DESC:FIELD OF THE INVENTION

The present invention relates to a stable topical gel composition comprising Tolfenamic acid with pharmaceutically acceptable excipients. Further it relates to the process for the preparation of the said composition and uses thereof.

BACKGROUND OF THE INVENTION

Tolfenamic acid is a non-steroidal anti-inflammatory drug (NSAID) having anti-inflammatory and analgesic activity. Tolfenamic acid is chemically known by various chemical names such as 2-[(3-chloro-2-methylphenyl)amino]benzoic acid; N-(3-chloro-o-tolyl)anthranilic acid; N-(2-methyl-3-chlorophenyl)anthranilic acid. The molecular formula of Tolfenamic acid is C14H12ClNO2 and it has following chemical structure:

Tolfenamic acid is approved in several dosage forms such as Capsules, Tablets and Injections under various trade names like Clotam® for human use, and Tolfedine® and Tolfine® for veterinary use for the treatment of inflammation and pain. Clotam Rapid® is a rapid release tablet approved for the treatment of acute migraine.

The slow absorption rate is one of the problems associated with Tolfenamic acid due to its poor solubility in water. Several approaches for solubility enhancement have been attempted to overcome this problem.

Patent Application No. WO9722340 discloses a rapid release tablet comprising tolfenamic acid as an active ingredient having a mean particle size of = 10 µm. Further, the examples within this patent application disclose the use of polyethylene glycol 6000, which can act as a solubility enhancer in the composition.

Another Patent Application No. WO9749405 discloses a topical gel composition comprising a combination of NSAID and xanthine derivative. Further, the examples within this patent application disclose the use of gelling agents and surfactants, for the preparation of the gel composition.

There is no marketed topical gel composition of Tolfenamic acid. Hence, there is a long-standing need to provide a stable topical gel composition comprising Tolfenamic acid as a single active ingredient for the treatment of inflammation and pain in mammals.

OBJECTS OF INVENTION

The primary object of the invention is to provide a stable topical gel composition comprising tolfenamic acid with pharmaceutically acceptable excipients.

Another object of the invention is to provide a stable topical gel composition comprising tolfenamic acid, wherein the total amount of Tolfenamic acid-related impurities is not more than 3.0%.

Another object of the invention is to provide a stable topical gel composition comprising tolfenamic acid, wherein the pH of the gel is about 4 to 7.

SUMMARY OF THE INVENTION

In a first embodiment, the invention relates to a stable topical gel composition comprising tolfenamic acid with pharmaceutically acceptable excipients.

In another embodiment, the invention relates to a stable topical gel composition comprising tolfenamic acid with at least one gelling agent, at least one penetration enhancer, at least one pH adjusting agent, and at least one solvent.

In another embodiment, the invention relates to a stable topical gel composition comprising tolfenamic acid, wherein the total amount of Tolfenamic acid-related impurities is not more than 3.0%.

In another embodiment, the invention relates to a stable topical gel composition comprising tolfenamic acid, wherein the pH of the gel is about 4.0 to 7.0.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a stable topical gel composition comprising tolfenamic acid with pharmaceutically acceptable excipients.

The present invention further relates to a stable topical gel composition comprising tolfenamic acid with at least one gelling agent, at least one penetration enhancer, at least one pH adjusting agent, and at least one solvent.

The amount of Tolfenamic acid in the gel composition is about 1 to 20%. Further, the tolfenamic acid can be included in the micronized form.

The “stable topical gel” of the present invention refers to the Tolfenamic acid gel composition with reduced amount of Tolfenamic acid-related impurities, wherein the total impurity is not more than 3% and the single unknown impurity is not more than 1%, upon analysis of gel stored for at least 3 months at 40°C and 75% RH.

The “gelling agent” of the present invention includes polyvinyl pyrrolidone (PVP), polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol such as carbomers (carbopols), alginates, preferably sodium alginate, hydroxyalkyl cellulose, especially hydroxyethyl cellulose (HEC), other polymeric gelling agents such as xanthan gum, guar gum, fatty alcohols, fatty acids and their alkali salts and mixtures thereof, as well as inorganic gelling agents.

Preferably, the gelling agent is selected from polyvinyl pyrrolidone, Carbopol, Sodium alginate, hydroxyethyl cellulose, xanthan gum, Guar gum, inorganic gelling agents and mixtures thereof. More preferably, the gelling agent is Carbopol 980.

The amount of gelling agent is not particularly critical, and can be selected to provide the desired product consistency or viscosity to allow for easy application to the skin. Generally, the concentration of gelling agent is about 0.1 to 5 %W/W of the composition.

