FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Complete Specification [See Sections 10 and rule 13]
Title: "Tolfenamic acid composition"
Applicant: (a) INTAS Pharmaceuticals Limited
(b) Nationality: Indian
(c) 2nd Floor, Chinubhai Centre, Ashram Road, Ahmedabad- 380009 Gujarat India
The following specification particularly describes.the invention and the manner in which it is to be performed:

Filed of Invention
The present invention relates to composition for oral administration comprising a hydrophobic drug, specifically Tolfenamic acid, without the use of surfactant / solubilizer or any other means of solubility enhancement, which complies with the regulatory requirement of dissolution for immediate release of solid oral dosage forms.
Background
Poor aqueous solubility of drugs is a major rate limiting step in absorption of hydrophobic drugs. Following is a representative list of some such drugs: amphotericin, anthralin. allopurinol, acetohexamide, beclomethasone, betamethasone, benzthiazide, camptothecin, curcumin, chlorpromazine, chlordiazepoxide, dexamethasone, genistein, haloperidol, indomethacine, lidocaine, lorazepam, methoxsalen, methylprednisone, nifedipine, oxazepam, oxyphenbutazone, paclitaxel, prednisone, prednisolone, pyrimethamine, phenindione, sulfisoxazole, sulfadiazine, sulfamerazine, trioxsalen, temazepam, tetracycline, tolfenamic acid, tretinoin.
There are various approaches reported for enhancement of solubility of such drugs. These approaches include chemical modifications like salt formation, co-crystallization, cosolvency, hydrotropic and physical modifications like particle size reduction, micronization, nano-suspension, modification of the crystal habit (polymorphs, pseudo-polymorphs), complexation, use of surfactants, microemulsion, self micro-emulsifying drug delivery system (SMEDDS), super critical fluid technology, solid dispersion and solid solutions etc.

Various approaches to enhance solubility known in the art have drawbacks like stability issue, extra processing steps which significantly enhance formulation development cost and time and scale up problems.
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-chlorophenyi)anthranilic acid. Tolfenamic acid is a non-steroidal anti¬inflammatory drug (NSAID) having anti-inflammatory and analgesic activity. Molecular formula of Tolfenamic acid is C14H12CINO2 and has following chemical structure:

Tolfenamic Acid
Tolfenamic acid is approved as capsule, DR capsule, ER capsule, tablet, DR tablet, ER tablet, rapid release tablet and marked under various trade name like Clotam® (Gea) for human use and Tolfedine® (Vetoquinol) for veterinary use for the treatment of inflammation and pain. Clotam Rapid® is rapid release tablet approved for the treatment of migraine in human.
Slow absorption rate is the problem associated with Tolfenamic acid composition due to its poor solubility in water. Several approaches reported to overcome this problem are as follows:
- Tolfedine approved for alleviation of acute episodes of inflammation and pain in chronic locomotor disease in small dogs and febrile syndrome (abscess, fever of

unknown origin) in cats as tablet comprises 6mg, 20mg and 60mg of Tolfenamic acid. Apart form Tolfenamic acid, Tolfedine contains inactive ingredients - calcium hydrogen phosphate dehydrate, wheat starch, docusate sodium, microcrystalline cellulose, magnesium stearate. The composition uses docusate sodium as surfactant.
- Clotam Rapid® approved for acute migraine for human use comprises 200mg Tolfenamic acid. The inactive ingredient are maize starch, sodium starch glycolate (type a), macrogol 6000, alginic acid, microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica, sodium stearyl fumarate. From composition it seems that the composition makes use of super-disintegrant (sodium starch glycolate type A, croscarmellose sodium); alginic acid which is used as binder as well as disintegrant (Handbook of pharmaceutical excipient, 5th edition) and macrogol 6000 which may play role in solubility enhancement.
- WO9722340 discloses a rapid release tablet comprising tolfenamic acid as an active ingredient having a mean particle size of < 10 u.m. The tablet comprises alginic acid or a pharmaceutical^ acceptable salt thereof in an amount of 1.5 - 6.0 % by weight and a superdisintegrant in an amount of at least 6 % by weight. According to WO9722340, Tolfenamic acid having particle size less than 10 urn, alginic acid as granulating agent and at least 6% by weight of superdisintegrant has important role to achieve high plasma drug concentration and less Tmax. Further, examples of WO9722340 disclose the use of polyethylene glycol 6000 which can act as a solubility enhancer in the composition.
Approaches found in the back-ground art disclose the use of surfactant / solubilizer in combination with disintegrant / super-disintegrant as excipients in the oral composition of Tolfenamic acid to obtain effective dissolution of Tolfenamic acid from the said composition.

