FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
The Patents Rules, 2003 COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention - NOVEL PHARMACEUTICAL
COMPOSITION COMPRISING MEFENAMIC ACID AND OTHER
ANALGESIC
2. Applicant(s)
(a) NAME : ZENVISION PHARMA LLP
(b) NATIONALITY : An Indian Company
(c) ADDRESS : First Floor, K.K. Chambers, SIR P.T. Road
Fort,
Mumbai, Maharashtra, India 400001
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed

FIELD OF THE INVENTION
The present invention relates to novel pharmaceutical composition comprising mefenamic acid and an other analgesic for the treatment of dysmenorrhea.
BACKGROUND OF THE INVENTION
Dysmenorrhea is the most commonly reported menstrual disorder. More than one half of women who menstruate have some pain for 1-2 days each month. Pain associated with menstruation is called dysmenorrhea. There are two types of dysmenorrhea i.e. primary dysmenorrhea and secondary dysmenorrhea. Primary dysmenorrhea is pain that comes from having a menstrual period or menstrual cramps. Primary dysmenorrhea is the most common type of dysmenorrhea, affecting more than 50% of women, and quite severe in about 15%. Primary dysmenorrhea is more likely to affect girls during adolescence. Secondary dysmenorrhea is pain that is caused by a disorder in the woman's reproductive organs, such as endometriosis, adenomyosis, uterine fibroids, or infection. Secondary dysmenorrhea is more likely to affect women during adulthood.
Treatment of dysmenorrhea relieves pain or symptoms either by affecting the physiological mechanisms behind menstrual pain or by relieving symptoms. In clinical practice, nonsteroidal anti-inflammatory drugs (NSAIDs) are considered the first-line therapeutic option for managing pain associated with dysmenorrhea. Also other analgesics, oral contraceptives are used in the treatment of dysmenorrhea.
Mefenamic Acid is member of the fenamate group of nonsteroidal anti-inflammatory drugs (NSAIDs). Chemically mefenamic acid is N-2,3-

xylylanthranilic acid and its molecular weight is 241.29. Its empirical formula is C15H15NO2. Mefenamic Acid is represented by compound of structural formula I

Mefenamic acid is a white to greyish-white, odorless, microcrystalline powder with a melting point of 230°-231°C and water solubility of 0.004% at pH 7.1.
Mefenamic acid capsules of Shionogi have been approved in USA prior to Jan 01, 1982 under the trade name PONSTEL® and are available in the strength of 250mg. The product is indicated for treatment of primary dysmenorrhea and for relief of mild to moderate pain.
Naproxen sodium is member of nonsteroidal anti-inflammatory drugs. Chemically Naproxen sodium is 2-naphthaleneacetic acid, 6-methoxy-a-methyl-sodium salt and its molecular weight is 252.24. Its empirical formula is C14H13NaO3. Naproxen sodium is represented by compound of structural formula II


Naproxen sodium is an odorless crystalline powder, white to creamy in color. It is soluble in methanol and water.
Naproxen sodium extended release tablet has been approved in USA as on Jan 5, 1996 under the trade name NAPRELAN® and is available in the strength of eq 375mg base, eq 500mg base and eq 750mg base. The product is indicated for treatment of rheumatoid arthritis (RA), osteoarthritis (OA), ankylosing spondylitis (AS), tendinitis, bursitis, acute gout, primary dysmenorrhea (PD) and the relief of mild to moderate pain.
U.S. Patent No. 6,929,805 discloses "a preparation which can be administered orally and contains a fixed combination of at least one locally acting analgesic with a rapid onset of action (element A) with at least one systemically acting analgesic with a sustained action (element B), wherein element A and element B provide distinct active analgesic compounds". This patent generically discloses combination of two analgesics with one rapid action and one with sustained action. However, U.S. Patent No. 6,929,805 does not disclose specific combination of mefenamic acid and other analgesic for the treatment of dysmenorrhea; wherein mefenamic acid is in the modified release form and other analgesic is in the immediate release form or vice versa.
The commercially available product as well as product known in the prior art for mefenamic acid alone or other analgesic alone are not efficacious in the treatment of dysmenorrhea. Also the commercially available immediate release product for the combination of mefenamic acid and other analgesic are not efficacious in the treatment of dysmenorrhea. Further commercially available product as well as product known in the prior art requires frequent administration and does not provide patient compliance in the treatment of dysmenorrhea.
Therefore there is an unmet need in the art to provide novel pharmaceutical composition comprising mefenamic acid and other analgesic which requires less

