DESC:FIELD OF INVENTION:
The present invention relates to topical composition for mouth ulcers more particular the invention relates to topical composition comprising hyaluronic acid, NSAIDs and local anesthetic.
BACKGROUND: 5
Mouth ulcers also known as Aphthous ulcers or canker sores are very commonly occurring conditions. Mouth ulcer generally occur on the lining of mouth or found on gums, inner lips, inner cheeks or tongue. These are characterized as a painful sores or small lesions which develops within the mucous membrane.
The exact cause of the mouth ulcers is not known but certain factors have been 10 identified which may include accidental bites, injuries due to dental braces or dental treatments, bacterial & viral infections, hormonal changes, iron deficiency, stress or anxiety, food allergy. Minors ulcers are generally self-healed and doesn¡¯t require any treatment however some ulcers take several days or weeks to heal and generally required treatment. 15 Indian patent IN417633 B discloses mucoadhesive gel composition for mouth ulcers, the mucoahesive gel of the prior art comprises ascorbic acid loaded microbeads and utilizes bio-adhesive polymer that can stick on to mucosal epithelial surface in the oral cavity and can provide better absorption characteristics.
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Patent application AU2021103597 A4 discloses polyherbal gel composition comprising extract of a blend of Azadirachta indica oil, Syzgiumaromaticum oil and Curcuma longa. The herbal composition of the prior art is used in oral sub mucous fibrosis, zinzivitis, and mouth ulcers due to chewing of tobacco without causing any side effects 5 Patent application US20120328537 A1 discloses an oral and extra-oral topical wound treatment gel comprising higher concentration of Xylitol with another non-Xylitol anti-microbial sweetener. Patent application WO98/10770 A1 discloses a topical composition containing fluocinonide in a base of glyceryl monooleate with a water content of less than 10 about 20 % W/W is provided for the treatment of oral ulcerations, inflammation and lesions of the oral cavity. The composition is smeared thinly over the ulcer and forms a very mucoadhesive film which holds the fluocinonide in contact with the ulcer for a prolonged period. The prior arts focuses only on the advancement in topical composition and are silent 15 on treatment of pain, inflammation and discomfort a person experience in mouth ulcers.
The aim of the treatment should decrease the pain and provide comfort and promote healing. General measures involve medicated toothpastes, antibacterial
4
mouth washes, liquid antacid for mouth pain, pain medicine such as use of acetaminophen and ibuprofen to reduce pain. Non-pharmacological approach includes intake of adequate fluids, keep yourself hydrated, intake soft foods which doesn¡¯t require chewing, avoid spicy and salty food, acidic fruit and using soft toothbrush and salt mouth wash. 5 The common treatment method includes use of oral gels. Oral gels are generally preferred over oral therapy or other methods as gels provide instant relief from pain as they are directly applied over the sores or lesions and provide rapid onset of action owing to high permeability of gel. The combination of anti-inflammatory pain reliever with local anesthetic is a 10 preferred choice of drugs for mouth ulcer Gels. Anti-inflammatory pain relievers such as diclofenac, choline salicylates, ibuprofen. These drugs help in relieving the pain and discomfort. Topical Nonsteroidal anti-inflammatory drugs (NSAIDs) are generally preferred as they block the production of enzyme cyclooxygenase (COX). The COX inhibitors are responsible for production of prostaglandins. Prostaglandins 15 are lipids which causes inflammatory response and pain in body, NSAIDs block the inhibition of prostaglandins which relieves the pain and reduces the inflammation. Local anesthetic such as lidocaine, Benzocaine, bupivacaine, ropivacaine, mepivacaine block the neural conduction by inhibiting the influx of sodium ions
5
through channels or ionophores within neuronal membranes and numb the tissues in a specific area. Thus combining NSAIDs with local anesthetic is a rational approach in treating pain, discomfort and inflammation associated with mouth ulcers. The aim of the present invention is to provide a synergistic composition in treatment of mouth ulcers, thus 5 the present invention provides a synergistic combination of NSAIDs and local anesthetic for effective management of pain, discomfort and inflammation associated with mouth ulcer. The applicant of the present invention has surprisingly found that adding hyaluronic acid with NSAIDs and local anesthetic is able to alleviate the symptoms more 10 efficiently, reduces the duration of ulceration than using mono-therapy. Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan found throughout the body's connective tissue. Topical use of 0.2% HA is clinically reported to be an effective and safe therapy in managing oral ulcer. HA coats the oral mucosa and accelerate tissue healing, reduces inflammation, pain and area of ulcers. Thus, combining HA with 15 NSAIDs and local anesthetic in single composition provides complementary mechanism of action, synergistic effects, cost effective, minimize dose frequency and provides improved therapeutic effectiveness than monotherapy. None of the prior art discloses or suggest a topical gel comprising triple combination of Hyaluronic acid (HA), NSAIDs and local anesthetic which provide effective 20
6