Considering the low solubility and slow absorption rate of Tolfenamic acid, there is a need for development of an oral composition which provides an in-vitro effective dissolution of Tolfenamic acid for immediate release from dosage form which would overcome the solubility and absorption issues related to Tolfenamic acid and provide an in-vitro effective dissolution from the dosage form.
Inventors of the present invention have surprising found that oral composition of Tolfenamic acid as disclosed in the present invention would provide an in-vitro effective dissolution wherein the said composition does not comprise of surfactant / solubilizer or any other means of solubility enhancement.
Objects of Invention
The first objective of the present invention is to provide an immediate release composition of Tolfenamic acid for oral administration wherein the said composition does not comprise of any surfactant / solubilizer or any other means of solubility enhancement.
The second objective of the present invention is to provide an oral composition of Tolfenamic acid which would provide an in-vitro effective dissolution of Tolfenamic acid from the said composition.
Summary of the invention
The present invention focuses on providing a composition of Tolfenamic acid for oral administration without using surfactant / solubilizer or any other means of solubility enhancement; wherein the composition would provide an in-vitro effective dissolution of Tolfenamic acid. The said composition of Tolfenamic acid may be dispensed as a solid oral dosage form and administered to the animals (mammals

preferably humans, cats, dogs, cattle, buffalo, horse, camels, etc.) in need thereof for an anti-inflammatory and analgesic medication.
Detailed Description of the Invention
From the prior art, use of surfactant / solubilizer or any other means which modify solubility characteristics of active ingredient is mandatory to achieve desired dissolution requirement for hydrophobic drugs like Tolfenamic acid. The present invention provides a composition which can be dispensed as a solid dosage form and provides an in-vitro effective dissolution of Tolfenamic acid to overcome the absorption issues of Tolfenamic acid. Further, the composition of the present invention achieves the in-vitro effective dissolution without the use of surfactant / solubilizer or any other means of solubility enhancements.
"Effective dissolution" according to the present invention defined as release of Tolfenamic acid from the solid dosage form prepared from the composition according to the present invention wherein more than 85% of release is achieved when assayed at 15 minutes of the dissolution test.
Dissolution test as per the present invention should be performed under test condition given in the table:

Dissolution test method / condition
Medium 900 mL 0.05 M Tris buffer pH 9.0 + 1 % sodium lauryl sulfate
Apparatus Paddle (USP apparatus II)
Speed 100 RPM
Temperature 37°C±0.5°C
Time point 10,15,20, 30, 45 & 60 minutes
Assay method for determination of Tolfenamic acid from the dissolution medium may comprise of chromatographic method or spectrophotometric method. Preferred

assay method for quantitative detection of Tolfenamic acid is carried out by using UV spectrophotometry method.
Process for dissolution test according to mentioned parameters is as under:
- Set dissolution parameters and fill the dissolution bowls with the required quantity of dissolution medium
- Drop 6 Tablet / Bolus in to 6 separate dissolution bowls (taking care to exclude air bubbles from the surface of the Tablet / Bolus) and immediately start the apparatus
In continuation of dissolution test, assay of Tolfenamic acid can be performed using chromatographic or spectrophotometry methods. These methods of performing assay are already disclosed in the art and well-known to the person skilled in the art.
According to present invention, the term "means of solubility enhancement" may include approaches known to person skilled in the art to enhance solubility like chemical modifications for example salt formation, co-crystallization, cosolvency, hydrotropic and physical modifications like particle size reduction, micronization, nano-suspension, modification of the crystal habit (polymorphs, pseudo-polymorphs), complexation, use of surfactants, microemulsions, SMEDDS, super critical fluid technology, solid dispersion and solid solutions.
Composition as disclosed in the present invention can be dispensed as a solid dosage form like tablets, bolus, capsules, caplets and like thereof for oral administration.
According to present invention, the solid dosage form can be prepared from the said composition by granulation methods e.g. dry granulation or wet granulation. Techniques of granulation, i.e. dry granulation or wet granulation are well known to

a person skilled in the art. Wet granulation is the preferred technique for the preparation of the solid dosage form.
The present invention provides a composition comprising Tolfenamic acid as an active ingredient and further comprising other excipients like diluent, binder, disintegrant, lubricant, and glidant, in specific amounts; wherein the composition does not comprise any surfactant / solubilizer or any other means for solubility enhancement.
According to present invention, diluent may include spray dried lactose, starch, dicalcium phosphate, calcium carbonate, corn starch, lactitol, potato starch, calcium phosphate tribasic, lactose anhydrous, lactose monohydrate, pregelatinized starch, calcium sulfate, cellulose microcrystalline, maltitol, cellulose microcrystalline powdered, maltodextrin, wheat starch, dextrates, maltose, sucrose, dextrin, mannitol, sugar compressible, dextrose, sorbitol, fructose, kaolin and mixtures thereof. Diluent(s) used according to the present invention are in an amount of 50% - 80% w/w of the composition.
According to present invention, binder may include acacia, ammonio methacrylate copolymer, carbomer, carboxymethylcellulose sodium, cellulose microcrystalline, copovidone, sucrose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, low-substituted hydroxypropyl cellulose, hypromellose, hypromellose acetate succinate, maltodextrin, maltose, methylcellulose, polyethylene oxide, povidone, starch, pregelatinized starch, pregelatinized starch modified, syrup and mixtures thereof. Binder(s) used according to the present invention are in an amount of 0.1% - 10% w/w of composition.