frequent administration, efficacious and provides better patient compliance in the treatment of dysmenorrhea.
OBJECTS OF THE INVENTION
Accordingly, it is an object of the present invention to provide novel pharmaceutical composition comprising mefenamic acid and other analgesic or salt thereof.
It is another object of the present invention to provide novel pharmaceutical composition comprising mefenamic acid and other analgesic or salt thereof; wherein mefenamic acid is in the modified release form and other analgesic is in the immediate release form or vice versa.
It is another object of the present invention to provide novel pharmaceutical composition comprising mefenamic acid and naproxen or salt thereof; wherein mefenamic acid is in the modified release form and naproxen or salt thereof is in the immediate release form or vice versa.
It is another object of the present invention to provide novel pharmaceutical composition comprising mefenamic acid and naproxen or salt thereof which is efficacious in the treatment of dysmenorrhea.
It is another object of the present invention to provide novel pharmaceutical composition comprising mefenamic acid and naproxen or salt thereof which provides less frequent administration preferably once day in the treatment of dysmenorrhea.
It is another object of the present invention to provide novel pharmaceutical composition comprising mefenamic acid and naproxen or salt thereof which provides better patient compliance in the treatment of dysmenorrhea.

SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide novel pharmaceutical composition comprising mefenamic acid and an other analgesic; wherein mefenamic acid is in the modified release form and the other analgesic is in the immediate release form or vice versa.
In another aspect of the present invention is to provide novel pharmaceutical composition comprising mefenamic acid and an other analgesic along with one or more pharmaceutically acceptable excipient; wherein mefenamic acid is in the modified release form and other analgesic is in the immediate release form or vice versa.
In another aspect of the present invention is to provide novel pharmaceutical composition comprising mefenamic acid and Naproxen or salt thereof; wherein mefenamic acid is in the modified release form and Naproxen or salt thereof is in the immediate release form or vice versa.
In another aspect of the present invention is to provide novel pharmaceutical composition comprising mefenamic acid and Naproxen or salt thereof along with one or more pharmaceutically acceptable excipient; wherein mefenamic acid is in the modified release form and Naproxen or salt thereof is in the immediate release form or vice versa.
In another aspect of the present invention is to provide process of manufacturing novel pharmaceutical composition comprising mefenamic acid and an other analgesic along with one or more pharmaceutically acceptable excipient; wherein mefenamic acid is in the modified release form and other analgesic is in the immediate release form or vice versa.

In another aspect of the present invention is to provide process of manufacturing novel pharmaceutical composition comprising mefenamic acid and Naproxen or salt thereof along with one or more pharmaceutically acceptable excipient; wherein mefenamic acid is in the modified release form and Naproxen or salt thereof is in the immediate release form or vice versa.
In another aspect of the present invention is to provide novel pharmaceutical composition comprising mefenamic acid and an other analgesic for the treatment of dysmenorrhea; wherein mefenamic acid is in the modified release form and other analgesic is in the immediate release form or vice versa. .
In another aspect of the present invention is to provide novel pharmaceutical composition comprising mefenamic acid and Naproxen or salt thereof for the treatment of dysmenorrhea; wherein mefenamic acid is in the modified release form and Naproxen or salt thereof is in the immediate release form.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates the dissolution profile of composition comprising Mefenamic acid modified release and Naproxen sodium immediate release in 0.05 M Tris Buffer (Example 1, Initial & after one month accelerated stability).
Figure 2 illustrates the dissolution profile of composition comprising Mefenamic acid modified release and Naproxen sodium immediate release in 0.05 M Tris Buffer (Example 2, Initial & after one month accelerated stability)
Figure 3 illustrates the dissolution profile of composition comprising Mefenamic acid modified release and Naproxen sodium immediate release in 0.05 M Tris Buffer (Example 3, Initial & after one month accelerated stability)

DETAIL DESCRIPTION OF THE INVENTION
The present invention relates to novel pharmaceutical composition comprising mefenamic acid and an other analgesic for the treatment of dysmenorrhea.
The novel pharmaceutical composition according to the present invention comprising mefenamic acid and an other analgesic; wherein mefenamic acid is in the modified release form and other analgesic is in the immediate release form or vice versa.
The term vice versa according to the present invention means an other analgesic may be present in the modified release form and mefenamic acid may be present in the immediate release form.
The term modified release form according to the present invention may be the delayed release, extended release or sustained release, controlled release, time dependent release.
The other analgesic of the present invention may be selected from the Nonsteroidal Anti-Inflammatory Drugs, Opioids, Corticosteroids or active ingredient which relieves pain.
The examples of other analgesic of the present invention may be selected from but not limited to the Naproxen or salt thereof, Ibuprofen, paracetamol, Bromfenac, Diclofenac, Diflunisal, Etodolac, Fenoprofen, Flurbiprofen, Indomethacin, Ketoprofen, Ketorolac, Meclofenamate, Meloxicam, Nabumetone, , Oxaprozin, Phenylbutazone, Piroxicam, Sulindac, Tolmetin, Celecoxib, Buprenorphine, Butorphanol, Codeine, Hydrocodone, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Nalbuphine, Oxycodone, Oxymorphone, Pentazocine, Propoxyphene, Tapentadol, Tramadol and like.