treatment against mouth ulcers. The present invention provides triple combination of active agents in effective treatment of mouth ulcers and provides complementary mechanism and act synergistically by: i. NSAIDs reduces pain, inflammation and swelling caused by sores/ulcers ii. Local anesthetic numbs the tissue for shorter period of time by blocking the 5 pathway of the pain signals along the nerves thereby provide temporary relief from the pain. iii. Hyaluronic acid accelerate tissue healing, reduces inflammation, pain and area of ulcers
Objective: 10 An objective of the present invention is to provide a pharmaceutical composition comprising triple combination of Hyaluronic acid (HA), NSAIDs and local anesthetic for effective treatment of mouth ulcers wherein pharmaceutical composition is a topical formulation. Another objective of the present invention is to provide topical formulation 15 comprising Hyaluronic acid (HA), NSAIDs and local anesthetic wherein NSAIDs is choline salicylates and local anesthetic is Lignocaine or pharmaceutical acceptable salts thereof.
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Yet another objective of the present invention is to provide topical formulation comprising Hyaluronic acid, choline salicylates and lignocaine hydrochloride wherein topical formulation is topical gel. The present invention also provides method of preparation thereof. Summary: 5 The present invention provides a topical formulation comprising fixed dose combination of Hyaluronic acid, choline salicylates and lignocaine hydrochloride for effective treatment of mouth ulcer. The topical formulation reduces pain, inflammation and discomfort, sore size associated with mouth ulcers. The topical formulation is a gel based preparation prepared with preservative and other 10 pharmaceutical excipients. The addition of Hyaluronic acid with choline salicylates and lignocaine hydrochloride provides synergistic effect as compare to monotherapy, thereby accelerate sore healing, reduces inflammation and pain, enhances skin permeation and skin retention properties as well as cost effective. In another aspect, provided here within is a method of preparing the topical gel 15 compositions. Detailed description: While the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention
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provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not delimit the scope of the invention. To facilitate the understanding of this invention, several terms are defined below. Terms defined herein have meanings as commonly 5 understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as "a", "an" and "the" are not intended to refer to only a singular entity but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in 10 the claims. The present invention provides a pharmaceutical composition comprising fixed dose combination of Hyaluronic acid, NSAIDs and local anesthetic wherein the composition of present invention is a topical formulation. In an embodiment Hyaluronic acid is present in an amount ranging from 0.05 to 2% 15 w/w of total weight of composition. In an another embodiment the topical formulation comprises NSAIDs selected from group consisting of diclofenac Flurbiprofen, Ketoprofen, Piroxicam, choline salt of salicylic acid (Choline salicylate), Etodolac, Ibuprofen, Naproxen or combinations thereof. NSAIDs helps in controlling inflammation and reduces pain. 20
9
In a preferred embodiment NSAIDs is selected from choline salt of salicylic acid also known as Choline salicylate present in an amount ranging from 5-10% w/w based on total weight of formulation. In an another embodiment the topical formulation comprises local anesthetic selected from group consisting of lidocaine, bupivacaine, ropivacaine, mepivacaine, 5 chloroprocaine, procaine, tetracaine or combination thereof. Local anesthetic generally numbs the affected areas and blocks the pain sensation and provides instant temporary relief from pain. In a preferred embodiment local anesthetic is selected from lidocaine or pharmaceutical acceptable salts thereof wherein hydrochloride salt is being 10 preferred. In an embodiment lidocaine hydrochloride is present in an amount ranging from 1-5% w/w based on total weight of formulation. In an embodiment the present invention provides a topical composition comprises: i. Hyaluronic acid present in an amount ranging from 0.05 to 2% w/w of total weight of composition and; 15 ii. Choline salicylate present in an amount ranging from 5-10% w/w based on total weight of formulation and; iii. Lidocaine hydrochloride present in an amount ranging from 1-5 % w/w based on total weight of formulation
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In an another embodiment the topical formulation can be formulated in form cream, gel, ointment, lotion or patches, in most preferred embodiment topical formulation is gel formulation. In a preferred embodiment the present invention provides a topical gel comprises: i. About 0.2% w/w Hyaluronic acid and; 5 ii. About 8.7% w/w choline salicylate and; iii. About 2.00% w/w lignocaine hydrochloride In a preferred embodiment the present invention provides a stable topical gel with improved permeability, enhanced therapeutic effects and better consistency. The topical gel of present invention is used for in the treatment of pain, inflammation 10 and discomfort, promote faster healing associated with oral ulcers. In an embodiment the topical gels further comprise pharmaceutical acceptable excipient selected from Preservative, Solubilizer, gelling agent, sweetener, pH adjuster, humectant, antioxidant, flavoring agent.
