DESC:TECHNICAL FIELD OF INVENTION
The invention provides pharmaceutical composition comprising fixed dose combination of paracetamol and dicyclomine or pharmaceutically acceptable salt thereof. This invention provides composition having rapid dissolution which gives immediate therapeutic action of active ingredients. The present invention further provides methods for efficient pain relief by administering said composition to the subject. Further, the invention also provides process for preparing pharmaceutical composition of paracetamol and dicyclomine or pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION
Pain is one of the most common medical conditions requiring interventions for millions of people in the world. Pain can be the result of a large number of medical conditions and can range in severity from mild to severe. Despite a broad range of therapeutic and non-therapeutic interventions, there is still a large unmet need for effective and safe pain medications.

Antipyretic analgesics are a group of heterogeneous substances including acidic (nonsteroidal antiinflammatory drugs, NSAIDs) and nonacidic (paracetamol, pyrazolinones) drugs. Paracetamol is from analgesic and antipyretic class, it is also known as N-acetyl-p-aminophenol and acetaminophen. It is widely used in prescription and non-prescription medicines. Paracetamol was first marketed in the 1950's and is now a commonly used agent. The precise mechanisms of paracetamol as analgesic and antipyretic remain unclear. Increasing the rate of absorption of paracetamol should enable a greater and more rapid analgesic effect after oral dosing. The paracetamol has chemical name N-(4-hydroxyphenyl) ethanamide N- (4-hydroxyphenyl) acetamide and has structural formula I:

Formula I: Paracetamol

Antispasmodics are the agents used for smooth muscle contraction, especially in tubular organs of the gastrointestinal tract. The peristalsis and muscular activity of the stomach, intestines, gall bladder, urinary bladder, lung, the uterus, and to a degree the heart are all largely controlled by smooth muscles.

Dicyclomine is a relatively new antispasmodic agent belonging to the class of anticholinergic agents. It is a smooth muscle relaxant, relieves muscle spasms and cramping in the gastrointestinal tract by blocking the activity of acetylcholine on cholinergic (or muscarinic) receptors on the surface of muscle cells. It also decrease spasm of gastrointestinal tract, biliary tract, ureter, and uterus without producing characteristic atropine effects on the salivary, sweat, or gastrointestinal glands, the eye, or the cardiovascular system, except in large doses. Dicyclomine is 2-(Diethylamino) ethyl 1-cyclohexyl-cyclohexanecarboxylate, with the following structural formula II:

Formula II: Dicyclomine HCl

There is an ever-increasing desire for combining active ingredients belonging to different therapeutic categories. These agents can be administered in combination by oral route. The combination of paracetamol and dicyclomine or salt thereof is marketed in India under the brand name Cyclopam. However, fast dissolution and rapid action of the active ingredients poses a major obstacle in combining these active ingredients in a single oral dosage form. Oral delivery is currently the gold standard in the pharmaceutical industry where it is regarded as the safe, most convenient and most economical method of drug delivery having the highest patient compliance.

Improving the rate and extent of absorption of active ingredients from oral formulations has been the subject of substantial research. In general, once a solid composition reaches the stomach, it undergoes disintegration and/or dissolution and passes into the small intestine where the active ingredient is absorbed across intestinal walls into the circulatory system via the portal vein and liver before reaching the site of action.

Several processes are presently available by which a solid dosage form like tablet can be prepared, which provides fast dissolution of active agent from dosage form when administered orally. However, compositions available in the market prepared by these methods have scope to improve dissolution profile of active ingredients from dosage form and to prepare composition having quick onset of therapeutic activity.

US Publication 20050276847 relates to composition comprising paracetamol. It also covers formulation comprising paracetamol which facilitates the rapid delivery of active into the circulatory system by oral administration.

US 7,993,673 patent relates to a solid dosage form which comprises paracetamol, low dose of sodium bicarbonate or potassium bicarbonate or mixtures thereof and pharmaceutically acceptable excipients.

US Publication 20120282335 relates to rapidly dispersing granules, orally disintegrating tablets and methods. The US ‘335 covers active pharmaceutical ingredient including dicyclomine.

US 5,464,632 patent relates to rapidly disintegrating tablet for oral administration with or without the use of water which comprises active substance and mixture of excipients.

