FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATIONS (SECTION 10)
"PHARMACEUTICAL COMBINATION COMPOSITION COMPRISING NON-STEROIDAL ANTI-INFLAMATORY AGENT AND AN ANTISPASMODIC AGENT"
UNICHEM LABORATORIES LIMITED,
A COMPANY REGISTERED UNDER THE INDIAN COMPANIES ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM BHAVAN,
PRABHAT ESTATE, OF S. V. ROAD, JOGESHWARI (WEST),
MUMBAI-400 102
MAHARASTRA, INDIA.
The following specification particularly describes the invention and the manner in which it is to be performed

Technical Field:
The present invention relates to an solid pharmaceutical combination composition and its method of manufacture for oral administration comprising an non-steroidal anti-inflammatory drug (NSAID) and an anti-spasmodic drug/muscle relaxant, wherein the two active pharmaceutical ingredients are present as separate entities in single solid dosage form like, a multilayer tablet containing the two active pharmaceutical ingredients in separate layers or a capsule containing the two active pharmaceutical ingredients in the form of pellets or tablets or mixtures thereof.
Background of the Invention
Low back pain (LBP) also referred to as lumbago, is a common symptom of musculoskeletal disorders or disorders involving the lumbar vertebrae and related soft tissue structures such as muscles, ligaments, nerves and intervertebral discs. It can be either acute, subacute or chronic in its clinical presentation. Mostly, low back pain may be due to skeletal degeneration or musculoligamentous injury and referred to as non-specific LBP. LBP is one of the most common causes of limited or restricted activity in people younger than 45 years of age, and one of the most common reasons for visiting a physician. Causes for LBP may be either one or combination of the following conditions like, mechanical (Apophyseal osteoarthritis, Diffuse idiopathic skeletal hyperostosis, Degenerative discs, Scheuemann's kyphosis, Spinal disc herniation (slipped disc), Spinal stenosis, Spondylolisthesis and other congenital abnormalities, Fractures, Leg length difference,-Restricted hip motion, Misaligned pelvis, Inflammatory (Seronegative spondylarthritides (e.g.: ankylosing spondylitis), Rheumatoid arthritis, Infection - epidural abscess or osteomyelitis etc.), Neoplastic ( Bone tumors, Intradural spinal tumors etc.), Metabolic (Osteoporotic fractures, Osteomalacia, Ochronosis, Chrndrocalcinosis etc.), Psychosomatic ( Tension mysotis syndrome), Paget's diease, Referred pain (Pelvic/abdominal disease, Prostate Cancer, Posture), Depression, oxygen deprivation. Conditions such as, cerebrovascular diseases, spastic spinal paralysis, cervical spondylosis, amyotrophic lateral sclerosis, spinocerebellar degeneration and other spinal vascular diseases are also accompanied by spasticity.
Severe musculoskeletal strains and sprains, trauma, and cervical or lumbar radiculopathy as a consequence of degenerative osteoarthritis, herniated disk, spondylitis or laminectomy, often cause moderate or severe and more chronic painful

skeletal muscle spasm. The principal symptoms include local pain, tenderness on palpation, increased muscle consistency and limitation of motion. For these patients skeletal muscle relaxants alone or in combination with an analgesic is frequently prescribed. Results of some studies have suggested that a formulation of a muscle relaxant and an analgesic agent provides greater benefit in patients with acute musculoskeletal problems than similar doses of an analgesic agent alone. For effective treatment of the above musculoskeletal disorders, combination therapy of Muscle Relaxant and NSAID is essential. The goal of present invention is to provide a combination composition which is maximally suppress muscular hypertonic symptoms in various conditions such as cervical syndrome, periarthritis of the shoulder and lumbago etc.
Centrally acting skeletal muscle relaxants are generally prescribed either as a single agents or as components of combination products. The United States Food and Drug Administration has approved indications for these medications as adjuncts to rest and physical therapy for relief of acute, painful musculoskeletal problems. Several central muscle relaxants have recently been developed for the treatment of various diseases in which the spasm is a chief complaint. These drugs mainly act at as a polysynaptic reflex mechanism to improve the symptoms of spasm. These drugs reduce spasticity; improve reflexes, walking capabilities and subjective symptoms of spastic paralysis. The oral medications that are most commonly used for the treatment of spasticity are Eperisone HCI, methocarbamol, tizanidine, baclofen, carisprodoi, cylcyobenzaprine, diazepam, chlorzoxazone, metaxalone, quinine, orphenadrine and dantrolene etc. Reasons for the limited use of most of the anti-spasmodic drugs include, hepatotoxicity and muscular weakness associated with benzodiazepines, poor tolerability of baclofen etc.
Eperisone HC] is useful for treatment of muscular hypertonic symptoms in patients with stroke. It reduces skeletal muscular spasticity via its actions within the CNS and relaxes vascular smooth muscle directly. It primarily acts at the spinal cord level and gamma motor neurons therefore it suppresses spinal reflexes and reduces the sensitivity of muscle spindles, also enhances blood circulation and has analgesic effects mainly in patients with cerebrovascular disturbance. Muscular stiffness in resting and walking conditions and difficulty in walking showed remarkable improvement with use of Eperisone HCI. Eperisone HCI is an effective drug for

reducing spasticity after stroke and has very few side effects with a good safety profile and tolerability.
An anti-inflammatory drug may be useful when there is edema and considerable damage of tissue. Most of the NSAIDs have common adverse drug reactions (ADRs) i.e., direct and indirect irritation of mucosa of the gastrointestinal tract (GIT). NSAIDs may directly irritate the gastric mucosa and inhibit COX 1 which lead to reduced levels of protective prostaglandins.
Commonly used NSAIDs include diclofenac free acid or its salts, aceclofenac, acetylsalicylic acid, fenbufen, flufenamic acid, flurbiprofen, ibuprofen, indomefhacin, ketorolac, meloxicam, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac, tenoxicam, difluntsai and tiaprofenic acid. Diclofenac free acid or its salts, widely used NSAID, is a phenylacetic acid derivative with potent anti-inflammatory and analgesic actions are highly utilized in the treatment of acute and chronic pain especially when associated with inflammation e.g. musculoskeletal injury and trauma, post operative pain, rheumatism, arthritis and gout.
Combination of NSAIDs with muscle relaxant drugs speed up the recovery. Hence, there is a need to provide a stable, safe and effective composition containing combination of NSAID and muscle relaxant/Anti-Spasmodic drug to prevent and/or treat spasm, inflammatory conditions and improvement of muscular hypertonic symptoms in conditions such as lower back pain, cervical syndrome and periarthritis of the shoulder.
US 5,260,337 (Robert T. S. et al, Nov. 9, 1993) patent discloses a combination of S-ibuprofen (NSAID) and cyclobenzaprine (muscle relaxant). Muscle relaxant used in the present composition is associated with severe side effects like, respiratory depression, decreased functionality of various muscles, depression, severe dizziness, blurred vision and vision damage. In addition, ibuprofen is not present in the enteric release form, which may lead to gastric ulceration.
US 5,876,751 (Singh A., et al, Mar. 02,3999). patent discloses a combination of diclofenac sodium (NSAID), pitofenone and fenpiverinium (anti-spasmodics) useful in the management of intestinal colic, ureteric colic and biliary colic. Manufacturing process of this invention involves non-aqueous granulation and non-aqueous coating, which are non-safe as well as expensive and hence increases the manufacturing cost. In addition, diclofenac sodium is not present in the enteric release form, which may lead to gastric ulceration etc.

