WO2009047802A2

WO2009047802A2 - Novel colon targeted modified release bioadhesive formulation of 5-amino salicylic acid or its salts and metabolites thereof

Info

Publication number: WO2009047802A2
Application number: PCT/IN2008/000654
Authority: WO
Inventors: Shirish Kumar Kulkarni; Rajesh Kulkarni; Pandarinath Jadhav; Umesh Badhe; Sushma Gupta
Original assignee: Lupin Limited
Priority date: 2007-10-10
Filing date: 2008-10-08
Publication date: 2009-04-16
Also published as: WO2009047802A3; JP2011500553A

Abstract

The present invention relates to a colon targeted modified release bioadhesive pharmaceutical composition of 5-amino salicylic acid or a pharmaceutically acceptable salt or enantiomer or polymorph or metabolites thereof, optionally one or more hydrophilic or hydrophobic release controlling agent(s) and pharmaceutical acceptable excipient(s), and the process of preparing it.

Description

NOVEL COLON TARGETED MODIFIED RELEASE BIOADHESIVE FORMULATION OF 5-AMINO SALICYLIC ACID OR ITS SALTS AND METABOLITES THEREOF

FIELD OF THE INVENTION

This invention relates to colon targeted modified release bioadhesive pharmaceutical composition of 5-amino salicylic acid or a pharmaceutically acceptable salt or enantiomer or polymorph or metabolites thereof, optionally one or more hydrophilic or hydrophobic release controlling agent(s) and pharmaceutical acceptable excipient(s, and the process of preparing it.

BACKGROUND OF THE INVENTION

Mesalazine, also known as Mesalamine or 5-aminosalicylic acid (5-ASA), is an antiinflammatory drug used to treat inflammation of the digestive tract (Crohn's disease) and mild to moderate ulcerative colitis. Mesalazine is a bowel-specific aminosalicylate drug that is metabolized in the gut and has its predominant actions there in the bowels, thereby having fewer systemic side effects Mesalazine is used in the treatment of Crohn's disease and ulcerative colitis due to its antiinflammatory activity on the intestinal mucosa.

Ulcerative colitis is a chronic inflammatory disease of the colon of unknown etiology. The disease causes inflammations of the mucosa of the colon, extending to the submucosa in severe cases.

The related disease, Crohn's disease, also known as regional enteritis or colitis granulomatosa, is most frequently located in the small intestine (small bowel), especially in the ileum, but may also affect the jejunum and any part of the colon, including the rectum. Generally, the inflammation differs from that of ulcerative colitis by progressing to layers deeper than the mucosa and affecting the epithelium to a lesser degree.

WO 81/02671 discloses a pharmaceutical composition for the treatment of IBD by oral administration. The invention was based on findings that an oral administration of 5-ASA has a useful therapeutic effect on ulcerative colitis, in particular when administered in the form of sustained-release tablets. WO 81/02671 further discloses a method for the preparation of sustained release tablets comprising the steps of preparing granules from 5-ASA and a solution of polyvinylpyrrolidone in isopropanol, evaporating the solvent, coating the granules with ethyl cellulose and compressing the granules into tablets.

U. S.4, 960,765 further discloses a method for the treatment of IBD comprising orally administering an effective amount of a composition consisting essentially of an ester of free 5-ASA in admixture with a pharmaceutically acceptable carrier so as to delay the release of 5-ASA from said composition essentially until it reaches the colon of the patient. Release dependent on pH in the colon is achieved by using a coating resulting in a gradual release of 5-ASA. The particles are coated with ethyl cellulose.

WO 97/23199 discloses a modified release composition for treatment of IBD comprising spherical granules comprising a core of 5-ASA and a spheronisation aid prepared in water as a solvent and coated with a rate limiting barrier material. The composition results in a minor release of 5-ASA in the stomach and the granules may be packed in sachets. These granules are not suitable for use in tablets.

EP 0704 208 A2 describes coating agents and binders for drug coverings soluble in intestinal juice. These comprise copolymers of 10 to 25% by weight methacrylic acid, 40 to 70% by weight methyl acrylate and 20 to 40% by weight methyl methacrylate. As well as monolayer coatings, the description mentions multilayer coating systems. These may be composed of a core, comprising for example a basic or a water-sensitive active ingredient, may have an insulating layer of another coating material, such as cellulose ethers, cellulose esters or a cationic polymethacrylate of the Eudragit.

EP 0704 207 A2 describes thermoplastic materials for drug coverings soluble in intestinal juice. These comprise copolymers of 16 to 40% by weight acrylic or methacrylic acid, 30 to 80% by weight methyl acrylate and 0 to 40% by weight other alkyl esters of acrylic acid and/or methacrylic acid. The minimum film-forming temperature (MFT according to DIN 53 778) is in the range between 0° and 25°C, so that processing is possible at room temperature without adding plasticizer. WO-A-83/00435 discloses compositions which can be administered orally and which are coated with an anionic polymer which is insoluble below pH 7 but is soluble in the colon, wherein capsules or tablets containing 5-aminosalicylic acid, Prednisolone or lndomethacin and provided with a coating containing Eudragit S100 are described. The disclosed drug forms are coated capsules or coated tablets, i.e. monolithic drug forms. Release is said to take place selectively in the colon.

Mesalamine is currently marketed as tablets at the dosage of 400 mg Tablet (Asacol), 250mg & 500mg capsules (Pentasa) and 1200mg Tablet (Lialda) for the treatment of ulcerative colitis. These marketed formulations are not recommended for pediatric use.