In another aspect of the present invention is to provide novel pharmaceutical composition comprising mefenamic acid and other analgesic preferably Naproxen or salt thereof; wherein mefenamic acid is in the modified release form and Naproxen or salt thereof is in the immediate release form or vice versa.
The novel pharmaceutical composition according to the present invention may be in the form of tablet, capsule, granule, pellet, bead or sachet.
The novel pharmaceutical composition according to the present invention may be preferably in the form of tablet or capsule or sachet.
The novel pharmaceutical composition of the present invention comprising mefenamic acid and an other analgesic along with one or more pharmaceutically acceptable excipient; wherein mefenamic acid is in the modified release form and an other analgesic is in the immediate release form or vice versa.
The novel pharmaceutical composition of the present invention can comprise any suitable amount of the mefenamic acid and other analgesic preferably Naproxen or salts thereof. The weight percentage of mefenamic acid ranges from 20% to 65%, preferably 30% to 60% based on the total weight of composition. The amount of mefenamic acid ranges from 200 mg to 600mg; preferably 250mg to 600mg; more preferably 200mg, 250mg, 275mg, 300mg, 350mg, 375mg, 400mg, 450mg, 500mg, 550mg, 600mg. The weight percentage of Naproxen sodium ranges from 20% to 80%, preferably 20% to 55% based on the total weight of composition. The amount of Naproxen sodium ranges from 200mg to 800mg; preferably 200mg to 750mg; more preferably 250mg, 275mg, 300mg, 350mg, 375mg, 400mg, 450mg, 475mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg.
The one or more pharmaceutically acceptable excipient according to present invention may be selected from the group consisting of diluents, disintegrants, binders, lubricant, release modifier, plasticizers, solubilizing agent, surfactant,

stabilizing agent, acidic agent, basic agent, sweeteners, flavor and pH regulating agent.
The examples of diluents include but not limited to mannitol, sorbitol, xylitol, cellulose derivatives, starch, maltodextrin, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide or mixture thereof. The diluent is present in the composition in an amount of about 0.5% to 40% based on the total weight of the composition; preferably in an amount of about 1% to 30 % based on the total weight of the composition.
The examples of disintegrant include but not limited to croscarmellose sodium, carboxymethyl cellulose, chitosan, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, starch, sodium starch glycolate or mixture thereof.
The examples of binder include but not limited to ethyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose sodium, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch or mixture thereof. The binder is present in the composition in an amount of about 0.005% to 10% based on the total weight of the composition; preferably in an amount of about 0.01% to 5% based on the total weight of the composition.
The examples of lubricant include but not limited calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or mixture thereof. The lubricant is present in the composition in an amount of about 0.05% to 5% based on the total weight of the composition; preferably in an amount of about 0.1% to 2% based on the total weight of the composition.

The examples of release modifiers include but not limited to cellulosic polymers, such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), methylcellulose (MC), powdered cellulose such as microcrystalline cellulose, cellulose acetate, sodium carboxymethylcellulose, calcium salt of carboxymethylcellulose, ethylcellulose; alginates, gums such as guar and xanthan gums; cross-linked polyacrylic acid derivatives such as carbomers available in various molecular weight grades; carageenan; polyvinyl pyrrolidone and its derivatives such as crospovidone; polyethylene oxides; and polyvinyl alcohol, glyceryl monostearate, mixtures of glyceryl monostearate and glyceryl monopalmitate, glycerylmonooleate, a mixture of mono, di and tri¬glycerides, glycerylmonolaurate, glyceryl behenate, paraffin, white wax, long chain carboxylic acids, long chain carboxylic acid esters and long chain carboxylic acid alcohols. Suitable pH-sensitive enteric polymers include cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic monoester copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer or mixture thereof. The release modifier is present in the composition in an amount of about 1% to 40% based on the total weight of the composition; preferably in an amount of about 2% to 30% based on the total weight of the composition.
The examples of plasticizers include but not limited to polyols like glycerol, propylene glycol, polyethylene glycol (PEG), organic esters like triethyl citrate, tributyl citrate, triacetin, diethyl phthalate, dibutyl phthalate and oils or glycerides like acetylated monoglycerides, castor oil, fractionated coconut oil or mixture thereof. The plasticizer present in the composition in an amount of about 0.01% to 1% based on the total weight of the composition; preferably in an amount of about 0.05% to 0.5% based on the total weight of the composition.