WO 2005/046650 Al (Sen N. et al., May 26, 2005) patent discloses pharmaceutical composition containing combination of valdecoxib and tizanidine. NSAID of the pharmaceutical composition of this invention is. released immediately in the upper gastrointestinal tract, which may lead to abrupt increase in its plasma levels and ultimately leading precipitation of side effects. Numerous side effects are associated with the valdecoxib used in this invention i.e., hypertension, gastrointestinal bleeding, duodenal ulcer, stomatitis, heartburn, angina, congestive heart failure, backache, bloody vomit, red blood in stools etc.
US2009/0175938 Al (Umit C. et al., Jul. 9, 2009) patent application discloses a combination of flurbiprofen (NSAID), tizanidine or thiocolchicoside (Muscle Relaxants). In this invention flurbiprofen is not present as enteric release form. This may lead to adverse effects like gastrointestinal bleeding and perforation. IJS20080279933 (Umit C. et al} Nov. 13, 2008) patent application discloses combination of flurbiprofen and with a a-2 adrenergic receptor agonist or a gamma-aminobutiric acid receptor agonist. Flurbiprofen present in this composition may induce gastric ulceration since it is not present as gastro protective enteric release form.
European Patent Application, EP 2085076 Al (Garcia-Salgado Lopez et al., Aug. 05, 2009) discloses pharmaceutical composition containing combination of meloxicam and tizanidine. In this composition meloxicam is released immediately whereas tizanidine is delay released. Immediate release of meloxicam in the stomach may result in the tinnitus, gastrointestinal toxicity and bleeding. Delayed release of tizanidine from the pharmaceutical composition of this invention may be of less useful in conditions like spasticity because of the non-availability of therapeutic levels of drug in plasma for immediate action. In addition, manufacturing involves compression of multi-coated micro-particles which may lead to loss in the integrity of coating around the inert core.
Even though pharmaceutical compositions containing NSAID and muscle relaxant were disclosed, most of them cause gastric ulceration due to the presence of NSAID in non-enteric release form. In addition, most of the muscle relaxants used were not safe and tolerable. Therefore, there is a need for the development of safe and tolerable pharmaceutical composition containing combination of NSAID and muscle relaxant, its methods of manufacture, which can eliminate all these disadvantages.

Object of the Invention:
An object of the present invention is to provide a pharmaceutical composition comprising combination of, anti-inflammatory effective amount of a non-steroidal anti-inflammatory drug and an effective amount of an anti-spasmodic drug along with the use of a non-toxic and pharmaceutically acceptable inert carrier thereof.
Another objective of the present invention is to prepare a safe, tolerable and novel pharmaceutical combination compositions.
Yet another objective of the present invention is to provide a combination of enteric release of NSAID and immediate release of antispasmodic drug , for minimizing the gastric ulceration and for rapid pain relief action respectively.
Yet another object of the present invention is to provide a stable, simple and cost effective pharmaceutical combination composition of anti-inflammatory (NSAID) and anti-spasmodic drug.
Yet another objective of the present invention is to provide a dual release solid pharmaceutical composition suitable for oral administration.
Further objective of the present invention is to provide various methods of manufacture of pharmaceutical composition containing combination of a NSAID and an anti-spasmodic drug in their therapeutically effective amounts along with other pharmaceutically acceptable excipients.
Another object of the present invention is to provide a pharmaceutical composition containing combination of NSAID and an anti-spasmodic drug which can be handled easily without the requirement of any special packaging.
Summary of the Invention
The present invention relates to a solid oral pharmaceutical combination composition comprising a non-steroidal antinflammatory drug (NSAID) and an antispasmodic

drug along with one or more pharmaceutically acceptable excipients, wherein the two drugs present is in the form of a mixture of one or more of pellets or tablets,
This dual release solid oral pharmaceutical composition comprising at least two separate regions, ok wherein a first region comprising at least one enteric release/delayed release non-steroidal antinflammatory drug (NSAID), and a second region comprising at least one immediate release antispasmodic drug.
Also, according to the present invention there is provided a various methods of manufacturing a dual release combination of an enteric release NSAID and an immediate release anti-spasmodic drug in their therapeutically effective amounts along with other pharmaceutically acceptable excipients.
These manufacturing combination pharmaceutical composition comprises combination of NSAID and an anti-spasmodic drug which includes either of the following processes.
a) a film coated tablet of Eperisone HC1 and enteric release pellets of Diclofenac Sodium,
b) a sugar coated tablet of Eperisone HC1 and Enteric release pellets of diclofenac sodium
c) pellets of Eperisone HO and enteric release pellets of Diclofenac sodium
d) a film coated Tablet of Eperisone HC1 and film coated tablet of diclofenac sodium (made using enteric release pellets of diclofenac sodium)
Detailed Description of the Invention:
The present invention is related to a solid pharmaceutical combination composition comprising combination of NSAID & anti-spasmodic drug offering a dual release with at least two separate regions.
According to the present invention there is provided a dual release solid oral pharmaceutical composition comprising combination of NSIAD (non steroidal antinflammatory drug) and an antispasmodic drug> wherein the two active pharmaceutical ingredients are present as separate regions in single solid dosage form like a multilayer tablet containing the two active pharmaceutical ingredients in

separate layers or a capsule containing the two active pharmaceutical ingredients separately in the form of granulates or tablets or mixtures thereof.
In accordance with the present invention, the first region or layer of the pharmaceutical composition comprises enteric release /delayed release formulation of NSAID which eliminates the undesirable effect of NSAID on gastric mucosa and thereby improves the patient compliance.
In accordance with the present invention, the second region or layer of the pharmaceutical composition comprises immediate release formulation of the antispasmodic drug, which is having a good safety profile and tolerability.
In accordance with the present invention, the first region of the pharmaceutical composition comprises enteric release formulation of NSAID which eliminates the undesirable effect of NSAID on gastric mucosa and thereby improves the patient compliance and the second region of the pharmaceutical composition comprises immediate release formulation of the anti-spasmodic drug, which is having a good safety profile and tolerability.
The present invention provides enteric release NSAID arid immediate release of antispasmodic, for effective management of low back pain, cervical syndrome, periarthritis of shoulder and other conditions requiring both the musculoskeletal relaxation and anti-inflammatory activity.
In accordance with the present invention, NSAID is selected from the group comprising of carboxylic acid derivatives, acetic acid derivatives, salicylic acid derivatives, propionic acid derivatives, enolic acid derivatives, and cox-II inhibitors. Preferably from acetic acid derivatives, carboxylic acid derivatives, and priopionic acid derivatives. More preferably from acetic acid derivatives.
Further more in the present invention, NSAID belonging to acetic acid derivatives is selected from the group of Diclofenac free acid or its salts, Aceclofenac, Indomethacin, Ketorolac, Sulindac and Tolmetin. Preferably from group of Diclofenac free acid or its salt, Aceclofenac, Indomethacin and Sulindac. More preferably the selected NSAID is Diclofenac free acid or its salt.
In accordance with the present invention, form of diclofenac used is diclofenac sodium.

