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 DICYCLOMINE OR SALT THEREOF
AND MEFENAMIC ACID
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

"NOVEL PHARMACEUTICAL COMPOSITION COMPRISING DICYCLOMINE OR SALT THEREOF AND MEFENAMIC ACID"
FIELD OF THE INVENTION
The present invention relates to a novel pharmaceutical composition comprising Dicyclomine or salt thereof and Mefenamic acid 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.
Dicyclomine hydrochloride is an antispasmodic and anticholinergic (antimuscarinic) agent. Chemically Dicyclomine hydrochloride is [bicyclohexyl]-1- carboxylic acid, 2-(diethylamino) ethyl ester, hydrochloride and its molecular

weight is 345.95. Its empirical formula is C19H35NO2HCl Dicyclomine hydrochloride is represented by compound of structural formula I

Dicyclomine hydrochloride occurs as a fine, white, crystalline, practically odorless powder with a bitter taste. It is soluble in water, freely soluble in alcohol and chloroform, and very slightly soluble in ether.
Dicyclomine hydrochloride capsule, injection and tablet of Allergan have been approved in USA as on Oct 15, 1984 under the trade name BENTYL and are available in the strengths of 10mg, 10mg/ml and 20mg respectively. The products are indicated for the treatment of patients with functional bowel/irritable bowel syndrome.
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 II

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.
IN Patent application No. 4886/MUM/2015 discloses "a preparation which is administered orally and contains a fixed dose combination of Mefenamic acid and Dicyclomine or pharmaceutically acceptable salt thereof with fast dissolution profile and immediate onset of therapeutic action by using superdisintegrant and effervescent agent". This patent discloses fast dissolving immediate release combination of Mefenamic acid and Dicyclomine or pharmaceutically acceptable salt thereof. However, IN Patent application No. 4886/MUM/2015 does not disclose combination of Dicyclomine and Mefenamic acid; wherein Dicyclomine is in immediate release form and Mefenamic acid is in the modified release form.
A thesis entitled, "Formulation and Characterization of Bilayer Tablet of Dicyclomine hydrochloride and Mefenamic acid for Colon Targeted Drug Delivery" by Chauhan Shefali Shantibhai (Student of Atmiya Institute of Pharmacy, "Yogidham Gurukul", Kalawad Road, Rajkot) submitted to Gujarat Technological University (May-2013) discloses, "Sustained release bilayer tablet of Dicyclomine hydrochloride and Mefenamic acid". However the said thesis does not disclose combination of Dicyclomine and Mefenamic acid, wherein Dicyclomine is in immediate release form and Mefenamic acid is in the modified release form.
The commercially available product as well as product known in the prior art for combination of Dicyclomine and Mefenamic acid are in the form of immediate release or in the sustained release dosage form. Also the combination is not

available as one with rapid onset of action and another with prolonged drug delivery throughout the day. The commercially available products for the combination of Dicyclomine and Mefenamic acid are not efficacious in the treatment of dysmenorrhea. Further immediate release commercially available product as well as product known in the prior art requires frequent administration which does not provide patient compliance in the treatment of dysmenorrhea. Also sustained release commercially available product as well as product known in the prior art does not provide rapid onset of action in the acute treatment of dysmenorrhea.
Therefore there is an unmet need in the art to provide novel pharmaceutical composition comprising Dicyclomine or salt thereof in the form of immediate release and Mefenamic acid in the form of modified release which provides immediate onset of action, act for longer duration, provides less frequent administration, efficacious and therefore 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 Dicyclomine or salt thereof and Mefenamic acid; wherein Dicyclomine or salt thereof is in the immediate release form and Mefenamic acid is in the modified release form.
It is another object of the present invention to provide novel pharmaceutical composition comprising Dicyclomine or salt thereof and Mefenamic acid which is efficacious in the treatment of dysmenorrhea.
It is another object of the present invention to provide novel pharmaceutical composition comprising Dicyclomine or salt thereof and Mefenamic acid which is efficacious in the treatment of acute and chronic dysmenorrhea.

