WO 2012/172413 Al 20 December 2012 (20.12.2012) P O P C T

Home , Eperisone

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/172413 Al 20 December 2012 (20.12.2012) P O P C T

(51) International Patent Classification: (74) Agent: NAIR, Manoj Vasudevan; M/s Lex Orbis (Intel A61K 9/20 (2006.01) A61K 31/4453 (2006.01) lectual Property Practice), 709/710, Tolstoy House, 15-17 A61K 31/196 (2006.01) A61K 47/12 (2006.01) Tolstoy Marg, New Delhi 110 001 (IN). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/IB20 12/00 1159 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (22) Date: International Filing CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, 15 June 2012 (15.06.2012) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (25) Filing Language: English HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (26) Publication Language: English MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (30) Priority Data: OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, 1759/MUM/201 1 16 June 201 1 (16.06.201 1) IN SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant (for all designated States except US) : ABBOTT HEALTHCARE PVT. LTD. [IN/IN]; 4, Corporate Park, (84) Designated States (unless otherwise indicated, for every Sion-Trombay Road, Mumbai 400 071, Maharashtra (IN). kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (72) Inventors; and UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (75) Inventors/Applicants (for US only): MANE, Vidya TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, [IN/IN]; Abbott Healthcare Pvt. Ltd., c/o Piramal Life Sci EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, LV, ences Limited, 1, Nirlon Complex, Goregaon (East), Mum MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, bai 400 063 (IN). PATIL, Prasad [IN/IN]; Abbott Health TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, care Pvt. Ltd., c/o Piramal Life Sciences Limited, 1, Nirlon ML, MR, NE, SN, TD, TG). Complex, Goregaon (East), Mumbai 400 063 (IN). GROVER, Manish [IN/IN]; Abbott Healthcare Pvt. Ltd., Published: c/o Piramal Life Sciences Limited, 1, Nirlon Complex, — with international search report (Art. 21(3)) Goregaon (East), Mumbai 400 063 (IN). JATHAR, Shri- — before the expiration of the time limit for amending the pad [IN/IN]; Abbott Healthcare Pvt. Ltd., c/o Piramal Life claims and to be republished in the event of receipt of Sciences Limited, 1, Nirlon Complex, Goregaon (East), amendments (Rule 48.2(h)) Mumbai 400 063 (IN).

(54) Title: PHARMACEUTICAL COMPOSITION COMPRISING A COMBINATION OF EPERISONE AND DICLOFENAC AND PROCESS FOR PREPARING THEREOF (57) Abstract: The present invention relates to a pharmaceutical composition comprising a combination of eperisone or its pharma ceutically acceptable salts and diclofenac or its pharmaceutically acceptable salts and process for preparing thereof. PHARMACEUTICAL COMPOSITION COMPRISING A COMBINATION OF EPERISONE AND DICLOFENAC AND PROCESS FOR PREPARING THEREOF

FIELD OF THE INVENTION: The present invention relates to a pharmaceutical composition comprising a combination of eperisone or its pharmaceutically acceptable salts and diclofenac or its pharmaceutically acceptable salts and process for preparing thereof.

BACKGROUND OF THE INVENTION:

Eperisone is chemically (2RS)-l-(4-ethylphenyl)-2-methyl-3-(l- piperidyl)propan-l-one, which is a centrally acting muscle relaxant. It acts by relaxing both skeletal muscles and vascular smooth muscles, and demonstrates a variety of effects such as reduction of myotonia, improvement of circulation, and suppression of the pain reflex. The drug inhibits the vicious cycle of myotonia by decreasing pain, ischaemia, and hypertonia in skeletal muscles, thus alleviating stiffness and spasticity, and facilitating muscle movement.

Diclofenac is chemically 2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid, which is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti- inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of diclofenac, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthesis inhibition. Diclofenac free acid is a benzene-acetic acid derivative. The usual approach in relieving muscle pain relies on trying to decrease muscle tone and breaking the pain-spasm-pain cycle. The basic pathologies of musculo¬ skeletal pain involve muscle spasm followed by pain, muscle relaxants are one of the drugs of choice in relieving it. Since pain in muscle spasm is one of the chief symptoms and is caused due to release of inflammatory mediators and sensitization of peripheral nociceptors, most guidelines recommend use of NSAID. NSAIDs are the most frequently prescribed medications worldwide and are widely used for patients with musculoskeletal pain. Although NSAIDs are devoid of any direct effect on skeletal muscle contraction, they are frequently used as a first-line treatment for conditions involving muscle pain.