While preparing sustained, controlled-release dosage forms of a medicament topically active in the gastrointestinal tract, it is important to ensure a controlled release following administration. The preparation of a sustained, controlled, delayed or anyhow modified release form can be carried out by use of inert matrices, hydrophilic matrices or bioerodable /biodegradable matrices.

A number of formulations based on inert lipophilic matrices have been described: Drug Dev. Ind. Pharm. 13 (6), 1001-1022, (1987) discloses a process making use of varying amounts of colloidal silica as a pore formation element for a lipophilic inert matrix in which the active ingredient is incorporated. WO 95/16451 discloses a composition only formed by a hydrophilic matrix coated with a gastro-resistant film for controlling the dissolution rate of Mesalazine.

PROBLEM AND SOLUTION :

In the treatment of diseases or ailments of the colon or rectum administration of the pharmacologically active agent to the affected site may be required. Orally administrable pharmaceutical compositions however have frequently been found ineffective in this respect as a result of the absorption of the pharmacologically active agent in the digestive tract before the colon or rectum is reached. Consequently, the delivery of pharmacologically active agents to the colon or rectum has conventionally been achieved by rectal administration, by the use of either suppositories or enemas. However, rectal administration generally is less convenient and less acceptable to a patient than oral administration. Further, said rectal administration is not suitable for treating the right side of the colon. In particular, suppositories are only effective in the rectum and enemas rarely reach beyond the left side of the colon.

5-ASA, or mesalamine, has now been established as a common treatment for IBD. Additionally, 5-ASA exhibits an efficacy profile that is less than maximal, reflected in high daily doses (1.5 g/day to 4 g/day), lower response and remission rates, and higher relapse rates, related to its site and mechanism of action and efficiency of delivery to the cells of the distal gut.

The administration of 5-ASA is hampered by some complications associated with its delivery. For example, the compound is unstable in gastric fluids, and its extensive absorption from the small intestine reduces its availability at distal sites in the gut, which are the sites of the therapeutic effect and the preferred sites of delivery, thereby necessitating high doses to be administered. Ideally, the compound should reach the distal gut (ileum and/or colon) in unchanged form (i.e. as the parent compound).

Once the dosage form reaches the distal gut, the compound should be released and subsequently absorbed at a rate consistent with maximal metabolism in the distal gut enterocyte. Therefore, the distal gut enterocyte (i.e., the site of action of the drug) has maximal exposure to the active form of the drug (i.e., the parent compound), thus minimizing the dose required and in addition the systemic exposure to the parent compound and its associated side effects are minimized by maximizing the pre-systemic metabolism (i.e., in the gut enterocyte).

Both extended/sustained release formulations and delayed release formulations have been developed, with the intent of limiting 5-ASA release in the upper gut and concentrating its release in the distal gut.

For example, a sustained release formulation (PENTASA^®) has been approved and used for many years. PENTASA^® releases 5-ASA continuously, with approximately 50% released in the small intestine and 50% available for release in the large intestine, and in its approved label form reports 20-30% systemic absorption. This absorption reflects the proximal release and absorption characteristics of this formulation in addition to any low level absorption from the distal gut, as in the distal gut, 5-ASA is incompletely released from PENTASA^® and poorly absorbed.

Significant effort has been spent on identifying ways to slow down the Gl transit of the active. The advantages of controlled release products are well known in the pharmaceutical field as these dosage forms are able to maintain the medicament at the required site of action over a comparatively longer period of time while increasing patient compliance by reducing the number of administrations necessary to achieve the same.

Marketed preparation like Asacol 400 mg Tablets (Procter & Gamble Pharmaceuticals) is a delayed release tablet coated with acrylic based resin, Eudragit S (Methacrylic acid copolymer B, NF) that dissolves at pH 7 or more. However certain disadvantages associated with Asacol are: it is not recommended for pediatric use, does not offer sustained release of drug, multiple dosing per day required, inconvenient to patient, Ulcerative Colitis patients (Jacbsen B et al: Digestive Diseases and Sciences, 1993, 38(11 ), 1989-1993) .who do not have Gl pH more than 7 resulting in incomplete or no dissolution of coating. Because of it's coating, all or none of the drug gets deposited in colon. It has been reported that some patients have excreted intact tablets in unchanged form. (Watts P et al Drug Development and Industrial Pharmacy. 1997, 23(9), 893-913.) Also Asacol does not offer bioadhesion of formulation, hence some of the drug may not get in close proximity of site of action (colonic mucosa).

The pack insert of Pentasa^® 250 mg & 500 mg CR Capsules (Shire Inc.) offers ethyl cellulose coated controlled release formulation (pellets) of Mesalamine designed to release therapeutic quantities of Mesalamine throughout gastrointestinal tract. However certain disadvantages associated with Pentasa are: it is not recommended for pediatric use, does not offer delayed release of drug, multiple dosing per day required, inconvenient to patient, releases drug in upper Gl sites where it gets variably absorbed (20-30%)and less drug is available for its site of action (colon), due to this, a larger dose (4 g) per day is required. Lialda tablet, 1200 mg (Shire Inc) is a controlled-release tablet formulation containing 1200 mg of 5-amino-salicylic acid in an inner lipophilic matrix and an outer hydrophilic matrix in which the lipophilic matrix is dispersed. The tablet is 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. However certain disadvantages associated with Lialda are: it is not recommended for pediatric use, it has lipophilic matrix which does not offer uniform release pattern, does not offer bioadhesion of formulation, hence some of the drug may not get in close proximity of site of action (colonic mucosa) and some UC patients do not have Gl pH more than 7 resulting in incomplete or no dissolution of coating. Because of no dissolution of coating, the drug may not get released in colon.