In an embodiment the topical gel comprises preservative wherein preservative are 15 added in formulation to avoid any microbial growth and helps in maintaining the stability of the formulation. In other embodiment preservatives are selected from group consisting of phenol, parabens, Benzalkonium Chloride, aryl and alkyl alcohols, Vitamin E, BHA (butylatedhydroxyanisole), BHT (Butylatedhydroxytoulene),
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propyl gallate or combinations thereof. In most preferred embodiment the preservative is selected from Benzalkonium chloride, parabens including methyl paraben and propyl paraben present in amount ranging from 0.005-2 % w/w based on total weight of Gel.
In an another embodiment, the topical gel comprises solubilizer wherein solubilizers 5 are added in formulation to aid the solubility of active agents in gel. The solubilizers used in present invention are selected from group consisting of sodium benzoate, sodium caprylate, sodium oleate, propylene glycol, Polysorbate 20, Polyoxyl 40 hydrogenated castor oil (Cremophor¢ç RH 40), Heptyl Glucoside (SEPICLEAR¢â G7), Caprylyl/Capryl Glucoside (ORAMIX¢â CG110) and combinations thereof. 10
In an embodiment solubilizer is present in an amount ranging from 2 to 10 % w/w based on total weight of gel.
In a preferred embodiment the preferred solubilizer is Polysorbate.
In another embodiment Gelation polymer are used gelling agent to form pharmaceutical Gel composition. Those include, without limitation, cellulose 15 derivatives such as hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, gums such as xanthan gum, neutralised homopolymers, copolymers and interpolymers having pendent carboxylic acid groups, or their esters, and/or having pendent anhydrides of dicarboxylic acid
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groups such as polyacrylic acid derivatives (e.g., Carbomer polymer) or polymethyl vinyl ether/maleic anhydride copolymers (e.g., Gantrez), and combinations thereof. In most preferred embodiment the gelling agent is selected from polyacrylic acid derivatives (e.g., Carbomer) present in an amount ranging from 1-4% w/w based on total weight of Gel. 5
In an embodiment the present invention further comprises sweetener wherein sweetener is selected from group consisting of artificial sweetener for example Acesulfame potassium, Advantame, Aspartame, Neotame, Saccharin, Sucralose, Monk Fruit, stevia leaf and combinations thereof. In a preferred embodiment 10 sweetener is selected from Aspartame present in an amount ranging from 0.05-1% w/w based on total weight of formulation. In an another embodiment topical gel further comprises pH modifier such as base in an amount to impart a desired pH to the gel, in a preferred embodiment the pH modifier is selected from Triethanolamine in amount ranging from 0.5-4 % w/w 15 based on total weight of Gel. In an embodiment topical gel of present invention further comprises humectant. The term ¡°humectant¡± refers to any substance that promotes retention of moisture in the composition. In an embodiment the humectant is selected from group consisting of polyethylene glycol, propylene glycol, glycerin, polyol, polyol 20
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derivatives. In a preferred embodiment humectant is selected from glycerin present in an amount ranging from 15-20% w/w based on total weight of gel. In an another embodiment topical gel further comprises antioxidant selected from Ascorbic acid, butylated hydroxy anisole (BHA), butylated hydroxyl toluene (BHT), Tocopherol, Mehionine, citric acid, Tartaric Acid, Phosphoric Acid, Ascorbic Acid, 5 Sodium Metabisulfite. In a preferred embodiment antioxidant is present in combination of butylated hydroxy anisole (BHA) and butylated hydroxyl toluene (BHT) present in an amount ranging from 0.005-1% w/w based on total weight of gel.