The examples of solubilizing agent include but not limited to polyethylene glycol, polyvinylpyrrolidone, dextran, or mixture thereof.
The examples of surfactant include but not limited to polysorbate, sodium lauryl sulphate, polyoxyethylene, polyoxypropylene glycol or mixture thereof.
The examples of stabilizing agent include but not limited to tocopherol, cyclodextrin, tetrasodium edetate, nicotinamide or mixture thereof.
The examples of acidic agents include but not limited to citric acid, malic acid, tartaric acid, fumaric acid, adipic acid, or mixture thereof.
The examples of basic agents include but not limited to potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or mixture thereof.
The examples of sweeteners include but not limited to saccharose, glucose, maltose, galactose, and artificial sweeteners, such as acesulfame potassium, sodium saccharin, cyclamates, sucralose or mixture thereof.
The examples of flavor include but not limited to fruit flavor, peppermint flavor or mixture thereof.
The examples of pH regulating agent include but not limited to fumarate, citrate, phosphate, carbonate, tartrate, acetate, amino acid salts or mixture thereof.
In another aspect of the present invention is to provide process of manufacturing novel pharmaceutical composition comprising mefenamic acid and other analgesic preferably Naproxen or salt thereof along with one or more pharmaceutically acceptable excipient; wherein mefenamic acid is in the modified

release form and other analgesic preferably naproxen or salt thereof is in the immediate release form or vice versa.
The process of manufacturing novel pharmaceutical composition comprising mefenamic acid and other analgesic preferably Naproxen or salt thereof along with one or more pharmaceutically acceptable excipient involves following step i. Preparing the modified release core of mefenamic acid. ii. Coating the modified release core of mefenamic acid by immediate release other analgesic preferably naproxen or salt thereof or vice versa.
The process of manufacturing novel pharmaceutical composition comprising mefenamic acid and other analgesic preferably Naproxen or salt thereof along with one or more pharmaceutically acceptable excipient may involves following steps i. Preparing the modified release core of mefenamic acid ii. Coating the modified release core of mefenamic acid with seal coat iii. Applying the extended release coat over seal coat. iv. Applying the immediate release coat of other analgesic preferably
naproxen or salt thereof over the extended release coat. v. Optionally applying the film coating over the immediate release coat of other analgesic preferably naproxen or salt thereof.
The novel pharmaceutical composition of the present invention may be in the form of bilayer tablet wherein one layer is of immediate release of other analgesic preferably naproxen of salt thereof and other layer is of modified release mefenamic acid.
The novel pharmaceutical composition of the present invention may be manufactured by process such as direct compression, dry granulation, wet granulation, roller compaction and hot melt extrusion.

The novel pharmaceutical composition of the present invention may be in the form of capsule which comprises combination of immediate and modified release granule, pellet, beads, spheres, or mini tablet and like.
The release profile of the active ingredient i.e. mefenamic acid which is modified release and other analgesic preferably naproxen or salt thereof which is immediate release or vice versa has been optimized by use of modified release polymer as well as manufacturing process involved in preparing the composition.
The novel pharmaceutical compositions of the present invention were evaluated for initial as well as after one month accelerated stability study at 40°C/75% Rh. The parameters like appearance, average weight, thickness, hardness, assay, release profile, related substance found to be in the compliance; therefore compositions of the present invention were found to be stable.
The novel pharmaceutical composition of the mefenamic acid and other analgesic preferably Naproxen or salt thereof according to present invention provides immediate onset of action by release of naproxen or salt thereof and sustain action throughout the day by release of mefenamic acid in the treatment of dysmenorrhea.
The novel pharmaceutical composition of the mefenamic acid and other analgesic preferably Naproxen or salt thereof according to present invention due to its immediate and modified release provides less frequent administration preferably once day in the treatment of dysmenorrhea.
The novel pharmaceutical composition of the mefenamic acid and other analgesic preferably Naproxen or salt thereof according to present invention provides flexibility in dosage administration in the treatment of acute as well as chronic pain of dysmenorrhea.