We have surprisingly found that the formulation or dosage form materials with are suitable to over come demerits of the above mentioned dosage forms bioadhesive characteristics, bioadhesiveness being defined as the ability of a material (synthetic or biologic) to adhere to biologic tissues for a prolonged period of time. The purpose of the bioadhesive dosage form is to keep a pharmaceutical dosage form in the required site of action for an extended period of time, ensuring release of effective amounts of the active ingredient.

Considering the properties of the gastrointestinal tract, the following characteristics are sought after in the system: for effective retention in the colon to suit the clinical demand; convenient intake (dosing) to facilitate patient compliance; sufficient drug loading capacity; sustained drug release profile for more than 8 hours; no release of drug in upper Gl tract, wherein coating dissolves in gastric juice, full degradation and evacuation of the system once the drug release is over; and no other local adverse effects.

The modified release profile of the formulation can extend from 8 -36 hours preferably 10 - 36 hours and most preferably 12-36 hours. In one of the embodiment involves preparation of novel colon targeted modified release matrix formulation, where in the composition is characterized by release profile of 8-36 hours and a dissolution profile:

2 hours: about more than 12% of drug is released. 4 hours: More than about 25% of drug is released.

8 hours: More than about 55% of drug is released.

12 hours: More than about 75% of drug is released.

16 hours: More than about 90% of drug is released.

With respect to the above reasons, to maximize the therapeutic efficacy of 5-ASA its salts and its metabolites, novel pharmaceutical formulations are provided herein and include, for example, modified release tablets, which adheres to the colonic mucosa reducing the chances for expulsion of the dosage form from the colon thus having increased residence time and prolonging contact thereby improving the efficacy of locally acting agents which improves patient compliance.

OBJECTIVE OF THE INVENTION:

This invention has mainly been attempted to avoid release in the stomach by application of a coating resistant to gastric juice, or to improve the delaying of release by combining coating materials.

The invention is therefore based on the objective of providing a pharmaceutical composition for slow release of active ingredient in the colon, which substantially over come the disadvantages mentioned above and which can be produced at a reasonable cost and with high reproducibility.

Another objective of the present invention is to provide a pharmaceutical composition, which permits slow release of active ingredient in the colon even when the active ingredient content is high and the excipient content is only low.

This objective is achieved according to the invention by a pharmaceutical composition for slow release of active ingredient in the gastrointestinal tract, comprising a extended release matrix core coated with coating comprising a polymer insoluble in gastric juices.

The composition of the invention is particularly suitable for targeted active ingredient release in the colon. However, in some cases it release of active ingredient may start even in the stomach, which can likewise be achieved with the composition of the invention. For example, it is desired in a few cases on treatment of Crohn's disease at a high location with 5-aminosalicylic acid that active ingredient be released in the lower part of the stomach in order to achieve an optimal effect in the short duodenal tract.

The composition of the invention has the advantage that the release of active ingredient takes place very substantially in a pH-independent manner and thus effects of biological differences between individual patients can be avoided almost completely.

The release delaying in the composition of the invention takes place due to a combination of at least three measures, each of which contributes to delaying the release of active ingredient, namely by mixing the active ingredient with a polymer insoluble in gastric juice, through the small pore size, which is related to a corresponding compaction of the core material, and by coating with a polymer insoluble in gastric juice.

Another object of the invention is to provide a pharmaceutical composition comprising Mesalamine administered once daily to increase patient compliance for treatment of Ulcerative colitis.

Yet another object of the present invention is to provide a pharmaceutical formulation comprising 5-ASA or a pharmaceutically acceptable salt or enantiomer or polymorph or metabolites having an in vitro dissolution profile, wherein at least about 80% of Mesalmine is released on or after 12 hours.

Yet another object of the invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of 5-ASA or a pharmaceutically acceptable salt or enantiomer or polymorph or metabolites thereof, pharmaceutically acceptable excipient(s), optionally one or more controlled release agent(s), wherein the composition is formulated to increase the residence time of 5-ASA or a pharmaceutically acceptable salt or enantiomer or polymorph or metabolites thereof in the gastrointestinal tract having an adhesive strength, measured as a force of detachment, of atleast 10OmN when measured using advanced force gauge equipment (manufactured by Mecmesin, West Sussex, England).

DETAIL DESCRIPTION OF THE INVENTION:

This invention relates to modified release bioadhesive pharmaceutical composition of 5- amino salicylic acid or a pharmaceutically acceptable salt or enantiomer or polymorph or metabolites thereof, optionally one or more hydrophilic or hydrophobic release controlling agent(s) and pharmaceutical acceptable excipients, and the process of preparing it.

"Therapeutically effective amount" means that the amount of active agent, which halts or reduces the progress of the condition being treated or which otherwise completely or partly cures or acts palliatively on the condition. A person skilled in the art can easily determine such an amount by routine experimentation and without an undue burden.