The “penetration enhancer” of the present invention includes, non-limiting examples, such as isopropyl myristate, alkanolamine salts of fatty acids, alkyl benzene sulphonates, alkyl ether sulphates, alkyl sulphates, anionic surface-active agents, benzyl benzoate, benzyl salicylate, butyl benzoate, butyl laurate, butyl myrisite, butyl stearate, cationic surface-active agents, decyl methyl sulfoxide, decyl oleate, dibutyl azelate, dibutyl phthalate, dibenzyl sebacate, dibutyl sebacate, dibutyl suberate, dibutyl succinate, dicapryl adipate, didecyl phthalate, diethylene glycol, diethyl sebacate, diethyl-m-toluamide, N,N-dimethyl formamide, 1,5-dimethyl-2-pyrrolidone, dimethyl sebacate, dimethyl sulphoxide, isopropyl isostearate, isopropyl palmitate, ocetyl alcohol, octylphenoxy polyethoxyethanol, oleic ethanolamide, propylene glycol, Polysorbate, sodium dioctyl sulphonsuccinate, sodium laurate, sodium lauryl ether sulphate, sodium lauryl sulphate, sugar esters. Preferably, the penetration enhancer is propylene glycol.

The stable topical gel of the present invention comprises at least one penetration enhancer, wherein the concentration of penetration enhancer is about 1 to 40 %W/W of the composition.

The “pH adjusting agent” of the present invention includes, non-limiting examples, such as monoethanolamine, triethanolamine, sodium hydroxide, ammonium hydroxide, calcium hydroxide, trolamine, di-isopropanolamine, and tri-isopropanolamine. Preferably, the pH adjusting agent is monoethanolamine.

The stable topical gel of the present invention comprises at least one pH adjusting agent such that the pH of the gel composition is about 4 to 7.

The “solvent” of the present invention includes, non-limiting examples, such as dehydrated alcohol (ethanol), monohydric and polyhydric alcohols, water, isopropanol, N-methyl pyrrolidone. Preferably, the solvent is N-methyl pyrrolidone. Generally, the amount of solvent is about 1 to 10 %W/W of the composition.

In another embodiment, the present invention relates to a stable topical gel composition comprising Tolfenamic acid, Carbopol 980, Propylene glycol, N-methyl pyrrolidone and Monoethanolamine, wherein the pH of the gel composition is about 4 to 7.

The preservatives may optionally be added into the gel composition. This includes, non-limiting examples, such as, butylparaben, methylparaben, propylparaben, benzyl alcohol, and ethylene diamine tetraacetate salts. The amount of preservative can be varied so long as it does not interfere significantly with the pharmacological activity of the active ingredients of the topical gel composition.

In addition to the above-mentioned ingredients, the stable topical gel composition may also comprise further pharmaceutically acceptable excipients (Eg. Rubefacient such as Menthol, Methyl Salicylate) that are suitable for topical compositions.

In order to further illustrate the present invention, the following examples are provided for the purpose of clarity of understanding. However, it is not intended in any way to limit the scope of present invention and it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the scope of the invention.

It will be appreciated that the final form of a topical composition plays an important role in its efficacy and its usage convenience. As it is described above, gels are highly advantageous for topical administration of tolfenamic acid.

Example 1: Stable topical gel composition of Tolfenamic acid.
Sr. No. Ingredients Concentration (% W/W)
1 Tolfenamic acid (Micronized) 1-20%
2 Penetration Enhancer 1-40%
3 Solvent / Solubilizer 1-10%
4 Rubefacient (Optional) 1-20%
5 Gelling Agent 0.1-5%
6 pH adjusting agent q.s. to pH 4-7
7 Preservative (Optional) 0.01-1%
8 Purified water q.s

The topical gel composition can be prepared by: (i) Mixing together weighted quantity of Solvent and Penetration enhancer. Stir well until a clear solution is formed. (ii) Adding weighed quantity of micronized tolfenamic acid and stir for 30-60 minutes. (iii) Adding weighted quantity of gelling agent to step (ii) and stir for 30-60 minutes. (iv) Adding required quantity of pH adjusting agent to adjust pH 4.5-6.5. (vi) Adding weighted quantity of preservative into it and stir for 10-30 minutes. (vii) Make the final weight with purified water and mix for 10-30 minutes.

Example 2: Stable topical gel composition of Tolfenamic acid.
Sr. No. Ingredients Quantity (mg/gm)
1 Tolfenamic acid (Micronized) 60.0*
2 Polysorbate 80 30.0
3 N-methyl pyrrolidone 30.0
4 Propylene glycol 30.0
5 Methyl salicylate 20.0
6 Menthol 50.0
7 Carbopol 980 5.0
8 Methyl paraben sodium 1.0
9 Propyl paraben sodium 0.1
10 Monoethanolamine q.s. to adjust pH
11 Purified water q.s. to 1 gm
*Mentioned quantity is considering assay as 100% on as is basis. Potency correction to be done while dispensing the actual on as is basis.