The synergism of mefenamic acid modified release and an other analgesic immediate release or vice versa plays vital role in achieving the desired concentration in the systemic circulation for the treatment of dysmenorrhea.
The optimized release profile and optimized concentration of active ingredient in the novel pharmaceutical composition of present invention allows better efficiency and patient compliance in the treatment of dysmenorrhea.
The optimized release profile and optimized concentration of active ingredient in the novel pharmaceutical composition of present invention also allows lesser adverse effect in the treatment of dysmenorrhea.
The novel pharmaceutical composition of the present invention packaged in suitable air tight containers and moisture proof packs. The novel pharmaceutical composition of the present invention preferably packaged in to the strip, blister, bottle or sachet.
EXAMPLES:
The following Examples are provided solely for illustrative purposes and are not
meant to limit the invention in any way.
Example 1:
Composition of Mefenamic acid 500 mg and Naproxen Sodium 250 mg

Sr.No Name of ingredient mg/unit % composition
Extended Release Mefenamic acid core 1 ayer
1. Mefenamic acid 500 50
2. Hypromellose (13275-24780 mPa.s) 36.5 3.65
3. Hypromellose (75000-140000 mPa.s) 37.0 3.7
4. Lactose monohydrate 20.0 2
Binder Solution
5. Hypromellose 0.5 0.05

(13275-24780 mPa.s)
6. Purified water q.s. q.s.
7. Magnesium stearate 6.0 0.6
Total 600 —
Seal Coat
8. Opadry white II 42 4.2
9. Purified water q.s. q.s.
Extended Release Coat
10. Ammonio methacrylate copolymer Type A 9.17 0.917
11. Ammonio methacrylate copolymer Type B 9.17 0.917
12. Triethyl citrate 0.917 0.0917
13. Acetone q.s. q.s.
14. Isopropyl alcohol q.s. q.s.
Immediate Release Coat of Naproxen Sodium
15. Naproxen Sodium equivalent to 250 mg Naproxen 275 27.5
16. Hypromellose (4-6 mPa.s) 25 2.5
17. Purified water q.s. q.s.
Film Coating
18. Opadry white II 30.0 3.0
19. Iron Oxide Yellow 8.743 0.874
20. Purified water q.s. —
Coated' Tablet Weight 1000.0 100.0
Manufacturing Procedure:
1) Mefenamic acid, hypromellose (13275- 24780 mPa.s), hypromellose (75000-140000 mPa.s) and lactose monohydrate were co-sifted through # 40 sieve.
2) Step 1 ingredients were mixed properly for 10 min using granulator.

3) Binder solution was prepared using hypromellose (13275-24780 mPa.s) and purified water.
4) Step 2 mixture was granulated in granulator using binder solution from step 3.
5) Step 4 wet granules were dried in suitable dryer till desired LOD was achieved.
6) Step 5 dried granules were passed through #20 sieve.
7) Magnesium stearate was dispensed as per the yield of dried granules and passed through # 60 sieve.
8) Step 7 magnesium stearate was added to step 6 sized granules and lubricated for 3 min in suitable blender.
9) Lubricated blend from step 8 was compressed into tablets using suitable toolings.
Seal Coating:
10) Required quantity of Opadry white II was dispersed in purified water and stirred to get homogenous dispersion.
11) Compressed tablets from step 9 were coated using coating dispersion from step 10 using autocoater till desired weight gain was achieved.
Extended Release Coating
12) Ammonio methacrylate copolymer Type A and Type B were added to the
mixture of acetone and isopropyl alcohol under continuous stirring to
obtain clear solution followed by addition of triethyl citrate under
continuous stirring.
13) Seal coated tablets of step 11 were further coated with coating solution of
step 12 using autocoater till desired weight gain was achieved.
Drug Layering (Coating of Naproxen IR layer on Extended Release Mefenamic acid core tablets):
14) Required quantity of Naproxen sodium and hypromellose (4-6 mPa.s)
were added to sufficient quantity of water under continuous stirring to
obtain clear solution.

15) Tablets of step 13 were coated with naproxen solution of step 14 till target
weight was achieved.
Opadry Coating:
16) Required quantities of Opadry white II and Iron oxide yellow were dispersed in purified water and stirred to get homogenous dispersion.
17) Tablets of step 15 were coated with coating dispersion of step 16 using autocoater till target weight was achieved.
Dissolution/Release Profile (Example 1):

12. Triethyl Citrate 0.917 0.08
13. Acetone q.s. q.s.
14. Isopropyl alcohol q.s. q.s.
Immediate release coat of Naproxen Sodium
15. Naproxen Sodium equivalent to 375 mg Naproxen 412.5 35.87
16. Hypromellose (4-6 mPa.s) 37.5 3.37
17. Purified water q.s. q.s.
Film coating
18. Opadry White II 30.0 2.60
19. Iron Oxide Red 8.74 0.76
20. Purified water q.s. ...
Coated Tablet weight 1150.0 100.0
Manufacturing Procedure:
1) Mefenamic acid, hypromellose ( 13275- 24780 mPa.s), hypromellose (75000-140000 mPa.s) and lactose monohydrate were co-sifted through # 40 sieve.
2) Step 1 ingredients were mixed properly for 10 min using granulator.
3) Binder solution was prepared using hypromellose (13275- 24780 mPa.s) and purified water.
4) Step 2 mixtures were granulated in granulator using binder solution from step 3.
5) Step 4 wet granules were dried in suitable dryer till desired LOD is achieved.
6) Step 5 dried granules were passed through #20 sieve.
7) Magnesium stearate was dispensed as per the yield of dried granules and passed through # 60 sieve
8) Step 7 Magnesium stearate was added to Step 6 sized granules and lubricated for 3 min in suitable blender.
20