The therapeutically active agents comprising of but not limited to anti-infectives, penicillins, cephalosporins, cyclines, beta-lactamase inhibitors, aminosides, quinolones, nitroimidazoles, sulfamides, antihistaminics, antiallergics, anesthetics, steroidal or nonsteroidal anti-inflammatory, analgesics with local or systemic effect, antispasmodics, anticancers, diuretics, beta-blockers, antihypertensives, antianginals, antiarrhythmics, vasodilators, bradycardic agents, calcium inhibitors, sedatives, cardiotonics, antifungals, antiulceratives, vasotonics, vasoprotectants, anti-ischemics, antiemetics, anticoagulants, antithrombotics, immunosuppressants, immunomodulators, antivirals, antiritrovirals, antidiabetics, hypolipidemics, agents for combating obesity, anticonvulsants, hypnotics, antiparkinsonians, antimigraines, neuroleptics, anxiolytics, antidepressants, psychostimulants, agents for promoting memory, bronchodilators, antitussives, agents for combating osteoporosis, peptides, hormones, proteins, steroids, enzymes, enzyme inhibitors, and melatoninergic agonists or antagonists or combinations thereof "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.

The term " modified release" formulation or dosage form or composition includes pharmaceutical preparations that achieve a desired release of the drug from the formulation. A modified-release formulation can be designed to modify the manner in which the active ingredient is exposed to the desired target. For example, a modified-release formulation can be designed to focus the delivery of the active agent entirely in the distal large intestine, beginning at the cecum, and continuing through the ascending, transverse, and descending colon, and ending in the sigmoid colon. Alternatively, for example, a modified-release composition can be designed to focus the delivery of the drug in the proximal small intestine, beginning at the duodenum and ending at the ileum. In still other examples, the modified- release formulations can be designed to begin releasing active agent in the jejunum and end their release in the transverse colon. The possibilities and combinations are numerous, and are clearly not limited to these examples.

The term "modified-release" encompasses "extended-release" and "delayed-release" formulations, as well as formulations having both extended-release and delayed-release characteristics. An "extended-release" formulation can extend the period over which drug is released or targeted to the desired site. A "delayed-release" formulation can be designed to delay the release of the pharmaceutically active compound for a specified period. Such formulations are referred to herein as "delayed-release" or "delayed-onset" formulations or dosage forms. Modified-release formulations of the present invention include those that exhibit both a delayed- and extended-release, e.g., formulations that only begin releasing after a fixed period of time or after a physicochemical change has occurred, for example, then continue releasing over an extended period. The modified release may also include pulasatile release, burst release and the like

By "pharmaceutically acceptable" is meant a carrier comprised of a material that is not biologically or otherwise undesirable. "Bioadhesion" is defined as the ability of a material to adhere to a biological tissue for an extended period of time. Bioadhesion over comes the problem of inadequate residence time resulting from stomach emptying and intestinal peristalsis, and from displacement by ciliary movement. For sufficient bioadhesion to occur, an intimate contact must exist between the bioadhesive and the receptor tissue, the bioadhesive must penetrate into the crevice of the tissue surface and/or mucus, and mechanical, electrostatic, or chemical bonds must form. Bioadhesive properties of polymers are affected by both the nature of the polymer and by the nature of the surrounding media. The term Bioadhesive and mucoadhesive can be used interchangeably.

Bioadhesion is achieved with polymers having affinity for colonic mucosa selected from a group comprising polycarbophils, carbomers, lectins, pectin, zein, modified zein, casein, gelatin, gluten, serum albumin, collagen, chitosan, oligosaccharides and polysaccharides such as cellulose their derivatives such as methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxybutylmethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, carboxymethyl cellulose, dextrans, polysaccharide, gellan, carrageenan; hyaluronic acid, polyhyaluronic acid, alginic acid, sodium alginate; gums like xanthan gum, guar gum, gum arabic locust bean gum; polyvinyl acetate, polyvinylalcohol, povidone/polyethylene oxide, acrylic and methacrylic acid their copolymers, polyalkylene oxides, polyvinyl esters, , polyvinylpyrrolidone, polyglycolides, polyurethanes, polystyrene, polymers of acrylic and methacrylic esters, polylactides, poly(butyric acid), poly(valeric acid), polyanhydrides, polyorthoesters, poly(fumaric acid), poly(maleic acid), mixtures thereof and the like. Bioadhesion is provided for a period ranging from about 0.5 hours to about 36 hours.

For purposes of this invention, residence time is the time required for a pharmaceutical dosage form to transit through the stomach to the rectum i.e. the pharmaceutical dosage forms of the invention may have an increased retention time in the stomach and/or small and/or large intestine and /or colon , or in the area of the gastrointestinal tract where the drug is released from the pharmaceutical dosage form. For example, pharmaceutical dosage forms of the invention can be retained in the small intestine (or one or two portions thereof, selected from the duodenum, the jejunum and the ileum). These pharmaceutical dosage forms as a whole, may include a bioadhesive polymeric coating that is applied to at least one surface of the dosage form.

In a preferred embodiment of the present invention the increase in residence time of Mesalamine formulation in the colonic mucosa is achieved by bioadhesion wherein bioadhesion is achieved using polymers having affinity for colonic mucosa. Examples of mucoadhesives for use in the embodiments disclosed herein include, but are not limited to, natural, semisynthetic and synthetic polymers.

Natural polymers include but are not limited to proteins (e.g., hydrophilic proteins), such as pectin, zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, chitosan, oligosaccharides and polysaccharides such as cellulose, dextrans, tamarind seed polysaccharide, gellan, carrageenan, xanthan gum, gum Arabic; hyaluronic acid, polyhyaluronic acid, alginic acid, sodium alginate.