US 5,178,878 patent relates to solid pharmaceutical dosage form which incorporates microparticles and are susceptible to rupture upon chewing or which are adapted to provide substantially immediate release of the pharmaceutically active ingredient contained in the microparticles. The microparticles are provided in a tablet with an effervescent disintegration agent.

The prior arts discloses oral dosage forms of active ingredients comprising paracetamol, dicyclomine or pharmaceutically acceptable salt thereof and one or more excipients, but there exist a need to develop a formulation having faster dissolution and immediate absorption of active ingredients to provide quick onset of therapeutic effect.

The inventors of the present invention surprisingly found that it is possible to develop combination of paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with fast dissolution profile to provide immediate therapeutic effect.

SUMMARY OF THE INVENTION
The invention relates to oral dosage forms, which provides combination of analgesic-antipyretic agent and antispasmodic agent which shows fast dissolution profile and immediate onset of therapeutic action. There is provided fixed dose pharmaceutical composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof. The present invention also relates to methods for inducing efficient pain relief or antispasmodic effect by the administration of the said composition. Further, the invention also provides process for preparing pharmaceutical composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof.

In one general aspect, there is provided fixed dose composition comprising
(a) paracetamol or pharmaceutically acceptable salt thereof;
(b) dicyclomine or pharmaceutically acceptable salt thereof; and
(c) one or more suitable pharmaceutically acceptable excipients.

In another general aspect, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, which further compressed in to solid dosage form.

In another general aspect, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the composition provides rapid dissolution of active agents from the dosage form.

In another general aspect, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein more than 90% active agents get dissolve within 10 minutes.

In another general aspect, there is provided composition comprising:
(a) paracetamol or pharmaceutically acceptable salt thereof; and
(b) dicyclomine or pharmaceutically acceptable salt thereof and one or more suitable pharmaceutically acceptable excipients;
wherein the pharmaceutical composition exhibits a dissolution profile such that more than about 90% of the paracetamol or dicyclomine is released within 5 minutes; and more than about 99% of the paracetamol or dicyclomine is released within 15 minutes when tested according to USP Apparatus II dissolution test method at 50 rpm using 500 ml, 0.01N hydrochloric acid.

In another general aspect, there is provided composition comprising:
(a) paracetamol or pharmaceutically acceptable salt thereof;
(b) dicyclomine or pharmaceutically acceptable salt thereof;
(c) one or more effervescent agents; and
(d) optionally, one or more superdisintegrant and other one or more suitable pharmaceutically acceptable excipients.

In another general aspect, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein dicyclomine or salt thereof is present in binder solution.

In another general aspect, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the composition comprises one or more effervescent agents such as modified sodium carbonate and sodium bicarbonate (Effer-Soda® 12).

In another general aspect, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the amount of paracetamol in the composition ranges from about 50% w/w to about 80% w/w of the composition.

In another general aspect, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the amount of dicyclomine or pharmaceutically acceptable salt thereof in the composition ranges from about 1% w/w to about 10% w/w of the composition.

In another general aspect, there is provided fixed dose composition comprises paracetamol, dicyclomine, effervescent agents and superdisintegrant with one or more suitable pharmaceutically acceptable excipients, wherein the amount of effervescent agents present in ranges from about 1% w/w to about 15% w/w of the composition.

In another general aspect, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with superdisintegrant and one or more suitable pharmaceutically acceptable excipients, wherein amount of the superdisintegrant present in the ranges from about 0.5% w/w to about 5% w/w of the composition.

In another general aspect, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with binders and one or more suitable pharmaceutically acceptable excipients, wherein amount of the binder present in the ranges from 0.5 % w/w to about 2.0% w/w of the composition.

In another general aspect, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with lubricant and one or more suitable pharmaceutically acceptable excipients, wherein amount of the lubricant present in the ranges from 0.2 % w/w to about 5% w/w of the composition.

In another general aspect, there is provided a fixed dose pharmaceutical composition comprising:
(a) 325mg of paracetamol or pharmaceutically acceptable salt thereof and one or more suitable pharmaceutically acceptable excipients;
(b) 20mg of dicyclomine or pharmaceutically acceptable salt thereof and one or more suitable pharmaceutically acceptable excipients;
(c) 45mg of modified sodium carbonate and sodium bicarbonate; and
(d) one or more suitable pharmaceutically acceptable excipients.

