DESC:FIELD OF THE INVENTION:
The present invention relates to formulations for use in functional bowel disorders, such as irritable bowel syndrome, functional dyspepsia, post-operative flatulence and gas pains. More particularly, the invention relates to formulations comprising combination of mebeverine and one or more antiflatulents.

BACKGROUND OF THE INVENTION:
Irritable bowel syndrome (IBS) is one of the most commonly encountered chronic gastrointestinal disorders, accounting for more than half of the patients reporting to gastroenterologists with Gastro-Intestinal (GI) symptoms. Most prevalent symptoms of IBS – colon specific, are painful, often colicky in nature and can occur anywhere in the abdomen, borborgymi, an audible intestinal rumbling - often associated with increased flatus or distended abdomen.

There are various methods employed for treatment of IBS, starting from use of dietary fibers to treatment with medicines such as antispasmodics.

Mebeverine is a musculotropic antispasmodic agent used for the symptomatic treatment of abdominal pain, cramps, bowel disturbances and intestinal discomfort associated with IBS. It has strong and selective action on the smooth muscle of gastrointestinal tract, particularly of the colon - relieving spasm without affecting normal gut motility. Mebeverine action is not mediated by autonomic nervous system and anticholinergic side effects are absent. Currently marketed dosage forms are immediate release film tablets and modified release capsules of Mebeverine Hydrochloride (MHC). The recommended daily oral intake is up to 400mg. However, the available products containing Mebeverine HCl are required to be taken three to four times daily, which adversely affects patient compliance.

IBS is often associated with flatulence, which causes pain and discomfort to the patient. For treating flatulence, an antiflatulent is recommended. Some known antiflatulents are simethicone and dimethicone. The methicones relieve flatulence and abdominal discomfort due to excess gastrointestinal gas/flatus. Simethicone or Dimethicone is a gastrointestinal protective agent with antifoaming action. They reduce surface tension of gas bubbles, combine into larger bubbles, whereby, gas bubbles burst and gas is released. Released gas is either absorbed or eliminated naturally. Simethicone or Dimethicone increases the rate at which gas exits the body, but without any effect on motility, secretion, and tonicity of the intestine. Simethicone or dimethicone is indicated for relief of flatulence and abdominal discomfort due to excess gastrointestinal gas.

However, there is still a requirement for effective treatment of functional bowel disorders, which provides both symptomatic relief, and also addresses the flatulence. Also, there is a requirement for a composition which improves patient compliance. Hence, there is a need to develop a stable oral formulation for use in functional bowel disorders, which improves patient compliance.

OBJECTS OF THE INVENTION:
The objective of this invention is to provide a dosage form comprising a combination of mebeverine and one or more antiflatulents.

It is also an object of the invention to provide modified release dosage form comprising a combination of mebeverine and one or more antiflatulents.

It is an object of the invention to provide a fixed dose combination of mebeverine and one or more antiflatulents.

It is another object of the present invention to provide a fixed dose combination of modified release mebeverine and an immediate release antiflatulent.

In a specific object, the present invention provides a fixed dose combination of modified release mebeverine hydrochloride (MHC) and immediate release simethicone.

In another specific object, the present invention provides a fixed dose combination of modified release mebeverine hydrochloride (MHC) and immediate release dimethicone.

It is also an object of the present invention to provide a pharmaceutical composition comprising mebeverine and one or more antiflatulents.

In another object, the present invention provides a pharmaceutical composition comprising modified release mebeverine and an immediate release antiflatulent.

In a specific object, the present invention provides a pharmaceutical composition comprising modified release mebeverine hydrochloride (MHC) and immediate release simethicone or dimethicone.

In yet another object, the present invention provides the process for preparation of pharmaceutical compositions comprising fixed dose combination of modified release mebeverine hydrochloride (MHC) and antiflatulent.

In yet another object, the present invention provides the method of treating functional bowel disorders using fixed dose combinations of modified release mebeverine hydrochloride (MHC) and one or more antiflatulent.

In yet another object, the present invention provides the method of treating functional bowel disorders using fixed dose combinations of modified release mebeverine hydrochloride (MHC) and simethicone or dimethicone.

Another object of the invention is to enhance drug product safety and reduce risk of adverse effects, thereby improving patient compliance.

It is also an object of the invention to increase the drug product safety by minimizing the risk for adverse effects in order to achieve better patient compliance.

Still another object of the invention is to provide long term stability of the final dosage form.

Another object of the invention is to overcome short intervals of administration of the drug for effective treatment.

The invention also provides for the processes for preparation of dosage forms and pharmaceutical compositions of the present invention. The invention also provides the processes for preparation of mebeverine composition and antiflatulent composition.

The invention also provides for the method of treating functional bowel disorders using the dosage forms, pharmaceutical compositions or fixed dose combinations of the present invention.

BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
Figure No. 1: Dissolution profiles of Mebeverine hydrochloride – Eudragit NE matrix tablets (batch 47616E30).
Figure No. 2: Dissolution profiles of Mebeverine hydrochloride – HPMC matrix tablets manufactured by fluidized bed granulation (batch 47616E37-E43).

DETAILED DESCRIPTION OF THE INVENTION
This invention relates to a modified release dosage form comprising mebeverine and an antiflatulent.

The term “modified release” as used herein in relation to the dosage form according to the invention means a combination of different types of release, selected from controlled release, sustained release, prolonged release, timed release, retarded release, extended release and delayed release, and immediate release. The term “modified release” as used herein in relation to mebeverine means a release which is modified to achieve the desired release of mebeverine in the lower part of gastro-intestinal tract and includes controlled release, sustained release, prolonged release, timed release, retarded release, extended release and delayed release.