When the bioadhesive polymer is a synthetic polymer, the synthetic polymer is typically selected from but are not limited to polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes, polystyrene, polymers of acrylic and methacrylic esters, polylactides, poly(butyric acid), poly(valeric acid), poly(lactide-co-glycolide), polyanhydrides, polyorthoesters, poly(fumaric acid), poly(maleic acid), and blends and copolymers or mixtures thereof.

Other polymers suitable for use in the invention include, but are not limited to, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxybutylmethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, cellulose sulfate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly (ethylene terephthalate), polyvinyl acetate), polyvinyl chloride, polystyrene, polyvinyl pyrrolidone, and polyvinylphenol. Polylactides, polyglycolides and copolymers thereof, poly(ethylene terephthalate), poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), poly[lactide-co- glycolide], polyanhydrides (e.g., poly(adipic anhydride)), polyorthoesters, blends and copolymers thereof.

Another group of polymers suitable for use as bioadhesive polymers but not necessarily limited to polymers having a hydrophobic backbone with at least one hydrophobic group pendant from the backbone. Suitable hydrophobic groups are groups that are generally non- polar. Examples of such hydrophobic groups include alkyl, alkenyl and alkynyl groups. Preferably, the hydrophobic groups are selected to not interfere and instead to enhance the bioadhesiveness of the polymers.

A further group of polymers suitable for use as bioadhesive polymers but not necessarily limited to polymers having a hydrophobic backbone with at least one hydrophilic group pendant from the backbone. Suitable hydrophilic groups include groups that are capable of hydrogen bonding or electrostatically bonding to another functional group. Example of such hydrophilic groups include negatively charged groups such as carboxylic acids, sulfonic acids and phosponic acids, positively charged groups such as (protonated) amines and neutral, polar groups such as amides and imines.

Preferably, the hydrophilic groups are selected to not to interfere and instead to enhance the bioadhesiveness of the polymers. In embodiments of the present invention, a pharmaceutical composition comprises an active agent and atleast one swellable polymer.

Swellable polymers include, but are not limited to, a crosslinked poly(acrylic acid), a poly(alkylene oxide), a polyvinyl alcohol, a polyvinyl pyrrolidone a polyurethane hydrogel, a maleic anhydride polymer, such as a maleic anhydride copolymer, a cellulose polymer, a polysaccharide, starch, and starch based polymers. Polymers can be modified by increasing the number of carboxylic groups accessible during biodegradation, or on the polymer surface. The polymers can also be modified by binding amino groups to the polymer. The polymers can be modified using any of a number of different coupling chemistry available in the art to covalently attach ligand molecules with bioadhesive properties to the surface-exposed molecules of the polymeric microspheres.

Pharmaceutically acceptable excipients include but are not limited to binders, diluents, lubricants, glidants and surface-active agents.

The amount of additive employed will depend upon how much active agent is to be used. One excipient can perform more than one function.

Binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone and the like and mixtures thereof. Fillers or diluents, which include, but are not limited to confectioner's sugar, compressible¹ sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate, and the like can be used.

Lubricants may be selected from, but are not limited to, those conventionally known in the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc. Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of ordinary skill in the art.

The pharmaceutical formulation according to the present invention include but is not limited to 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.

Matrix-type dosage form comprises an aminosalicylate active agent its salts or metabolites, mixed with either water-soluble, e.g., hydrophilic polymers, or water-insoluble, e.g., hydrophobic polymers. Generally, the properties of the polymer used in a modified-release dosage form will affect the mechanism of release. For example, the release of the active agent from a dosage form containing a hydrophilic polymer can proceed via both surface diffusion and/or erosion. Mechanisms of release from pharmaceutical systems are well known to those skilled in the art. Matrix-type systems can also be monolithic or multiunit, and can be coated with water-soluble and/or water-insoluble polymeric membranes.

Matrix formulations of the present invention can be prepared by using, for example, direct compression or wet granulation or any conventional method known in the prior art. A functional coating, as noted above, can then be applied in accordance with the invention. Additionally, a barrier or sealant coat can be applied over a matrix tablet core prior to application of a functional coating.

In a matrix-based dosage form in accordance with the present invention, the drug and/or pro-drug or metabolites and optionally pharmaceutically acceptable excipient(s) are dispersed within a polymeric matrix, which typically comprises one or more water-soluble polymers and/or one or more water-insoluble polymers. The drug can be released from the dosage form by diffusion and/or erosion.

Suitable water-soluble polymers include, but are not limited to, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose.hydroxypropylcellulose.hydroxypropylmethylcellulose, or polyethylene glycol, and/or mixtures thereof and the like.

Suitable water-insoluble polymers also include, but are not limited to, ethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), and poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), poly (ethylene), poly (ethylene) low density, poly (ethylene) high density, poly (ethylene oxide), poly (ethylene terephthalate), poly (vinyl isobutyl ether), poly (vinyl acetate), poly (vinyl chloride) or polyurethane, and/or mixtures thereof and the like.

hydrophilic polymer is selected from the group comprising carbohydrates like celluloses their derivatives such as ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose; gums like xanthan gum, guar gum, locust bean gum; alginates; carbomer; poly vinylacetatae, polyvinylalcohol, povidone/polyethylene oxide, acrylic and methacrylic acid copolymers and mixtures thereof.

the rate controlled release agent is selected from a group comprising cellulose and cellulose derivatives, waxes, carbomers, polyalkylene polyols, polycarbophils, methacrylic acid derivatives, gelatins, polyethylene oxides, polyvinyl pyrrolidone, ethylcellulose, cellulose acetate, vinyl acetate/vinyl chloride copolymers, acrylate/methacrylate copolymers, hydroxypropyl methylcellulose, carageenan, alginic acid and salts thereof, hydroxyethyl cellulose, hydroxypropyl cellulose, karaya gum, acacia gum, tragacanth gum, locust bean gum, guar gum, sodium carboxymethyl cellulose, methyl cellulose, beeswax, carnauba wax, cetyl alcohol, hydrogenated vegetable oils, and the mixtures thereof.