In another general aspect, there is provided a fixed dose pharmaceutical composition comprising:
(a) 650mg of paracetamol or pharmaceutically acceptable salt thereof and one or more suitable pharmaceutically acceptable excipients;
(b) 40mg of dicyclomine or pharmaceutically acceptable salt thereof and one or more suitable pharmaceutically acceptable excipients;
(c) 90mg of modified sodium carbonate and sodium bicarbonate; and
(d) one or more suitable pharmaceutically acceptable excipients.

In another general aspect, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the composition provides rapid dissolution of active ingredients from the dosage form.

In another general aspect, there is provided a fixed dose pharmaceutical composition comprising:
(a) 50% w/w to 80% w/w paracetamol or pharmaceutically acceptable salt thereof;
(b) 1% w/w to 10% w/w dicyclomine or pharmaceutically acceptable salt thereof;
(c) 0.5% w/w to 5% w/w croscarmellose sodium;
(d) 5% w/w to 15% w/w of modified sodium carbonate and sodium bicarbonate and one or more pharmaceutically acceptable excipients; wherein said pharmaceutical composition exhibits a dissolution profile such that more than about 90% of the paracetamol or dicyclomine is released within 5 minutes; and more than about 99% of the paracetamol or dicyclomine is released within 15 minutes when tested according to USP Apparatus 1 dissolution test method at 100 rpm using 900ml of pH 4.5 acetate buffer.

In another general aspect, there is provided a fixed dose pharmaceutical composition comprising:
(a) 325mg of paracetamol or pharmaceutically acceptable salt thereof;
(b) 20mg of dicyclomine or pharmaceutically acceptable salt thereof;
(c) 5mg of croscarmellose sodium;
(d) 45mg of modified sodium carbonate and sodium bicarbonate;
(e) 2.5mg stearic acid and one or more pharmaceutically acceptable excipients; wherein said pharmaceutical composition exhibits a dissolution profile such that more than about 90% of the paracetamol or dicyclomine is released within 5 minutes; and more than about 99% of the paracetamol or dicyclomine is released within 15 minutes when tested according to USP Apparatus II dissolution test method at 50 rpm using 500 ml, 0.01N hydrochloric acid.

In another general aspect, there is provided a fixed dose pharmaceutical composition comprising:
(a) 650mg of paracetamol or pharmaceutically acceptable salt thereof;
(b) 40mg of dicyclomine or pharmaceutically acceptable salt thereof;
(c) 10mg of croscarmellose sodium;
(d) 90mg of modified sodium carbonate and sodium bicarbonate;
(e) 5mg stearic acid and one or more pharmaceutically acceptable excipients; wherein said pharmaceutical composition exhibits a dissolution profile such that more than about 90% of the paracetamol or dicyclomine is released within 5 minutes; and more than about 99% of the paracetamol or dicyclomine is released within 15 minutes when tested according to USP Apparatus II dissolution test method at 50 rpm using 500 ml, 0.01N hydrochloric acid.

In another general aspect, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the composition provides fast disintegration and rapid dissolution of active ingredients from the dosage form.

In another general aspect, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the composition present in form of tablets, multilayer tablet, bilayer tablet, minitablets, pellets and powder.

In another general aspect, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the composition is in the form of tablet dosage form.

In another general aspect, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the composition is used for the treatment of pain.

In another general aspect, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein pharmaceutically acceptable excipients are selected from the group comprising of fillers or diluents, binders, disintegrants and/or superdisintegrants, sorbents, antiadherents, lubricants, glidants, preservatives, flavoring agents, effervescent agents, colouring agent, solvents or vehicles or combination thereof.

In another general aspect, there is provided process for preparing composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof; wherein the process comprises (a) sifting of paracetamol or pharmaceutically acceptable salt thereof and other pharmaceutical acceptable excipients;
(b) mixing of material obtained in step (a);
(c) preparing binder solution, comprising dicyclomine or pharmaceutically acceptable salt thereof and polyvinyl pyrrolidone;
(d) granulating the dry mixture obtained in step (b) with the binder solution obtained in step (c);
(e) drying and sifting of granules obtained in step (d); and
(f) lubricating the dried granules obtained in step (e).