The term “dosage form” denotes any form of the formulation that contains a sufficient amount of both active ingredients, first active ingredient, and second active ingredient, to achieve a therapeutic effect with a single administration. The term “dosage form” includes such formulations that contain different compositions of the first active ingredient and the second active ingredient in a single formulation to achieve a therapeutic effect with a single administration.

The term “first active ingredient” refers to mebeverine and its salts, polymorphs, esters, solvates, or any other form which is intended for use of mebeverine as the drug.

The reference to term “mebeverine” includes any of its pharmaceutically acceptable salts, polymorphs, esters, solvates, pure forms, isomers, pro-drugs, metabolites or any other form which is intended for use as mebeverine.

The term “second active ingredient” refers to an antiflatulent and includes simethicone, dimethicone and any other form of simethicone or dimethicone, including activated form of dimethicone, which is intended for use as simethicone or dimethicone.

The term “pharmaceutical composition” refers to a formulation that contains a sufficient amount of both active ingredients, first active ingredient, and second active ingredient, to achieve a therapeutic effect with a single administration, and the compositions comprising first active ingredient and second active ingredient are contained in a single composition.

The term “mebeverine composition” refers to a composition of mebeverine with other pharmaceutically acceptable excipients, and does not include the second active ingredient.

The term “antiflatulent composition” refers to a composition of one or more antiflatulents with other pharmaceutically acceptable excipients, and does not include the first active ingredient.

The term “fixed dose combination” refers to “dosage form” and “pharmaceutical composition” of the present invention that contains a sufficient pre-determined amount of both active ingredients, first active ingredient, and second active ingredient, to achieve a therapeutic effect with a single administration. A combination of mebeverine composition and antiflatulent composition is also encompassed within the definition of fixed dose combination.

The term “formulation” refers to any pharmaceutical formulation for oral administration, including tablets (single layered tablets, multilayered tablets, mini tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified release tablets, pulsatile release tablets, timed release tablets), pellets, beads, granules, sustained release formulations, capsules, microcapsules, tablets in capsules and microspheres, matrix formulations, microencapsulation and powder/pellets/granules for suspension.

The term “functional bowel disorders” refers to any bowel disorders, such as irritable bowel syndrome, functional dyspepsia, post-operative flatulence and gas pains.

The combination of Mebeverine and an anti-flatulent provides better effect in functional bowel disorders. Mebeverine is a musculotropic with antispasmodic properties used for the management of abdominal pain, bowel disturbances and intestinal discomfort associated with irritable bowel syndrome (IBS). The addition of an antiflatulent relieves flatulence and abdominal discomfort due to excess gastrointestinal gas without any effect on motility, secretion, and tonicity of the intestine.

Mebeverine is chemically known as 4-[ethyl-[1-(4-methoxyphenyl)propan-2- yl]amino]butyl3,4-dimethoxybenzoate;hydrochloride. Mebeverine is white to off-white crystalline powder and is non-hygroscopic. It is freely soluble in water and ethanol, and practically insoluble in diethylether.

Simethicone is chemically known as Methoxy-dimethyl-trimethylsilyloxysilane. Simethicone is liquid of greasy consistency and is non-hygroscopic. It is insoluble in water.

Dimethicone, known as Polydimethylsiloxane (PDMS) is a polymeric organosilicon compound. Dimethicone has viscoelastic properties, and hence, poses problems in formulating free flowing granules. It tends to form a sticky mass when combined with other ingredients, and hence, it is difficult to formulate a free flowing powder/granule of dimethicone.

The present invention provides a combination of mebeverine and antiflatulents like simethicone or dimethicone. Such a combination not only provides better efficacy in the treatment of IBS over the earlier known formulations of mebeverine, but also improves patient compliance. One skilled in the art would know the importance of achieving good patient compliance to achieve better therapeutic efficacy. Whatever be the efficacy of a drug formulation, a poor patient compliance would not achieve the desired therapeutic result. Hence, a formulation which achieves a better patient compliance provides enhanced therapeutic efficacy. The fixed dose combination of the present invention avoids the need for a patient to take multiple formulations, and thereby improves the patient compliance and thereby achieves enhanced therapeutic efficacy.

Further, developing a fixed dose combination has its own challenges. In the present invention, a fixed dose combination of mebeverine and simethicone or dimethicone is provided. Where mebeverine exists as white to off-white crystalline powder, simethicone and dimethicone exist as viscous liquids. Preparing a fixed dose combination of such components having different physico-chemical properties is a challenge and requires detailed study and inventive faculty. However, the present invention could achieve a fixed dose combination wherein mebeverine and simethicone or mebeverine and dimethicone are formulated in a single formulation and yet achieve the desired effect.

Mebeverine is crystalline powder and is non-hygroscopic. It is freely soluble in water and ethanol, and practically insoluble in diethylether. Simethicone is liquid of greasy consistency and is non-hygroscopic, but it is insoluble in water. Dimethicone has viscoelastic properties, and hence, poses problems in formulating free flowing granules. It tends to form a sticky mass when combined with other ingredients, and hence, it is difficult to formulate a free flowing powder/granule of dimethicone. However, the inventors of the present invention could prepare various formulations of combination of mebeverine and simethicone or dimethicone, overcoming the formulation difficulties.

The dosage forms of the present invention can be provided in different formulations, achieving the objectives of the present invention.

In one embodiment, modified release mebeverine composition is combined with immediate release antiflatulent composition and provided in a single formulation. More specifically, granules of modified release mebeverine are combined with immediate release antiflatulent granules/powder and filled in capsules.

In another embodiment, bilayer tablets of modified release mebevereine composition and immediate release antiflatulent composition are prepared.

In still another embodiment, modified release mebeverine composition is coated with an antiflatulent composition. More specifically, granules of modified release mebeverine are coated with antiflatulent composition and filled in capsules. In another embodiment, tablets of modified release mebeverine composition are coated with antiflatulent composition.