It is another object of the present invention to provide novel pharmaceutical composition comprising Dicyclomine or salt thereof and Mefenamic acid which provides immediate onset of action in the treatment of acute dysmenorrhea.
It is another object of the present invention to provide novel pharmaceutical composition comprising Dicyclomine or salt thereof and Mefenamic acid which act for longer duration and provides less frequent administration preferably once day in the treatment of chronic dysmenorrhea.
It is another object of the present invention to provide novel pharmaceutical composition comprising Dicyclomine or salt thereof and Mefenamic acid 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 Dicyclomine or salt thereof and Mefenamic acid; wherein Dicyclomine or salt thereof is in the immediate release form and Mefenamic acid is in the modified release form.
In another aspect of the present invention is to provide novel pharmaceutical composition comprising Dicyclomine or salt thereof and Mefenamic acid along with one or more pharmaceutically acceptable excipient; wherein Dicyclomine or salt thereof is in the immediate release form and Mefenamic acid is in the modified release form.
In another aspect of the present invention is to provide process of manufacturing novel pharmaceutical composition comprising Dicyclomine or salt thereof and Mefenamic acid along with one or more pharmaceutically acceptable excipient; wherein Dicyclomine or salt thereof is in the immediate release form and Mefenamic acid is in the modified release form.

In another aspect of the present invention is to provide novel pharmaceutical composition comprising Dicyclomine or salt thereof and Mefenamic acid for the treatment of dysmenorrhea; wherein Dicyclomine or salt thereof is in the immediate release form and Mefenamic acid is in the modified release form.
DETAIL DESCRIPTION OF THE INVENTION
The present invention relates to novel pharmaceutical composition comprising Dicyclomine or salt thereof and Mefenamic acid; wherein Dicyclomine or salt thereof is in the immediate release form and Mefenamic acid is in the modified release form.
The novel pharmaceutical composition according to the present invention means composition of Dicyclomine or salt thereof and Mefenamic acid; wherein Dicyclomine or salt thereof is in the immediate release form and Mefenamic acid is in the modified release form in the treatment of dysmenorrhea.
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 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 Dicyclomine or salt thereof and Mefenamic acid along with one or more pharmaceutically acceptable excipient; wherein Dicyclomine or salt thereof is in the immediate release form and Mefenamic acid is in the modified release form.

The novel pharmaceutical composition of the present invention can comprise any suitable amount of the Dicyclomine or salt thereof and Mefenamic acid. The weight percentage of Dicyclomine or salt thereof ranges from 1% to 30%, preferably 1.5% to 20% based on the total weight of composition. The amount of Dicyclomine or salt thereof ranges from 2.5mg to 50mg; preferably 5mg to 30mg; more preferably 2.5mg, 5mg, 7.5mg, 10mg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg, 27.5mg, 30mg, 32.5mg, 35mg, 37.5mg, 40mg, 42.5mg, 45mg, 47.5mg and 50mg. The weight percentage of Mefenamic acid ranges from 20% to 85%, preferably 30% to 80% based on the total weight of composition. The amount of Mefenamic acid ranges from 200mg to 600mg; preferably 250mg to 600mg; more preferably 200mg, 250mg, 275mg, 300mg, 350mg, 375mg, 400mg, 450mg, 500mg, 550mg, 600mg.
The one or more pharmaceutically acceptable excipient according to present invention may be selected from the group consisting of diluents, binders, release modifiers, lubricants, plasticizers, disintegrants, solubilizing agents, surfactants, stabilizing agents, antiadherent, glidant, acidic agents, basic agents, sweeteners, flavor and pH regulating agent.
The examples of diluent 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 l%o to 30 % based on the total weight of the composition.
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 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 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 3% 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 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 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 antiadherent include but not limited to talc, corn starch, colloidal silica, DL-leucine, sodium lauryl sulphate, stearates or mixture thereof.

The examples of glidant include but not limited to colloidal silica, pyrogenic silica, hydrated sodium silicoaluminate, magnesium stearate, sodium stearyl fumarate, fumed silica (colloidal silicon dioxide), starch, talc 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 Dicyclomine or salt thereof and Mefenamic acid along with one or more pharmaceutically acceptable excipient; wherein Dicyclomine or salt thereof is in the immediate release form and Mefenamic acid is in the modified release form.
The process of manufacturing novel pharmaceutical composition comprising Dicyclomine or salt thereof and Mefenamic acid 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 of Dicyclomine or salt thereof.
The process of manufacturing novel pharmaceutical composition comprising Dicyclomine or salt thereof and Mefenamic acid 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 Dicyclomine or salt thereof over
the extended release coat. v. Optionally applying the film coating over the immediate release coat of Dicyclomine or salt thereof.
The novel pharmaceutical composition of the present invention may be in the form of bilayer tablet wherein Dicyclomine or salt thereof layer is of immediate release 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. Dicyclomine or salt thereof which is immediate release and Mefenamic acid which is immediate release has been optimized by use of modified release polymer as well as manufacturing process involved in preparing the composition.