In another general aspect, there is provided process for preparing composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof; wherein the process comprises (a) sifting of paracetamol or pharmaceutically acceptable salt thereof and other pharmaceutical acceptable excipients;
(b) mixing of material obtained in step (a);
(c) preparing binder solution, comprising dicyclomine or pharmaceutically acceptable salt thereof and polyvinyl pyrrolidone;
(d) granulating the dry mixture obtained in step (b) with the binder solution obtained in step (c);
(e) drying and sifting of granules obtained in step (d);
(f) lubricating the dried granules obtained in step (e); and
(g) further compressing the granules to provides solid dosage form.

In another general aspect, there is provided process for preparing composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof; wherein compression provides solid dosage composition.

In another general aspect, there is provided process for preparing composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof; wherein the process provides tablet dosage form.

DETAILED DESCRIPTION OF THE INVENTION
The terms "active," "active ingredient" and “active agent” are used interchangeably and are meant to refer to a substance intended to be delivered, the substance being capable of imparting a desired action or effect. Such substances include, but are not limited to, pharmaceuticals, medicaments, drugs, therapeutic agents, diagnostic agents, cosmetic agents, nutritional supplements and mixtures thereof. More specifically, without limiting the scope of the invention, such substances include pain relievers, cough and cold ingredients, antiinflammatories, analgesic, antipyretic, anticholinergic or antispasmodics, antibiotics, sedatives, stimulants, antihistamines, antiallergenics, diuretics, expectorants, hormones, antipsychotics, narcotics and mixtures thereof.

The term "pharmaceutically acceptable excipients" includes a pharmaceutically acceptable material, vehicle, suitable for administering an active pharmaceutical ingredient. Each excipient should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

The term "dicyclomine" as used herein refers to dicyclomine base or its salts, solvates, prodrugs, hydrates, enantiomers or polymorphs thereof.

The term "paracetamol" as used herein refers to paracetamol base or its salts, solvates, prodrugs, hydrates, enantiomers or polymorphs thereof.

The term "subject" refers to an animal, preferably a mammal, and most preferably a human, who is the object of treatment, observation or experiment.

The term “pharmaceutically acceptable salt” or “salt” as used herein refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature. Such pharmaceutically acceptable salts thus includes but are not limited to acetate, hydrochloride salt, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, phenylbutyrate, beta-hydroxybutyrate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate, mesylate, nitrate, oxalate, phthalate, phosphate, monohydro phenylpropionate, salicylate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, xylenesulfonate, tartarate, and the like.

The term “fast disintegration dosage form”, as used herein, refers to pharmaceutical compositions which disintegrate within 5 minutes after oral administration.

The term “pain” as used in the present invention, can be spastic pain, colic pain, abdominal pain, pain during menses and pain due to renal calculi (stones).

The term “effervescent agent” as used herein, includes compounds or agents which evolve gas.

The term "superdisintegrant" used herein, refers to a substance, or a mixture of substances, employed in the dosage form to facilitate its breakup or disintegration of active agent and other excipients after administration.

The term effer-soda sued herein, refers to mixture of surface modified sodium carbonate and sodium bicarbonate powder developed for use in pharmaceutical and nutraceutical applications. This is accomplished by modifying the surface of the sodium bicarbonate with a desiccant skin of sodium carbonate that surrounds the sodium bicarbonate core.

The present invention provides composition comprising fixed dose combination of paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with one or more suitable pharmaceutically acceptable excipients. This invention provides composition having rapid dissolution which gives immediate therapeutic action of active ingredients. The inventors of present invention have surprisingly found that, by using effervescent agents and one or more superdisintegrant in the present invention can provides fast dissolution of active agents. The inventors of present invention also found that, by dissolving dicyclomine or pharmaceutically acceptable salt thereof in binder solution provides faster dissolution of active agent.

In one general embodiment, there is provided composition comprising:
(a) paracetamol or pharmaceutically acceptable salt thereof;
(b) dicyclomine or pharmaceutically acceptable salt thereof; and
(c) one or more suitable pharmaceutically acceptable excipients.

In embodiment, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, which further compressed in to solid dosage form.

In another embodiment, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein dicyclomine or salt thereof is present in binder solution which shows fast dissolution profile from the dosage form and provides rapid absorption of the active agents from dosage form.