In another embodiment, the amount of mebeverine in the dosage forms is 200 mg of mebeverine hydrochloride. The amount of simethicone in the dosage forms is 160 mg. The amount of activated dimethicone in the dosage forms is 125 mg.

In one embodiment, the present invention provides fixed dose combination of mebeverine and antiflatulent.

In another embodiment, the present invention provides fixed dose combination of modified release mebeverine and antiflatulent.

In yet another embodiment, the present invention provides fixed dose combination of modified release mebeverine hydrochloride (MHC) and immediate release antiflatulent.

In yet another embodiment, the present invention provides fixed dose combination of modified release mebeverine hydrochloride (MHC) and immediate release simethicone.

In yet another embodiment, the present invention provides fixed dose combination of modified release mebeverine hydrochloride (MHC) and immediate release dimethicone.

In yet another embodiment, the present invention provides a pharmaceutical composition comprising fixed dose combination of mebeverine hydrochloride (MHC) and antiflatulent and one or more excipients.

In yet another embodiment, the present invention provides a pharmaceutical composition comprising fixed dose combination of modified release mebeverine hydrochloride (MHC) and antiflatulent and one or more excipients.

In yet another embodiment, the present invention provides a pharmaceutical composition comprising fixed dose combination of modified release mebeverine hydrochloride (MHC) and immediate release antiflatulent and one or more excipients.

In yet another embodiment, the present invention provides a pharmaceutical composition comprising fixed dose combination of modified release mebeverine hydrochloride (MHC) and immediate release simethicone and one or more excipients.

In yet another embodiment, the present invention provides a pharmaceutical composition comprising fixed dose combination of modified release mebeverine hydrochloride (MHC) and immediate release dimethicone and one or more excipients.

In yet another embodiment, the present invention provides a pharmaceutical composition comprising fixed dose combination of modified release mebeverine hydrochloride (MHC) and immediate release simethicone or dimethicone, and one or more excipients wherein the said composition is in the form of stable oral dosage form such as tablets (single layered tablets, multilayered tablets, mini tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified release tablets, pulsatile release tablets, timed release tablets), pellets, beads, granules, sustained release formulations, capsules, microcapsules, tablets in capsules and microspheres, matrix formulations, microencapsulation and powder/pellets/granules for suspension.

In specific embodiment, the present invention provides a pharmaceutical composition comprising fixed dose combination of modified release mebeverine hydrochloride (MHC) and immediate release simethicone or dimethicone, and one or more excipients wherein the said composition is in the form of stable oral capsules.

In yet another specific embodiment, the present invention provides a pharmaceutical composition comprising fixed dose combination of modified release mebeverine hydrochloride (MHC) and immediate release simethicone or dimethicone, and one or more excipients wherein the said composition is in the form of stable oral tablets.

In yet another embodiment, the present invention comprises of from 5 % w/w to 60%w/w of mebeverine hydrochloride; more preferably, the present invention comprises 20%w/w to 50%w/w of mebeverine hydrochloride.

In yet another embodiment, the present invention comprises of from 5%w/w to 50% w/w of antiflatulent, more preferably the present invention comprises of from 5%w/w to 50%w/w of simethicone or dimethicone; more preferably, the present invention comprises 10%w/w to 40 % w/w of simethicone or dimethicone.

In yet another embodiment, the present invention provides a fixed dose combination of modified release mebeverine hydrochloride (MHC), immediate release activated dimethicone, at least one release controlling polymer and one or more other excipients.

In yet another embodiment, the present invention comprises of from 3%w/w to 50% w/w of at least one release controlling polymer; more preferably, the present invention comprises of from 5%w/w to 40% w/w of at least one release controlling polymer.

In yet another embodiment, the present invention provides pharmaceutical composition in the form of capsule comprising of:
a) modified release mebeverine hydrochloride (MHC);
b) immediate release antiflatulant; and
c) one or more other excipients.

In yet another embodiment, the present invention provides pharmaceutical composition in the form of capsule comprising of one or more adsorbent.

In yet another embodiment, the present invention provides pharmaceutical composition in the form of capsule comprising of at least one release controlling polymer.

In yet another embodiment, the present invention provides pharmaceutical composition in the form of capsule comprising of:
a) from 5 % w/w to 60%w/w of modified release mebeverine hydrochloride (MHC) granules;
b) from 5 % w/w to 50%w/w of immediate release antiflatulant granules; and
c) one or more excipients.

In yet another embodiment, the present invention provides pharmaceutical composition in the form of capsule wherein the immediate release antiflatulant granules comprises one or more adsorbent.

In yet another embodiment, the present invention provides pharmaceutical composition in the form of capsule wherein the immediate release antiflatulant granules comprises from 20%w/w to 60 % w/w of one or more adsorbent.

The present invention provides free flowing granules of dimethicone/simethicone, which can be combined with modified release granules of Mebeverine HCl, and formulated into solid oral formulations.

The present invention provides activated dimethicone/simethicone free flowing powder/granules by adsorbing activated dimethicone on an adsorbent. As per the present invention, an adsorbent is an inert substance, which has the capacity to adsorb dimethicone/simethicone.

The present invention also provides dimethicone/simethicone free flowing powder/granules having desired density to achieve formulating a solid dosage form containing the desired/effective amount of dimethicone/simethicone.

The adsorbents can be selected from dicalcium phosphate, tricalcium phosphate, calcium carbonate, light magnesium carbonate, heavy magnesium carbonate, magnesium aluminometasilicate (Neusilin® US2), light magnesium oxide, silicified microcrystalline cellulose (PROSOLV SMCC® 50), or any other suitable mineral adsorbent, or a combination thereof.