However both classes of drugs have limitations in the treatment of musculoskeletal pain which can be decreased by combining them together. In case of NSAIDs they are devoid of any direct effect on skeletal muscle contraction while on the other hand the mechanism of analgesia for skeletal muscle relaxants is not fully known. Combining an NSAID to muscle relaxant takes care of the limitation of both groups in relieving muscle pain. The combination would much more effectively break the pain-spam-pain cycle and allow faster mobilization and better relief.

Treatment of spastic paralysis, in cerebrovascular diseases, spastic spinal paralysis, cervical spondylosis, post-op sequelae, spinal trauma, head injury, amyotrophic lateral sclerosis, cerebral palsy, spinocerebellar degenerations, spinal vascular diseases & other encephalomyelopathies. Improvement of myotonic conditions caused by the following diseases: neck-shoulder-arm syndrome, scapulohumeral periarthritis and low back pain. Some of the disclosed studies comprising eperisone and/or NSAIDs like diclofenac are described as below. U.S. Patent No. 5073375 relates to a pharmaceutical preparation for percutaneous administration containing eperisone or tolperisone or a salt thereof which exhibits excellent skin penetration, wherein the said pharmaceutical preparation comprises a monoglyceride of an aliphatic acid having 8 to 12 carbon atoms and an ester of lactic acid with an aliphatic alcohol having 12 to 18 carbon atoms or a monoglyceride of an aliphatic acid having 8 to 12 carbon atoms.

U.S. Patent Application No. 20100029704 Al relates to a salt, particularly an ionic liquid which is a 1:1 salt, of a non-steroidal anti-inflammatory drug (NSAID) comprising a carboxylic acid and an organic amine compound, as well as a method of producing such a salt, wherein the said NSAID may be like diclofenac and the said organic amine compound may be like eperisone. The said salt compound is stable at ambient temperature, and shows an improved solubility in a liposoluble solvent. Therefore, it can increase the content of the carboxylic acid NSAID in an external preparation such as a patch and the like. As the result, transdermal absorbability and skin permeability of the efficacy ingredient can be enhanced.

U.S. Patent Application No. 20100273746 A l relates to pharmaceutical formulation containing tolperisone or its pharmaceutically acceptable salts or tolperisone combined with a non-steroidal anti-inflammatory drug or their salts, gel forming macromolecule, solvent, and if required thickening agent, penetration enhancer and pH adjuvant or the mixture thereof. The invention also relates to the manufacturing process of the above mentioned pharmaceutical compositions, further the use of these formulations, particularly for transdermal treatment and the containers suitable for the dosage, which are dual compartment containers consisting of two separated chambers.

PCT Application No. WO20 10 103544 A2 provides novel sustained release pharmaceutical preparations and process for making such compositions of tolperisone and/or eperisone and/or a pharmaceutically acceptable salt thereof. The present invention provides a sustained release formulation of tolperisone and eperisone either single or in combination or otherwise in combination with other drugs selected from the classes such as analgesic, antipyretic, neuroprotective agents, other muscle relaxants which can be formulated either in a fixed dose or as combination kit for oral administration. The composition is suitable for once a day administration into mammals and provides sustained and prolonged drug release till 24 hours which helps to reduce dosing frequency. The composition comprises therapeutically effective amount of active substance, release retarding polymers and other pharmaceutically acceptable excipients.

None of the above cited prior arts comprising a combination of eperisone and NSAIDs relates to provide oral immediate release pharmaceutical composition. Moreover a mere combination of eperisone or its pharmaceutically acceptable salts and diclofenac or its pharmaceutically acceptable salts is incompatible and decrease the stability of the active ingredients, which causes not only decrease of the effective amount of the ingredients, but also change of external appearance during the course of time like change in the color of dosage form.

The present inventors have surprisingly found that pharmaceutical composition comprising a combination of eperisone or its pharmaceutically acceptable salts and diclofenac or its pharmaceutically acceptable salts can be formulated as a single unit dosage form such as tablet.

SUMMARY OF THE INVENTION; The present invention relates a pharmaceutical composition comprising a combination of eperisone or its pharmaceutically acceptable salts and diclofenac

Or its pharmaceutically acceptable salts, wherein the said pharmaceutical composition is a unit dosage form. The present invention further relates to a pharmaceutical composition comprising a combination of eperisone or its pharmaceutically acceptable salts and diclofenac or its pharmaceutically acceptable salts, wherein the said pharmaceutical composition is an oral solid unit dosage form.