•
9) Lubricated blend from step 8 was compressed into tablets using suitable
toolings.
Seal Coating:
10) Required quantity of Opadry white II was dispersed in purified water and
stirred to get homogenous dispersion.
11) Compressed tablets from step 9 were coated using coating dispersion
from step 10 using autocoater till desired weight gain is achieved.
Extended Release Coating
12) Ammonio methacrylate copolymer Type A and Type B were added to the mixture of acetone and isopropyl alcohol under continuous stirring to obtain clear solution followed by addition of triethyl citrate under continuous stirring.
13) Seal coated tablets of step 11 were further coated with coating solution of step 12 using autocoater till desired weight gain was achieved.
Drug Layering (Coating of Naproxen IR layer on Extended Release Mefenamic acid core tablets):
14) Required quantity of Naproxen sodium and hypromellose (4-6 mPa.s) were added to sufficient quantity of water under continuous stirring to obtain clear solution.
15) Tablets of step 13 were coated with naproxen solution of step 14 till target weight was achieved.
Opadry Coating:
16) Required quantities of Opadry white II and Iron oxide red were dispersed in purified water and stirred to get homogenous dispersion.
17) Tablets of step 15 were coated with coating dispersion of step 16 using autocoater till target weight was achieved.
21

A) Dissolution/Release Profile (Example 2):

Dissolution condition Medium: 0.05 M tris buffer,
Appts: Type II (Paddle),
RPM: 50
Volume: 900 ml
Drug release % Release of Mefenamic acid % Release of Naproxen sodium
Initial 1 Month
(40°C/75%
Rh) Initial 1 Month
(40°C/75%
Rh)
Time (Hours) Mean Mean Mean Mean
0 0 0 0 0
0.083 0 0 39 38
0.16 0 0 71 73
0.25 0 0 82 87
0.5 0 0 86 92
1 0 0 87 93
2 0 0
3 0 1
4 1 2
6 9 12
8 25 28
10 39 43
12 50 55
16 65 73
20 78 85
24 88 93
B) Related Substances (%) (Example 2):

Active Ingredient → Mefenamic acid Naproxen sodium
Impurity↓ Initial 1 Month
(40°C/75% Rh) Initial 1 Month
(40°C/75% Rh)
Maximum Unknown Impurity 0.02 0.01 Not Detected Not Detected
Total Impurities 0.02 0.01 Not Detected Not Detected

Example: 3
Composition of Mefenamic acid 500 mg and Naproxen Sodium 500 mg

Sr.No Name of ingredient mg/unit % composition
Extended Release Mefenamic acid core layer
1. Mefenamic acid 500 38.46
2. Hypromellose (13275- 24780 mPa.s) 36.5 2.81
3. Hypromellose (75000-140000 mPa.s) 37.0 2.85
4. Lactose Monohydrate 20.0 1.54
Binder Solution
5. Hypromellose (13275- 24780 mPa.s) 0.5 0.04
6. Purified water q.s. q.s.
7. Magnesium stearate 6.0 0.46
Total 600 ...
Seal Coat
8. Opadry white II 42 3.23
9. Purified water q.s. q.s.
Extended Release Coat
10. Ammonio methacrylate copolymer Type A 9.17 0.71
11. Ammonio methacrylate copolymer Type B 9.17 0.71
12. Triethyl citrate 0.917 0.071
13. Acetone q.s. q.s.
14. Isopropyl alcohol q.s. q.s.
Immediate release coat of Naproxen Sodium
15. Naproxen Sodium equivalent to 500 mg Naproxen 550 42.31
16. Hypromellose (4-6 mPa.s) 50 3.85
17. Purified water q.s. q.s.
Film coating
23