In accordance with the present invention, anti-spasmodic drug is selected from group of drugs viz., Eperisone HC1, Methocarbamol, Tizanidine, Baclofen, Carisprodol, Cylcyobenzaprine, Diazepam, Chlorzoxazone, Metaxalone, Quinine, Orphenadrine and Dantrolene. Preferably from Eperisone HC1, Tizanidine, Carisprodol, Cylcyobenzaprine, Orphenadrine and Dantrolene etc. More preferably the selected anti-spasmodic drug is Eperisone HC1.
According to the present invention, selected therapeutic dose for Diclofenac, acid or sodium or potassium salts ranges from about 25 mg to about 150 mg per dosage form, preferably from about 25 mg to about 100 mg per dosage form, more preferably from about 25 mg to about 75 mg; and selected therapeutic dose for Eperisone HC1 is from about 50 mg to about 150 mg, preferably from about 50 mg to about 125 mg, more preferably 50 mg to about 100 mg.
Further, inccordance with the present invention, granules or pellets of two active pharmaceutical ingredients are prepared by anyof the following methods viz., wet granulation method, dry granulation .method, direct compression method and meit granulation method. Preferably by wet granulation method or melt granulation method. More preferably by convention! wet granulation method using rapid mixer granulator or spray granulation method using fluid bed processor.
In particular, the present invention is a novel combination of delayed release diclofenac sodium, and an immediate release eperisone HC1 and one or more of pharmaceutically acceptable excipients.
In accordance with the present invention, the said composition comprises one or more of release retardant materials and immediate release carriers. These two elements are selected in order to allow an enteric release of the non-steroidal anti-inflammatory agent for protecting the gastric mucosa and to provide immediate release of antispasmodic drug for quick relief from pain.
In accordance with the present invention, active pharmaceutical ingredient containing granules or tablets are optionally being coated with a protective coating.
In accordance with the present invention, protective coating includes sugar coating or film coating.

In accordance with the present invention, hardness of film coated delayed release
tablets of Diclofenac Sodium is the range of 90-140N, preferably in the range of 100-
130N, more preferably in the range of 100-120N.
In accordance with the present invention, hardness of sugar coated tablet of Eperisone
HC1 is the range of 30-70N, preferably in the range of 30-60N, more preferably in the
range of 30-50N and hardness of the film coated tablet of eperisone HC1 is in the
range of 50- 110N, preferably in the range of 60-100N, more preferably in the range of
70-90N.
Pharmaceutically acceptable excipients used in the present invention for improving
the immediate release comprises one or more of that binders, diluents, disintegrants,
lubricants and the like.
In accordance with the present invention, pharmaceutically acceptable excipients used for improving the immediate release of said antispasmodic agent offers a fast disintegration, resulting in a short dissolution period, followed by a quick absorption of the said antispasmodic agent. Therefore, following the administration of the pharmaceutical composition according to the present invention, the quick appearance of the antispasmodic agent in the blood is advantageous as it can start working immediately.
In accordance with the present invention, pharmaceutically acceptable excipients used for manufacturing the enteric release region comprises one or more of release retardant polymer, diluents, disintegrants, lubricants etc.
In accordance with the present invention, release retardant excipients used are one or more of polymers for enteric release such as methacrylic acid copolymers, hydroxypropylomethyl cellulose acetate phthalate, hyroxypropylmethyl cellulose acetate succinate, cellulose acetate succinate, cellulose acetate phthalate and polyvinyl acetate phthalate.
Preferred release retardant excipients include one or more of methacrylic acid copolymers, hydroxypropylomethyl cellulose acetate phthalate, cellulose acetate phthalate and polyvinyl acetate phthalate.
More preferred release retardant excipients include one or more of methacrylic acid copolymers, cellulose acetate phthalate and polyvinyl acetate phthalate.

The binders used in the present invention may be one or more of polyvinyl pyrrolidone, magnesium aluminum silicate, co-povidone, acacia, agar, carbomers, carrageenan, cellulose acetate pthalate, ceratonia, xanthan gum, guar gum, karaya gum, gellan gum, hupu gum, carob gum, caramania gum, sodium alginate and alginic acid, sugar, dextrin, glyceryl behenate, polyethylene oxide, sorbitol, corn starch, pregelatinized starch and cellulose derivatives like carboxymethyl cellulose sodium, ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylcellulose and microcrystalline cellulose.
Preferred binders used in the present invention may be one or more of polyvinyl pyrrolidone, co-povidone, carrageenan, xanthan gum, guar gum, karaya gum, gellan gum, hupu gum, carob gum, caramania gum, sodium alginate and alginic acid, glyceryl behenate, polyethylene oxide, corn starch, pregelatinized starch and cellulose derivatives like carboxymethyl cellulose sodium, ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylcellulose and microcrystalline cellulose.
More preferred binders used in the present invention may be one or more of povidone, co-povidone, polyethylene oxide, corn starch and cellulose derivatives like carboxymethyl cellulose sodium, ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylcellulose and microcrystalline cellulose
The diluents used in the present invention may be one or more of lactose, starch, dibasic calcium phosphate dihydrate, mannitol, sorbitol, calcium sulphate dihydrate, dextrose, cellulose acetate, compressible sugar, ethyl cellulose, sodium alginate, tragacanth, xylitol and microcrystalline cellulose.
Preferred diluents used in the present invention may be one or more of lactose, starch, compressible sugar, dibasic calcium phosphate dihydrate, mannitol, ethyl celullose sodium alginate, tragacanth, xylitol and microcrystalline cellulose.
More preferred diluents used in the present invention may be one or more of lactose, starch, dibasic calcium phosphate dihydrate, Mannitol, and microcrystalline cellulose.
The disintegrants used in the present invention may be one or more of croscarmellose sodium, sodium starch glycollate, crospovidone, starch, pregelatinized starch, microcrystalline cellulose, emcosoy (Soya polysaccharide) and potassium polacrilin. Preferred disintegrants are one or more of croscarmellose sodium, sodium starch

glycollate, crospovidone, starch, pregelatinized starch, microcrystalline cellulose. More preferred disintegrants are one or more of croscarmellose sodium, sodium starch glycollate, crospovidone.
Lubricants used in the present invention may be one or more of magnesium stearate, talc, stearic acid, wax, sodium stearyl fumerate, polyethylene glycol, glyceryl behenate, glyceryl palmitostearate, hydrated silicone dioxide, hydrogenated castor oil, magnesium lauryl sulfate, palmitic acid, poloxamer, sodium benzoate, sodium lauryl sulfate, and calcium stearate.
Preferred lubricants used in the present invention may be one or more of magnesium stearate, talc, stearic acid, sodium stearyl fumerate, glyceryl behenate, glyceryl palmitostearate, hydrated silicone dioxide, hydrogenated castor oil, magnesium lauryl sulfate and calcium stearate.
More preferred lubricants used in the present invention may be one or more of magnesium stearate, talc, stearic acid, hydrated silicone dioxide, hydrogenated castor oil and calcium stearate.
In accordance with the present invention, the region containing NSAID may contain from about 1% to about 98% of NSAID, from about 1% to about 40% of one or more of release modifying agents, from about 1% to about 60% of one or more diluents, from about 1% to about 20% of one or more of disintegrants, from about 0.1% to about 5% of one or more lubricants
In accordance to the present invention, region for enteric release of NSAID contains from about 1% to 98% of Diclofenac sodium, preferably from about 1% to 94% of Diclofenac sodium or more preferably from about 1% to about 90% of Diclofenac sodium; from about 1% to about 40% of the release modifying agents, preferably from about 1% to about 30% of the release modifying agents, more preferably from about 1% to about 20% of the release modifying agents; from about 1% to about 60% of the diluents, preferably from about 1% to about 50% of the diluents, more preferably from about 1% to about 40% of the diluents ; from about 1% to about 20% of the disintegrants, preferably in between from about 1% to about 15% of the disintegrants, more preferably in between from about 1% to about 10% of the disintegrants ; from about 0.1% to about 5% of the lubricants, preferably in between