Hydrophilic polymer is selected from the group comprising carbohydrates like celluloses their derivatives such as ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose; gums like xanthan gum, guar gum, locust bean gum; alginates; carbomer; poly vinylacetatae, polyvinylalcohol, povidone/polyethylene oxide, acrylic and methacrylic acid copolymers and mixtures thereof

The amounts and types of polymers, and the ratio of water-soluble polymers to water- insoluble polymers in the inventive formulations are generally selected to achieve a desired release profile of the drug or pro-drug or metabolites or its salts, as described below. Preferably amino methacrylate co-polymers such as Eudragit RS and Eudragit RL (Rohm Pharma) are suitable for use in the modified-release formulations of the present invention. These polymers are insoluble in pure water, dilute acids, buffer solutions, or digestive fluids over the entire physiological pH range. The polymers swell in water and digestive fluids independent of pH. In the swollen state they are then permeable to water and dissolved actives. The permeability of the polymers depends on the ratio of ethylacrylate (EA), methyl methacrylate (MMA), and trimethylammonioethyl methacrylate chloride (TAMCI) groups in the polymer. Those polymers having EA:MMA:TAMCI ratios of 1 :2:0.2 (Eudragit RL) are more permeable than those with ratios of 1 :2:0.1 (Eudragit RS). Polymers of Eudragit RL are insoluble polymers of high permeability. Polymers of Eudragit RS are insoluble films of low permeability.

The amino methacrylate co-polymers can be combined in any desired ratio. For example, a ratio of Eudragit RS.Eudragit RL (90:10) can be used. The ratios can furthermore be adjusted to provide a delay in release of the drug or pro-drug. For example, the ratio of Eudragit RS:Eudragit RL can be about 100:0 to about 80:20, about 100:0 to about 90:10, or any ratio in between.

The amino methacrylate co-polymers can be combined with the methacrylic acid co- polymers within the polymeric material in order to achieve the desired delay in release of the drug or pro-drug. Ratios of ammonio methacrylate co-polymer (e.g., Eudragit RS) to methacrylic acid co-polymer in the range of about 99:1 to about 20:80 can be used. The two types of polymers can also be combined into the same polymeric material, or provided as separate coats that are applied to the core.

In addition to the Eudragit polymers described above, a number of other such copolymers can be used to delay drug release. These include methacrylate ester co-polymers (e.g., Eudragit NE 30D). Further information on the Eudragit polymers can be found in "Chemistry and Application Properties of Polymethacrylate Coating Systems," in Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (ed. James McGinity, Marcel Dekker Inc., New York, pg 109-114). Methyl acrylate copolymers and ammoniomethacrylate copolymers under the tradename Eudragit.RTM. RS/RL/NE are particularly preferred. As functional groups, these polymers have ester groups (Eudragit.RTM. NE) or ammonium groups (Eudragit.RTM. RL/RS). Poly(ethyl acrylate, methyl methacrylate) and poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) are preferred. These polymers are obtainable, for example, as poly(ethyl acrylate, methyl methacrylate) 2:1 in 40% strength aqueous dispersion as Eudragit.RTM. NE 40 D and as poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 :2:0.1 in 12.5% strength isopropanolic solution as Eudragit.RTM. RS 12.5 and in the composition 1 :2:0.2 as Eudragit.RTM. RL 12.5.

The formulations of the present invention are intended to include formulations that are generic to treating all forms of IBD, and thus target their contents to both the distal small intestine and the large intestine. Other formulations within the scope of the invention include those that are more specifically designed for treating a specific disease. For example, a formulation for treating ulcerative colitis can be designed to deliver its contents entirely to the colon.

The formulations of the present invention can exist as multi-unit or single-unit formulations. The term "multi-unit" as used herein means a plurality of discrete or aggregated particles, beads, pellets, granules, tablets, or mixtures thereof, for example, without regard to their size, shape, or morphology. Single-unit formulations include, for example, tablets, caplets, and pills.

The methods and formulations of the present invention are intended to encompass all possible combinations of components that exhibit modified-release and extended-release properties. For example, a formulation and/or method of the invention can contain components that exhibit extended-release and modified-release properties, or both delayed- release and modified-release properties, or a combination of all three properties. The modified release once daily composition comprises 200-2400 mg of 5-Amino salicylic acid or a pharmaceutically acceptable salt or enantiomer or polymorph or metabolites are selected from the group consisting of Mesalamine, Balsalazide, Olsalazine , sulfasalazine.

The modifications in the rates of release, such as to create a delay or extension in release, can be achieved in any number of ways. Mechanisms can be dependent or independent of local pH in the intestine, and can also rely on local enzymatic activity to achieve the desired effect.