The present invention further relates to a process of preparing a pharmaceutical composition comprising a combination of eperisone or its pharmaceutically acceptable salts and diclofenac or its pharmaceutically acceptable salts wherein the process has following steps: (a) preparing granules of eperisone or its pharmaceutically acceptable salts with pH adjusting agent(s), (b) preparing granules of diclofenac or its pharmaceutically acceptable salts, (c) optionally coating the granules of (a) and (b) and / or converting the granules of (a) and (b) into a suitable pharmaceutical dosage form; wherein the said pharmaceutical composition is an oral solid unit dosage form

DETAILED DESCRIPTION OF THE INVENTION: Definitions: The term "unit dosage form" as used herein refers to pharmaceutical composition comprising tablets, chewable tablets, capsules, single dosage sachets, preferably tablets, layered tablets, more preferably bilayer tablets.

The term "pharmaceutically acceptable excipients" as used herein means a component of a pharmaceutical product that is not an active ingredient for example, fillers/diluents, binders, disintegrants, lubricants, glidants, carriers and the like. The excipients that are useful in preparing a pharmaceutical composition are preferably generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for pharmaceutical use.

The most of these excipients are described in detail in, e.g., Howard C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, (7th Ed. 1999); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy, (20th Ed. 2000); and A. Kibbe, Handbook of Pharmaceutical Excipients, (3rd Ed. 2000), which are incorporated by reference herein.

The term "eperisone" as used in the invention is meant to cover eperisone or its pharmaceutically acceptable salt(s), hydrate(s), solvate(s) and physiologically functional derivative(s) and precursors thereof. Preferably, eperisone hydrochloride. The term also includes all polymorphic forms, whether crystalline or amorphous of eperisone hydrochloride.

The term "diclofenac" as used in the invention is meant to cover diclofenac or its pharmaceutically acceptable salt(s), hydrate(s), solvate(s) and physiologically functional derivative(s) and precursors thereof. Preferably, diclofenac free acid. The term also includes all polymorphic forms, whether crystalline or amorphous of diclofenac.

The term "pH adjusting agent" as used in the present invention means an agent that creates a suitable micro pH environment in the composition that imparts stability to composition for required period of time.

The pharmaceutical composition according to present invention will, in general comprise of one or more excipients. Examples of pharmaceutically acceptable excipients include, but are not limited to binders, fillers or diluents, lubricants, glidants, disintegrants. A combination of excipients may also be used. The amount of excipient(s) employed will depend upon how much active agent is to be used. One excipient can perform more than one function.

Binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose such as products known under the registered trade marks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, combinations thereof and other materials known to one of ordinary skill in the art and mixtures thereof.

Fillers or diluents, may include, but are not limited to confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate, and the like can be used.

Lubricants may include, but are not limited to, those conventionally known in the art such as Mg, Al, Ca, Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc.

Glidants may include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of ordinary skill in the art.

The pharmaceutical composition according to present invention may also comprise a disintegrant which may be included in all or part of the oral dosage form to ensure rapid disintegration of the dosage form or part of the dosage form (for example, one of the layers in a bilayer tablet) after administration.

Disintegrants may include, but are not limited to: alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, sodium alginate, sodium starch glycolate and starches and other materials known to one of ordinary skill in the art and combinations thereof.

The pharmaceutical composition of the present invention can optionally have one or more coatings such as film coating, sugar coating, extended release coating, enteric coating, bioadhesive coating and other coatings known in the art. These coatings help formulations to release the drug at and for the required time. The coating is present from about l%w/w to about 50%w/w of the total composition weight, preferably from about l%w/w to about 15%w/w. In addition to coating ingredients, sometimes commercially available pre-mixed coating materials such as Opadry® Clear 03K19229 (contains hydroxypropylmethyl cellulose, triacetin and talc), Opadry® Clear YS-1 R-7006 (contains hydroxypropylmethyl cellulose, PEG 400 and PEG 6000), Opadry® White OY 58900 (contains hydroxypropylmethyl cellulose, PEG 400, and titanium dioxide), and Lusterclear®, etc. will be used. These typically require only mixing with a liquid before use. These coating comprises one or more excipients selected from the group comprising plasticizers, coating agents, opacifiers, fillers, polishing agents, colouring agents, anti-tacking agents and the like. The various embodiments of the present invention can be assembled in several different ways:

In one embodiment the present invention provides a pharmaceutical composition comprising a combination of eperisone or its pharmaceutically acceptable salts and diclofenac or its pharmaceutically acceptable salts; wherein the said pharmaceutical composition is an oral solid unit dosage form.

In yet another embodiment the present invention provides a pharmaceutical composition comprising a combination of eperisone or its pharmaceutically acceptable salts and diclofenac or its pharmaceutically acceptable salts; wherein the said pharmaceutical composition is a tablet dosage form.

In yet another embodiment of the present invention provide a process of preparing a pharmaceutical composition comprising a combination of eperisone or its pharmaceutically acceptable salts and diclofenac or its pharmaceutically acceptable salts; wherein the said pharmaceutical composition is an oral solid unit dosage form.