The selection of a suitable adsorbent or a mixture of adsorbents is critical to achieve a desired flow and density. A low density product will not help in achieving the desired amount of dimethicone to be incorporated in the final formulation.

The invention also provides for use of diluents, binders, glidants, lubricants, and other excipients for preparing free flowing activated dimethicone powder/granules.

In one specific embodiment, a binder is added to dimethicone/simethicone and adsorbent to increase the mass of granules, achieving high density.

Selection of adsorbent is critical to achieve the desired free flow, desired density and desired disintegration time.

The binder may be selected from Eudragit E100, PVP, PVP-K30, HPMC E5, etc. The diluent may be selected from Microcrystalline cellulose, colloidal silicone dioxide, etc.

In yet another embodiment, the present invention provides a pharmaceutical composition in the form of tablet comprising of:
a) core tablet comprising mebeverine hydrochloride (MHC), one or more release controlling polymer and one or more excipients, and
b) coating composition comprising immediate release antiflatulant and one or more other excipients.

In yet another embodiment, the present invention provides a pharmaceutical composition in the form of tablet comprising of:
a) core tablet comprising from 5% w/w to 60%w/w of mebeverine hydrochloride (MHC); from3%w/w to 50% w/w of at least one release controlling polymer; and one or more other excipients, and
b) coating composition comprising from 5% w/w to 50%w/w of immediate release antiflatulant; and one or more other excipients.

In yet another embodiment, the present invention provides a pharmaceutical composition in the form of capsule comprising of:
a) from 5% w/w to 60%w/w of modified release mebeverine hydrochloride (MHC) granules;
b) from 5% w/w to 50%w/w of immediate release antiflatulant granules;
c) an adsorbent in an amount of from 20%w/w to 60 % w/w of the immediate release antiflatulent granules; and
d) optionally one or more excipients.

In yet another embodiment, the present invention provides a pharmaceutical composition comprising fixed dose combination of modified release mebeverine hydrochloride (MHC) and immediate release simethicone or dimethicone, and one or more excipients wherein the said composition is stable, safe and patient compliant.

In yet another embodiment, the present invention provides a process of preparing pharmaceutical composition comprising fixed dose combination of modified release mebeverine hydrochloride (MHC) and antiflatulents and one or more excipients.

In yet another embodiment, the present invention provides a process of preparing pharmaceutical composition comprising fixed dose combination of modified release mebeverine hydrochloride (MHC) and simethicone or dimethicone and one or more other excipients, wherein the said process comprises steps of:
a) sifting and mixing one or more adsorbent, simethicone or dimethicone and one or more other excipients,
b) preparing granules of simethicone or dimethicone by dry granulation or wet granulation method,
c) drying, milling and sifting the granules of simethicone or dimethicone,
d) preparing modified release mebeverine HCl (MHC) granules using one or more excipients,
e) mixing modified release mebeverine HCl (MHC) granules and dried granules of simethicone or dimethicone,
f) filling modified release mebeverine HCl (MHC) granules and dried granules of simethicone or dimethicone in capsule.

In yet another embodiment, the present invention provides a process of preparing pharmaceutical composition comprising fixed dose combination of from 5 % w/w to 60%w/w of modified release mebeverine hydrochloride (MHC), from 5 % w/w to 50%w/w simethicone or dimethicone, and one or more excipients, wherein the said process comprises steps of:
a) sifting and mixing one or more adsorbent, simethicone or dimethicone and one or more other excipients,
b) preparing granules of simethicone or dimethicone by dry granulation or wet granulation method,
c) drying, milling and sifting the granules of activated simethicone or dimethicone,
d) Preparing modified release mebeverine HCl (MHC) granules using one or more excipients,
e) mixing modified release mebeverine HCl (MHC)granules and dried granules of simethicone or dimethicone,
f) filling modified release mebeverine HCl (MHC) granules and dried granules of simethicone or dimethicone in capsule.

In yet another embodiment, the present invention provides a process of preparing pharmaceutical composition comprising fixed dose combination of modified release mebeverine hydrochloride (MHC) and antiflatulent, one or more release controlling polymer and one or more other excipients, wherein the said process comprises steps of:
a) preparing the granulation fluid using one or more release controlling polymers and one or more other excipients,
b) preparing modified release granules of mebeverine hydrochloride using granulation fluid,
c) compressing mebeverine hydrochloride granules and one or more excipients to form tablet,
d) preparing sugar coating solution containing antiflatulent using one or more excipients,
e) applying sugar coating on modified release mebeverine hydrochloride tablets.

In yet another embodiment, the present invention provides a process of preparing pharmaceutical composition comprising fixed dose combination of from 5 % w/w to 60%w/w of modified release mebeverine hydrochloride (MHC) and from 5 % w/w to 50%w/w of simethicone or dimethicone, from 3 % w/w to 50% w/w of one or more release controlling polymers and one or more excipients, wherein the said process comprises steps of:
a) preparing the granulation fluid using from one or more release controlling polymers and one or more other excipients,
b) preparing modified release granules of mebeverine hydrochloride using granulation fluid,
c) compressing mebeverine hydrochloride granules and one or more excipients to form tablet,
d) preparing sugar coating solution containing simethicone or dimethicone using one or more excipients,
e) applying sugar coating on modified release mebeverine hydrochloride tablets.

In yet another embodiment, the present invention provides a process of preparing pharmaceutical composition comprising fixed dose combination of from 5% w/w to 60%w/w of modified release mebeverine hydrochloride (MHC) granules, from 5% w/w to 50%w/w of immediate release antiflatulant granules, an adsorbent in an amount of from 20%w/w to 60 % w/w of the immediate release antiflatulent granules; and optionally one or more excipients wherein the said process comprises the steps of:
a) sifting and mixing one or more adsorbent, simethicone or dimethicone, and one or more other excipients,
b) preparing granules using binder, simethicone or dimethicone and one or more excipients, by wet granulation method,
c) drying, milling and sifting the granules of simethicone or dimethicone,
d) preparing modified release mebeverine HCl (MHC) granules using one or more excipients,
e) mixing modified release mebeverine HCl (MHC) granules and dried granules of simethicone or dimethicone,
f) filling modified release mebeverine HCl (MHC) granules and dried granules of simethicone or dimethicone in capsule.

