DESC:BACKGROUND OF THE INVENTION
Pain is one of the most common medical condition 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.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of drugs that provides analgesic and antipyretic effect and in higher doses gives anti inflammatory effects. NSAIDs work by reducing the production of prostaglandins. Prostaglandins are chemicals that promote inflammation, pain, and fever. The NSAIDs includes Ibuprofen, Naproxen, diclofenac, Isoxicam, Mefenamic acid, tolfenamic acid, parecoxib. The mefenamic acid is used to treat moderate pain and menstrual pain. The mefenamic acid has chemical name 2-(2,3-dimethylphenyl) aminobenzoic acid and has structural formula I:

Formula I: Mefenamic acid

Mefenamic acid is rapidly absorbed after oral administration. It is an anthranilic acid derivative and member of the fenamate group of NSAIDs belonging to the BCS class II drugs. Mefenamic acid binds the prostaglandin synthetase receptors COX-1 and COX-2, inhibiting the action of prostaglandin synthetase. As these receptors have a role as a major mediator of inflammation and/or a role for prostanoid signaling in activity-dependent plasticity, the symptoms of pain are temporarily reduced.

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 different route of administration but most convenient route is oral route. The combination of mefenamic acid and dicyclomine or salt thereof is marketed in India under the trade name Meftal Spas. Combination of mefenamic acid and dicyclomine hydrochloride is indicated for treatment of spastic/colic/abdominal pain, pain during menses and due to renal calculi (stones).

A formulation with 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.

Various formulations discloses composition of active agents with provides fast dissolution and process for preparing fast dissolving compositions and are presently available in the market, these pharmaceutical composition provides fast disintegration or dissolution of active agent from dosage form when administered orally. However, the compositions available in the market have scope to improve dissolution profile of active ingredients from dosage form and its quick onset of therapeutic activity.

PCT publication number WO 2007072503 discloses pharmaceutical compositions comprising at least one analgesic and anti-inflammatory compound(s) that inhibits both cyclooxygenase (COX) and lipooxygenase (LOX) as active agent in combination with at least one another active agent(s) optionally with other pharmaceutically, acceptable excipients.

PCT publication number WO 2014203140 discloses solid oral pharmaceutical compositions comprising fixed dose combination of acetaminophen, dicyclomine and dextropropoxyphene or salts thereof with one or more alkalizers.

European patent application number EP 0863758 discloses composition exempt of paracetamol containing fenamic acid derivative in association with codeine.

European patent application number EP 0465234 discloses analgesic pharmaceutical composition for treating pain and the symptoms of nonsteroidal anti-inflammatory drug induced gastrointestinal distress.

US publication number US 20140364513 discloses oral formulation which disintegrates quickly in the oral cavity; a fast-disintegrating tablet having fast disintegration and high hardness.

US publication number US 20090169620 discloses orally disintegrating tablet composition comprising a therapeutically effective amount of at least one drug; binder polymer; a sugar alcohol and/or saccharide and a disintegrant.

Various formulations have been disclosed in the prior arts to improve the drug release from the fixed dose combination formulations, it is highly uncertain to develop an ideal formulation of a particular drug combination by legitimate selection of excipients which gives fast dissolution of active agents or to achieve desirable or improved drug release. Also, the prior arts mentioned above discloses orally disintegrating dosage forms of active ingredients which comprises mefenamic acid or dicyclomine or pharmaceutically acceptable salt thereof and one or more excipients, but it has some disadvantages like permeability barrier of the oral mucosa, it produce grittiness in the mouth and absorption may differ depend upon active drug, also this route has relatively small surface area for drug absorption. To overcome these problems, solid dosage forms having fast dissolution needs to be developed to administer in oral route.

Although several formulations of NSAIDs and antispasmodic agents or combination thereof are available in the market, but these formulations still do not exhibit the desired release profile of the active ingredients by oral route of administration. Hence, there still exists an enduring need to formulate an alternate therapy with improved release profile of fixed dose combination of dicyclomine and mefenamic acid with one or more pharmaceutically acceptable excipients.

The inventors of the present invention surprisingly found that by using superdisintegrant and effervescent agent in the fixed dose combination of mefenamic acid and dicyclomine or pharmaceutically acceptable salt thereof it is possible to it is possible to achieve desirable or improved drug release.