In yet another embodiment the present invention provides a process of preparing a pharmaceutical composition comprising a combination of eperisone or its pharmaceutically acceptable salts and diclofenac or its pharmaceutically acceptable salts wherein the process has following steps: (i) preparing granules of eperisone or its pharmaceutically acceptable salts with pH adjusting agent(s), (ii) preparing granules of diclofenac or its pharmaceutically acceptable salts, (iii) optionally coating the granules of (i) and (ii) and/or converting the granules of (i) and (ii) into a suitable pharmaceutical dosage form, wherein the said pharmaceutical composition is an oral solid unit dosage form. In yet another embodiment the present invention provides a pharmaceutical composition in the form of tablet comprising a combination of eperisone or its pharmaceutically acceptable salts and diclofenac or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.

In yet another embodiment the present invention provides a pharmaceutical composition in the form of bilayer tablet comprising a) first layer comprising eperisone or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients; b) second layer comprising diclofenac or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients and optionally; c) coating layer.

In yet another embodiment the present invention provides a process of preparing a pharmaceutical composition in the form of bilayer tablet comprising a) first layer comprising eperisone or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients b) second layer comprising diclofenac or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients and optionally ; c) coating layer; wherein the process has following steps: (i) preparing granules of eperisone or its pharmaceutically acceptable salts with pH adjusting agent(s), (ii) preparing granules of diclofenac or its pharmaceutically acceptable salts, (iii) optionally coating the granules of (i) and (ii) and compressing the granules of (i) and (ii) into a bilayer tablet. In yet another embodiment the present invention provides a pharmaceutical composition in the form of bilayer tablet comprising a) first layer comprising eperisone or its pharmaceutically acceptable salts thereof and one or more pH adjusting agents and one or more pharmaceutically acceptable excipients b) second layer comprising diclofenac or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients and optionally ; c) coating layer.

In yet another embodiment the present invention provides a pharmaceutical composition in the form of bilayer tablet comprising a) first layer comprising from about 50 mg to about 150 mg eperisone hydrochloride and one or more pH adjusting agents and one or more pharmaceutically acceptable excipients b) second layer comprising from about 50 mg to about 200 mg diclofenac free acid and one or more pharmaceutically acceptable excipients and optionally ; c) coating layer.

In yet another embodiment the present invention provides a pharmaceutical composition in the form of bilayer tablet comprising d) first layer comprising from about 1% w/w to about 35% mg eperisone hydrochloride and one or more pH adjusting agents and one or more pharmaceutically acceptable excipients e) second layer comprising from about 1% w/w to about 35% w/c diclofenac free acid and one or more pharmaceutically acceptable excipients and optionally ; f coating layer. The pharmaceutical compositions in accordance with the present invention contains eperisone or its pharmaceutically acceptable salts, preferably eperisone hydrochloride in the amount of from about 50 mg to about 150 mg and diclofenac or its pharmaceutically acceptable salts, preferably diclofenac free acid in the amount from about 50 mg to about 200 mg w/w of the composition.

The pharmaceutical compositions in accordance with the present invention contains eperisone or its pharmaceutically acceptable salts, preferably eperisone hydrochloride in the amount of from about l%w/w to about 35%w/w of diclofenac or its pharmaceutically acceptable salts.

The pH adjusting agent(s) according to present invention may be selected from the group comprising of citric acid, tartaric acid, glutamic acid, maleic acid, fumaric acid, succinic acid and the like or combinations thereof, preferably citric acid and the like.

The pharmaceutical compositions in accordance with the present invention contains pH adjusting agents from about 0.01%w/w to about 15%w/w of the composition .

Another aspect of the present invention provides a process of preparing a pharmaceutical composition comprsing a combination of eperisone or its pharmaceutically acceptable salts and diclofenac or its pharmaceutically acceptable salts wherein the granulates comprising eperisone or its pharmaceutically acceptable salts, preferably eperisone hydrochloride with pH adjusting agent(s) like citric acid and granulates comprising diclofenac or its pharmaceutically acceptable salts, preferably diclofenac free acid can be prepared by methods known to a person skilled in the art like wet granulation or dry granulation. The prepared granulates can optionally be coated followed by converting into a suitable pharmaceutical dosage form. Alternatively the present invention can also be prepared by direct compression wherein eperisone or its pharmaceutically acceptable salts, preferably eperisone hydrochloride with pH adjusting agent(s) like citric acid and diclofenac or its pharmaceutically acceptable salts can be compressed with other pharmaceutically acceptable excipients followed by optionally coating and converting into a suitable pharmaceutically acceptable dosage form.