In yet another embodiment, the present invention provides method of treating functional bowel disorders by administering fixed dose combination of modified release mebeverine hydrochloride (MHC) and immediate release simethicone/dimethicone.

The composition of the present invention may also contain other excipients, such as release controlling polymers, solubilizers, adsorbent, binders, glidents, lubricants, solvents, disintegrants, fillers or diluents.

The excipients that are useful in preparing composition are preferably safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for human use.

The release controlling polymers according to present invention may be selected from the group consisting of but not limiting to cellulose based polymers such as ethyl cellulose, methyl cellulose, hydroxyl propyl cellulose, various grades of hydroxypropylmethyl cellulose, sodium alginate, xanthan gum, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimellitate cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, carboxymethylethylcellulose, ethylhydroxyethylcellulose phthalate and the like. Acrylic copolymer such as styrene, acrylic acid copolymer, methyl acrylate, acrylic acid copolymer, methyl acrylate, methacrylic acid copolymer, butyl acrylate, styrene, acrylic acid copolymer, methacrylic acid, methyl methacrylate copolymer, Poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), Poly(methacrylic acid-co-ethyl acrylate), Poly(methacrylic acid-co-methyl methacrylate), the commercially available under brand name Eudragit NE, Eudragit FS 30D, Eudragit L 100-55, Eudragit L 30D-55, EUDRAGIT(R) L 100, EUDRAGIT(R) L 12,5, EUDRAGIT(R) S 100, EUDRAGIT(R) S 12,5 from Evonik. Maleic copolymer such as vinylacetate, maleic acid anhydride copolymer, styrene maleic acid anhydride copolymer, styrene maleic acid monoester copolymer, vinylmethylether maleic acid anhydride copolymer, ethylene maleic acid anhydride copolymer, vinylbutylether maleic acid anhydride copolymer, acrylonitrile methyl acrylate maleic acid anhydride copolymer, butyl acrylate styrene maleic acid anhydride copolymer and other materials known to one of ordinary skill in the art and combinations thereof. The preferred release controlling polymers used in the present invention are cellulose based polymers such as ethyl cellulose, hydroxypropylmethyl cellulose, and various grades of Eudragit.

The solubilizers according to present invention may be selected from the group consisting of but not limiting to Polaxamer, Stearic acid, Sorbiton monooleate, Cetylpyridine chloride, Glyceryl monostearate, Polysorbate 80, Polyoxy140 stearate and other materials known to one of ordinary skill in the art and combinations thereof. The preferred solubilizers used in the present invention are Polysorbate 80 and Glyceryl monostearate.

The adsorbent according to present invention may be selected from the group consisting of but not limiting to kaolin, bentonite, alginates, silica gel, silicates, aluminosilicates, carbonates, magnesium aluminometa silicate, Light magnesium carbonate, heavy magnesium carbonate, dicalcium phosphate, tricalcium phosphate, calcium carbonate, light magnesium oxide, silicified microcrystalline cellulose (PROSOLV SMCC® 50), aluminometasilicate (Neusilin® US2) or any other suitable mineral adsorbent, and other materials known to one of ordinary skill in the art and combinations thereof. The preferred adsorbents used in the present invention are magnesium aluminometa silicate and Light magnesium carbonate.

The binders according to present invention may be selected from the group consisting of but not limiting to starches such as potato starch, wheat starch, maize starch; microcrystalline cellulose such as products known under the registered trademarks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum, arabic gum; liquid glucose, dextrin, syrup, polyethylene oxide, polyvinyl pyrrolidone (povidone), poly-N-vinyl amide, polyethylene glycol, alginate, gelatin, poly propylene glycol, tragacanth and other materials known to one of ordinary skill in the art and combinations thereof. The preferred binders used in the present invention are polyvinyl pyrrolidone (povidone), hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, sodium carboxy methyl cellulose, arabic gum and maize starch. More particularly the binder may be selected from Eudragit E100, PVP, PVP-K30, HPMC E5, etc.

The glidants according to present invention may be selected from the group consisting of but not limiting to magnesium stearate, magnesium trisilicate, colloidal silicon dioxide, tribasic calcium phosphate, calcium silicate, silicon hydrogel, pregelatinized starch, powdered cellulose, talc and other materials known to one of ordinary skill in the art and combinations thereof. The preferred glidants used in the present invention are magnesium stearate, colloidal silicon dioxide, pregelatinized starch and talc.

The lubricants according to present invention may be selected from the group consisting of but not limiting to fats such as vegetable stearin, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, talc, silica, colloidal anhydrous silica Mg, Al, Ca, Zn stearate or stearic acid, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax and other materials known to one of ordinary skill in the art and combinations thereof. The preferred lubricants used in the present invention are talc, stearic acid, polyethylene glycol and magnesium stearate.

The solvents according to present invention may be selected from the group consisting of but not limiting to benzyl alcohol, isopropyl alcohol, glycerin, mineral oil, polyethylene glycol, propylene glycol, triacetin and other materials known to one of ordinary skill in the art and combinations thereof. The preferred solvents used in the present invention are isopropyl alcohol and polyethylene glycol.

