, polyethylene glycol and a combination thereof.

18. The composition as claimed in claim 8, wherein the humectant is selected from a group comprising: glycerin, hyaluronic acid, propylene glycol, honey, urea and a combination thereof.
19. The composition as claimed in claim 8, wherein the chelating agent is selected from a group comprising: disodium edetate, tetrahydroxypropyl ethylenediamine and a combination thereof.

20. The composition as claimed in claim 8, wherein the penetration enhancer is selected from a group comprising: sulphoxides, azones, pyrrolidone, alcohols, alkanols, glycols and a combination thereof.

21. The composition as claimed in claim 8, wherein the sweetener is selected from a group comprising: sodium saccharin, sodium cyclamate, sucrose, lactose, maltose, fructose, aspartame, sucralose, neotame, advantame, saccharin, sorbitol and a combination thereof.

22. The composition as claimed in claim 8, wherein the flavourant is selected from a group comprising: volatile oil, aldehyde, ginger oil, peppermint oil, menthol, lemongrass oil, fruit, citrus, cherry and a combination thereof.

23. A stable pharmaceutical gel composition, wherein the composition comprises:
a. Octenidine or its pharmaceutically acceptable salt in an amount ranging from 0.01 to 10% by weight of the composition;
b. Metronidazole or its pharmaceutically acceptable salt in an amount ranging from 0.1 to 10% by weight of the composition;
c. Solubilizer in an amount ranging from 5 to 40 % by weight of the composition;
d. Emulsifier in an amount ranging from 0.5 to 20 % by weight of the composition;
e. Gelling agents in an amount ranging from 0.1 to 10 % by weight of the composition;
f. Sweetener in an amount ranging from 0.01 to 5 % by weight of the composition;
g. Antioxidant in an amount ranging from 0.01 to 5% by weight of the composition;
h. Flavourant in an amount ranging from 0.01 to 2 % by weight of the composition;
i. pH modifier in an amount ranging from 0.05 to 5 % by weight of the composition; and
j. Vehicle in an amount ranging from 40 to 90 % by weight of the composition.
24. The stable pharmaceutical gel composition as claimed in claim 23, wherein the composition comprises:
a. Octenidine Dihydrochloride in an amount ranging from 0.01 to 10% by weight of the composition;
b. Metronidazole Benzoate in an amount ranging from 0.1 to 10% by weight of the composition;
c. Propylene glycol in an amount ranging from 5 to 20 % by weight of the composition;
d. Glycerin in an amount ranging from 5 to 20 % by weight of the composition;
e. Polyoxyl 40 Hydrogenated Castor Oil in an amount ranging from 0.5 to 20 % by weight of the composition;
f. Sorbitol solution 70% in an amount ranging from 5 to 20 % by weight of the composition;
g. Hydroxyethyl cellulose in an amount ranging from 0.5 to 10 % by weight of the composition;
h. Carbomer in an amount ranging from 0.5 to 10 % by weight of the composition;
i. Sucralose in an amount ranging from 0.01 to 5 % by weight of the composition;
j. Butylated Hydroxytoluene in an amount ranging from 0.05 to 5 % by weight of the composition;
k. Flavourant in an amount ranging from 0.01 to 2 % by weight of the composition;
l. Triethanolamine in an amount ranging from 0.05 to 5 % by weight of the composition; and
m. Purified water in an amount ranging from 40 to 90 % by weight of the composition.

25. A process for preparing a pharmaceutical composition, said process comprising:
a. providing Octenidine, or its pharmaceutically acceptable salts thereof;
b. providing Metronidazole, or its pharmaceutically acceptable salts thereof; and
c. combining Octenidine, or its pharmaceutically acceptable salts, Metronidazole, or its pharmaceutically acceptable salts with one or more pharmaceutically acceptable excipients.

26. The process for preparing a pharmaceutical composition as claimed in claim 25, wherein the composition is in a gel form, the process comprises:
a. preparing a clear solution of sweetener and emulsifier;
b. preparing a clear solution of Octenidine dihydrochloride;
c. preparing a dispersion of Metronidazole benzoate;
d. dissolving an antioxidant in a suitable solubilizer;
e. adding the clear solution of Octenidine dihydrochloride to the clear solution of step (a);
f. adding the dispersion of Metronidazole benzoate to the clear solution of step (e) to obtain uniform dispersion;
g. adding the clear solution of antioxidant to dispersion obtained in step (f);
h. adding a gelling agent to the dispersion of step (g) to obtain the gel;
i. adding a flavourant to the gel obtained in step (h);
j. adding a pH modifier to step (i) to obtain a pH in the range 4 to 7; and
k. making up the weight by adding vehicle to step (j) to obtain the final composition.