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

In one general aspect, there is provided a solid pharmaceutical composition comprising mefenamic acid and dicyclomine or a 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 general aspect, there is provided a solid pharmaceutical composition for oral administration comprising:
a) mefenamic acid or a salt thereof,
b) dicyclomine or a salt thereof,
c) a superdisintegrant,
d) an effervescent agent, and
e) one or more pharmaceutically acceptable excipients.

The composition comprising mefenamic acid or a salt thereof and dicyclomine or a salt thereof with one or more pharmaceutically acceptable excipients, wherein the mefeneamic acid present in the micronized form.

In another general aspect, there is provided a solid pharmaceutical composition for oral administration comprising:
a) mefenamic acid or a salt thereof,
b) dicyclomine or a salt thereof,
c) a superdisintegrant,
d) an effervescent agent, and
e) a binder,
wherein the weight ratio of superdisintegrant to the effervescent agent is about 1:3 to about 1:7.

In another general aspect, there is provided a solid pharmaceutical composition for oral administration comprising: a) mefenamic acid or a salt thereof, b) dicyclomine or a salt thereof, c) a superdisintegrant, and d) an effervescent agent, wherein weight ratio of amount of effervescent agent to mefenamic acid is in the range from about 1:5 to about 1: 7.5.

In another general aspect, there is provided a solid pharmaceutical composition for oral administration comprising: a) mefenamic acid or a salt thereof, b) dicyclomine or a salt thereof, c) a superdisintegrant, and d) an effervescent agent, wherein weight ratio of amount of effervescent agent to the amount of dicyclomine is in the range of from about 1: 0.1 to about 1:04.

In another general aspect, there is provided a solid pharmaceutical composition comprising mefenamic acid and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the amount of mefenamic acid in the composition ranges from about 50% w/w to about 60% w/w of the total composition.

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

In another general aspect, there is provided a solid pharmaceutical composition for oral administration comprising:
a) from about 50% w/w to about 60% w/w of mefenamic acid or a salt thereof,
b) from about 1.5% w/w to about 4% w/w of dicyclomine or a salt thereof,
c) from about 1% w/w to about 4%w/w of a superdisintegrant,
d) from about 4% w/w to about 25% w/w of an effervescent agent,
e) from about 0.5% w/w to about 2.0% w/w of an binder, and
f) optionally, one or more pharmaceutically acceptable excipients.

In another general aspect, there is provided a solid pharmaceutical composition comprising:
(a) mefenamic acid or a salt thereof,
(b) dicyclomine or a salt thereof, and
(c) one or more suitable pharmaceutically acceptable excipients;
wherein the composition exhibits a dissolution profile of mefenamic acid or a salt thereof such that more than 70% of the total active is released within 10 minutes and more than 80% of the active is released within 20 minutes when tested according to USP apparatus II dissolution test method at 50 rpm using 500 ml of tris buffer and 1 % sodium lauryl sulfate at pH 9.0.

In another general aspect, there is provided a solid pharmaceutical composition comprising:
(a) mefenamic acid or asalt thereof,
(b) dicyclomine or a salt thereof and
(c) one or more suitable pharmaceutically acceptable excipients;
wherein the composition exhibits a dissolution profile of dicyclomine or pharmaceutically acceptable salt thereof is such that more than 80% of the dicyclomine or its salt is released within 10 minutes and more than 90% of the dicyclomine or its salt is released within 20 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, the superdisintegrant can be selected from the group comprising carboxymethylcellulose sodium, colloidal silicon dioxide, crosscarmellose sodium (Acdisol), crospovidone, guar gum, magnesium aluminum silicate, maize starch, methyl cellulose, microcrystalline cellulose or combination thereof.

In another general aspect, there is provided a solid pharmaceutical composition comprising mefenamic acid and dicyclomine or a 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 a solid pharmaceutical composition comprising mefenamic acid and dicyclomine or a 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 a solid pharmaceutical composition comprising mefenamic acid and dicyclomine or a 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 a solid pharmaceutical composition comprising mefenamic acid and dicyclomine or a salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the composition provides fast dissolution profile of active agents and may provide immediate onset of therapeutic action.