The disintegrants according to present invention may be selected from the group consisting of but not limiting to alginic acid and alginates, carboxymethylcellulose calcium, carboxymethylcellulose sodium, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, sodium alginate, sodium starch glycolate, pregelatinised starch, starches and other materials known to one of ordinary skill in the art and combinations thereof. The preferred disintegrants used in the present invention are croscarmellose sodium, crospovidone, pregelatinised starch and carboxymethyl cellulose sodium.

Fillers or diluents, according to present invention may be selected from the group consisting of but not limiting to maize starch, white sugar, confectioner's sugar, compressible sugar, dextrates, dextrin, glucose, dextrose, fructose, lactitol, mannitol, sucrose, starch, pregelatinized starch, lactose, xylitol, sorbitol, kaolin, talc, microcrystalline cellulose, colloidal silicone dioxide, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate and other materials known to one of ordinary skill in the art and combinations thereof. The preferred fillers or diluents used in the present invention are calcium carbonate, microcrystalline cellulose and maize starch.

The composition may be coated using a sugar-based agent, an agent for water-soluble film-coating base, enteric film-coating agent or a modified release film-coating agent. The coating agent may also contain a plasticizer.

Suitable examples of coating agents include but not limited to polyvinyl alcohol, hydroxypropyl methylcellulose, carboxymethyl cellulose, carnauba wax, Opadry®. Opadry® contains hydroxypropyl methyl cellulose, plasticizers selected from triacetin, triethyl citrate, polyethylene glycol, antitacking agent such as Talc, opacifiers such as titanium dioxide. Preferred Opadry® are Opadry® White 03A580003 which contains Hypromellose, Talc, Titanium dioxide, Opadry® Yellow 03A520003 which contains Hypromellose, Talc, Titanium dioxide & Iron oxide yellow, Opadry® Pink 03A540021 which contains Hypromellose, Titanium dioxide, Talc, Iron oxide red and Iron oxide yellow, Opadry® II Brown 85F565047 which contains Polyvinyl alcohol, Polyethylene glycol, Titanium dioxide, Talc, Red iron oxide, Black iron oxide and Yellow iron oxide, Opadry® II pink 85F540084 which contains Polyvinyl alcohol, Polyethylene glycol, Titanium dioxide, Talc, Red iron oxide and Yellow iron oxide , Opadry® 03A570000 Beige and Opadry® 03A570001 Beige which contains Hypromellose, titanium dioxide, Talc, Iron oxide red and Iron oxide yellow. The preferred coating agents used in the present invention are carnauba wax and titanium dioxide. Solvents that may be used for coating include purified water.

EXAMPLES
Example No. 1:
Tablet dosage form:
Table 1. Batch Formulas of Mebeverine hydrochloride tablets (200 mg) - amount per dose:
Ingredients Formulation (mg/dose)
Batch No.
47616E30 47616E37 47616E39 47616E42
47616E43

Mebeverine hydrochloride 200.0 200.0 200.0 200.0 200.0
Dibasic Calcium Phosphate 200.0 - - - -

Hydroxy Propyl Methyl Cellulose (High Viscosity) 122.4 218.0 190.8 190.8 190.8
Eudragit®NE 80.0 - - - -
Microcrystalline cellulose - 89.5 116.7 116.7 116.7
Glycerol Monostearate 4.0 - - - -
Colloidal silicon dioxide - 5.45 5.5 5.5 5.5
Talc - 10.9 10.9 10.9 10.9
Polysorbate 80 1.6 - - - -
Magnesium Stearate 3.0 5.45 5.5 5.5 5.5
Hydroxypropylmethyl cellulose (Low viscosity) - 15.5 15.5 15.5 15.5
Purified water - - 223.0 223.0 -

Table 2. Batch formula of simethicone sugar coating (160 mg) on mebeverine hydrochloride tablets (200 mg) – amount per dose
Ingredients Batch No. 47616E42D1
Formulation (mg/dose)
Sugar 145.0
Calcium carbonate 10.0
Colloidal silicon dioxide 20.35
Riboflavin -
Copovidone 10.0
Maize starch 15.0
Talc 73.8
Saccharose solution (dry substance) 86.0 mg 117.0
59.15 mg 80.4
Glucose syrup (dry substance 2.0 mg) 2.5
Polysorbate 80 3.0
Purified water 56.5
Arabic gum 31.0
Povidone (Kollidon) 25 1.0
Titanium dioxide 2.4
Carnauba wax 0.2

Process for manufacturing of modified release mebeverine hydrochloride tablets
Granulation fluid

The hydroxypropylmethyl cellulose containing granulation fluid was prepared by gently pouring the binder into the required quantity of purified water while stirring with a blade stirrer until a clear and bubble-free solution was obtained. Total solid content of the resulting binder solution was 6.5%w/w.

Eudragit®NE granulation fluid was prepared by dilution of the polymer dispersion with purified water and subsequent addition of talc. Total solids content of the dispersion was 15% w/w. In the case of glycerol monostearate (GMS) used as anti-tacking agent the polysorbate80 was dissolved in an initial quantity of purified water. The solution was then heated to minimum 80°C and GMS was added carefully. Stirring continued for atleast30 min until complete emulsion of GMS. The solution was then cooled to room temperature. Subsequently Eudragit®NE dispersion was added to obtain a 15% w/w solid spray dispersion. Dispersions were constantly stirred during spraying.

Fluidized bed granulation

All fluidized bed granulations were performed in fluidized bed granulator in top spray mode.

Eudragit®NE granules:

Mebeverine hydrochloride and dibasic calcium phosphate were granulated with a 15% w/w Eudragit®NE suspension. The targeted polymer weight gain was 30%w/w based on total solids. Intermediate samples were withdrawn at pre-determined time-points and used for compression trials.

HPMC granules:
Mebeverine hydrochloride and microcrystalline cellulose were granulated with purified water only or by using 6.5% w/w hydroxypropylmethylcellulose (HPMC) solutions. The targeted weight gain was 5% of binder (based on total solids). If necessary the granulation was performed in sub-lots.