0.1% to about 3.5% of the lubricants, more preferably in between 0.1% to about 1.5 % of the lubricants.
In accordance with the present invention, the region containing anti-spasmodic agent may contain from about 1% to about 95% of antispasmodic agent, from about 1% to abut 45% of one or more diluents, from about 1% to about 30% of one or more disintegrants, from about 1% to about 15% of one or more binders, from about 0.1% to about 5% of one or more lubricants.
In accordance with the present invention, the region containing antispasmodic formulation may contain from about 1% to about 95% of Eperisone HC1, preferably from about 1% to about 85% of Eperisone HC1 and more preferably from about 1% to about 65% of Eperisone HC1; from about 1% to about 45% of one or more diluents, preferably from about 1% to about 35% of one or more diluents and more preferably from about 1% to about 25% of one or more diluents; from about 1% to about 30% of one ore more disintegrants, preferably from about 1% to about 20% of one or more disintegrants and more preferably from about 1% to about 10% of one or more disintegrants; from about 1% to about 15% of one or more binders, preferably from about 1% to about 10% of one or more binders and more preferably from about 1% to about 5% of one or more binders; from about 0.1% to about 5% of the lubricants, preferably in between 0.1% to about 3.5% of the lubricants, more preferably in between 0.1% to about 1.5 % of the lubricants.
In accordance with the invention, novel solid oral pharmaceutical composition, comprising combination of NSAID and anti-spasmodic drug, is in the form of a solid oral dosage form. Preferably, the solid oral dosage form is a multilayer tablet or a capsule filled with a mixture of pellets and tablets . More preferably, the solid oral dosage form is a capsule.
In accordance with the present invention, active pharmaceutical ingredients are present in two different regions.
In accordance with the present invention, wherein the active pharmaceutical ingredient containing region in the form of tablet may be coated. Preferably sugar coated or film coated.

In accordance with the present invention, pharamaceutical composition present in the form multilayer tablet, containing NSAID in one layer and antispasmodic drug in another layer, is film coated.
Pharmaceutically acceptable excipients used in the present invention for sugar coating include one or more of seal coating agents, polysaccharides, lubricants, binders| opacifiers. plasticizers, polishing agents etc.
In accordance with the present invention, composition for film coating comprises one or more of film forming agents, opacifiers and plasticizers etc.
In accordance with the present invention, seal coating agents used in sugar coating may be one or more of different types of shellac (Orange shellac, Dewaxed orange shellac, regular bleached (white) shellac, refined bleached shellac); cellulose acetate phthalate and zein; preferably one or more of different types of shailac (Orange shellac, Dewaxed orange shellac, regular bleached (white) shellac, refined bleached shellac); and zein and more preferably one or more of different types of shailac (Orange shellac, Dewaxed orange shellac, regular bleached (white) shellac, refined bleached shellac).
Polysaccharides used in the sugar coating may be one or more of sucrose, acacia gum, pullulan etc. More preferably sucrose, and pullulan.
Opacifieres used in the coating may be one or more of titanium dioxide, ethylene glycol patmitostearate, acetates such as zinc acetate, silicates such as talc and aluminium silicate, carbonates such as magnesium carbonate, calcium carbonate etc., stearates such as aluminium stearate and zinc stearate etc., sulfates such as calcium sulfate, oxides such as magnesium oxide and hydroxides such as aluminiuim hydroxides.
Preferred opacifieres include one or more of titanium dioxide, ethylene glycol palmitostearate, acetates such as zinc acetate, silicates such as talc and aluminium silicate, carbonates such as magnesium carbonate, calcium carbonate etc., stearates such as aluminium stearate and zinc stearate etc., and oxides such as magnesium oxide.
More preferred opacifieres include titanium dioxide, silicates such as talc and carbonates such as calcium carbonate.

Plasticizers used in the coating of the present invention may be one or more of polyethylene glycol, propylene glycol, glycerine, caster oil, acetyltriethyl citrate, benzyl benzoate, chlorbutanol, dextrin, acetyltributyl citrate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, glyceryl monooleate, glyceryl monostearate, 2-pyrrolidone, sorbitol, stearic acid, palmitic acid, triacetin, tributyl citrate, triethyl citrate, triethanolamine, surfactants like polysorbates, sorbitan esters and organic acid esters and mixtures thereof.
Preferred plasticizers used in the present invention may be one or more of polyethylene glycols, propylene glycol, glycerine, acetyltriethyl citrate, benzyl benzoate, chlorbutanol, acetyltributyl citrate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, glyceryl monooleate, glyceryl monostearate, 2-pyrrolidone, sorbitol, stearic acid, palmitic acid, triacetin, tributyl citrate, triethyl citrate, triethanolamine, surfactants like polysorbates, sorbitan esters and organic acid esters and mixtures thereof.
More preferred plasticizers used in the present invention may be one or more of polyethylene glycols, propylene glycol, glycerine, stearic acid, triacetin, triethyl citrate, surfactants like polysorbates, sorbitan esters and organic acid esters and mixtures thereof.
The binders used in the sugar coating of the present invention may be one or more of povidone, magnesium aluminum silicate, co-povidone, acacia, agar, carbomers, carrageenan, ceratonia, xanthan gum, guar gum, karaya gum, gellan gum, hupu gum, carob gum, caramania gum, sodium alginate and alginic acid, sugar, dextrin, polyethylene oxide, sorbitol, corn starch, glyceryl behenate, pregelatinized starch cellulose derivatives like ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose sodium, cellulose acetate pthalate, methylcellulose, microcrystalline cellulose.
Preferred binders used in the sugar coating of present invention may be one or more of povidone, co-povidone, carrageenan, xanthan gum, guar gum, karaya gum, gellan gum, hupu gum, carob gum, caramania gum, sodium alginate and alginic acid, glyceryl behenate, polyethylene oxide, corn starch, and pregelatinized starch and cellulose derivatives like ethyl cellulose, hydroxypropylmethyl cellulose,

hydroxypropyl cellulose, carboxymethyl cellulose sodium, methylcellulose and microcrystalline cellulose.
More preferred binders used in the sugar coating of present invention may be one or more of povidone, co-povidone, polyethylene oxide, corn starch and cellulose derivatives like ethyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl cellulose and methylcellulose.
Lubricants used in the sugar coating of the present invention may be one or more of magnesium stearate, talc, stearic acid, wax, sodium stearyl fumerate, polyethylene glycol, glyceryl behenate, glyceryl palmitostearate, hydrated silicone dioxide, hydrogenated castor oil, magnesium lauryl sulfate, palmitic acid, poloxamer, sodium bensoate, sodium lauryl sulfate, and calcium stearate.
Preferred lubricants used in the sugar coating of the present invention may be one or more of magnesium stearate, talc, stearic acid, sodium stearyl fumerate, glyceryl behenate, glyceryl palmitostearate, hydrated silicone dioxide, hydrogenated castor oil, magnesium lauryl sulfate and calcium stearate.
More preferred lubricants used in the sugar coating of the present invention may be one or more of magnesium stearate, talc, stearic acid, hydrated silicone dioxide, hydrogenated castor oil and calcium stearate.
Polishing agents used in sugar coating of the present invention may be one or more of carnauba wax and white bees wax. More preferably carnauba wax.
Film forming agents used in the film coating of present invention may be one or more of cellulose derivatives such as ethyl cellulose, hydroxypropylmethyl cellulose, hydt-oxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose acetate succinate; polyethylene glycol, polyvinyl alcohol, povidone, chitosan, maltodextrin, isomalt, ammonium alginate, gelatin, carrageen, ethyl lactate, acrylate polymers like dimethyl aminoethyl methylmethacrylate and other neutral methacrylic acid esters, polymethacrylates, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, and mixture thereof.
Preferred film forming agents used in the present invention may be one or more of cellulose derivatives such as ethyl cellulose, hydroxypropylmethyl cellulose, hydi-oxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose; polyethylene glycol, polyvinyl alcohol, povidone, chitosan, maltodextrin,