The present inventors surprisingly found that microenvironment pH of the eperisone composition was critical in achieving overall stability of unit dosage form comprising eperisone or its pharmaceutically acceptable salts and diclofenac or its pharmaceutically acceptable salts. The present inventors further found that eperisone hydrochloride formulation layer was stable in pH range 0 to 6.0 and substantial degradation of eperisone was observed above pH 6.0. Further the eperisone hydrochloride formulations were stable in preferably pH range of 0 to 4.0. For compositions of diclofenac or its pharmaceutically acceptable salts, pH did not show any significant impact on stability of the composition

The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the present invention. The examples should not be read as limiting the scope of the present invention. EXAMPLES; Example 1 [Composition with pH adjusting agent]

Table No. 1 Procedure: a) Preparation of lubricated granules of eperisone hydrochloride • Following ingredients were sifted through sieve 40 #. Eperisone hydrochloride, mannitol, citric acid monohydrate, colloidal silicon dioxide, starch 1500 • Sifted ingredients were mixed in rapid mixer granulator (RMG). • HPMC was dissolved in purified water under stirring for using as binder. • Dried mixed materials of RMG were granulated using prepared binder followed by drying in fluidized bed dryer at 50 °C to achieve loss on drying (LOD) of 2-2.5 % (105°C/10 min) and sifting of dried granules through sieve 30# and milling of granules retained on 30 #. • Sifted granules were lubricated and blended with following extragranular ingredients. Primojel, starch 1500, colloidal silicon dioxide, talc, sodium stearyl fumarate

b) Preparation of lubricated granules of diclofenac free acid

• Compression: Eperisone hydrochloride lubricated granules and diclofenac free acid lubricated granules were compressed as bilayer tablet on bilayer compression machine. • Coating: Preparation of coating solution - Dispersion of coating ready mix in IPA was stirred for 5 min, followed by addition of dichloromethane and stirring for 40 min. • Film coating of compressed tablets was done using previously prepared coating solution.

Three different batches (A,B,C,) using composition as shown in Table No. 1 were manufactured and subjected to stability study and results obtained are presented in Table No. 4.

Example No. 2 [Composition free from pH adjusting agent] Table No 2 Sodium stearyl fumarate 6.00 b) Diclofenac layer Diclofenac free acid 50.00 Mannitol IP 55.00 Maize starch IP 55.00

Pregelatinized starch USP 25.00 Primojel 9.00 Ferric Oxide red 0.13 Purified water qs Primojel 4.00 Talc IP 3.00

Colloidal silicon dioxide IP 2.00 Sodium stearyl fumerate USP 6.80 c) Coating layer HPMC 11.40 Iso propyl alcohol 109.61 Dichloromethane 121.06

Procedure: a) Preparation of lubricated granules of eperisone hydrochloride • Following ingredients were sifted through sieve 40 #. Eperisone hydrochloride, mannitol, maize starch, primojel, colloidal silicon dioxide, starch 1500 • Sifted ingredients were mixed in rapid mixer granulator (RMG). • Dry mixed materials of RMG were granulated using purified water, where internal binder (starch 1500) was included in dry mix , followed by drying in fluidized bed dryer at 50 °C to achieve loss on drying (LOD) of 2-2.5 % (105°C/10 min) and sifting of dried granules through sieve 30# and milling of granules retained on 30 #. • Sifted granules were lubricated and blended with following extragranular ingredients: Primojel, colloidal silicon dioxide, talc, sodium stearyl fumarate

b) Preparation of lubricated granules of diclofenac free acid

• Following ingredients were sifted through sieve 40 #. Diclofenac free acid, mannitol, maize starch, pregelatinized starch, primojel, instacoat oxide of iron • Sifted ingredients were dried and mixed in rapid mixer granulator (RMG). • Dry mixed materials of RMG were granulated using purified water, where internal binder (starch 500) was included in dry mix , followed by drying in fluidized bed dryer at 50°C to achieve loss on drying (LOD) of 2-2.5 % (105°C/10 min) and sifting of dried granules through sieve 30# and milling of granules retained on 30 # . • Sifted granules were lubricated and blended with following extragranular ingredients: Primojel, talc, colloidal silicon dioxide, sodium stearayl fumarate c) Compression of bilayer tablet

• Compression: Eperisone hydrochloride lubricated granules and diclofenac free acid lubricated granules were compressed as bilayer tablet on bilayer compression machine. • Coating: Preparation of coating solution - Dispersion of coating ready mix in IPA was stirred for 5 min, followed by addition of dichloromethane and stirring for 40 min. · Film coating of compressed tablets was done using previously prepared coating solution. Three different batches (D,E,F,) using composition as shown in Table No. 2 were manufactured and subjected to stability study and results obtained are presented in Table No. 4.