In an another embodiment topical gel further comprises Flavoring agent selected 10 from group consisting of aromatic oils (e.g., caraway, clove, lemon, spearmint, rose, and peppermint); ginger; raspberry; maltol; syrups (e.g., citric acid, sarsaparilla, and cherry); glycerin; cocoa; licorice; vanillin; and ethyl vanillin. In a preferred embodiment flavoring agent is selected from clove present in amount ranging from 0.05-1% w/w based on total weight of gel. 15
In a preferred embodiment the one or more excipients are selected from:
i. preservatives present in amount ranging from 0.005-2 % w/w based on total weight of gel and;
ii. Solubilizer present in an amount ranging from 2 to 10 % w/w based on total weight of gel and; 20
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iii. Gelling agent present in an amount ranging from 1-4% w/w based on total weight of gel and;
iv. Sweetener present in an amount ranging from 0.05-1% w/w based on total weight of gel and;
v. pH modifier presents in an amount ranging from 0.5-4 % w/w based on total 5 weight of gel and; vi. humectant present in an amount ranging from 15-20% w/w based on total weight of gel and; vii. antioxidants present in an amount ranging from 0.005-1% w/w based on total weight of gel. 10 viii. Flavouring agent present in an amount ranging from 0.05-1% w/w based on total weight of gel
In an embodiment the present invention comprises water as a vehicle present in sufficient amount wherein the topical formulation is an aqueous gel based preparation. 15
In an another embodiment the topical gel is an aqueous gel preparation comprising:
i. about 8.70 % w/w choline salicylate solution eq. to choline salicylate
ii. about 2.00 % w/w Lignocaine Hydrochloride
iii. about 0.2% w/w Hyaluronic acid
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iv. about 0.010 % w/w Benzalkonium Chloride Solution; about 0.100% w/w Methyl Paraben and about 0.020 % w/w Propyl Paraben as preservative
v. about 0.200 % w/w Aspartame as sweetener
vi. about 2.00 %w/w Triethanolamine as pH Adjuster
vii. about 20.00 %w/w Glycerin as Humectant 5
viii. about 0.100 %w/w Butylated Hydroxy Toluene (BHT) & 0.010 % w/w Butylated Hydroxy Anisol (BHA) as antioxidants
ix. about 0.200 %w/w clove as flavouring agent The topical gel of present invention is a clear transparent gel which is applied directly over the affected area and around the ulcers or sores which provide instant 10 relief from pain, irritation and prevent the swelling of the ulcer. The present invention provides a stable, clear transparent gel with pH range between 3 to 10 more preferably between 5 to 7. In an another embodiment the present invention provides method of preparation of topical gel wherein process comprises following steps: 15 i. Preparation of aqueous phase by mixing carbomer, water and Glycerin ii. Addition of Lignocaine hydrochloride in aqueous phase iii. Adding choline salicylate and Aspartame solution into the aqueous phase comprising lignocaine hydrochloride
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iv. Preparation of Antioxidant & Preservative phase by mixing BHT, BHA, Methyl paraben & Propyl paraben in Polysorbate 20. v. Preparation and Addition of Hyaluronic acid vi. Preparation and additional of Benzalkonium chloride solution into above mixed liquid solution to obtain translucent liquid 5 vii. Addition of clove flavor viii. Adjusting the pH to the obtained translucent liquid with Triethanolamine to obtain transparent gel with flavor. ix. Volume making the final formulation with water to obtain transparent gel with transparent gel. 10 The present invention is illustrated by means of the following examples representative of the pharmaceutical formulations included in the present invention, which should not be considered as restrictions of the scope of the same. EXAMPLE 1 Table 1: Topical Gel formulation comprising Choline Salicylate, Lignocaine 15 Hydrochloride and Hyaluronic Acid S. No. Material Name % w/w Rationale
1.
