THE PHARMACEUTICAL FORMULATION OF MESALAMINE

INTRODUCTION

The present invention describes about the pharmaceutical formulation of Mesalamine.
The present invention particularly relates to pharmaceutical compositions comprising Mesalamine or its pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof for oral administration.

Inflammatory bowel disease (IBD) refers to a group of chronic intestinal diseases characterized by inflammation of the bowel (the large or small intestine). The most common types of IBD are ulcerative colitis and Crohn's disease.

Mesalamine is the adopted name for the compound 5-amino-2-hydroxybenzoic acid, or 5-aminosalicylic acid (5-ASA), and is in a class of medications called anti-inflammatory agents. It is a tan, pink crystalline powder that exhibits a needle-like morphology. Mesalamine has structural Formula I.

Mesalamine is slightly soluble in water, very slightly soluble in dehydrated alcohol, acetone, and methyl alcohol, insoluble in chloroform, ether, butyl alcohol, and ethyl acetate, and soluble in dilute hydrochloric acid and dilute alkali metal hydroxide solutions.

Mesalamine exhibits local action in the large intestine and has been formulated using various technologies to release the active at the site for the treatment of inflammation in the distal part of small intestine and colon and the treatment of inflammatory bowel disease ("IBD").

Commercially, Mesalamine is available in various dosage forms. For example, PENTASA™ (Mesalamine 400 mg extended release capsules; Shire Inc., USA), ASACOL™ (Mesalamine 200 mg and 400 mg delayed release tablets; Procter and Gamble, USA), and LIALDA™ (Mesalamine 1.2 g delayed release tablets; Shire Inc., USA), for oral administration.

LIALDA™ tablets are coated with a gastro-resistant pH dependent polymer film, which breaks down at or above pH 7, normally in the terminal ileum where Mesalamine then begins to be released from the tablet core. The tablet core contains Mesalamine with hydrophilic and lipophilic excipients. LIALDA™ is indicated for the treatment of diseases such as mild to moderate ulcerative colitis.

U.S. Patent Nos. 5,541,170 and 5,541,171 disclose delayed release tablets containing Mesalamine. U.S. Patent No. 5,686,105 describes enteric coated multi-particulate dosage forms for colonic delivery .U.S. Patent No. 6,773,720 discloses controlled release oral pharmaceutical compositions comprising Mesalamine and a lipophilic matrix. U.S. Patent Application Publication No. 2003/0138495 discloses a method for preparation of Mesalamine granules using extrusion technology. U.S. Patent Application Publication No. 2007/0059368 discloses modified release formulations of anti-irritability drugs. U.S. Patent Application Publication No. 2006/0210631 discloses a multi-particulate modified-release composition. U.S. Patent Application Publication No. 2006/0223787 discloses modified release formulations and a method of treating inflammatory bowel disease. International Application Publication No. WO 2004/087113 describes a delayed release single dosage unit composition of Mesalamine for colonic delivery.

There remains a need for compositions providing ease of manufacturing and minimizing the use of pharmaceutical excipients, to deliver high unit doses of Mesalamine.

SUMMARY

The present invention describes about the pharmaceutical formulation of Mesalamine.

The pharmaceutical formulation comprising an inner core, and active is premixed with hydrophilic polymer which is layered onto the said inner core, wherein layering of drug is more than about 80 wt% of pellet.

The present invention particularly relates to pharmaceutical compositions comprising Mesalamine or its pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof for oral administration.

An aspect of the present invention includes a pharmaceutical formulation comprising an inner core, and active ingredient is premixed with hydrophilic polymer which is layered onto the said inner core, wherein layering of the drug is more than about 80 wt% of pellet.

Further aspect includes a pharmaceutical formulation comprising premixed active wherein the active is granulated with hydrophilic polymer and said active polymer to hydrophilic polymer ratio is about 1:99 to 1:20.

Further another aspect of the present invention includes highly drug loaded pharmaceutical compositions comprising pharmaceutical active ingredient for oral administration, wherein said composition is prepared by

a) granulating active ingredient using hydrophilic polymer and milling thereby obtaining premix powder.

b) spraying or layering on the beads.

c) applying the rate controlling coating around the drug layer.

Further aspect of the invention includes a method of preparing highly drug loaded pellets having controlled release profile consists of applying a drug layer to an inert core where in drug layer consist of

a) 60 - 99 wt wt% of drug, 0.3-10 wt% of hydrophilic matrix polymer, 0 - 65 wt% of filler and 0 - 5 wt% of glidant.

b) preparing a drug layer that essentially involves granulation and size reduction.