The concentration of Dicyclomine or salt thereof and Mefenamic acid in the pharmaceutical composition of present invention has been optimized by considering the pharmacokinetics, pharmacodynamics of active ingredient and as per need for treating dysmenorrhea.
The novel pharmaceutical compositions of the present invention were evaluated for 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 dissolution of the novel pharmaceutical compositions of the present invention were carried out using 0.01 N HCl Medium with Type II (Paddle) apparatus at 50 RPM for 1 hour and 0.05 M tris buffer with 1% SLS medium with Type II (Paddle) apparatus at 50 RPM upto 24 hour.
The novel pharmaceutical compositions of the present invention, wherein at least 90% of the Dicyclomine or salt thereof should be released within 1 hours when measured in 0.01 N HCl Medium with Type II (Paddle) apparatus at 50 RPM
The novel pharmaceutical compositions of the present invention, wherein at least 90% of the Mefenamic acid should not be released within 20 hours when measured in 900ml 0.05M Tris buffer with 1% SLS in a type 2 dissolution apparatus at 50 rpm.
The novel pharmaceutical composition of the Dicyclomine or salt thereof and Mefenamic acid according to present invention provides immediate onset of action by release of Dicyclomine 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 Dicyclomine or salt thereof and Mefenamic acid 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 Dicyclomine or salt thereof and Mefenamic acid according to present invention provides flexibility in dosage administration in the treatment of acute as well as chronic pain of dysmenorrhea.
The synergism of Dicyclomine or salt thereof immediate release and Mefenamic acid modified release 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 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 250mg and Dicyclomine HCl 10mg

Sr.No Name of ingredient mg/unit % composition
Extended Release Mefenamic acid core layer
1. Mefenamic acid 250.000 70.820
2. Hypromellose (Methocel K15M Premium CR) (13275-24780 mPa.s) 18.250 5.170

3. Hypromellose ( Methocel K100M Premium) CR (75000-140000 mPa.s) 18.500 5.250
4. Lactose monohydrate (Pharmatose 200 M 10.000 2.830
Binder Solution
5. Hypromellose (Methocel K15M Premium CR) (13275-24780 mPa.s) 0.250 0.070
6. Purified water q.s. -
7. Magnesium stearate 3.000 0.850
Total 300 —
Seal Coat
8. Opadry white II 21.000 5.950
9. Purified water q.s. -
Extended Release Coat
10. Eudragit RL 30 D 2.940 0.830
11. Eudragit RS 30 D 2.940 0.830
12. Triethyl citrate 1.180 0.330
13. Talc 2.940 0.830
14. Purified water q.s. q.s
Immediate Release Coat of Dicyclomine HCI
15. Dicyclomine HC1 10.000 2.83
16. Hypromellose (4-6 mPa.s) (Methocel E5 Premium LV) 1.000 0.280
17. Purified water q.s. -
Film Coating
18. Opadry Yellow II 11.000 3.120
19. Purified water q.s. q.s.
Coated Tablet Weight 353.000 100.0

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 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) Talc and Triethyl citrate were homogenized in purified water for 10 min and this suspension slowly poured in to Eudragit dispersion with conventional stirrer. Suspension was pass through 0.5 mm sieve.
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 Dicyclomine HCl IR layer on Extended Release Mefenamic acid core tablets):
14) Required quantity of Dicyclomine HC1 and hypromellose (4-6 mPa.s) were added to sufficient quantity of water under continuous stirring to obtain suspension.
15) Tablets of step 13 were coated with Dicyclomine HC1 suspension of step 14 till target weight was achieved.
Opadry Coating:
16) Required quantity of Opadry was 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):

Dissolution condition Medium: 0.01 NHCL
Appts: Type II (Paddle)
RPM:50
Volume: 500 ml Medium: 0.05 M Tris buffer
with 1% SLS
Appts: Type II (Paddle)
RPM:50
Volume: 900 ml
Time (Hours) % Release of Dicyclomine HC1 % Release of Mefenamic acid
0 0 -
0.083 104 -
0.16 110 -
0.25 113 -
0.5 115 -
1 116 0
2 NA 2
3 NA 6
4 NA 15
6 NA 27
8 NA 57
10 NA 64
12 NA 74
16 NA 90
20 NA 96
24 NA 96