The present invention is not limited to any of the particular azo-bis compounds (5-ASA) described herein. The present invention extends to the use and formulation of any azo-bis compound that yields either 4-ASA and/or 5-ASA. Modified-release formulations of any such azo-bis compound are specifically contemplated. Thus, as used herein in association with the present invention, the term "drug" refers to compounds useful in treating IBD or other diseases according to this invention, including but not limited to sulphasalazine, 5-ASA, and/or 4-ASA; the term "pro-drug" refers to any compound that yields such drugs, including but not limited to olsalazine, balsalazine, and/or any other azo-containing compound that yields such drug or drugs.

These coating layers comprises one or more excipients selected from the group comprising coating agents, opacifiers, taste-masking agents, fillers, polishing agents, coloring agents, antitacking agents and the like.

Pharmaceutical dosage forms of the invention can be coated by a wide variety of methods. Suitable methods include compression coating, coating in a fluidized bed or a pan and hot melt (extrusion) coating. Such methods are well known to those skilled in the art.

Non-permeable coatings of insoluble polymers, e.g., cellulose acetate, ethylcellulose, can be used as enteric coatings for delayed/modified release (DR/MR) by inclusion of soluble pore formers in the coating, e.g., PEG, PVA, sugars, salts, detergents, triethyl citrate, triacetin, etc. Also, coatings of polymers that are susceptible to enzymatic cleavage by colonic bacteria are another means of ensuring release to distal ileum and ascending colon. Materials such as calcium pectinate can be applied as coatings to dosage form and multiparticulates and disintegrate in the lower gastrointestinal tract, due to bacterial action. Calcium pectinate capsules for encapsulation of bioadhesive multiparticulates are also available.

The pharmaceutical dosage form of the invention can optionally have one or more coatings such as film coating, sugar coating, enteric coating, bioadhesive coating and other coatings known in the art. These coatings help pharmaceutical formulations to release the drug at the required site of action. In one example, the additional coating prevents the dosage from contacting the stomach contents. In another example, the additional coating remains intact until reaching the small intestine particularly colon specific (e.g., an enteric coating).

In a preferred embodiment, the process of making the pharmaceutical formulation of the invention comprises as described below:

- Granulation and Slugging of Active ingredient

- Addition of mixed excipients followed by granulation, Lubrication and Compression of granules to form tablet core

- Seal Coating followed by enteric coating

Compaction of the blend into coprimate may be carried out using a slugging technique or roller compaction. The milling of the granules may be carried out according to conventional milling methods.

In one of the embodiment of the present invention involves preparation of modified release matrix formulation, which comprises a therapeutically effective amount of Balsalazide or a pharmaceutically acceptable salt or enantiomer or polymorph thereof, optionally one or more hydrophilic or hydrophobic release controlling agent(s) and pharmaceutical acceptable excipient(s) thereof, wherein the composition is coated with coating comprises anionic copolymer of methacrylic acid and methacrylic acid ester soluble in gastric juice and in intestinal juice, which release maximum amount in the colon, wherein the composition is formulated to increase the residence time in the colon which release maximum amount of the drug over the period of about 10 to about 36 hours in the colon, wherein the composition is formulated to increase the residence time in the colon where in the dissolution profile shows more than 90% of drug released after 16 hours

In one of the embodiment of the present invention involves preparation of modified release matrix formulation, which comprises a therapeutically effective amount of Mesalamine or prodrug or a pharmaceutically acceptable salt or enantiomer or polymorph thereof, optionally one or more hydrophilic or hydrophobic release controlling agent(s) and pharmaceutical acceptable excipient(s) thereof, wherein the composition is coated with coating comprises anionic copolymer of methacrylic acid and methacrylic acid ester soluble in gastric juice and in intestinal juice, which release maximum amount in the colon, wherein the composition is formulated to increase the residence time in the colon which release maximum amount of the drug over the period of about 10 to about 36 hours in the colon, wherein the composition is formulated to increase the residence time in the colon where in the dissolution profile shows more than 90% of drug released after 16 hours

DISSOLUTION

The formulations of the invention have a prolonged in vitro release rate. The in vitro test used to measure release rate of the active agent from a formulation of the invention was as follows. The apparatus contained a paddle and rotated at a speed of 50 rpm. The tablet formulation was placed in the apparatus and dissolution was periodically measured. The in vitro dissolution studies are shown below:

In a preferred embodiment of the present invention in order to improve the patient compliance and target the formulation in colon, a bioadhesive, controlled release once daily (600 mg) of 5-Amino salicylic acid or a pharmaceutically acceptable salt or enantiomer or polymorph or metabolites thereof is explored.

The foregoing examples are illustrative embodiments of the invention and are merely exemplary. A person skilled in the art may make variations and modifications without deviating from the spirit and scope of the invention. All such modifications and variations are intended to be included within the scope of the invention.

EXAMPLES: Example 1 :

Procedure:

Granulation of Mesalmine

Sift Mesalamine through #20 and kept aside. Granulate with a solution of Povidone dissolved in lsopropyl alcohol. The dried granules were lubricated.

Preparation of Excipient Blend

Mix Xanthan Gum, Sodium Alginate, Hypromellose (CR premium) and Calcium sulphate dihydrate were passed through desired sieve and kept aside.

Granulation, Lubrication and Compression: Mix granules of Mesalamine and excipient blend and granulate with a solution. The prepared granules were dried and compressed into tablets. The compressed tablet core were coated with the seal coating solution and finally coated with enteric coating material .

Dissolution data (pH6.5 ,6.8, 7.0 and ^pH 7.2 Phosphate Buffer)

EXAMPLE 2:

Procedure:

Granulation of Balsalazide

Sift Balsalazide through #20 and kept aside. Granulate with a solution of Povidone dissolved in lsopropyl alcohol. The dried granules were lubricated.