Hyaluronic Acid
0.200
Active
2.
Choline Salicylate Solution
8.700
Active
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3.
Lignocaine Hydrochloride
2.000
Active
4.
Benzalkonium Chloride Solution
0.010
Preservative
5.
Polysorbate 20
4.000
Solubilizer
6.
Carbopol Polymer
1.600
Gelling Agent
7.
Methyl Paraben
0.100
Preservative
8.
Propyl Paraben
0.020
Preservative
9.
Aspartame
0.200
Sweetener
10.
Triethanolamine
2.000
pH Adjuster
11.
Glycerin
20.00
Humectant
12.
Butylated Hydroxy Toluene
0.100
Antioxidant
13.
Butylated Hydroxy Anisol IP
0.010
Antioxidant
14.
Clove flavour
0.200
Flavour
15.
Purified Water
q.s to 100
Vehicle
Example 2 Process of preparation of Topical gel: Preparation of Aqueous Phase: In SS Container, carbomer and water were mixed and homogenized to form a lump 5 free solution. The solution was heated up to 70-75¢ªC and to this heated solution glycerin was added and mixed well at 30-40 rpm.
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End Point: - Clear lumps free solution obtained. Addition of Lignocaine Hydrochloride: In another S.S container, Lignocaine hydrochloride was mixed with purified water to obtain a clear liquid solution, this solution was transferred into the main manufacturing vessel with continuous stirring at 20-30 rpm. 5 End Point: - Translucent liquid obtained.
Addition of Choline Salicylate & Aspartame Solution: In another S.S container, choline salicylate solution and Aspartame were mixed and was transferred into main manufacturing vessel with continuous stirring at 20-30 rpm. 10 End Point: - Translucent liquid obtained. Preparation & Addition of Antioxidant & Preservative phase: In another S.S container, Polysorbate 20 was heated up to 70-75¢ªC, in this BHT, BHA, methyl paraben and Propyl paraben was added and mixed it well until homogenous solution was obtained. The solution was cooled down and transfer into the main 15 manufacturing vessel with continuous stirring at 20-30 rpm fir 15 minutes. End Point: - Translucent liquid obtained. Preparation & Addition of Hyaluronic Acid:
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In another S.S container, Hyaluronic Acid & Purified water, was mixed well until homogeneous mixture was obtained and was transferred in to main manufacturing vessel with continuous stirring at 20-30 rpm for 10 minutes. End Point: - Translucent liquid obtained. Addition of Benzalkonium Chloride Solution: 5 In main manufacturing vessel, Benzalkonium Chloride solution was added slowly- slowly, with continuous stirring at 20-30 rpm for 10 minutes. End Point: - Translucent liquid obtained.
Addition of Flavour:
In main manufacturing vessel, flavour Clove was added with continuous stirring at 10 20-30 rpm for 10 minutes.
End Point: - Translucent liquid with flavour obtained.
pH Adjustment Phase:
In another S.S container, purified water & Triethanolamine was mixed well & was transferred in a required quantity into the main manufacturing vessel with 15 continuous stirring at 20-30 rpm.
(pH- Between 5.00 - 7.00)
End Point: - clear transparent gel with flavour obtained.
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Weight Make Up Phase:
The final batch was volume make up with remaining quantity of purified Water & was mixed well for 20 minutes.
End Point: - clear transparent gel with flavour obtained.
Example-3: 5
The stability of packaged topical gel has been analyzed at different temperature and relative humidity:
i. Temp. 25¡ÆC ¡¾ 2¡ÆC & relative humidity (RH) 60% ¡¾5%;
ii. Temp. 30¡ÆC ¡¾ 2¡ÆC & relative humidity (RH) 75% ¡¾5%
iii. Temp. 40¡ÆC ¡¾ 2¡ÆC & relative humidity (RH) 75% ¡¾5% 10
Table 2: Stability study condition: Temp. 25¡ÆC ¡¾ 2¡ÆC & RH 60% ¡¾5%
Test
Acceptance criteria
Initial testing
After 03 months
Description
Clear transparent gel with flavor filled in laminated tube.
Clear transparent gel with flavor filled in laminated tube.