In another general aspect, there is provided a solid pharmaceutical composition comprising mefenamic acid and dicyclomine or a salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the composition is stable for more than 6 months when stored at 40°C and 75% relative humidity.

In another general aspect, there is provided a solid pharmaceutical composition comprises mefenamic acid, dicyclomine or a salt thereof, effervescent agents and superdisintegrant with one or more suitable pharmaceutically acceptable excipients, wherein the composition retains at least 90% w/w of the potency of dicyclomine or a salt thereof and mefenamic acid or a salt thereof after 9 months when stored at 40°C and 75% relative humidity.

The method used for determination of the total water content in the composition can be determined by Karl Fischer Titration.

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

DETAILED DESCRIPTION OF THE INVENTION
The terms "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 “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 "dicyclomine" as used herein refers to dicyclomine base or its salts, solvates, prodrugs, hydrates, enantiomers or polymorphs thereof.

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

The term “fast dissolution”, as used herein, refers to pharmaceutical compositions which dissolve more than 70% by weight of active agent within 10 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 "stable" means the quantitative composition does not significantly change over the time, during the entire shelf-life of the composition for at least 3 months, advantageously for at least 6 months, more advantageously for at least 9 months.

The term "potency" relates to the amount of efficacious component. Typically, as used herein, it refers to the efficacious amount of a given component at a given time in comparison to the efficacious amount of the same component at a second time. Typically, potency is expressed as a percentage. For example, a 10% reduction in potency of component A after three months means that the efficacious amount of component A present after a three month period is 90% of the original efficacious amount of component A.

The effervescent agent used herewith can be surface modified sodium bicarbonate, whereas the said effervescent agent is highly stable, surface modified, free flowing white powder which is marketed by SPI Pharma under the trade name Effer-Soda® 12.

The invention provides a solid pharmaceutical composition for oral administration comprising mefenamic acid and dicyclomine or a salt thereof with one or more suitable pharmaceutically acceptable excipients. This invention provides composition having fast dissolution which gives immediate therapeutic action of active ingredients. The inventors of this invention have surprisingly found that, by using an effervescent agent and a superdisintegrant in the composition fast dissolution of active agents can be provided. The inventors of this invention also found that, by dissolving dicyclomine or a salt thereof in binder solution provides faster dissolution of active agent.

In one general embodiment, there is provided a solid pharmaceutical composition comprising mefenamic acid and dicyclomine or a 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, there is provided a solid pharmaceutical composition for oral administration comprising:
a) mefenamic acid or a salt thereof,
b) dicyclomine or a salt thereof,
c) a superdisintegrant,
d) an effervescent agent, and
e) one or more pharmaceutically acceptable excipients.

The composition comprising mefenamic acid or a salt thereof and dicyclomine or a salt thereof with one or more pharmaceutically acceptable excipients, wherein the mefeneamic acid present in the micronized forms having average particle size is less than 60 micron.

In another embodiment, there is provided a solid pharmaceutical composition for oral administration comprising: a) mefenamic acid or a salt thereof, b) dicyclomine or a salt thereof, c) a superdisintegrant, and d) an effervescent agent, wherein the weight ratio of superdisintegrant to the effervescent agent in the ranges from about 1:3 to about 1:7, more specifically the ratio is about 1:5.

In same embodiment, the effervescent agent is surface modified sodium bicarbonate and the superdisintegrant is crosscarmellose sodium.

In another embodiment, there is provided a solid pharmaceutical composition for oral administration comprising: a) mefenamic acid or a salt thereof, b) dicyclomine or a salt thereof, c) a superdisintegrant, and d) an effervescent agent, wherein weight ratio of amount of effervescent agent to the amount of mefenamic acid is in the range from about 1:5 to about 1: 7.5, more specifically about 1:6.25.

In another embodiment, there is provided a solid pharmaceutical composition for oral administration comprising: a) mefenamic acid or a salt thereof, b) dicyclomine or a salt thereof, c) a superdisintegrant, and d) an effervescent agent, wherein weight ratio of amount of effervescent agent to the amount of dicyclomine is in the range of about 1: 0.1 to about 1:04, preferably about 1:0.2, 1:0.25, or 1:0.3.