18. Opadry White II 30.0 2.30
19. Iron Oxide Red 4.37 0.33
20. Iron Oxide Yellow 4.37 0.33
21. Purified water q.s. ...
Coated Tablet weight 1300.0 100.0
Manufacturing Procedure:
1) Mefenamic acid, hypromellose ( 13275- 24780 mPa.s), hypromellose (75000-140000 mPa.s) and lactose monohydrate were co-sifted through # 40 sieve.
2) Step 1 ingredients were mixed properly for 10 min using granulator.
3) Binder solution was prepared using Hypromellose (13275- 24780 mPa.s) and purified water.
4) Step 2 mixture were granulated in granulator using binder solution from step 3.
5) Step 4 wet granules were dried in suitable dryer till desired LOD is achieved.
6) Step 5 dried granules were passed through #20 sieve.
7) Magnesium stearate was dispensed as per the yield of dried granules and passed through # 60 sieve.
8) Step 7 magnesium stearate was added to Step 6 sized granules and lubricated for 3 min in suitable blender.
9) Lubricated blend from step 8 was used for compression using suitable toolings.
Seal Coating:
10) Required quantity of Opadry white II was dispersed in purified water and
stirred to get homogenous dispersion.
11) Compressed tablets from step 9 were coated using coating dispersion from
step 10 using autocoater till desired weight gain was achieved.
Extended Release Coating
24

12) Ammonio methacrylate copolymer Type A and Type B were added to the mixture of acetone and isopropyl alcohol under continuous stirring to obtain clear solution followed by addition of triethyl citrate under continuous stirring.
13) Seal coated tablets of step 11 were further coated with coating solution of step 12 using autocoater till desired weight gain was achieved.
Drug Layering (Coating of Naproxen IR layer on Extended Release Mefenamic acid core tablets):
14) Required quantity of Naproxen sodium and hypromellose (4-6 mPa.s) were added to sufficient quantity of water under continuous stirring to obtain clear solution.
15) Tablets of step 13 were coated with naproxen solution of step 14 till target weight was achieved.
Opadry Coating:
16) Required quantities of Opadry white II, Iron oxide red and Iron oxide yellow were dispersed in purified water and stirred to get homogenous dispersion.
17) Tablets of step 15 were coated with coating dispersion of step 16 using autocoater till target weight was achieved.
A) Dissolution/Release Profile (Example 3):

Dissolution condition Medium: 0.05 M tris buffer
Appts: Type II (Paddle),
RPM: 50,
Volume: 900 ml
Drug release % Release of Mefenamic acid % Release of Naproxen sodium

Initial 1 Month
(40°C/75%
Rh) Initial 1 Month
(40°C/75%
Rh)
Time (Hours) Mean Mean Mean Mean
0 0 0 0 0
0.083 0 0 32 33
0.16 0 0 64 66
0.25 0 0 80 81
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0.5 0 0 90 87
1 0 0 90 88
2 0 0
3 0 1
4 1 1
6 5 7
8 25 25
10 37 40
12 48 51
16 64 67
20 78 81
24 88 90
B) Related Substances (%) (Example 3):

Active Ingredient → Mefenamic acid Naproxen sodium
Impurity ↓ Initial 1 Month
(40°C/75%
Rh) Initial 1 Month
(40°C/75%
Rh)
Maximum Unknown Impurity 0.10 0.01 Not Detected Not Detected
Total Impurities 0.15 0.01 Not Detected Not Detected
Example: 4
Composition of Mefenamic acid 375 mg and Naproxen Sodium 500 mg

Sr. No Name of ingredient mg/unit % composition
Extended Release Mefenamic acid core layer
1. Mefenamic acid 375 34.69
2. Hypromellose (13275-24780 mPa.s) 28.0 2.59
3. Hypromellose (75000-140000 mPa.s) 28.0 2.59
4. Lactose Monohydrate 14.5 1.34
Binder Solution
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5. Purified water q.s. q.s.
6. Magnesium stearate 4.5 0.42
Total 450 ...
Immediate release coat of Naproxen Sodium
7. Naproxen Sodium equivalent to 500 mg Naproxen 550.0 50.88
8. Hypromellose (4-6 mPa.s) 50.0 4.63
9. Purified water q.s. ...
Film coating
10. Opadry white II 31.5 2.91
11. Purified water q.s. ...
Coated Tablet weight 1081.5 100.0
Manufacturing Procedure:
1) Mefenamic acid, hypromellose (13275- 24780 mPa.s), hypromellose (75000-140000 mPa.s) and lactose monohydrate were co-sifted through # 40 sieve.
2) Step 1 ingredients were mixed properly for 10 min.
3) Step 2 mixture was granulated using water as binder.
4) Step 3 wet granules were passed through #8 sieve and dried in suitable dryer till desired LOD is achieved.
5) Step 4 dried granules were passed through #20 sieve.
6) Magnesium stearate was dispensed as per the yield of dried granules and passed through # 60 sieve
7) Step 6 magnesium stearate was added to step 5 sized granules and lubricated for 5 min in suitable blender.
8) Lubricated blend from step 7 was compressed into tablets using suitable tooling.
Drug Layering (Coating of Naproxen IR layer on Extended Release Mefenamic acid core tablets):
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9) Required quantity of Naproxen sodium and hypromellose (4-6 mPa.s) were added to sufficient quantity of water under continuous stirring to obtain clear solution.
10) Tablets of step 8 were coated with naproxen solution of step 9 till target weight was achieved.
Opadry Coating:
11) Required quantity of Opadry white was dispersed in purified water and stirred to get homogenous dispersion.
12) Tablets of step 10 were coated with coating dispersion of step 11 using autocoater till target weight was achieved.