Example 2:
Composition of Mefenamic acid 500mg and Dicyclomine HCl 20mg

Sr.No Name of ingredient mg/unit % composition
Extended Release Mefenamic acid core I ayer
1. Mefenamic acid 500.000 69.540
2. Hypromellose (Methocel K15M Premium CR) (13275-24780 mPa.s) 36.500 5.070
3. Hypromellose (Methocel K100M Premium CR) (75000-140000 mPa.s) 37.000 5.140
4. Lactose monohydrate (Pharmatose 200M) 20.000 2.780
Binder Solution
5. Hypromellose (Methocel K15M Premium CR) (13275-24780 mPa.s) 0.500 0.070
6. Purified water q.s. -
7. Magnesium stearate 6.000 0.830
Total 600.000 —
Seal Coat
8. Opadry white II 42.000 5.840
9. Purified water q.s.
Extended Release Coat
10. Eudragit RL 30 D 5.880 0.810
11. Eudragit RS 30 D 5.880 0.810
12. Triethyl citrate 2.360 0.320
13. Talc 5.880 0.810
14. Purified water q.s. q.s
Immediate Release Coat of Dicyclomine HCl
15. Dicyclomine HC1 20.000 2.780
16. Hypromellose (4-6 mPa.s) (Methocel E5 Premium LV) 2.000 0.270
17. Purified water q.s. q.s

Film Coating
18. Opadry Brown II 35.000 4.860
19. Purified water q.s. q.s
Coated Tablet Weight 719.000 100.0
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 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) Talc and Triethyl citrate were homogenized in purified water for 10 min and this suspension slowly poured in to Eudragit dispersion with conventional stirrer. Suspension was passing through 0.5 mm sieve.
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 Dicyclomine HCl IR layer on Extended Release Mefenamic acid core tablets):
14) Required quantity of Dicyclomine HC1 and hypromellose (4-6 mPa.s) were added to sufficient quantity of water under continuous stirring to obtain suspension.
15) Tablets of step 13 were coated with Dicyclomine HC1 suspension of step 14 till target weight was achieved.
Opadry Coating:
16) Required quantity of Opadry brown II was 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 2):

Dissolution condition Medium: 0.01 NHCl
Appts: Type II (Paddle)
RPM: 50
Volume: 500 ml Medium: 0.05 M Tris buffer
with 1% SLS
Appts: Type II (Paddle)
RPM: 50
Volume: 900 ml
Time (Hours) % Release of Dicyclomine HC1 % Release of Mefenamic acid
0 0 -
0.083 64 -
0.16 81 -
0.25 88 -
0.5 98 -
1 97 0
2 NA 1
3 NA 4
4 NA 10

6 NA 26
8 NA 37
10 NA 47
12 NA 55
16 NA 71
20 NA 85
24 NA 92

CLAIMS
1. A pharmaceutical composition comprising Dicyclomine or salt thereof and Mefenamic acid; wherein Dicyclomine or salt thereof is in the form of immediate release and Mefenamic acid is in the form of modified 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 with 1% SLS in a type 2 dissolution apparatus at 50 rpm.
3. A pharmaceutical composition according to claim 1; wherein the composition may be in the form of tablet, capsule, granule, pellet, bead or sachet.
4. A pharmaceutical composition according to claim 1; wherein concentration of Dicyclomine or salt thereof is at least 3% based on total weight of the composition and concentration of Mefenamic acid is at least 30% based on total weight of the composition.
5. A pharmaceutical composition according to claim 1; wherein concentration of Dicyclomine or salt thereof ranges from 2.5mg to 50mg.
6. A pharmaceutical composition according to claim 1; wherein concentration of Mefenamic acid ranges from 250mg"to 750mg.
7. A pharmaceutical composition according to claim 1; further comprises one or more excipient selected from the group consisting of diluents, disintegrants, binders, solubilizing agents, surfactants, stabilizing agents, release modifiers, lubricants, antiadherent, glidant, acidic agents, basic agents, plasticizers, sweeteners, flavor and pH regulating agent.
8. 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 canoxymethylcellulose, 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.
9. A process of manufacturing pharmaceutical composition comprising immediate release Dicyclomine or salt thereof and modified release Mefenamic acid as claimed in claim 1 comprising the step of preparing the modified release core of Mefenamic acid and coating the core with immediate release of Dicyclomine or salt thereof.
10. A process of manufacturing pharmaceutical composition comprising immediate release Dicyclomine or salt thereof and modified release Mefenamic acid as claimed in claim 1 comprising the step of preparing a biliyer wherein one layer is of immediate release Dicyclomine or salt thereof and other layer is of modified release Mefenamic acid.