isomalt, ammonium alginate, gelatin, carrageen, ethyl lactate, acrylate polymers like dimethyl aminoethyl methylmethacrylate and other neutral methacrylic acid esters, polymethacrylates, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, and mixture thereof.
More preferred film forming agents used in the present invention may be one or more of cellulose derivatives such as ethyl cellulose, hydroxypropylmethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose; polyethylene glycol, polyvinyl alcohol, povidone and mixture thereof.
Suitable solvents used in the manufacturing of pharmaceutical composition of present invention include one or more of purified water, ethyl acetate, acetone, isopropyl alcohol, n-propanol, ethanol and mixtures thereof,
The pharmaceutical composition according to the present invention is suitable for the treatment of spasm, inflammatory conditions and improvement of muscular hypertonic symptoms in conditions such as low back pain, spastic spinal paralysis, cervieal syndrome such as cervical spondylosis, spinocerebellar degeneration and other spinal vascular diseases accompanied by spasticity associated with inflammation, periarthritis of the shoulder and lumbago.
The pharmaceutical composition according to the present invention contains diclofenac sodium in analgesic and anti-inflammatory effective amount and Eperisone HC1 in anti-spasmodic effective amount.
The pharmaceutical composition according to the present invention can be used in the management of low back pain, spastic spinal paralysis, cervical spondylosis, spinocerebellar degeneration and other spinal vascular diseases accompanied by spasticity associated with inflammation.
The active ingredients in the present composition, i.e., both the NSAID and the antispasmodic drug, may be administered in the form of a pharmacologically acceptable acid, salt, ester, amide, prodrug or analogue or as a combination thereof.
The active ingredients in the present composition, i.e., both the NSAID and the antispasmodic drug, may be administered in the form of a pharmacologically acceptable acid, salt, ester, amide, prodrug or analogue or as a combination thereof.

The invention is not limited with respect to the selectively mentioned NSAIDs; the dual and stabilised compositions of the present invention may contain any NSAID, NSAID derivative, or combination of NSAIDs. Typical NSAIDs include, but are not limited to, aceclofenac, acetylsalicylic acid, diclofenac, fenbufen, flufenamic acid, flurbiprofen, ibuprofen, indomethacin, ketorolac, meloxicam, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac, tenoxicam, diflunisal and tiaprofenic acid. Pharmaceutically acceptable analogues of such NSAIDs are suitable as well; particularly analogues of aceclofenac, diclofenac, ketoprofen, piroxicam, meloxicam, naproxen, tenoxicam and their salts are preferred..
The antispasmodic drugs used in the present invention may include but are not limited to: eperisone HCI, methocarbamol, tizanidine, baclofen, carisprodol, cylcyobenzaprine, diazepam, chlorzoxazone, metaxalone, quinine, orphenadrine and dantrolene etc.
In accordance with the present invention, preparation of pharmaceutical composition containing combination of NSAID and an anti-spasmodic drug include either of the following combinations processes-
I) a film coated tablet of Eperisone HCI and enteric release pellets of Diclofenac Sodium.
a) Preparation of film coated tablets of Eperisone HCI
1. Preparation of binder solution.
2. Co-sifting of active pharmaceutical ingredient and intra-granular excipients through ASTM #40 mesh and mixing.
3. Granulation of step 2 blend with step 1 binder solution.
4. Drying of wet mass of step 3 at a temperature less than 60 °C.
5. Sifting of dried granules of step 4 through ASTM #30 mesh, mixing with extra-granular excipients previously sifted through ASTM #40 mesh and lubrication.
6. Compression of lubricated blend of step 5.
7. Preparation of film coating agent.
8. Film coating of tablets of step 6 with film coating agent of step 7 till a coat gain of 5% w/w is achieved.
b) Preparation of enteric release pellets of diclofenac sodium:
1. Preparation of aqueous dispersion of enteric polymer.

2. Granulation of diclofenac sodium with step 1 aqueous dispersion of enteric polymer
3. Drying of wet mass of step 2 at a temperature less than 60 °C.
4. Sifting of dried granules of step 3 through ASTM #16 mesh.
c) Filling of enteric release pellets of diclofenac sodium of along with one film coated tablet of eperisone HC1 in a capsule.
II) a sugar coated tablet of Eperisone HC1 and Enteric release pellets of
diclofenac sodium
a) Preparation of sugar coated tablets of Eperisone HC1
1. Preparation of binder solution.
2. Co-sifting of active pharmaceutical ingredient and intra-granular excipients through ASTM #40 mesh and mixing.
3. Granulation of step 2 blend with step 1 binder solution.
4. Drying of wet mass of step 3 at a temperature less than 60 °C.
5. Sifting of dried granules of step 4 through ASTM #30 mesh, mixing with extra-granular excipients previously sifted through ASTM #40 mesh and lubrication.
6. Compression of lubricated blend of step 5.
7. Preparation sugar coating agent.
8. Sugar coating of tablets of step 6 till a coat gain of 100% w/w is achieved.
b) Preparation of enteric release pellets of diclofenac sodium:
1. Preparation of aqueous dispersion of enteric polymer.
2. Granulation of diclofenac sodium with step 1 aqueous dispersion of
enteric polymer
3. Drying of wet mass of step 2 at a temperature less than 60 °C.
4. Sifting of dried granules of step 3 through ASTM #16 mesh.
c) Filling of enteric release pellets of diclofenac sodium along with one sugar
coated tablet of eperisone HC1 in a capsule.
III) pellets of Eperisone HC1 and enteric release of Diclofenac sodium
a) Preparation of pellets of Eperisone HC1
1. Preparation of binder solution.

2. Co-sifting of active pharmaceutical ingredient and intra-granular excipients through ASTM #40 mesh and mixing.
3. Granulation of step 2 blend with step 1 binder solution.
4. Drying of wet mass of step 3 at a temperature less than 60 °C.
5. Sifting of dried granules of step 4 through ASTM #20 mesh to obtain pellets of eperisone HC1.
b) Preparation of enteric release pellets of diclofenac sodium:
1. Preparation of aqueous dispersion of enteric polymer.
2. Granulation of diclofenac sodium with step 1 aqueous dispersion of enteric polymer
3. Drying of wet mass of step 2 at a temperature less than 60 °C.
4. Sifting of dried granules of step 3 through ASTM #16 mesh.
c) Filling of enteric release pellets of diclofenac sodium along with pellets of
eperisone HC1 in a capsule.
IV) a film coated Tablet of Eperisone HC1 and film coated tablet of diclofenac sodium (made using enteric release pellets of diclofenac sodium
a) Preparation of film coated tablets of Eperisone HC1
1. Preparation of binder solution.
2. Co-sifting of active pharmaceutical ingredient and intra-granular excipients through ASTM #40 mesh and mixing.
3. Granulation of step 2 blend with step 1 binder solution.
4. Drying of wet mass of step 3 at a temperature less than 60 °C.
5. Sifting of dried granules of step 4 through ASTM #30 mesh, mixing with extra-granular excipients previously sifted through ASTM #40 mesh and lubrication.
6. Compression of lubricated blend of step 5.
7. Preparation of film coating agent.
8. Film coating of tablets of step 6 with film coating agent of step 7 till a coat gain of 5% w/w is achieved.
b) Preparation of enteric release pellets of diclofenac sodium:
1 - Preparation of aqueous dispersion of enteric polymer.
2. Granulation of diclofenac sodium with step 1 aqueous dispersion of enteric polymer
3. Drying of wet mass of step 2 at a temperature less than 60 °C.