In another embodiment, the binder solution comprising:
(a) dicyclomine or pharmaceutically acceptable salt thereof;
(b) polyvinyl pyrrolidone; and
(c) optionally one or more pharmaceutically acceptable excipients.

In another embodiment, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the composition comprises one or more effervescent agents such as modified sodium carbonate and sodium bicarbonate (Effer-Soda® 12).

In another embodiment, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein more than 90% active agents dissolved within 10 minutes.

In another embodiment, there is provided composition comprising:
(a) paracetamol or pharmaceutically acceptable salt thereof;
(b) dicyclomine or pharmaceutically acceptable salt thereof; and
(c) one or more suitable pharmaceutically acceptable excipients;
wherein the pharmaceutical composition exhibits a dissolution profile such that more than about 90% of the paracetamol or dicyclomine is released within 5 minutes; and more than about 99% of the paracetamol or dicyclomine is released within 15 minutes when tested according to USP Apparatus II dissolution test method at 50 rpm using 500 ml, 0.01N hydrochloric acid.

In another embodiment, there is provided composition comprising:
(a) paracetamol or pharmaceutically acceptable salt thereof;
(b) dicyclomine or pharmaceutically acceptable salt thereof;
(c) one or more effervescent agents; and
(d) optionally, one or more superdisintegrant and other one or more suitable pharmaceutically acceptable excipients.

In another embodiment, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the amount of paracetamol in the composition ranges from about 50% w/w to about 80% w/w of the composition.

In another embodiment, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the amount of dicyclomine or pharmaceutically acceptable salt thereof in the composition ranges from about 1% w/w to about 10% w/w of the composition.

In another embodiment, there is provided fixed dose composition comprises paracetamol, dicyclomine, effervescent agents and superdisintegrant with one or more suitable pharmaceutically acceptable excipients wherein the amount of effervescent agent present in ranges from about 1% w/w to about 15% w/w of the composition.

In another embodiment, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with superdisintegrant and one or more suitable pharmaceutically acceptable excipients, wherein amount of the superdisintegrant present in the ranges from 0.5% w/w to about 5% w/w of the composition.

In another embodiment, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with one or more binders and one or more suitable pharmaceutically acceptable excipients, wherein amount of the binder present in the ranges from 0.5 % w/w to about 2.0% w/w of the composition.

In another embodiment, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with one or more lubricant and one or more suitable pharmaceutically acceptable excipients, wherein amount of the lubricant present in the ranges from 0.2% w/w to about 5% w/w of the composition.

In embodiment, there is provided a fixed dose pharmaceutical composition comprising:
(a) 325mg of paracetamol or pharmaceutically acceptable salt thereof and one or more suitable pharmaceutically acceptable excipients;
(b) 20mg of dicyclomine or pharmaceutically acceptable salt thereof and one or more suitable pharmaceutically acceptable excipients;
(c) 45mg of modified sodium carbonate and sodium bicarbonate; and
(d) one or more suitable pharmaceutically acceptable excipients.

In embodiment, there is provided a fixed dose pharmaceutical composition comprising:
(a) 650mg of paracetamol or pharmaceutically acceptable salt thereof and one or more suitable pharmaceutically acceptable excipients;
(b) 40mg of dicyclomine or pharmaceutically acceptable salt thereof and one or more suitable pharmaceutically acceptable excipients;
(c) 90mg of modified sodium carbonate and sodium bicarbonate; and
(d) one or more suitable pharmaceutically acceptable excipients.

In another embodiment, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the composition provides fast disintegration and rapid dissolution of active ingredients from the dosage form.

In another embodiment, there is provided a fixed dose pharmaceutical composition comprising:
(a) 50% w/w to 80% w/w paracetamol or pharmaceutically acceptable salt thereof;
(b) 1% w/w to 10% w/w dicyclomine or pharmaceutically acceptable salt thereof;
(c) 0.5% w/w to 5% w/w croscarmellose sodium;
(d) 5% w/w to 15% w/w of modified sodium carbonate and sodium bicarbonate and one or more pharmaceutically acceptable excipients; wherein said pharmaceutical composition exhibits a dissolution profile such that more than about 90% of the paracetamol or dicyclomine is released within 5 minutes; and more than about 99% of the paracetamol or dicyclomine is released within 15 minutes when tested according to USP Apparatus 1 dissolution test method at 100 rpm using 900ml of pH 4.5 acetate buffer.