According to present invention, disintegrant may include cellulose microcrystalline, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, maltose, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch and mixtures thereof in an amount of 1% - 5% w/w of the composition.
According to present invention, lubricant may include calcium stearate, glyceryl behenate, magnesium stearate, mineral oil light, polyethylene glycol, castor oil, sodium stearyl fumarate, starch, stearic acid, talc, hydrogenated vegetable oil, zinc stearate, sodium benzoate and mixtures thereof in an amount of 0.1% - 5% w/w of the composition.
According to present invention, glidant may include calcium silicate, magnesium silicate, colloidal silicon dioxide, talc and mixtures thereof in an amount of 0.1% -1% w/w of the composition.
According to present invention, Tolfenamic acid composition is devoid of surfactant / solubilizer or any other means of solubility enhancement.
According to present invention, composition comprises of Tolfenamic acid in an amount of 10% - 30% w/w of the composition.
According to the present invention, the said composition can be used for the treatment and prognosis of animals in need thereof, wherein the animals includes mammals, preferably humans, cats, dogs, cattle, buffalo, horse, camel etc. Depending on the weight of the animal, the dose of the Tolfenamic acid can be orally administered through solid oral dosage form, wherein the amount of Tolfenamic acid in the said dosage form would be within a range of 50mg to lOOOmg.

According to present invention, in-vitro release of Tolfenamic acid from the solid dosage form prepared from the said composition of the present invention is more than 85% when assayed at 15 minutes of the dissolution test.
According to the preferred embodiment of the present invention, Tolfenamic acid composition for the preparation of solid dosage form for oral administration comprises of Tolfenamic acid as an active ingredient; dicalcium phosphate, starch and microcrystaliine cellulose as preferred diluent(s); starch and gelatin as preferred binder(s); magnesium stearate, talc and sodium benzoate as preferred lubricant(s); sodium starch glycolate as preferred disintegrant and colloidal silicon dioxide as preferred glidant.
Example
The present invention has been described by way of example only, and it is to be recognized that modifications thereto falling within the scope and spirit of appended claims, and which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be within the scope of this invention.
According to the present invention, a generalized composition is as follows:

Tolfenamic acid composition
Sr. no. Ingredient Amount in % w/w per composition
a Tolfenamic acid 10-30
b Diluent(s) 50-80
c Binder (s) 0.1 -10
d Disintegrant(s) \-5
e Lubricant(s) 0.1-5
f Glidant(s) 0.1 -1

Process for the preparation:
Process for the preparation of solid dosage form from the said composition may involve granulation techniques, eg. dry granulation or wet granulation. These techniques are already known to the person skilled in the art.
As per the preferred embodiment for the preparation of solid dosage form, granulation process involves the following steps:
1. Tolfenamic acid and diluents are mixed to form a dry-mix.
2. Binder solution / paste is prepared using by dissolving / suspending binding agent in suitable medium.
3. Dry-mix obtained in step 1 is granulated using the binder paste obtained in step 2.
4. Wet granules were dried at 60°C to obtain dried granules which are sieved using appropriate sieves.
5. Dry granules obtained in step 4 can be filled in the capsules, or compressed as tablets or bolus or filled in sachets.
Release of Tolfenamic acid from the solid dosage form prepared from the composition according to the present invention would be more than 85% when assayed at 15 minutes of the dissolution test.
Example 1: Tolfenamic acid composition for 500mg dose Composition and procedure:

Tolfenamic acid composition containing Tolfenamic (For 750 bolus). acid (500mg)
Sr. no. Ingredient Quantity
Dry mixing stage
1 Tolfenamic acid 375 gm
2 Starch 800 gm