Example No. 3 [Composition with pH adjusting agent] Table No. 3 a) Preparation of lubricated granules of eperisone hydrochloride • Following ingredients were sifted through sieve 40 #. Eperisone hydrochloride, mannitol, citric acid monohydrate, colloidal silicon dioxide, starch 1500 • Sifted ingredients were mixed in rapid mixer granulator (RMG). • HPMC was dissolved in purified water under stirring for using as binder. • Dried mixed materials of RMG were granulated using prepared binder followed by drying in fluidized bed dryer at 50 °C to achieve loss on drying (LOD) of 2-2.5 % (105°C/10 min) and sifting of dried granules through sieve 30# and milling of granules retained on 30 #. • Sifted granules were lubricated and blended with following extragranular ingredients. Primojel, starch 1500, colloidal silicon dioxide, talc, sodium stearyl fumarate

b) Preparation of lubricated granules of diclofenac free acid

• Following ingredients were sifted through sieve 40 #. Diclofenac free acid, mannitol, primojel, instacoat oxide of iron • Sifted ingredients were mixed in rapid mixer granulator (RMG). • HPMC was dissolved in purified water under stirring for using as binder. • Dried mixed materials of RMG were granulated using prepared binder followed by drying in fluidized bed dryer at 50°C to achieve loss on drying (LOD) of 2-2.5 % (105°C/10 min) and sifting of dried granules through sieve 30# and milling of granules retained on 30 #. • Sifted granules were lubricated and blended with following extragranular ingredients: starch 1500, talc, colloidal silicon dioxide, sodium stearayl fumarate c) Compression of bilayer tablet Compression: Eperisone hydrochloride lubricated granules and diclofenac free acid lubricated granules were compressed as bilayer tablet on bilayer compression machine. Coating: Preparation of coating solution - Dispersion of coating ready mix in IPA was stirred for 5 min, followed by addition of dichloromethane and stirring for 40 min. Film coating of compressed tablets was done using previously prepared coating solution.

Three different batches (G,H,I) using composition as shown in Table No. 3 were manufactured and subjected to stability study and results obtained are presented in Table No. 4

Table No. 4 E 103.1 99.8 98.2 - - F 100.1 97.9 97.8 - - G 100.8 101.9 101.9 101.6 101.9 H 102.9 1.01.8 101.4 100.5 102.2 I 103.9 104.4 99.8 101.0 102.1 A ND 0.30 0.30% 0.42% - B ND 0.26 0.32% 0.43% - C ND 0.27 0.36% 0.45% - D ND 3.62 4.40% - - RS Max Total Imp. (%) E ND 2.80 3.40% - - F ND 3.39 3.95% - - G 0.26 0.36 0.42 0.48 0.81 H 0.25 0.39 0.42 0.44 0.81 I 0.26 0.37 0.41 0.46 0.83 NLT: Not Less than M : Month ND: Not detected RH: Relative Humidity

It can be concluded from stability data as presented in Table No. 4 that the compositions containing eperisone and diclofenac and their salts having pH stabilizing agent in eprerisone layer (i.e. A,B,C,G,H,I) have improved stability as compared to compositions without pH stabilizing agent in eprerisone layer (i.e. E,F,G)

Example No. 4: Composition having pH adjusting agent Table No. 5 Colloidal silicon dioxide IP 4.00 Talc IP 5.00 Sodium stearayl fumarate USP 5.75 b) Diclofenac layer Diclofenac potassium 50.00 Mannitol 120.00 Primojel 14.00 Instacoat Oxide of Iron (brown ) 0.07 HPMC E5 12.00 Purified water qs Starch 1500 21.00 Talc IP 2.50 Colloidal Silicon Dioxide IP 2.50 Sodium stearayl fumarate USP 3.00 c) Coating layer HPMC 14.71 Iso propyl alcohol 141.48 Dichloromethane 156.26