Clear transparent gel with flavor filled in laminated tube.
Identification
As below
As below
As below
pH
Between 5.00-7.00
5.79
5.781
Weight per ml
0.90 -1.10 gm/ml
1.0673 gm/ml
1.0747 gm/ml
Microbial contamination
As below
As below
NA
Total viable count
As below
As below
NA
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Total aerobic bacterial count
Not more than 100 cfu/gm
<10 cfu/gm
NA
Total combined yeast & mould count
Not more than 10 cfu/gm
<10 cfu/gm
NA
Assay
Shelf life limit
Choline salicylate solution eq. to choline salicylate 8.7% w/w (by titration)
Not less than 7.83% w/w.
(Not less than 90.00% of label claimed)
9.12% w/w
104.70%
9.44% w/w
108.53%
Lignocaine hydrochloride 2.0% w/w (by HPLC)
NLT 1.80% w/w &
NMT 2.20% W/W
(NLT 90.00% NMT 110.00% of label claimed)
2.02% w/w
101.09%
2.0154% w/w
100.77%
Preservative content
As below
Benzalkonium chloride solution 0.01% w/w (by HPLC)
NLT 0.008% w/w &
NMT 0.012% w/w
(NLT 80% & NMT 120% of labeled claim)
0.0100% w/w
100.40% w/w
0.0104% w/w
104.00%
CONCLUSIONS: The topical gel prepared by example- 1& 2 was found to be stable after 03-month stability at temperature 25¡ÆC ¡¾ 2¡ÆC & relative humidity (RH) 60% ¡¾ 5%.
5
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Table 3: Stability study condition: Temp. 30¡ÆC ¡¾ 2¡ÆC & RH 75% ¡¾5%
Test
Acceptance criteria
Initial testing
After 03 months
Description
Clear transparent gel with flavor filled in laminated tube.
Clear transparent gel with flavor filled in laminated tube.
Clear transparent gel with flavor filled in laminated tube.
Identification
As below
As below
As below
pH
Between 5.00-7.00
5.81
5.892
Weight per ml
0.90 -1.10 gm/ml
1.0679 gm/ml
1.0754 gm/ml
Microbial contamination
As below
As below
NA
Total viable count
As below
As below
NA
Total aerobic bacterial count
Not more than 100 cfu/gm
<10 cfu/gm
NA
Total combined yeast & mould count
Not more than 10 cfu/gm
<10 cfu/gm
NA
Assay
Shelf life limit
Choline salicylate solution eq. to choline salicylate 8.7% w/w (by titration)
Not less than 7.83% w/w.
(Not less than 90.00% of label claimed)
9.59% w/w
110.23%
9.45% w/w
108.63%
Lignocaine hydrochloride 2.0% w/w (by HPLC)
NLT 1.80% w/w &
NMT 2.20% W/W
(NLT 90.00% NMT 110.00% of label claimed)
1.99 % w/w
99.53 %
1.9361 % w/w
96.81 %
Preservative content
As below
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Benzalkonium chloride solution 0.01% w/w (by HPLC)
NLT 0.008% w/w &
NMT 0.012% w/w
(NLT 80% & NMT 120% of labeled claim)
0.0101 % w/w
101.10% w/w
0.0103% w/w
103.00%
CONCLUSIONS: The topical gel prepared by example- 1& 2 was found to be stable after 03-month stability at temperature 30¡ÆC ¡¾ 2¡ÆC & RH 75% ¡¾ 5%.
Table 4: Stability study condition: Temp. 40¡ÆC ¡¾ 2¡ÆC & RH 75% ¡¾5%
Test
Acceptance criteria
Initial testing
After 03 months
Description
Clear transparent gel with flavor filled in laminated tube.
Clear transparent gel with flavor filled in laminated tube.
Clear transparent gel with flavor filled in laminated tube.
Identification
As below
As below
As below
pH
Between 5.00-7.00
5.79
5.793
Weight per ml
0.90 -1.10 gm/ml
1.0673 gm/ml
1.0751 gm/ml
Microbial contamination
As below
As below
NA
Total viable count
As below
As below
NA
Total aerobic bacterial count
Not more than 100 cfu/gm
<10 cfu/gm
NA
Total combined yeast & mould count
Not more than 10 cfu/gm
<10 cfu/gm
NA
Assay
Shelf life limit ,CLAIMS:A pharmaceutical composition comprising Hyaluronic acid, NSAIDs and local anesthetic wherein the composition is a topical formulation.