4. Sifting of dried granules of step 3 through ASTM #16 mesh, mixing with extra-granular excipients previously sifted through ASTM #40 mesh and lubrication.
5. Compression of the lubricated blend of step 4 into tablets.
6. Film coating of the tablets of step 5.
c) Filling of one film coated tablet of diclofenac sodium (prepared using enteric release pellets)along with one film coated tablet of eperisone HC1 in a capsule.
In accordance to the present invention, the pharmaceutical compositions may be administered in the form of tablets or capsules.
In accordance with the present invention, inert carrier present in the form of capsules may be hard gelatin capsules or hydroxypropylmethyl cellulose capsules.
Upon ingestion, the capsule dissolves, which liberates the two regions (or portions) of the dosage form and allows the dual release. Details on other suitable materials and theJr quantities are well known by the skilled in the pharmaceutical art as are available technologies to manufacture and control capsules containing multiple units.
Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.
Examples:
The following examples are presented for illustration only, and are not intended to
limit the scope of the invention or appended claims.
Example-1: Combination containing a film coated tablet of Eperisone HCI and
enteric release pellets of Diclofenac Sodium
Table 1: Composition of film coated Eperisone HCI tablet of Example-1

S. No. Ingredients Quantity / Unit (nig)
Intragranutar
1. Eperisone HC1 50.0
2. Cross carmellose sodium 5.0
3. Hydroxypropyl cellulose 3.0
4. Corn starch 11.5
5. Purified water q.s.
Extragranular
6. Microcrystalline cellulose PH 112 5.0
7. Cross carmellose sodium 5.0
8. Calcium stearate 0.5
Sub total weight (mg) 80.0
Composition for film coating
9. HPMC 5cps 1.0
10. Titanium dioxide 0.35
11. Poly ethylene glycol 400 0.25
12. Purified water q.s

Total weight (nig) 84.0

Table 2: Composition of enteric release pellets of diclofenac sodium of example-1

S.No. Ingredients Quantity in mg
1. Diclofenac sodium 50.00
2. Methacrylic acid - Ethyl acrylate co-polymer 11.53
3. Purified water q.s.
Table 3: Capsule content of example-1

S.No. Ingredients Quantity / Unit
1. Film coated tablet of eperisone HC1 1 number
2. Enteric release pellets of diclofenac sodium Equivalent to 50
mg of diclofenac
sodium
Manufacturing process:
1. A binder solution containing 12% w/w HPC was prepared by dissolving the required quantity of HPC in purified water.
2. Eperisone HC1, cross carmellose sodium and cornstarch were co-sifted through ASTM #40 mesh and mixed well.
3. Blend of step 2 was granulated using the binder solution obtained in step I.
4. Wet mass of step 3 was dried at a temperature less than 60 °C.
5. The dried granules of step 4 were passed through ASTM #30 mesh, mixed with macrocrystalline cellulose (ASTM #40 mesh) and cross carmellose sodium (ASTM #40 mesh) and lubricated with calcium stearate (ASTM #40 mesh).
6. Lubricated blend of step 5 was then compressed into tablets and film coated with HPMC 5 cps. Film coating was done till a weight gain of 5%w/w was achieved.
7. Aqueous dispersion of methacrylic acid - ethyl acrylate co-polymer was prepared.
8. Diclofenac sodium was granulated with aqueous dispersion of methacrylic acid -ethyl acrylate co-polymer.
9. Wet mass of step 8 dried at a temperature less than 60 °C.

10. Dried granules of step 9 were sifted through ASTM #16 mesh to obtain enteric release pellets.
11. Enteric release pellets equivalent to 50 mg of diclofenac sodium along with one film coated tablet of eperisone HO were filled in a capsule.
Dissolution studies of capsules of example-1 was carried out in USP Type-II apparatus with the paddle speed of 100 rpm using 750 ml of 0.1N HO maintained at 37±2° C for 2 hours and then in 1000 ml of pH 6.8 phosphate buffer maintained at 37±2° C for 45 minutes.
Table 4: Dissolution profile of formulation of example-1

Time (min) % drug released
Eperisone HO in 0.1NHC1
5 0.2
10 4.7
15 37.7
30 98.2
45 100.8
Diclofenac Na in 0..lN HCl
120 1.0
Diclofenac Na in pH 6.8 phosphate buffer
5 69.7
10 82.3
15 88.6
30 104.0
45 103.1
Example-2 : Combination containing a sugar coated tablet of Eperisone HC1 and Enteric release pellets of diclofenac sodium

Table 5: Composition of Eperisone HCI sugar coated tablet of example-2

S.No. Ingredients Quantity / Unit (mg)
Intragranular
L Eperisone HCI 50.0
2. Cross carmellose sodium 5.0
3. Hydroxypropyl cellulose 3.0
4- Corn starch 11.5
5. Purified water q.s.
Extragranular
6. Microcrystalline cellulose PH 112 5.0
7. Cross carmellose sodium 5.0
8. Calcium stearate 0.5
Tablet weight (mg) 80.0
Coatinj * Material
9. Pullulan 0.60
10. Macrogol 6000 0.30
11. Calcium carbonate 3.00
12. Talc 12.20
13. Titanium oxide 8.20
14. Corn starch 2.10
15. Povidone 1.40
16. Hydrated silicon dioxide 1.50
17. White shellac 0.30
18. Hydroxypropyl cellulose 0.11
19. Stearic acid 0.01
20. Carnauba wax 0.08
21. Sucrose 52.2
22. Purified water q.s.
Sub total weight (mg) 82.0
Total tablet weight (mg) 162


Table 6: Composition of enteric release pellets of diclofenac sodium of example- 2

S.No. Ingredients Quantity in mg
1. Diclofenac sodium 50.00
2. Methacrylic acid - Ethyl acrylate co-polymer 11.53
3. Purified water q.s.
Table 7: Capsule content of example-2
S.No. Ingredients Quantity / Unit
1. Eperisone HC1 sugar coated tablet 1No.
2. Enteric release pellets of diclofenac sodium Equivalent to 50 mg of diclofenac sodium
Manufacturing process;
1. A binder solution containing 12% w/w HPC was prepared by dissolving the required quantity of HPC in purified water.
2. Eperisone HO, cross carmellose sodium and corn starch were co-sifted through ASTM #40 mesh and mixed well.
3. Blend of step 2 was granulated using the binder solution obtained in step 1.
4. Wet mass of step 3 was dried at a temperature less than 60 °C.
5. The dried granules of step 4 were passed through ASTM #30 mesh, mixed with microcrystalline cellulose (ASTM #40 mesh) and cross carmellose sodium (ASTM #40 mesh) and lubricated with calcium stearate (ASTM #40 mesh).
6. Lubricated blend of step 5 was then compressed into tablets and sugar coating was done.
7. Aqueous dispersion of methacrylic acid - ethyl acrylate co-polymer was prepared,
8. Diclofenac sodium was granulated with aqueous dispersion of methacrylic acid -ethyl acrylate co-polymer.
9. Wet mass of step 8 dried at a temperature less than 60 °C.
10. Dried granules of step 9 were sifted through ASTM #16 mesh to obtain enteric release pellets.
11. Enteric release pellets equivalent to 50 mg of diclofenac sodium along with one sugar coated tablet of eperisone HC1 were filled in a capsule.

Dissolution studies of capsules of example-2 was carried out in USP Type-II apparatus with the paddle speed of 100 rpm using 750 ml of 0.1N HC1 maintained at 37±2° C for 2 hours and then in 1000 ml of pH 6.8 phosphate buffer maintained at 37±2° C for 45 minutes.
Table 8: Dissolution profile of formulation of example- 2.