Procedure: a) Preparation of lubricated granules of eperisone hydrochloride • Following ingredients were sifted through sieve 40 #. Eperisone hydrochloride, mannitol, citric acid monohydrate, colloidal silicon dioxide, starch 1500 • Sifted ingredients were mixed in rapid mixer granulator (RMG). • HPMC was dissolved in purified water under stirring for using as binder. • Dried mixed materials of RMG were granulated using prepared binder followed by drying in fluidized bed dryer at 50 °C to achieve loss on drying (LOD) of 2-2.5 % (105°C/10 min) and sifting of dried granules through sieve 30# and milling of granules retained on 30 #. • Sifted granules were lubricated and blended with following extragranular ingredients. Primojel, starch 1500, colloidal silicon dioxide, talc, sodium stearyl fumarate

b) Preparation of lubricated granules of diclofenac potassium

• Following ingredients were sifted through sieve 40 #. Diclofenac potassium, mannitol, primojel, instacoat oxide of iron • Sifted ingredients mixed in rapid mixer granulator (RMG). • HPMC was dissolved in purified water under stirring for using as binder. • Dried mixed materials of RMG were granulated using prepared binder followed by drying in fluidized bed dryer at 50°C to achieve loss on drying (LOD) of 2-2.5 % (105°C/10 min) and sifting of dried granules through sieve 30# and milling of granules retained on 30 #. • Sifted granules were lubricated and blended with following extragranular ingredients: starch 1500, talc, colloidal silicon dioxide, sodium stearayl fumarate c) Compression of bilayer tablet

• Compression: Eperisone hydrochloride lubricated granules and diclofenac potassium lubricated granules were compressed as bilayer tablet on bilayer compression machine. • Coating: Preparation of coating solution - Dispersion of coating ready mix in IPA was stirred for 5 min, followed by addition of dichloromethane and stirring for 40 min. Film coating of compressed tablets was done using previously prepared coating solution. Example No. 5: Composition having pH adjusting agent

Table No. 6

Procedure: a) Preparation of lubricated granules of eperisone hydrochloride • Following ingredients were sifted through sieve 40 #. Eperisone hydrochloride, mannitol, citric acid monohydrate, colloidal silicon dioxide, starch 1500 • Sifted ingredients were mixed in rapid mixer granulator (RMG). • HPMC was dissolved in purified water under stirring for using as binder. • Dried mixed materials of RMG were granulated using prepared binder followed by drying in fluidized bed dryer at 50 °C to achieve loss on drying (LOD) of 2-2,5 % (105°C/10 min) and sifting of dried granules through sieve 30# and milling of granules retained on 30 #. • Sifted granules were lubricated and blended with following extragranular ingredients. Primojel, starch 1500, colloidal silicon dioxide, talc, sodium stearyl fumarate

b) Preparation of lubricated granules of diclofenac sodium

• Following ingredients were sifted through sieve 40 #. Diclofenac sodium, mannitol, primojel, instacoat oxide of iron • Sifted ingredients were mixed in rapid mixer granulator (RMG). • HPMC was dissolved in purified water under stirring for using as binder. • Dried mixed materials of RMG were granulated using prepared binder followed by drying in fluidized bed dryer at 50°C to achieve loss on drying (LOD) of 2-2.5 % (105°C/10 min) and sifting of dried granules through sieve 30# and milling of granules retained on 30 #. • Sifted granules were lubricated and blended with following extragranular ingredients: starch 1500, talc, colloidal silicon dioxide, sodium stearayl fumarate ompression of bilayer tablet

• Compression: Eperisone hydrochloride lubricated granules and diclofenac sodium lubricated granules were compressed as bilayer tablet on bilayer compression machine. • Coating: Preparation of coating solution - Dispersion of coating ready mix in IPA was stirred for 5 min, followed by addition of dichloromethane and stirring for 40 min. Film coating of compressed tablets was done using previously prepared coating solution. We claim:

1. A pharmaceutical composition in the form of tablet comprising a combination of eperisone or its pharmaceutically acceptable salts and diclofenac or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients. 2. A pharmaceutical composition according to claim 1 wherein eperisone or pharmaceutically acceptable salts thereof is present from about 1% w/w to about 35% w/w of composition. 3. A pharmaceutical composition according to claim 1 wherein diclofenac or pharmaceutically acceptable salts thereof is present from about 1% w/w to about 35% w/w of composition. 4. A pharmaceutical composition according to claim 1 wherein the composition further comprises of one or more pH adjusting agents which can be selected from the group consisting of citric acid, tartaric acid, glutamic acid, maleic acid, fumaric acid, succinic acid and combinations thereof. 5. A pharmaceutical composition according to claim 4 wherein pH adjusting agent is present from about 0.01% w/w to about 15% w/w of composition. 6. A pharmaceutical composition in the form of bilayer tablet comprising a) first layer comprising eperisone or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients; b) second layer comprising diclofenac or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients and optionally; c) coating layer. 7. A pharmaceutical composition according to claim 6 wherein eperisone or pharmaceutically acceptable salts thereof is present from about 1% w/w to about 35% w/w of composition. 8. A pharmaceutical composition according to claim 6 wherein diclofenac or pharmaceutically acceptable salts thereof is present from about 1% w/w to about 35% w/w of composition. 9. A pharmaceutical composition according to claim 6 wherein the tablet further comprises of one or more pH adjusting agents which can be selected from the group consisting of citric acid, tartaric acid, glutamic acid, maleic acid, fumaric acid, succinic acid and combinations thereof. 10. A pharmaceutical composition according to claim 9 wherein pH adjusting agent is present from about 0.01% w/w to about 15% w/w of composition. 11. A pharmaceutical composition in the form of bilayer tablet comprising a) first layer comprising eperisone or its pharmaceutically acceptable salts thereof and one or more pH adjusting agents and one or more pharmaceutically acceptable excipients; b) second layer comprising diclofenac or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients; and optionally; c) coating layer. 12. A pharmaceutical composition according to claim 1 wherein eperisone or pharmaceutically acceptable salts thereof is present from about 1% w/w to about 35% w/w of composition.