Dated this 3rd day of September, 2018
(Signed) ^V*^
Dr. B.V. Sivakumar
Managing Partner & CEO Zenvision Pharma LLP

28

200245152

CLAIMS
1. A pharmaceutical composition comprising Mefenamic acid and another analgesic or salt thereof; wherein mefenamic acid is in the form of modified release and other analgesic or salt thereof is in the form of immediate release.
2. A pharmaceutical composition according to claim 1, wherein at least 90% of the mefenamic acid should not be released within 20 hours when measured in 900ml 0.05M Tris buffer in a type 2 dissolution apparatus at 100 rpm.
3. A pharmaceutical composition according to claim 1, wherein the other analgesic is selected from the group consisting of Naproxen or salt thereof, Ibuprofen, paracetamol, Bromfenac, Diclofenac, Diflunisal, Etodolac, Fenoprofen, Flurbiprofen, Indomethacin, Ketoprofen, Ketorolac, Meclofenamate, Meloxicam, Nabumetone, , Oxaprozin, Phenylbutazone, Piroxicam, Sulindac, Tolmetin, Celecoxib, Buprenorphine, Butorphanol, Codeine, Hydrocodone, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Nalbuphine, Oxycodone, Oxymorphone, Pentazocine, Propoxyphene, Tapentadol or Tramadol.
4. A pharmaceutical composition according to claim 3, wherein the other analgesic is Naproxen or salt thereof.
5. A pharmaceutical composition according to claim 1; wherein the composition may be in the form of tablet, capsule, granule, pellet, bead or sachet.
6. A pharmaceutical composition according to claim 1; wherein concentration of mefenamic acid is at least 30% based on total weight of the composition.
7. A pharmaceutical composition according to claim 1; wherein concentration of the other analgesic or salt thereof is at least 30% based on total weight of the composition.
8. A pharmaceutical composition according to claim 1; wherein concentration of mefenamic acid ranges from 200 mg to 600 mg.
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9. A pharmaceutical composition according to claim 1; wherein concentration of the other analgesic or salt thereof ranges from 250 mg to 750 mg.
10. A pharmaceutical composition according to claim 1; further comprises one or more excipient selected from the group consisting of diluents, disintegrants, binders, lubricant, release modifier, plasticizer, solubilizing agent, surfactant, stabilizing agent and acidic agent, basic agent, sweeteners, flavors and pH regulating agent.
11. A pharmaceutical composition according to claim 1, wherein release modifiers are selected from the group consisting of cellulosic polymers, such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), methylcellulose (MC), powdered cellulose such as microcrystalline cellulose, cellulose acetate, sodium carboxymethylcellulose, calcium salt of carboxymethylcellulose, ethylcellulose; alginates, gums such as guar and xanthan gums; cross-linked polyacrylic acid derivatives such as Carbomers available in various molecular weight grades; carageenan; polyvinyl pyrrolidone and its derivatives such as crospovidone; polyethylene oxides; and polyvinyl alcohol, glyceryl monstearate, mixtures of glyceryl monostearate and glyceryl monopalmitate, glycerylmonooleate, a mixture of mono, di and tri-glycerides, glycerylmonolaurate, glyceryl behenate, paraffin, white wax, long chain carboxylic acids, long chain carboxylic acid esters and long chain carboxylic acid alcohols. Suitable pH-sensitive enteric polymers include cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic monoester copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer or mixture thereof
12. A process of manufacturing pharmaceutical composition comprising modified release Mefenamic acid and immediate release other analgesic or

salt as claimed in claim 1 comprising the step of preparing the modified release core of mefenamic acid and coating the core with immediate release other analgesic or salt thereof. 13. A process of manufacturing pharmaceutical composition comprising modified release Mefenamic acid and immediate release other analgesic or salt as claimed in claim 1 comprising the step of preparing a bilayer wherein one layer is of modified release mefenamic acid and other layer is of immediate release of other analgesic.