Compression

If not otherwise mentioned mebeverine hydrochloride granules and excipients were screened on a 1.0 mm hand sieve and subsequently blended in a PE-bag for 10 min in order to obtain a visual homogenous blend. For batch sizes above 1.5 kg a container blender (BohleLM20) at 18-22 rpm for 20 min was used. The lubricant was screened on a 0.5 mm hand-sieve prior to addition. The final blending step was performed at 18-22 rpm for 2 or 5min respectively. Compression of the resulting final blends was conducted on a rotary press with 10X17 mm oval, 8x19mm oblong punch sets depending on the total tablet weight.

Placebo cores for sugar coating were manufactured by direct compression. Excipients were screened (1.0mm screen), blended in a container blender and subsequently compressed on a rotary press using a 10x17 mm oval punch set.

Coating on mebeverine hydrochloride and placebo tablets
Sugar coating

Sugar coating was divided in three process steps and was conducted in a pan sized 15L. Inlet air was adapted to obtain product temperatures <40°C. The sugar solution and simethicone powder blend were applied manually. Firstly, cores were coated with an isolating layer of shellac. Subsequently, the simethicone powder blend was sugar coated on the cores by alternated application of sugar solution and simethicone powder coating. Besides simethicone the powder blend contained mostly talc and calcium carbonate in order to harden the waxy simethicone layer. Subsequently, a sugar suspension was applied. The distribution and drying times were adapted so as to obtain smooth and even surfaces. Finally, a layer of carnauba wax was applied to the sugar coated tablets.

Example No. 2:
Capsule Dosage form:
Table 3: Activated Dimethicone Free Flowing powder
Ingredients Quantity (in kg)
Intra granular
Activated Dimethicone 1.050
Light Magnesium Carbonate 1.200
Colloidal Silicon Dioxide 0.015
Binder Solution
Povidone (Kollidon 30) 0.0525
Isopropyl Alcohol 0.600
Lubrication
Purified Talc 0.015

Table 4: Modified release Mebeverine HCl Granules
Ingredients Quantity
Intra granular
Modified release Mebeverine HCl granules 2.550 (in kg)
Capsule size ‘00’ Maroon/White 12000 (numbers)

Procedure for preparation of capsule dosage form comprising modified release mebeverine and immediate release activated dimethicone:
1. Sifting: Sift separately light magnesium carbonate and colloidal silicon dioxide through #20 sieve using vibratory sifter and collect in polybag-lined container.
2. Binder Solution: Dissolve Povidone (Kollidon 30) in Isopropyl Alcohol with continuous stirring in a SS container until a clear solution is obtained.
3. Dry Mixing and Drug addition:
(i) Load the sifted material into the main bowl of RMG and mix for 10 minutes at slow speed at Impeller ‘ON’ and chopper ‘OFF’
(ii) After dry mixing, add the activated Dimethicone into the RMG at slow speed and after drug addition mix it for 1 minute at Impeller ‘ON’ fast speed and chopper ‘OFF’, till a coherent mass is formed.
4. Granulation: After completion of step 3, add the binding solution slowly into the RMG at Impeller ‘ON’ slow speed and chopper ‘OFF’ and mix it for 1 minute at Impeller ‘ON’ fast speed and chopper ‘OFF’.
5. Drying: Transfer the wet granules from the step 4 into FBD bowl and air dry the granules till the solvent completely evaporates.
6. Sifting and Milling: Sift the dried granules through 20# mesh. Collect the retains and pass through multi-mill fitted with 1.5 mm screen using knives forward at medium speed.
7. Final Drying: Transfer the semi-dried sifted and milled granules from the step 6 into FBD bowl and dry the granules till the required LOD is achieved at inlet 55ºC + 5ºC and exhaust temperature 50ºC + 5ºC, and collect the dried granules in clean drum lined with double polybag.
8. Lubrication: Load the sifted purified talc into blender along with dried granules and mix for 5 minutes and collect the blend into containers lined with double lined polyethylene bag.
9. Filling:
(i) Load modified release mebeverine HCl granules in one hopper of the filling machine and adjust the machine for modified release granules fill weight.
(ii) Load activated dimethicone free flowing powder in another hopper of the filling machine and adjust the machine for capsule weight.
(iii) Fill the capsules with the loaded granules.
3 batches of the capsule dosage form were prepared as per example no. 2. The dissolution profile of modified release mebeverine HCl granules is shown in table no. 5
Table No 5: Dissolution Profiles of modified release Mebeverine HCl granules equivalent to Mebeverine HCl IP as per example no. 2.

Sr. No Time Drug released (%) Release limits (%)
1 1.5 hrs 23.0-27.7 10.0-30.0
2 3.0 hrs 43.4-46.2 25.0-50.0
3 6.0 hrs 66.9-73.0 55.0-80.0
4 12.0 hrs 88.01-94.8 NLT 75.0

Table no. 6: Long Term stability studies report for composition as per example no: 2

Table no. 7: Long Term stability studies report for composition as per example no: 2

Table no. 8: Additional condition stability studies report for composition as per example no: 2

Table no. 9: Additional condition stability studies report for composition as per example no: 2