In another embodiment, there is provided composition comprising mefenamic acid and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the amount of mefenamic acid in the composition ranges from about 50% w/w to about 60% w/w, more preferably from about 56 % w/w to about 57% w/w of the composition.

In another embodiment, there is provided composition comprising mefenamic acid 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 1.5 % w/w to 4 % w/w, more preferably from about 2 % w/w to about 3 % w/w of the composition.

In another embodiment, there is provided fixed dose composition comprises mefenamic acid, dicyclomine or pharmaceutically acceptable salt thereof, effervescent agents and superdisintegrant with one or more suitable pharmaceutically acceptable excipients, wherein the amount of effervescent agents present in ranges from 4 % w/w to about 25 % w/w, preferably from about 6 % w/w to about 12 %w/w, and more preferably about 9.1 % w/w of the composition.

In another embodiment, there is provided a solid pharmaceutical composition for oral administration comprising: a) mefenamic acid or a salt thereof, b) dicyclomine or a salt thereof, c) a superdisintegrant, and d) an effervescent agent, wherein the amount of superdisintegrant presents in the composition ranges from about 1 % w/w to about 4 %w/w, preferably from about 1.5%w/w to about 2.5% w/w, more preferably about 1.8% w/w of the composition.

In another embodiment, there is provided composition comprising mefenamic acid 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 about 0.5 % w/w to about 2.0% w/w, preferably from about 1 % w/w to about 1.5 %w/w of the composition.

In another embodiment, there is provided a solid pharmaceutical composition for oral administration comprising:
a) from about 50% w/w to about 60% w/w of mefenamic acid or a salt thereof,
b) from about 1.5% w/w to about 4% w/w of dicyclomine or a salt thereof,
c) from about 1% w/w to about 4%w/w of a superdisintegrant,
d) from about 4% w/w to about 25% w/w of an effervescent agent,
e) from about 0.5% w/w to about 2.0% w/w of an binder, and
f) optionally, one or more pharmaceutically acceptable excipients.

In another embodiment, there is provided a solid pharmaceutical composition comprising mefenamic acid and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, which is further compressed in to solid dosage form, preferably in the form of tablet dosage form.

In another embodiment, there is provided a solid pharmaceutical composition comprising mefenamic acid and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the composition provides fast dissolution of active agents from the dosage form.

In another embodiment, there is provided a solid pharmaceutical composition comprising mefenamic acid and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein more than 70% active agents dissolved within 10 minutes.

In another embodiment, there is provided a solid pharmaceutical composition comprising:
(a) mefenamic acid or a salt thereof,
(b) dicyclomine or a salt thereof, and
(c) one or more suitable pharmaceutically acceptable excipients;
wherein the composition exhibits a dissolution profile of mefenamic acid or pharmaceutically acceptable salt thereof is such that more than 70% of the active is released within 10 minutes and more than 80% of the active is released within 20 minutes when tested according to USP apparatus II dissolution test method at 50 rpm using 500 ml of tris buffer and 1 % sodium lauryl sulfate at pH 9.0.

In another embodiment, there is provided composition comprising:
(a) mefenamic acid or pharmaceutically acceptable salt thereof,
(b) dicyclomine or pharmaceutically acceptable salt thereof, and
(c) one or more suitable pharmaceutically acceptable excipients;
wherein the composition exhibits a dissolution profile of dicyclomine or pharmaceutically acceptable salt thereof is such that more than 80% of the dicyclomine or its salt is released within 10 minutes and more than 90% of the dicyclomine or its salt is released within 20 minutes when tested according to USP apparatus II dissolution test method at 50 rpm using 500 ml, 0.01N hydrochloric acid.

There is provided a solid pharmaceutical composition for oral administration comprising: a) mefenamic acid or a salt thereof, b) dicyclomine or a salt thereof, c) a superdisintegrant, and d) an effervescent agent, wherein the pharmaceutical composition according to claim 1, wherein the composition retains at least 90% w/w of the potency of dicyclomine or a salt thereof and mefenamic acid or a salt thereof after 9 months when stored at 40°C and 75% relative humidity.

In another embodiment, there is provided a solid pharmaceutical composition comprising mefenamic acid and dicyclomine or a salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof, wherein the composition is stable for more than 6 months, more specifically the composition is stable after 9 months when stored at 40°C and 75% relative humidity.