An aspect of the present invention provides drug pellets which are further filled into capsules or sachets or compressed into tablets, optionally using carrier.

An aspect of the present invention provides orally administrable controlled release pharmaceutical unit dose compositions comprising more than about 60 wt% of Mesalamine, preferably more than about 80 wt% of Mesalamine, more preferably about 90 wt% of the Mesalamine, optionally with pharmaceutically acceptable excipients.

An aspect of the present invention provides controlled release pharmaceutical compositions wherein the release profile of the Mesalamine is in delayed manner or an extended manner or in a combination of delayed and extended manners.

An aspect of the present invention provides methods of treating colonic and rectal disorders and the treatment of inflammatory bowel diseases, comprising administering to a patient suffering such disorder an effective amount of a composition of the present invention.

Further another aspect of the present invention is extended to the actives such as low to medium dense materials. Preferably extended to low dense materials. Here the density of the material is less than 0.5 g/cc. Bulk density is measured by known processes.

Low dense active materials are such as Mebeverine HCI, Oseltamivir, Etodolac, Dipiridamol, Dexlansoprazole and Fexofenadine etc.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides the dissolution profile of Mesalamine Extended Release Capsule.

DETAILED DESCRIPTION

The present invention relates to pharmaceutical compositions comprising Mesalamine or its pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof for oral administration.

The pharmaceutical formulation comprising an inner core, and active is premixed with hydrophilic polymer which is layered onto the said inner core.

An aspect of the present invention includes a pharmaceutical formulation comprising an inner core, and active ingredient is premixed with hydrophilic polymer which is layered onto the said inner core.

Further aspect includes a pharmaceutical formulation comprising premixed active wherein the active is granulated with hydrophilic polymer and said active polymer to hydrophilic polymer ratio is about 1:99 to 1:20.

Further another aspect of the present invention includes highly drug loaded pharmaceutical compositions comprising pharmaceutical active ingredient for oral administration, wherein said composition is prepared by

a) granulating active ingredient using hydrophilic polymer and milling thereby obtaining premix powder.

b) spraying or layering on the beads.

c) applying the rate controlling coating around the drug layer.

Further aspect of the invention includes a method of preparing highly drug loaded pellets having controlled release profile consists of applying a drug layer to an inert core where in drug layer consist of

a) 60 - 99 wt% of drug, 0.3-10 wt% of hydrophilic matrix polymer, 0 - 65 wt% of filler and 0 - 5 wt% of glidant.

b) Preparing a drug layer that essentially involves granulation and size reduction.

An aspect of the present invention provides drug pellets which are further filled into capsules or compressed into tablets optionally using carrier.

An aspect of the present invention provides orally administrable controlled release pharmaceutical unit dose compositions comprising more than about 60 wt% of Mesalamine, preferably more than about 80 wt% of Mesalamine, more preferably about 90 wt% of the Mesalamine, optionally with pharmaceutically acceptable excipients.

An aspect of the present invention preferably relates to pharmaceutical compositions comprising Mesalamine or its pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof for oral administration.

In the context of the present invention, the terms like "active" or "active agent" or "active ingredient" or "active substance" or "active pharmaceutical ingredient (API)",
"pharmacologically active agent" "pharmaceutical substance" or "drug" or "drug substance" may be used synonymously for Mesalamine or its pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof.

The term "inflammatory bowel disease" includes, but is not limited to, ulcerative colitis and Crohn's disease. Other diseases contemplated for treatment or prevention by the present invention includes non-ulcerative colitis, and carcinomas, polyps, and/or cysts of the colon and/or rectum. All of these diseases fall within the scope of the term "inflammatory bowel disease" as used in this specification, yet the invention does not require the inclusion of each recited member. Thus, for example, the invention may be directed to the treatment of Crohn's disease, to the exclusion of all the other members; or to ulcerative colitis, to the exclusion of all the other members; or to any single disease or condition, or combination of diseases or conditions, to the exclusion of any other single disease or condition, or combinations of diseases or conditions.

By an "effective" amount or a "therapeutically effective amount" of a drug or pharmacologically active agent is meant a nontoxic but sufficient amount of the drug or agent to provide the desired effect, i.e., relieving the symptoms or lessening the discomfort associated with inflammatory GI tract disorders. It is recognized that the effective amount of a drug or pharmacologically active agent will vary depending on the route of administration, the selected compound, and the species to which the drug or pharmacologically active agent is administered. It is also recognized that one of skill in the art will determine appropriate effective amounts by taking into account such factors as metabolism, bioavailability, and other factors that affect plasma levels of a drug or pharmacologically active agent following administration within the unit dose ranges disclosed further herein for different routes of administration.