In another embodiment, there is provided a fixed dose pharmaceutical composition comprising:
(a) 325mg of paracetamol or pharmaceutically acceptable salt thereof;
(b) 20mg of dicyclomine or pharmaceutically acceptable salt thereof;
(c) 5mg of croscarmellose sodium;
(d) 45mg of modified sodium carbonate and sodium bicarbonate;
(e) 2.5mg stearic acid and one or more pharmaceutically acceptable excipients; wherein said pharmaceutical composition exhibits a dissolution profile such that more than about 90% of the paracetamol or dicyclomine is released within 5 minutes; and more than about 99% of the paracetamol or dicyclomine is released within 15 minutes when tested according to USP Apparatus II dissolution test method at 50 rpm using 500 ml, 0.01N hydrochloric acid.

In another embodiment, there is provided a fixed dose pharmaceutical composition comprising:
(a) 650mg of paracetamol or pharmaceutically acceptable salt thereof;
(b) 40mg of dicyclomine or pharmaceutically acceptable salt thereof;
(c) 10mg of croscarmellose sodium;
(d) 90mg of modified sodium carbonate and sodium bicarbonate;
(e) 5mg stearic acid and one or more pharmaceutically acceptable excipients; wherein said pharmaceutical composition exhibits a dissolution profile such that more than about 90% of the paracetamol or dicyclomine is released within 5 minutes; and more than about 99% of the paracetamol or dicyclomine is released within 15 minutes when tested according to USP Apparatus II dissolution test method at 50 rpm using 500 ml, 0.01N hydrochloric acid.

In another embodiment, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, which further compressed in to oral solid dosage form.

In another embodiment, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the composition present in form of tablets, multilayer tablet, bilayer tablet, minitablets, pellets and powder. Particularly the present invention provides tablet dosage form.

In another embodiment, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the composition is used for the treatment of pain.

In another embodiment, there is provided process for preparing composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof; wherein the process comprises:
(a) sifting of paracetamol or pharmaceutically acceptable salt thereof and other pharmaceutical acceptable excipients;
(b) mixing of material obtained in step (a);
(c) preparing binder solution, comprising dicyclomine or pharmaceutically acceptable salt thereof and polyvinyl pyrrolidone;
(d) granulating the dry mixture obtained in step (b) with the binder solution obtained in step (c);
(e) drying and sifting of granules obtained in step (d); and
(f) lubricating the dried granules obtained in step (e).

In another embodiment, there is provided process for preparing composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof; wherein the process comprises:
(a) sifting of paracetamol or pharmaceutically acceptable salt thereof and other pharmaceutical acceptable excipients;
(b) mixing of material obtained in step (a);
(c) preparing binder solution, comprising dicyclomine or pharmaceutically acceptable salt thereof and polyvinyl pyrrolidone;
(d) granulating the dry mixture obtained in step (b) with the binder solution obtained in step (c);
(e) drying and sifting of granules obtained in step (d);
(f) lubricating the dried granules obtained in step (e); and
(g) further compressing the granules to provides solid dosage form.

In another embodiment, there is provided process for preparing composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof; wherein compression provides solid dosage composition.

In another embodiment, there is provided process for preparing composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof; wherein the process provides tablet dosage form.

In another embodiment, there is provided composition comprising paracetamol and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein pharmaceutically acceptable excipients are selected from the group comprising fillers or diluents, binders, disintegrants and/or superdisintegrants, sorbents, antiadherents, lubricants, glidants, preservatives, flavoring agents, effervescent agents, colouring agent, solvents or vehicles or combination thereof.

In another embodiment, the stable pharmaceutical composition of the invention retains at least 90% w/w of total potency of each active after storage at 40°C and 75% relative humidity for at least 6 months.

Examples of the fillers or diluents suitable for use in the composition of the present invention are selected from group comprises but are not limited to starch, such as potato starch, rice starch, maize starch, wheat starch, pregelatinized starch, fully pregelatinized starch, cellulose, such as microcrystalline cellulose or silicified microcrystalline cellulose, mannitol, erythritol, calcium salts, such as calcium hydrogen phosphate dihydrate, anhydrous dibasic calcium phosphate, xylitol, sorbitol, lactose monohydrate, magnesium stearate, mannitol or mixtures thereof.