In another embodiment, there is provided a solid pharmaceutical composition comprises mefenamic acid, dicyclomine or a salt thereof, effervescent agents and superdisintegrant with one or more suitable pharmaceutically acceptable excipients, wherein the composition retains at least 90% w/w of the potency of dicyclomine or a salt thereof and mefenamic acid or a salt thereof after 9 months when stored at 40°C and 75% relative humidity.

The method used for determination of the total water content in the composition can be determined by Karl Fischer Titration.

In another embodiment, there is provided a pharmaceutical composition composition comprising mefenamic acid 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 a process for preparing composition comprising mefenamic acid and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof; wherein the process comprises:
(a) sifting of mefenamic acid or salt thereof,
(b) dry mixing of material obtained in step (a) with one or more fillers,
(c) preparing binder solution, comprising dicyclomine or pharmaceutically acceptable salt thereof,
(d) granulating the dry mixture obtained in step (b) with the binder solution prepared 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 a provided a process for preparing composition comprising mefenamic acid and dicyclomine or pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable excipients or mixture thereof; wherein the process comprises:
(a) sifting of mefenamic acid or salt thereof,
(b) dry mixing of material obtained in step (a) with one or more fillers,
(c) preparing binder solution, comprising dicyclomine or pharmaceutically acceptable salt thereof,
(d) granulating the dry mixture obtained in step (b) with the binder solution prepared 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 obtained in step (f) to provides solid dosage form.

In another embodiment, there is provided a process for preparing composition comprising mefenamic acid 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 a process for preparing composition comprising mefenamic acid 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 a pharmaceutical composition comprising mefenamic acid 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.

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, 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 methylcellulose, polyvinyl pyrrolidone K30 (povidone/ PVPK 30), copolymers of vinylpyrrolidone with other vinylderivatives (copovidone), hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), powdered acacia, gelatin, guar gum 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, Aerosil (fused silica), 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 surface modified sodium bicarbonate (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: Mefenamic acid and dicyclomine composition
Table 1
Sr. No. Ingredients Qty/Tablet (mg)
Dry Mixing
1 Mefenamic acid 250
2 Pregelatiised starch 70-110
Binder
3 Polyvinylpyrrolidone K 30 2-8
4 Dicyclomine HCl 10
5 Purified Water q.s.
Lubrication
6 surface modified sodium bicarbonate 30-50
7 Microcrystalline Cellulose 20-50
8 Croscarmellose sodium 4-12
9 Colloidal silicon dioxide 0.5-3
10 Magnesium Stearate 1-3.5
Total 440

Process:
(a) Mefenamic acid was passed through #20 mesh size and starch was passed through #40 mesh size separately and further blended,
(b) Dicyclomine HCl was dissolved in half quantity of warm water,
(c) Polyvinylpyrrolidone K-30 was dissolved in half quantity of purified water and the solution obtained in step (b) were added and mixed for 5 minutes,
(d) Dry blend of step (a) granulated with solution obtained in step (c),
(e) Granules obtained in step (d) were dried until the LOD is less than 5.0%,
(f) Dried granules of step (e) were passed through # 18 mesh size,
(g) Surface modified sodium bicarbonate, microcrystalline cellulose, croscarmellose sodium and Colloidal silicon dioxide were passed through # 40 mesh size and mixed,
(h) Pre-lubricate the granules with step (g) materials in double cone blender,
(i) Magnesium stearate was weighed and passed through # 60 mesh size,
(j) Lubricate the blend of step (h) with magnesium stearate obtained in step (i),
(k) The blend obtained in step (j) was compressed to obtain suitable solid dosage form.

Example 2: Mefenamic acid and dicyclomine composition
Table 2
Sr. No. Ingredients Qty/Tablet mg)
Dry Mixing
1 Mefenamic acid 250
2 Pregelatiised starch 90
Binder
3 Polyvinylpyrrolidone K 30 5
4 Dicyclomine HCl 10
5 Purified Water q.s.
Lubrication
6 surface modified sodium bicarbonate 40
7 Microcrystalline Cellulose 33.50
8 Croscarmellose sodium 8
9 Colloidal silicon dioxide 1.5
10 Magnesium Stearate 2
Total 440

Process:
Same as mentioned in example 1.