The term "core" used according to the present invention is particle or material or carrier or base , on which drug is loaded or drug is mixed or drug is partially/fully coated or in contact with it. Core may be of any size.

The term "pellet" used according to the present invention is any functional or non functional coating on core, pellets generally also known as granules or minitablets.

The term "drug layering" is intended to refer to the layering process comprises the deposition of successive layer(s) of drug entities from solution, suspension or dry
powder on nuclei (core) which may be crystals or granules of the same material or inert starter seeds.

The term "controlled release" is intended to refer to any drug containing formulation in which release of the drug is not immediate, i.e., with a "controlled release" formulation, oral administration does not result in immediate release of the drug into an absorption pool. Controlled release include delayed release, sustained (or extended) release, and combinations thereof.

An aspect of the present invention provides controlled release pharmaceutical compositions wherein the release profile of the Mesalamine is in delayed manner or an extended manner or in a combination of delayed and extended manners.

The term "premix" used according to the present invention is physical mixture of drug and hydrophilic polymer, where drug and hydrophilic polymer are in contact.

In certain aspects of the invention, the API is in the form of a premix with one or more hydrophilic polymers. Such premixes are prepared by granulation methods such as wet granulation or dry granulation or slugging or roller compaction or granules are prepared by both processes and mixed together. These granules were then subjected to size reduction to obtain fine premix powder.

The premix so obtained is further be processed, with pharmaceutical acceptable excipients, to formulate desired dosage forms like tablets and capsules, using techniques known in the art. Formulation of the present invention obtained by the following process.

1) A premix of Mesalamine with hydrophilic polymer is obtained by a process
comprising:

i. granulation methods (dry or wet granulation) ii. granules were milled to form fine powder.

2) The above obtained premix powder was layered on to the sugar sphere seeds in a centrifugal granulator to obtain pellets.

3) The prepared pellet material was coated with rate controlling polymer in a fluid bed apparatus.

4) The obtained coated pellets are filled into capsules or sachets or compressed into tablets, optionally using carrier.

The pharmaceutical formulations may further comprise pharmaceutical excipients which include but are not limited to any one or more of diluents, disintegrants, binders, glidants, lubricants, solvents, stabilizers, and colouring agents. Various other functional ingredients, such as buffering agents, solubilizers and surfactants, may also be included to improve or optimize the release and/or stability performance of the formulation system.

Various hydrophilic polymers are used in the formulation, wherein hydrophilic polymers are water-soluble or water-swellable polymers. Preferably hydrophilic polymers are with high molecular weight have been used in hydrophilic matrices, such as hypromellose (hydroxypropyl methylcellulose (HPMC)), hydroxypropylcellulose (HPC), methyl cellulose(MC), polyethylene oxide (PEO), sodium carboxymethylcellulose (Na CMC), sodium alginate, xanthan gum, carbomers, polymers of acrylic acid, methacrylic acid copolymers and hypromellose acetate succinate etc and mixtures thereof. Preferable polymer such as HPMC is used in the present invention.

Various useful diluents include but are not limited to starches, lactose, mannitol, cellulose derivatives and the like or mixtures thereof. Different grades of lactose include but are not limited to lactose monohydrate, lactose anhydrous and others. Different grades of starches include but are not limited to maize starch, potato starch, rice starch, wheat starch, pregelatinized starch and Starch 1500, Starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starch (commercially available as National 78-1551 from Essex Grain Products) and others. Different cellulose compounds that is used include crystalline cellulose and powdered cellulose. Examples of crystalline cellulose products include but are not limited to CEOLUS™ KG801, Avicel™ PH 101, PH102, PH301, PH302 and PH-F20, microcrystalline cellulose. Other useful diluents include but are not limited to carmellose, sugar alcohols such as sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.

Various useful glidants or antisticking agents include but are not limited to talc, silica derivatives, and colloidal silicon dioxide etc or mixtures thereof.