13. A pharmaceutical composition according to claim 11 wherein diclofenac or pharmaceutically acceptable salts thereof is present from about 1% w/w to about

35%> w/w of composition.

14. A pharmaceutical composition according to claim 1 1 wherein pH adjusting agents can be selected from the group consisting of citric acid, tartaric acid, glutamic acid, maleic acid, fumaric acid, succinic acid and combinations thereof.

15. A pharmaceutical composition according to claim 11 wherein pH adjusting agent is present from about 0.0 1% w/w to about 15% w/w of composition. 16. A pharmaceutical composition in the form of bilayer tablet comprising a) first layer comprising from about 1% w/w to about 35% w/w eperisone hydrochloride and one or more pH adjusting agents and one or more pharmaceutically acceptable excipients b) second layer comprising from about 1% w/w to about 35% w/w diclofenac free acid and one or more pharmaceutically acceptable excipients and optionally ; c) coating layer. 17. A pharmaceutical composition according to claim 16 wherein the pH adjusting agent can be selected from the group consisting of citric acid, tartaric acid, glutamic acid, maleic acid, fumaric acid, succinic acid and combinations thereof. 18. A pharmaceutical composition according to claim 16 wherein pH adjusting agent is present from about 0.01% w/w to about 15% w/w of composition. 19. A process of preparing a pharmaceutical composition in the form of bilayer tablet wherein the process has following steps: (i) preparing granules of eperisone or its pharmaceutically acceptable salts with pH adjusting agent(s), (ii) preparing granules of diclofenac or its pharmaceutically acceptable salts, (iii) optionally coating the granules of (i) and (ii) and compressing the granules of (i) and (ii) into a bilayer tablet. A . CLASSIFICATION O F SUBJECT MATTER INV. A61K9/20 A61K31/196 A61K31/4453 A61K47/12 ADD.

According to International Patent Classification (IPC) or to both national classification and IPC

B . FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)

EPO-Internal , BIOSIS, EMBASE, WPI Data

C . DOCUMENTS CONSIDERED TO B E RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

WO 2010/103544 A2 (PATEL DINESH SHANTI LAL 1-19 [IN] ; PATEL SACHIN DINESH [IN] ; KURANI SHASHI KA) 16 September 2010 (2010-09-16) ci ted i n the appl i cati on exampl es 3, 4, 15-18

US 2005/147671 Al (REINER ALBERTO [IT] ET 1-19 AL) 7 July 2005 (2005-07-07) exampl es 1, 2, 5, 11 , 13

□ Further documents are listed in the continuation of Box C . See patent family annex. * Special categories of cited documents : "T" later document published after the international filing date or priority date and not in conflict with the application but cited to understand "A" document defining the general state of the art which is not considered the principle or theory underlying the invention to be of particular relevance "E" earlier application or patent but published o n or after the international "X" document of particular relevance; the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive "L" documentwhich may throw doubts on priority claim(s) orwhich is step when the document is taken alone cited to establish the publication date of another citation or other "Y" document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve an inventive step when the document is "O" document referring to an oral disclosure, use, exhibition or other combined with one o r more other such documents, such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report

15 October 2012 22/10/2012

Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL - 2280 HV Rijswijk Tel. (+31-70) 340-2040, Fax: (+31-70) 340-3016 Frel i chowska, J Patent document Publication Patent family Publication cited in search report date member(s) date

O 2010103544 A2 16 -09 -2010 CN 102438597 A 02-05-2012 EA 201171109 Al 30-03-2012 EP 2405900 A2 18-01-2012 O 2010103544 A2 16-09-2010 us 2005147671 Al 07 -07 -2005 US 6974595 Bl 13-12-2005 US 2005147671 Al 07-07-2005 US 2005214363 Al 29-09-2005 US 2005215643 Al 29-09-2005