Time (min) % drug released
Eperisone HC1 in 0.1NHC1
5 8.1
10 49.6
15 82.7
30 99.8
45 98.5
Diclofenac Na in 0.1N HC1
120 1.3
Diclofenac Na in pH 6.8 phosphate buffer
5 41.0
10 66.9
15 88.1
30 96.1
45 95.3

Example-3 : Combination containing pellets of Eperisone HC1 and enteric release pellets of Diclofenac sodium
Table 9: Composition of pellets of eperisone HC1

S.No. Ingredients Quantity / Unit (mg)
1. Eperisone HCI 50.0
2. Croscarmellose Sodium 10.0
3. Microcrystalline Cellulose PHI 12 5.0
4. Hydroxy propyl cellulose 3.0
5. Corn starch 12.0
6. Purified Water q.s.
Total 80.0
Table 10: Composition of enteric release pellets of diclofenac sodium of example-3

S. No. Ingredients Quantity in mg
1. Diclofenac sodium 50.00
2. Methacrylic acid - Ethyl acrylate copolymer 11.53
3. Purified water q.s.
Table 11: Capsule content of example-3

Ingredients Quantity / Unit
1. Eperisone HCI Pellets Equivalent to 50 mg of Eperisone HCI Pellets
2. Enteric release pellets of diclofenac sodium Equivalent to 50 mg of Diclofenac sodium

Manufacturing process:
1. A binder solution containing 12% wAv HPC was prepared by dissolving the required quantity of HPC in purified water.
2. Eperisone HC1, cross carmellose sodium and corn starch were co-sifted through ASTM #40 mesh and mixed well.
3. Blend of step 2 was granulated using the binder solution obtained in step 1.
4. Wet mass of step 3 was dried at a temperature less than 60 °C.
5. The dried granules of step 4 were passed through ASTM #20 mesh to obtain pellets of eperisone HC1.
6. Aqueous dispersion of methacrylic acid - ethyl acrylate co-polymer was prepared.
7. Diclofenac sodium was granulated with aqueous dispersion of methacrylic acid -ethyl acrylate co-polymer.
8. Wet mass of step 7 dried at a temperature less than 60 °C.
9. Dried granules of step 8 were sifted through ASTM #16 mesh to obtain enteric release pellets.
10. Enteric release pellets equivalent to 50 mg of diclofenac sodium along with pellets of eperisone HC1 equivalent to 50 mg were filled in a capsule.

Dissolution studies of capsules of example-3 was carried out in USP Type-II apparatus with the paddle speed of 100 rpm using 750 ml of 0.1N HC1 maintained at 37±2° C for 2 hours and then in 1000 ml of pH 6.8 phosphate buffer maintained at 37±2° C for 45 minutes.
Table 12: Dissolution profile of formulation of example- 3.

Time (min) % drug released
Eperisone HC1 in 0.1NHCI
5 96.7
10 102.9
15 102.5
30 102.1
45 101
Diclofenac Na in 0.1 .N. HCl
120 2.8
Diclofenac Na in pH 6.8 phosphate buffer
5 74.8
10 96
15 102.9
30 106.8
45 107

Example- 4 : Combination containing a film coated Tablet of Eperisone HC1 and film coated tablet of diclofenac sodium (made using enteric release pellets of diclofenac sodium)
Table 13: Composition of eperisone HC1 film coated tablet of examp]e-4

S.No. Ingredients Quantity / Unit (mg)
Intra granular
1. Eperisone HC1 50.0
2. Croscarmellose sodium 5.0
3. Hydroxypropyl cellulose 3.0
4. Corn starch 11.5
5. Purified Water q.s.
Extra granular
6. Microcrystalline Cellulose PHI 12 5.0
7. Croscarmellose Sodium 5.0
8. Calcium Stearate 0.5 (
Tablet weight (nig) 80.0
Composition of film coating
9. HPMC 5cps 1.0
10. Titanium dioxide 0.35
11. Poly Ethylene Glycol 400 0.25
12. Purified water q.s.

Total weight (mg) 84.0
Table 14: Composition of enteric- retease pellets of diclofenac sodium of example-4

S.No. Ingredients Quantity in mg
1. Diclofenac sodium 50.00
2. Methacrylic acid - Ethyl acrylate copolymer 11.53
3. Purified water q.S.

Table 15: Composition of diclofenac sodium film coated tablet of example-4

S.No. Ingredients Quantity/unit
(mg)
1. Eneric release pellets equivalent to 50 mg of diclofenac sodium 58.94
2. Avicel pH 200 36.26
3. Croscarmellose Sodium 4.0
4. Magnesium stearate 0.8
Sub total weight (mg) 100,0
Composition for film coating
5. HPMC 5cps 1.0
6. Titanium dioxide 0.35
7. Poly Ethylene Glycol 400 0.25
8. Purified water q.s.

Total weight (mg) 105.0
Table 16: Capsule content of example-4

S.No. Ingredients Quantity / Unit
1. Eperisone HC1 Film Coated Tablet INo.
2. Diclofenac Sodium Film Coated Tablet prepared using enteric release pellets of Diclofenac INo.
Manufacturing process:
1. A binder solution containing 12% w/w HPC was prepared by dissolving the required quantity of HPC in purified water.
2. Eperisone HC1, cross carmellose sodium and cornstarch were co-sifted through ASTM #40 mesh and mixed well.
3. Blend of step 2 was granulated using the binder solution obtained in step 1.
4. Wet mass of step 3 was dried at a temperature less than 60 °C.
5. The dried granules of step 4 were passed through ASTM #30 mesh, mixed with microcrystalline cellulose (ASTM #40 mesh) and cross carmellose sodium (ASTM #40 mesh) and lubricated with calcium stearate (ASTM #40 mesh).

6. Lubricated blend of step 5 was then compressed into tablets and film coated with HPMC 5 cps. Film coating was done till a weight gain of 5%w/w was achieved.
7. Aqueous dispersion of methacrylic acid - ethyl acrylate co-polymer was prepared.
8. Diclofenac sodium was granulated with aqueous dispersion of methacrylic acid -ethyl acrylate co-polymer.
9. Wet mass of step 8 dried at a temperature less than 60 °C.
10. Dried granules were sifted through ASTM #16 mesh to obtain enteric release pellets.
11. Diclofenac sodium pellets were mixed with microcrystalline cellulose (ASTM #40 mesh) and croscarmellose sodium (ASTM #40 mesh).
12. Blend obtained from step 11 was lubricated with magnesium stearate (ASTM #40 mesh) and compressed into tablets.
13. Tablets obtained from step 12 were film coated till a weight gain of 5% w/w was achieved.
14. Film coated tablet of diclofenac sodium along with one film coated tablet of eperisone HCI were filled in a capsule.
Dissolution studies of capsules of example-4 was carried out in USP Type-II apparatus with the paddle speed of 100 rpm using 750 ml of 0.1 N HCI maintained at 37±2° C for 2 hours and then in 1000 ml of pH 6.8 phosphate buffer maintained at 37±2° C for 45 minutes.
Table 17: Dissolution profile of formulation of example-4.