3 Microcrystalline cellulose powder (MCC) 843 gm
Binder paste*
4 Starch lOOgm
5 Gelatin 10 gm
6 Sodium benzoate 2gm
Lubrication stage
7 Magnesium stearate 40 gm
8 Talc 30 gm
9 Sodium starch glycolate (SSG) 45 gm
10 Aerosil 5gm
* - Aqueous medium q.s. used for preparing binder paste, which is not present in final composition
Manufacturing procedure:
1) Tolfenamic acid, starch and MCC are mix together to form a dry-mix.
2) Prepare a binder paste by mixing starch, gelatin and sodium benzoate in an aqueous medium.
3) Granulate the dry-mix prepared in step 1 with binder paste as prepared in step 2 to obtain granules.
4) Dry the granules and then pass them through a sieve to obtain granules of defined size.
5) Lubricate the granules obtained in step 4 with Magnesium stearate, Talc, SSG and Aerosil.
6) Lubricated granules obtained in step 5 may be filled in capsules, or compresses to provide tablets or bolus.
Dissolution profile of the composition:
In-vitro dissolution studies were carried out in USP dissolution apparatus type II (paddle) in 900 mL 0.05 M Tris buffer pH 9.0 + 1 % sodium lauryl sulfate at 100 RPM and 37°C ± 0.5°C temperature.

Results:

Unit 10 min 15 min 20 min 30 min 45 min 60 min
1 77.3 86.9 86.3 89.6 88.7 93.3
2 77.9 87.) 89.0 92.0 94.9 101.3
3 83.3 90.6 89.0 93.3 96.1 99.6
4 83.7 87.2 90.8 94.2 94.2 102.9
5 81.4 88.0 91.1 90.3 91.5 99.6
6 83.1 89.1 91.6 90.7 96.1 91.9
Mean 81 88 90 92 94 98
Min 77 87 86 90 89 92
Max 84 91 92 •94 96 103
% RSD 3.5 1.6 2.2 2.0 3.1 4.6
Tolfenamic acid Assay method: UV spectrophotometry; wherein absorbance of standard and sample preparations was measured at 286 nm using UV/VIS spectrophotometer.
According to the present invention, said Tolfenamic acid composition is used for the preparation of solid oral dosage form, wherein the composition does not comprise of a surfactant / solubilizer or any other means of solubility enhancement. Further, the solid oral dosage form shows an in-vitro effective dissolution i.e. release of 85% of Tolfenamic acid for the solid oral dosage form is achieved at 15 minutes of the dissolution study.

We claim:
1) An immediate release composition comprising Tolfenamic acid; which when dispensed as an oral dosage form, provides an in-vitro effective dissolution of atleast 85% of Tolfenamic acid within 15 minutes.
2) The composition according to claim 1, wherein the said composition is devoid of any surfactant, solubilizer or any means of solubility enhancement.
3) The composition according to claim 1, wherein the said composition comprises of

(a) 10 - 30 % w/w of Tolfenamic acid,
(b) 50 - 80 % w/w of diluent(s),
(c) 0.1 - 10 % w/w of binder(s),
(d) 1 - 5 % w/w of disintegrant(s) and optionally
(e) 0.1-5 % w/w of lubricant(s) and / or (f)0.1- 1 %w/wofglidant(s),
of the total composition.
4) The composition according to claim 1, wherein the said composition can be dispensed as an oral dosage form like tablets, bolus, capsules, caplets and the likes thereof.
5) A Tolfenamic acid composition, wherein the composition comprises of

(a) 10 - 30 w/w % of Tolfenamic acid,
(b) 50 - 80 w/w % of diluent(s), (c)0.1 - 10w/w%binder(s),
(d) 1 - 5 w/w % disintegrant(s) and optionally

(e) 0.1-5 w/w % lubricant(s) and / or
(f) 0.1 - 1 w/w % giidant(s), of the total composition;
wherein the said composition when dispensed as an immediate release oral dosage form in the form of tablets, bolus, capsules, caplets and the likes thereof, provides an in-vitro effective dissolution of atleast 85% of Tolfenamic acid within 15 minutes.
6) An orally administered immediate release Tolfenamic acid dosage form,
wherein the said dosage form is prepared from a composition of
(a) 10 - 30 w/w % of Tolfenamic acid,
(b) 50 - 80 w/w % of diluent(s), (c)0.1 - 10w/w%binder(s),

(d) 1 - 5 w/w % disintegrant(s) and optionally
(e) 0.1-5 w/w % lubricant(s) and / or
(f) 0.1 - 1 w/w % glidant(s), of the total composition;
wherein the dosage form provides an in-vitro effective dissolution of atleast 85% of Tolfenamic acid within 15 minutes.
7) The orally administered immediate release Tolfenamic acid dosage form according to claim 6, wherein the said dosage form is devoid of any surfactant, solubilizer or any means of solubility enhancement.
8) The orally administered immediate release Tolfenamic acid dosage form according to claim 6, wherein the said dosage form is prepared preferably using dry granulation or wet granulation method.

9) The orally administered immediate release Tolfenamic acid dosage form according to claim 6, where the said dosage form is administered to animals, including mammals, in need thereof.
10) An immediate release composition comprising Tolfenamic acid as described in the description.