2. A topical composition as claimed in claim 1, wherein NSAIDs is choline salicylate present in an amount ranging from 5-10% w/w based on total 5 weight of formulation.
3. A topical composition as claimed in claim 1, wherein local anesthetic is lidocaine hydrochloride is present in an amount ranging from 1-5% w/w based on total weight of formulation.
4. A topical composition as claimed in claim 1-3 is topical gel comprising: 10
i. Hyaluronic acid present in an amount ranging from 0.05 to 2% w/w of total weight of composition and;
ii. Choline salicylate present in an amount ranging from 5-10% w/w based on total weight of formulation and;
iii. Lidocaine hydrochloride present in an amount ranging from 1-5 % 15 w/w based on total weight of formulation
5. A topical gel as claimed in claim 4 comprises: i. About 0.2% w/w Hyaluronic acid and ii. About 8.7% w/w choline salicylate and iii. About 2.00% w/w lignocaine hydrochloride 20
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6. A topical gel as claimed in claim 5 further comprising pharmaceutical acceptable excipient selected from Preservative, Solubilizer, gelling agent, sweetener, pH adjuster, humectant, antioxidant, flavoring agent 7. A topical gel as claimed in claim 6 comprising wherein:
i. preservatives present in amount ranging from 0.005-2 % w/w based 5 on total weight of gel and;
ii. Solubilizer present in an amount ranging from 2 to 10 % w/w based on total weight of gel and;
iii. Gelling agent present in an amount ranging from 1-4% w/w based on total weight of gel and; 10
iv. Sweetener present in an amount ranging from 0.05-1% w/w based on total weight of gel and;
v. pH modifier presents in an amount ranging from 0.5-4 % w/w based on total weight of gel and; vi. humectant present in an amount ranging from 15-20% w/w based on 15 total weight of gel and; vii. antioxidants present in an amount ranging from 0.005-1% w/w based on total weight of gel. viii. Flavouring agent present in an amount ranging from 0.05-1% w/w based on total weight of gel 20
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8. A topical gel as claimed in claim 1-7 comprising: i. about 8.70 % w/w choline salicylate solution eq. to choline salicylate and;
ii. about 2.00 % w/w Lignocaine Hydrochloride and;
iii. about 0.2% w/w Hyaluronic acid and; 5
iv. about 0.010 % w/w Benzalkonium Chloride Solution; about 0.100% w/w Methyl Paraben and about 0.020 % w/w Propyl Paraben as preservative
v. about 0.200 % w/w Aspartame as sweetener
vi. about 2.00 %w/w Triethanolamine as pH Adjuster 10
vii. about 20.00 %w/w Glycerin as Humectant
viii. about 0.100 %w/w Butylated Hydroxy Toluene (BHT) & 0.010 % w/w Butylated Hydroxy Anisol (BHA) as antioxidants
ix. about 0.200 %w/w clove as flavouring agent
9. A topical gel as claimed in above claim is stable, clear transparent gel with pH 15 of about 5 to 7.
10. A process of preparing topical gel comprises following steps:
i. Preparation of aqueous phase by mixing carbomer, water and Glycerin ii. Addition of Lignocaine hydrochloride in aqueous phase 20
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iii. Adding choline salicylate and Aspartame solution into the aqueous phase comprising lignocaine hydrochloride iv. Preparation of Antioxidant & Preservative phase by mixing BHT, BHA, Methyl paraben & Propyl paraben in Polysorbate 20. v. Preparation and Addition of Hyaluronic acid 5 vi. Preparation and additional of Benzalkonium chloride solution into above mixed liquid solution to obtain translucent liquid vii. Addition of clove flavor viii. Adjusting the pH to the obtained translucent liquid with Triethanolamine to obtain transparent gel with flavor. 10 ix. Volume making the final formulation with water to obtain transparent gel with transparent gel.
Dated this March 11th 2023
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Siddhartha Dulakakhoria
DGM | IPR
Akums Drugs & Pharmaceuticals limited
Authorized representative of applicant