Various rate controlling polymers include but are not limited to cellulose derivatives such as soluble alkyl- or hydroalkyl-cellulose derivatives such as methyl celluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxymethyethyl celluloses, hydroxypropyl methylcelluloses, sodium carboxymethyl celluloses, etc., acidic cellulose derivatives such as cellulose acetate phthalates, cellulose acetate trimellitates and methylhydroxypropylcellulose phthalates, polyvinyl acetate phthalates, etc., insoluble cellulose derivatives such as ethylcelluloses and the like, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrylic acid, polyvinylalcohols, polyvinyl acetates, polyvinylpyrrolidones, polymethacrylates and derivatives thereof (Eudragit™), chitosan and derivatives thereof, shellac and derivatives thereof, waxes, and fat substances or mixtures thereof.

If required, the films may contain additional adjuvants for coating processing such as plasticizers, polishing agents, colorants, pigments, antifoam agents, opacifiers, antisticking agents, and the like.

Various solvents that are useful in processing include but are not limited to water, lower alcohols like methanol, ethanol, and isopropanol, acidified ethanol, acetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, dimethylformamide, and tetrahydrofuran etc or mixtures thereof.

Various useful plasticizers include but are not limited to castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, and triethyl citrate etc or mixtures thereof.

Various useful colorants include but are not limited to Food Yellow No. 5, Food Red No. 2, Food Blue No. 2, and the like, food lake colorants, and iron oxides etc or mixtures thereof. Useful opacifier includes but is not limited to titianium dioxide.

An aspect of the present invention includes the active to be a low to medium dense materials. Preferably low dense materials, more preferably the density of the material is less than 0.5 g/cc. Bulk density is measured by known processes.

Low dense materials such as Mebeverine HCI, Oseltamivir, Etodolac, Dipiridamol, Dexlansoprazole and Fexofenadine etc.

EXAMPLES

Following are the few examples describing the invention but not limiting the invention.

EXAMPLE 1: Mesalamine Extended Release Pellets

* Evaporates during processing Manufacturing process:

a) Hydroxypropyl methylcellulose binder was prepared using mixture of water and Isopropyl alcohol.

b) Active was granulated using above binder and then dried.

c) Dried granules were milled to form fine premix powder.

d) This premix powder was then layered on to the sugar seeds in a centrifugal granulator.

e) The prepared pellet material was dried and then coated with rate controlling polymer in a fluid bed apparatus.

EXAMPLE 2: Capsules prepared from Example 1 is subjected to dissolution testing in 0.05 M pH 7.5 phosphate buffer, 900 ml medium, using USP Apparatus 2 at 100 rpm, for time points as 1, 2, 4, and 8 hours. The dissolution data is tabulated below.

Release profile of the Mesalamine is described in Fig1.

EXAMPLE 3: Mesalamine Extended Release Pellets

Process is same as described in examplel.

Claims:

1. A pharmaceutical formulation comprising an inner core, and active premixed with hydrophilic polymer which is layered onto the said inner core, wherein layering of drug is more than about 80 wt% of pellet.

2. A pharmaceutical formulation according to claim 1 comprising premixed active wherein the active is granulated with hydrophilic polymer and said active and polymer ratio is about 1:99 to 1:20.

3. A pharmaceutical formulation according to proceeding claims active and polymer ratio in the premix is preferably about 1:99 to 1:60 and most preferably about 1:99 to 1:90.

4. A pharmaceutical formulation according to proceeding claims the active is low dense materials such as Mesalamine, Mebeverine HCI, Oseltamivir, Etodolac, Dipiridamol, Dexlansoprazole and Fexofenadine etc.

5. A pharmaceutical formulation according to proceeding claims the preferably active is Mesalamine or its pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof.

6. A pharmaceutical formulation according to claim 1 where in the hydrophilic polymer is selected from hydroxypropyl methylcellulose, hydroxypropylcellulose, methyl cellulose, polyethylene oxide, sodium carboxymethylcellulose, sodium alginate, xanthan gum, carbomers, polymers of acrylic acid, methacrylic acid copolymers and hypromellose acetate succinate etc and mixtures thereof.

7. A pharmaceutical formulation according to claim 1, pellets were further coated with controlled release or enteric polymers.

8. A pharmaceutical formulation according to claim 1, pellets and further with one or more pharmaceutical excipients filled into capsule/sachet or compressed into tablet.

9. A pharmaceutical formulation according to proceeding claims is prepared by the following process.

a) A premix of Mesalamine with hydrophilic polymer is obtained by a process comprising:

i) granulation methods by dry or wet granulation, ii) granules were milled to form fine powder.

b) The above obtained premix powder was layered on to the core to obtain pellets.

c) The prepared pellet material was coated with rate controlling polymer in a fluid bed apparatus.

d) The obtained coated pellets are filled into capsules or sachets or compressed into tablets, optionally using carrier.