,CLAIMS:We Claim:
1. A fixed dose combination comprising mebeverine and one or more antiflatulents.
2. The fixed dose combination according to claim 1, wherein the said antiflatulent is selected from simethicone or dimethicone.
3. The fixed dose combination according to claim 1, wherein the mebevereine is modified release mebevereine.
4. A pharmaceutical composition comprising a fixed dose combination of modified release mebeverine hydrochloride and antiflatulent, and one or more excipients.
5. The pharmaceutical composition according to claim 4, wherein the said composition comprises from 5%w/w to 60% w/w of mebeverine hydrochloride.
6. The pharmaceutical composition according to claim 4, wherein the said composition comprises from 5%w/w to 50% w/w of simethicone or dimethicone.
7. The pharmaceutical composition according to claim 4, wherein the said composition is in the form of stable oral dosage form such as tablets, pellets, beads, granules, sustained release formulations, capsules, microcapsules, tablets in capsules and microspheres, matrix formulations, microencapsulation and powder/pellets/granules for suspension.
8. The pharmaceutical composition according to claim 4, wherein the said composition is in the form of stable oral capsule.
9. The pharmaceutical composition according to claim 4, wherein the said composition is in the form of stable oral tablet.
10. The pharmaceutical composition according to claim 4, wherein the said one or more excipients are selected from group consisting of release controlling polymers, solubilizers, adsorbents, binders, glidents, lubricants, solvents, disintegrants, fillers or diluents.
11. The pharmaceutical composition according to claim 10, wherein the release controlling polymer is selected from cellulose based polymers such as ethyl cellulose, hydroxypropylmethyl cellulose, and various grades of Eudragit.
12. The pharmaceutical composition according to claim 10, wherein the adsorbent is selected from magnesium aluminometa silicate and Light magnesium carbonate.
13. A pharmaceutical composition in the form of capsule comprising of:
a) from 5% w/w to 60%w/w of modified release mebeverine hydrochloride (MHC) granules;
b) from 5% w/w to 50%w/w of immediate release antiflatulant granules; and
c) one or more excipients.
14. A pharmaceutical composition in the form of capsule comprising of:
a) from 5% w/w to 60%w/w of modified release mebeverine hydrochloride (MHC) granules;
b) from 5% w/w to 50%w/w of immediate release antiflatulant granules;
c) an adsorbent in an amount of from 20%w/w to 60 % w/w of the immediate release antiflatulent granules; and
d) optionally one or more excipients.
15. The pharmaceutical composition according to claim 14, wherein the said adsorbent is selected from the group consisting of kaolin, bentonite, alginates, silica gel, silicates, aluminosilicates, carbonates, magnesium aluminometa silicate, Light magnesium carbonate and combinations thereof.
16. The pharmaceutical composition according to claim 13 or 14, wherein the said composition comprises at least one release controlling polymer.
17. A pharmaceutical composition in the form of tablet comprising of:
a) core tablet comprising from 5% w/w to 60%w/w of mebeverine hydrochloride (MHC); from 3%w/w to 50% w/w of at least one release controlling polymer; and one or more other excipients, and
b) coating composition comprising from 5% w/w to 50%w/w of immediate release antiflatulant; and one or more other excipients.
18. The pharmaceutical composition according to claim 16, wherein the release controlling polymer is selected from the group consisting of cellulose based polymers such as ethyl cellulose, hydroxypropylmethyl cellulose, and various grades of Eudragit.
19. A process of preparing a pharmaceutical composition comprising fixed dose combination of from 5% w/w to 60%w/w of modified release mebeverine hydrochloride (MHC), from 5% w/w to 50%w/w simethicone or dimethicone, and one or more excipients, wherein the said process comprises the steps of:
a) sifting and mixing one or more adsorbent, simethicone or dimethicone, and one or more other excipients,
b) preparing granules of simethicone or dimethicone by dry granulation or wet granulation method,
c) drying, milling and sifting the granules of activated simethicone or dimethicone,
d) preparing modified release mebeverine HCl (MHC) granules using one or more excipients,
e) mixing modified release mebeverine HCl (MHC) granules and dried granules of simethicone or dimethicone, and
f) filling modified release mebeverine HCl (MHC) granules and dried granules of simethicone or dimethicone in capsule.
20. A process of preparing pharmaceutical composition comprising fixed dose combination of from 5% w/w to 60%w/w of modified release mebeverine hydrochloride (MHC), from 5% w/w to 50%w/w of simethicone or dimethicone, from 3% w/w to 50%w/w of one or more release controlling polymers and one or more excipients, wherein the said process comprises the steps of:
a) preparing the granulation fluid using one or more release controlling polymers and one or more other excipients,
b) preparing modified release granules of mebeverine hydrochloride using granulation fluid,
c) compressing mebeverine hydrochloride granules and one or more excipients to form tablet,
d) preparing sugar coating solution containing simethicone or dimethicone using one or more excipients,
e) applying sugar coating to modified release mebeverine hydrochloride tablets.
21. A process of preparing pharmaceutical composition comprising fixed dose combination of from 5% w/w to 60%w/w of modified release mebeverine hydrochloride (MHC) granules, from 5% w/w to 50%w/w of immediate release antiflatulant granules, an adsorbent in an amount of from 20%w/w to 60 % w/w of the immediate release antiflatulent granules; and optionally one or more excipients wherein the said process comprises the steps of:
a) sifting and mixing one or more adsorbent, simethicone or dimethicone, and one or more other excipients,
b) preparing granules using binder, simethicone or dimethicone and one or more excipients, by wet granulation method,
c) drying, milling and sifting the granules of simethicone or dimethicone,
d) preparing modified release mebeverine HCl (MHC) granules using one or more excipients,
e) mixing modified release mebeverine HCl (MHC) granules and dried granules of simethicone or dimethicone,
f) filling modified release mebeverine HCl (MHC) granules and dried granules of simethicone or dimethicone in capsule.
22. The pharmaceutical composition according to claim 21, wherein the binder is selected from the group consisting of polyvinyl pyrrolidone (povidone), hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, sodium carboxy methyl cellulose, arabic gum, Eudragit E100, PVP-K30, HPMC E5 and maize starch.
23. The fixed dose combination according to any of the preceding claims for use in treating functional bowel disorders.