The topical gel composition can be prepared by: (i) Mixing together weighted quantity of propylene glycol, Polysorbate 80, N-methyl pyrrolidone, menthol and methyl salicylate. Stir well until a clear solution is formed. (ii) Adding weighed quantity of micronized tolfenamic acid and stir for 30-60 minutes. (iii) Adding weighted quantity of Carbopol to step (ii) and stir for 30-60 minutes. (iv) Adding required quantity of monoethanolamine to adjust pH 4.5 - 6.5. (vi) Adding weighted quantity of propyl paraben sodium and methyl paraben sodium into it and stir for 10-30 minutes. (vii) Make the final weight with purified water and mix for 10-30 minutes.

Example 3: Stability study of topical tolfenamic acid gel.
Product Name TOLFENAMIC ACID GEL 6% W/W (Batch size: 400 gm)
Condition Description Assay of Tolfenamic acid Single impurity Total impurity
Limit White color viscous gel 90 - 110 % of
the label claim Not more than 1.0 % Not more than 3.0 %
Initial White color viscous gel 100.6 0.042 0.056
40°C-1M White color viscous gel 100.5 0.067 0.092
40°C-2M White color viscous gel 100.4 0.069 0.110
40°C-3M White color viscous gel 100.3 0.077 0.110
40°C-6M White color viscous gel - 0.140 0.140

Example 4: Stability study of topical Tolfenamic acid gel.
Product name TOLFENAMIC ACID GEL 6% W/W (Batch size: 500 gm)
Condition Description pH Measurement Assay of Tolfenamic acid Single impurity Total Impurity
Limit White color viscous gel pH Limit:
4.0 to 7.0 90 - 110 % of
the label claim Not more than 1.0 % Not more than 3.0 %
Initial White color viscous gel 6.31 102.0 0.063 0.099
40°C-1M White color viscous gel 6.39 101.9 0.065 0.110
40°C-2M White color viscous gel 5.79 101.8 0.067 0.140
40°C-3M White color viscous gel 5.50 101.8 0.120 0.150
30°C-6M White color viscous gel 5.83 102.0 0.079 0.170
25°C-6M White color viscous gel 5.87 101.9 0.067 0.140

Above stability studies of Tolfenamic acid topical gel composition confirms that the topical gel compositions of the present invention remains stable with reduced amount of Tolfenamic acid-related impurities.

In accordance with the present invention, the total impurity is not more than 3% and the single unknown impurity is not more than 1%, upon analysis of gel stored for at least 3 months at 40°C and 75% RH. ,CLAIMS:1. A stable topical gel composition comprising tolfenamic acid with at least one gelling agent, at least one penetration enhancer, at least one pH adjusting agent, and at least one solvent.
2. The stable topical gel composition according to claim 1, wherein the gelling agent is selected from polyvinyl pyrrolidone, Carbopol, Sodium alginate, hydroxyethyl cellulose, xanthan gum, Guar gum, inorganic gelling agents and mixtures thereof, and wherein the concentration of gelling agent is about 0.1 to 5 %W/W of the composition.
3. The stable topical gel composition according to claim 1, wherein the gelling agent is Carbopol 980.
4. The stable topical gel composition according to claim 1, wherein the concentration of penetration enhancer is about 1 to 40 %W/W of the composition.
5. The stable topical gel composition according to claim 1, wherein the penetration enhancer is Propylene glycol.
6. The stable topical gel composition according to claim 1, wherein the solvent is selected from dehydrated alcohol, monohydric and polyhydric alcohols, water, isopropanol, N-methyl pyrrolidone.
7. The stable topical gel composition according to claim 1, wherein the pH of the gel composition is about 4 to 7.
8. The stable topical gel composition according to claim 1, wherein the total impurity is not more than 3% and the single unknown impurity is not more than 1%, upon analysis of gel stored for at least 3 months at 40°C and 75% RH.
9. A stable topical gel composition comprising Tolfenamic acid, Carbopol 980, Propylene glycol, N-methyl pyrrolidone and Monoethanolamine, wherein the pH of the gel composition is about 4 to 7.
10. The stable topical gel composition according to claim 9, wherein the total impurity is not more than 3% and the single unknown impurity is not more than 1%, upon analysis of gel stored for at least 3 months at 40°C and 75% RH.