Examples of the disintegrants or superdisintegrants suitable for use in the composition of the present invention are selected from group comprises but are not limited to alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, crosscarmellose sodium (Acdisol), crospovidone, guar gum, magnesium aluminum silicate, maize starch, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate and starch.

Examples of the binder suitable for use in the composition of the present invention are selected from group comprises but are not limited to polyvinyl pyrrolidone K30 (povidone/ PVPK 30), copolymers of vinylpyrrolidone with other vinylderivatives (copovidone), hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose (hypromellose), powdered acacia, gelatin, guar gum and carbomer such as carbopol, polymethacrylates and starch or mixtures thereof.

Examples of the lubricant/glidant suitable for use in the composition of the present invention are selected from group comprises but are not limited to stearic acid, talc, siliconised talc, colloidal silicone dioxide, micronised talc, colloidal silicon dioxide (Aerosil), sodium stearyl fumarate and magnesium stearate.

Examples of effervescent agents used in the composition of present invention are selected from group comprises but are not limited to sodium bicarbonate such as "Effer-Soda", sodium carbonate, sodium sesqui-carbonate, potassium carbonate, potassium bicarbonate, ammonium bicarbonate, calcium carbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, arginine carbonate, zinc carbonate, and mixtures thereof.

Solvent is a substance that can chemically different liquid, solid or gas. Examples of solvent suitable for use in oral pharmaceutical composition are selected from group comprises but not limited to purified water, isopropyl alcohol, dichloromethane, glycerol, propylene glycol, ethanol, chlordiazepoxide hydrochloride or mixture thereof.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

The invention now will be described in particularity with the following illustrative examples; however, the scope of the present invention is not intended to be, and shall not be, limited to the exemplified embodiments below.

EXAMPLES
Example 1: Paracetamol and Dicyclomine Composition
Table 1
Sr. No. Ingredients Qty/Tablet (%w/w)
Dry Mixing
1 Paracetamol 67.71
2 Starch 1500 15.0
Binder
3 Polyvinyl pyrrolidone K 30 0.90
4 Dicyclomine HCl 4.17
5 Purified Water q.s.
Lubrication
6 modified sodium carbonate and sodium bicarbonate 8.08
7 Starch 1500 1.95
8 Croscarmellose Sodium
1.15
9 Colloidal silicon dioxide 0.40
10 Stearic acid 0.64
Total 100

Process:
(a) paracetamol and starch were passed through mesh separately and further blended,
(b) dicyclomine HCl was dissolved in warm water,
(c) PVPK-30 was dissolved in water and prepared solution were added to solution obtained in step (b),
(d) dry blend of step (a) rotated in rapid mixing granulator and further granulated with solution obtained in step (c),
(e) granules obtained in step (d) were dried until the LOD is less than 2.5%,
(f) dried granules of step (e) were passed through suitable mesh,
(g) modified sodium carbonate and sodium bicarbonate (Effer-soda® 12), starch, croscarmellose sodium, and colloidal silicon dioxide were weighed and passed through suitable mesh,
(h) pre-lubricate the granules with step (g) materials in double cone blender,
(i) stearic acid was weighed and passed through suitable mesh,
(j) lubricate the blend of step (h) with the stearic acid,
(k) blend obtained in step (j) was compressed to obtain suitable solid dosage form.

Example 2: Paracetamol and Dicyclomine Composition
Table 2
Sr. No. Ingredients Qty/Tablet (%w/w)
Dry Mixing
1 Paracetamol 67.71
2 Starch 1500 10.5
Binder
3 Polyvinyl pyrrolidone K 30 1.20
4 Dicyclomine HCl 4.17
5 Purified Water q.s.
Lubrication
6 modified sodium carbonate and sodium bicarbonate 11.25
7 Starch 1500 3.16
8 Croscarmellose Sodium
0.97
9 Colloidal silicon dioxide 0.64
10 Stearic acid 0.40
Total 100

Process:
Same as mentioned in example 1.