Time (min) % drug released
Eperisone HC1 in 0.1NHC1
5 20.3
10 87.0
15 98.1
30 99.1
45 98.4
Diclofenac Na in 0.1N HCI


120 0.8
Diclofenac Na in pH 6.8 phosphate buffer
5
10 38.3
15 51.7
30 61.7
45 83.5

We Claim:
1. An oral solid pharmaceutical composition comprising combination of a nonsteroidal antinflammatory drug (NSAID) and an antispasmodic drug along with one or more pharmaceutically acceptable excipients, wherein the two drugs are present in the form of a mixture of one or more pellets and tablets.
2. An oral solid pharmaceutical composition of claim 1, wherein release of NSAID shows delayed release pattern, and the antispasmodic drug shows immediate release pattern.
3. An oral solid pharmaceutical composition of claim 1, wherein the dosage form comprises multilayer tablet, hard gelatin capsule filled with a mixture of pellets and tablets.
4. An oral solid pharmaceutical composition of claim 1, wherein the tablet dosage form or pellets are prepared by wet granulation, dry granulation, melt granulation and direct compression, more preferably by wet granulation method.
5. An oral solid pharmaceutical composition of claim 1, wherein the NSAID is selected from the group comprising of carboxylic acid derivatives, acetic acid derivatives, salicylic acid derivatives, propionic acid derivatives, enolic acid derivatives and Cox-II inhibitors.
6. An oral solid pharmaceutical composition of claim 1, wherein the NSAID comprises Diclofenac sodium, Aceclofenac, Indomethacin, Ketorolac, Sulindac and Tolmetin, preferably Diclofenac sodium.
7. An oral solid pharmaceutical composition of claim 1, wherein the said NSAID, diclofenac sodium is present in an amount of 25mg to 150mg, preferably from 25mg to IOOmg, more preferably from 25mg to 75 mg.
8. An oral solid pharmaceutical composition of claim 1, wherein Diclofenac Sodium is present in the form of delayed release pellets or tablets.
9. An oral solid pharmaceutical composition of claim 8, wherein delayed release tablets Diclofenac Sodium is of film coated. -
10. An oral solid pharmaceutical composition of claim 1, wherein the anti-spasmodic drug comprises Eperisone HC1, Methocarbamol, Tizanidine, Baclofen, Carisprodol, Cylcyobenzaprine, Diazepam, Chlorzoxazone, Metaxalone, Quinine, Orphenadrine and Dantrolene, preferably Eperisone HC1.

11. An oral solid pharmaceutical composition of claim 1, wherein the said antispasmodic drug, Eperisone HC1, is present in an amount of 50 mg to 150 mg, preferably from 50mg to 125 mg, more preferably from 50 mg to 100 mg.
12. An oral solid pharmaceutical composition of claim 1, wherein Eperisone HC1 is present in the form of immediate release pellets or tablets.
)3. An oral solid pharmaceutical composition of claim 12, wherein immediate release tablets of Eperisone HC1 are either sugar coated or film coated.
14. An oral solid pharmaceutical composition of claim 1, wherein pharmaceutically acceptable excipients comprises one or more of diluents, binders, disintegrants and lubricants.
15. An oral solid pharmaceutical composition of claim 14, wherein diluents comprises one or more of lactose, starch, dibasic calcium phosphate dihydrate mannitol, and microcrystalline cellulose.
16. An oral solid pharmaceutical composition of claim 14, wherein binders comprises one or more of polyvinyl pyrrolidone, co-povidone, polyethylene oxide, corn starch and cellulose derivatives.
17. An oral solid pharmaceutical composition of claim 14, wherein disintegrants are one or more of croscarmellose sodium, sodium starch glycollate, crospovidone.
18. An oral solid pharmaceutical composition of claim 14, wherein lubricants are
one or more of magnesium stearate, talc, stearic acid, hydrated silicone dioxide,
hydrogenated castor oil and calcium stearate.
19. An oral solid pharmaceutical composition of claim 9, wherein the polymers used for delayed release includes, one or more of methacrylic acid copolymers, cellulose acetate phthalate and polyvinyl acetate phthalate
20. An oral solid pharmaceutical composition of claims 9 and 13, wherein the composition of film coating includes one or more of film forming agents, opacifiers & plasticizers.
21. An oral solid pharmaceutical composition of claim 20, wherein film forming agents include one or more of cellulose derivatives, polyethylene glycol, polyvinyl alcohol and povidone; opacifieres include one or more of titanium dioxide and silicates such as talc and carbonates such as calcium carbonate; and plasticizers include one or more of polyethylene glycols, propylene glycol,

stearic acid, triacetin and triethyl citrate, surfactants like polysorbates, sorbitan esters and organic acid esters and mixtures thereof.
22. The solid oral pharmaceutical composition of claim 13, wherein the composition of sugar coating includes one or more seal coating agents, polysaccharides, lubricants, binders, opacifiers, plasticizers & polishing agents
23. An oral solid pharmaceutical composition of claim 22, wherein seal coating agents include one or more of different types of shallac; polysaccharides include one or more of sucrose, and pullulan; lubricants include one or more of magnesium stearate, talc, stearic acid, hydrated silicone dioxide, hydrogenated castor oil and calcium stearate; binders include one or more of povidone, co-povidone, polyethylene oxide, corn starch and cellulose derivatives; opacifieres include one or more of titanium dioxide, silicates such as talc and carbonates such as calcium carbonate; plasticizers include one or more of polyethylene glycols, propylene glycol, stearic acid, triacetin, triethyl citrate, surfactants like polysorbates, sorbitan esters and organic acid esters and mixtures thereof; and polishing agent include carnauba wax.
24. An oral solid pharmaceutical composition of claims 16, 21 and 23, wherein the cellulose derivative is one or more of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose, ethyl cellulose, methyl cellulose or mixtures thereof.
25. An oral solid pharmaceutical composition of claim 1, wherein delayed release NSAID contains from about 1% to 98% of Diclofenac sodium, preferably from about 1% to 94% or more preferably from about 1% to about 90%; from about 1% to about 40% of the release modifying agents, preferably from about 1% to about 30%, more preferably from about 1% to about 20%; from about 1% to about 60% of the diluents, preferably from about 1% to about 50%, more preferably from about 1% to about 40%; from about 1% to about 20% of the disintegrants, preferably in between from about 1% to about 15%, more preferably in between from about 1% to about 10%; from about 0.1% to about 5% of the lubricants, preferably in between 0.1% to about 3.5%, more preferably in between 0.1% to about 1.5 %.
26. An oral solid pharmaceutical composition of claim 1, wherein the antispasmodic formulation may contain from about 1% to about 95% of Eperisone HC1,

preferably from about 1% to about 85% and more preferably from about 1% to about 65%; from about 1% to about 45% of one or more diluents, preferably from about 1% to about 35% and more preferably from about 1% to about 25%; from about 1% to about 30% of one ore more d is integrants, preferably from about 1% to about 20% and more preferably from about 1% to about 10%; from about 1% to about 15% of one or more binders, preferably from about 1% to about 10% and more preferably from about 1% to about 5%; from about 0.1% to about 5% of the lubricants, preferably in between 0.1% to about 3.5%, more preferably in between 0.1% to about 1.5 %.
27. Process for an oral solid pharmaceutical composition of claim 1 comprises either
of the following combination processes-
a) a film coated tablet of Eperisone HC1 and enteric release pellets of Diclofenac Sodium,
b) a sugar coated tablet of Eperisone HCI. and Enteric release pellets of diclofenac sodium,

c) pellets of Eperisone HC1 and enteric release pellets of Diclofenac sodium,
d) a film coated Tablet of Eperisone HCI and film coated tablet of diclofenac sodium

28. The solid oral pharmaceutical composition of claims 9 and 13, wherein the hardness of film coated tablets of Diclofenac Sodium is in the range of 300-120N; hardness of film coated tablets of Eperisone HCI is the range of 70-90N and hardness of sugar coated tablet of Eperisone HCI is in the range of 30-50N.
29. The solid oral pharmaceutical composition of claim 1, is used for reducing the pain and inflammation, wherein Diclofenac sodium is present in analgesic and anti-inflammatory effective amount and Eperisone HCI is present in antispasmodic effective amount.
30. The solid oral pharmaceutical composition of claim 1, wherein the dosage form is used in the management of low back pain, spastic spinal paralysis, cervical spondylosis, spinocerebellar degeneration and other spinal vascular diseases accompanied by spasticity associated with inflammation.
31. The solid oral pharmaceutical composition of claim 1, wherein the dosage form is suitable for oral administration.

32. The solid oral pharmaceutical composition substantially as herein described and illustrated with reference to the accompanying examples