Dissolution data:
a) Cumulative drug release study of dicyclomine or its salt in Meftal Spas verses example 2.
Table 3
Time (minutes) % drug release (Mean ± 5%)
dicyclomine
(from Meftal Spas) dicyclomine example 2
5 53 92
10 67 91
20 75 91
30 84 91
45 86 91

Figure 1

Figure 1: Cumulative release of dicyclomine from Meftal Spas verses example 2, when tested according to USP apparatus II dissolution test method at 50 rpm using 500 ml of Tris Buffer at pH 9.0

b) Cumulative drug release study of mefenamic acid in Meftal Spas verses example 2
Table 4
Time (minutes) % drug release (Mean ± 5%)
mefenamic acid
(from Meftal Spas) mefenamic acid from example 2
5 27 58
10 40 74
20 54 83
30 63 86
45 72 86

Figure 2

Figure 2: Cumulative release of mefenamic acid from Meftal Spas verses example 2 when tested according to USP apparatus II dissolution test method at 50 rpm using 500 ml of 0.01N hydrochloric acid.

Stability data:
Table 5
Polyvinyl Chloride Clear Blister Pack
Description Month (M)
Initial 1M 2M 3M 6M 9M
40/75 40/75 30/65 40/75 30/65 40/75 30/65
Water by Karl Fischer 5.01 5 4.97 4.76 4.30 4.75 4.63 4.31
Mefenamic acid
Assay 98.2 100.5 101.2 97.8 97.9 97.5 98.3 98.7
Dicyclomine HCL
Assay 99.8 97.1 96.3 96.2 94.3 98 98.6 97.6
,CLAIMS:1. A solid pharmaceutical composition for oral administration comprising:
a) 50 % w/w to 60 % w/w mefenamic acid or a salt thereof,
b) 1.5 % w/w to 4 % w/w dicyclomine or a salt thereof,
c) a superdisintegrant, and
d) an effervescent agent,
wherein the weight ratio of superdisintegrant to the effervescent agent is about1:5.

2. The solid pharmaceutical composition according to claim 1, wherein the mefenamic acid is in micronized form having average particle size is less than about 60 micron.

3. The solid pharmaceutical composition according to claim 1, wherein the amount of superdisintegrant presents in the composition ranges from about 1 % w/w to about 4 %w/w.

4. The solid pharmaceutical composition according to claim 1, wherein the amount of effervescent agent present in the composition ranges from about 4 %w/w to about 25 %w/w.

5. The solid pharmaceutical composition according to claim 1, wherein the weight ratio of amount of effervescent agent to the amount of mefenamic acid is about 1:6.25.

6. The solid pharmaceutical composition according to claim 1, wherein the weight ratio of amount of effervescent agent to the amount of dicyclomine is about 1:0.25.

7. The solid pharmaceutical composition according to claim 1, wherein the superdisintegrant is selected from the group comprising of carboxymethylcellulose sodium, colloidal silicon dioxide, crosscarmellose sodium crospovidone, magnesium aluminum silicate, maize starch, methyl cellulose, microcrystalline cellulose and the effervescent agent is dried sodium bicarbonate.

8. The solid pharmaceutical composition according to claim 1, wherein the effervescent agent is dried sodium bicarbonate.

9. The solid pharmaceutical composition according to claim 1, wherein the composition exhibits a dissolution profile of dicyclomine or a salt thereof such that
a) more than 80% of the dicyclomine or a salt thereof is released at 10 minutes and more than 90% of the dicyclomine or a salt thereof is released at 20 minutes, when tested according to USP apparatus II dissolution test method at 50 rpm using 500 ml of Tris Buffer at pH 9.0.
b) more than 70% of the mefenamic acid is released at 10 minutes and more than 80% of the mefenamic acid is released at 20 minutes, when tested according to USP apparatus II dissolution test method at 50 rpm using 500 ml of 0.01N hydrochloric acid.

10. The solid pharmaceutical composition according to claim 1, wherein the composition retains at least 90% w/w of the potency of dicyclomine or a salt thereof and mefenamic acid or a salt thereof after 9 months when stored at 40°C and 75% relative humidity.