Example 3: Paracetamol and Dicyclomine Composition
Table 3
Sr. No. Ingredients Unit Qty. (mg) Unit Qty. (mg)
Dry Mixing
1 Paracetamol 325.00 650.00
2 Starch 1500 65.00 130.00
Binding Solution
3 Polyvinyl pyrrolidone -30 5.0 10.0
4 Dicyclomine HCl 20.0 40.0
5 Purified Water
Lubrication
6 modified sodium carbonate and sodium bicarbonate 45.0 90.0
7 Starch 1500 10.00 20.00
8 Croscarmellose Sodium
5.0 10
9 Colloidal silicon dioxide 2.50 5.00
10 Stearic acid 2.50 5.00
Total 480.00 960.00

Process:
Same as mentioned in example 1.

Dissolution data:
a) Cumulative drug release study of paracetamol or its salt in Cyclopam verses example 1 or example 2.
Table 4
Time (minutes) % Paracetamol release
From cyclopam From example 1 or 2
5 39 96
10 67 98
15 81 100
20 86 100
30 92 101
45 93 100
60 93 103

b) Cumulative drug release study of dicyclomine or its salt in Cyclopam verses example 1 or example 2
Table 5
Time (minutes) % Dicyclomine release
From cyclopam From example 1 or 2
5 26 100
10 62 102
15 79 100
20 85 100
30 91 99
45 92 100
60 92 99

,CLAIMS:1. A fixed dose pharmaceutical composition comprising:
(a) paracetamol or pharmaceutically acceptable salt thereof;
(b) dicyclomine or pharmaceutically acceptable salt thereof; and
(c) one or more suitable pharmaceutically acceptable excipients.

2. The pharmaceutical composition of claim 1, wherein the one or more suitable pharmaceutically acceptable excipients comprises modified sodium carbonate and sodium bicarbonate.

3. The pharmaceutical composition of claim 1, wherein the amount of paracetamol in the composition ranges from about 50% w/w to about 80% w/w of the composition.

4. The pharmaceutical composition of claim 1, wherein the amount of dicyclomine or pharmaceutically acceptable salt thereof in the composition ranges from about 1% w/w to about 10% w/w of the composition.

5. The pharmaceutical composition of claim 1, wherein the amount of effervescent agents in the composition ranges from about 1% w/w to about 15% w/w of the composition.

6. The pharmaceutical composition of claim 1, wherein the amount of superdisintegrant in the composition ranges from about 0.5% w/w to about 5% w/w of the composition.

7. A fixed dose pharmaceutical composition comprising:
(a) 325mg of paracetamol or pharmaceutically acceptable salt thereof and one or more suitable pharmaceutically acceptable excipients;
(b) 20mg of dicyclomine or pharmaceutically acceptable salt thereof and one or more suitable pharmaceutically acceptable excipients;
(c) 45mg of modified sodium carbonate and sodium bicarbonate; and
(d) one or more suitable pharmaceutically acceptable excipients.

8. A fixed dose pharmaceutical composition comprising:
(e) 650mg of paracetamol or pharmaceutically acceptable salt thereof and one or more suitable pharmaceutically acceptable excipients;
(f) 40mg of dicyclomine or pharmaceutically acceptable salt thereof and one or more suitable pharmaceutically acceptable excipients;
(g) 90mg of modified sodium carbonate and sodium bicarbonate; and
(h) one or more suitable pharmaceutically acceptable excipients.

9. The pharmaceutical composition of claim 1, wherein the said pharmaceutical composition exhibits a dissolution profile such that more than about 90% of the paracetamol or dicyclomine is released within 5 minutes; and more than about 99% of the paracetamol or dicyclomine is released within 15 minutes when tested according to USP Apparatus II dissolution test method at 50 rpm using 500 ml, 0.01N hydrochloric acid.

10. A fixed dose pharmaceutical composition comprising:
(a) 50% w/w to 80% w/w paracetamol or pharmaceutically acceptable salt thereof;
(b) 1% w/w to 10% w/w dicyclomine or pharmaceutically acceptable salt thereof;
(c) 0.5% w/w to 5% w/w croscarmellose sodium;
(d) 5% w/w to 15% w/w of modified sodium carbonate and sodium bicarbonate and one or more pharmaceutically acceptable excipients; wherein said pharmaceutical composition exhibits a dissolution profile such that more than about 90% of the paracetamol or dicyclomine is released within 5 minutes; and more than about 99% of the paracetamol or dicyclomine is released within 15 minutes when tested according to USP Apparatus II dissolution test method at 50 rpm using 500 ml, 0.01N hydrochloric acid.