Preparation of Excipient Blend

Mix Xanthan Gum, Sodium Alginate, Hypromellose and Calcium sulphate dihydrate were passed through desired sieve and kept aside.

Granulation, Lubrication and Compression: Mix granules of Balsalazide and excipient blend and granulate with granulation solution. The prepared granules were dried and compressed into tablets. The compressed tablet core were coated with the seal coating solution and finally coated with enteric coating material

EXAMPLE 3:

Procedure:

Granulation of Olsalazine

Sift Olsalazine through #20 and kept aside. Granulate with granulation solution of Povidone dissolved in lsopropyl alcohol. The dried granules were lubricated and slugging and deslugging were performed to get granules of active.

Preparation of Excipient Blend Mix Xanthan Gum, Sodium Alginate, Hypromellose and Calcium sulphate dihydrate were passed through desired sieve and kept aside.

Granulation, Lubrication and Compression:

Mix granules of Olsalazine and excipient blend and granulate with granulation solution. The prepared granules were dried and compressed into tablets. The compressed tablet core were coated with the seal coating solution and finally coated with enteric coating material

EXAMPLE 4:

DETERMINATION OF BIOADHESION

Bioadhesion was determined by tensometric method. For the determination, an advanced force gauge equipment (mfg. by Mecmesin, West Sussex, England) was used. Freshly excised Sheep intestinal tissue was taken and stored in a Tyrode solution at 4°C until used for the experiment. The tissue was cut into pieces (3x4 cm) and mounted on the glass slide and tightened with a thread. 0.5ml Phosphate buffered saline (PBS) was placed on the tissue. The bioadhesive tablet of example 1 was placed on this tissue and another 0.5 ml PBS was placed on the tablet. A glass slide with a 10 g weight was placed on the tablet and it was allowed to hydrate for 10min., 30 min., 60 min., and 840 min. At the specific time interval, the hydrated tablet along with slide was mounted on the stage of the bioadhesion apparatus. Probe was then lowered at fixed speed of 0.2 mm/sec, and upper slide was attached to the hook ofjhe probe by means of a thread. The peak detachment force was considered as the bioadhesive force. The force required to separate the tablet from biological substrate was recorded in mN.

Observation:

Bioadhesion Measurement

Hydration time (min)

Other than in the examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instance by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon desired properties sought to be obtained herein. Notwithstanding that the numerical ranges and parameters setting forth the broad scope are approximations, the numerical values set forth in the specific examples are reported as precisely as possible.

The invention is further illustrated by reference to the following examples. It will be apparent to those skilled in the art that many modifications, both to the materials and methods, can be practiced without departing from the purpose and scope of the invention

Example: 5

In vivo study was conducted to evaluate once daily oral mesalamine formulation in treatment of patients suffering from mild to moderate Ulcerative Colitis.

Method

In a multicentre, randomized, open label, comparative, parallel study, once daily oral formulation of mesalamine was administered as 2 tablets of 1200 mg and 6 tablets of 400 mg for a period of 8 weeks in patients with mild to moderate Ulcerative Colitis. Efficacy was assessed by measuring the UC-Disease Activity Index (UC-DAI). The parameters included are: Physician global assessment, Stool frequency, Rectal bleeding and Sigmoidoscopic findings.

The total scoring was summarized as

Percentage of patients responded to Mesalamine therapy:

Thus Meslamine when given orally in a dose of 2 tablets of 1200 mg and 6 tablets of 400 mg for a period of 8 weeks in patients with mild to moderate Ulcerative Colitis, maximum patients were reported improvement in terms of disease activity with Meslamine therapy. Some patients experienced remission while rest ware maintained with therapy. None of the patients reported worsening of disease.

Claims

1. A colon targeted bioadhesive modified release formulation, comprising a therapeutically active agents or a pharmaceutically acceptable salt or enantiomer or polymorph or metabolites thereof, and rate controlled release agent / material, wherein the composition is optionally coated with coating comprising anionic copolymer of methacrylic acid and methacrylic acid ester soluble in gastric juice, which release the drug over a period of about 10 to about 36 hours in the colon.

2. A colon targeted bioadhesive modified release formulation, comprising a therapeutically effective amount of 5-amino salicylic acid or a pharmaceutically acceptable salt or enantiomer or polymorph or metabolites thereof, and rate controlled release agent / material, wherein the composition is further coated with coating comprising anionic copolymer of methacrylic acid and methacrylic acid ester soluble in gastric juice, which release the drug over a period of about 12 to about 36 hours in the colon, wherein the composition is formulated to increase the residence time in the colon.

3. A pharmaceutical composition according to claim 1 , wherein rate controlled release agent is selected from the group comprising hydrophilic polymer or hydrophobic polymer or combinations thereof.

4. A pharmaceutical composition as in claim 3, wherein the rate controlled release agent is selected from a group comprising cellulose and cellulose derivatives, waxes, carbomers, polyalkylene polyols, polycarbophils, methacrylic acid derivatives, gelatins, polyethylene oxides, polyvinyl pyrrolidone, ethylcellulose, cellulose acetate, vinyl acetate/vinyl chloride copolymers, acrylate/methacrylate copolymers, hydroxypropyl methylcellulose, carageenan, alginic acid and salts thereof, hydroxyethyl cellulose, hydroxypropyl cellulose, karaya gum, acacia gum, tragacanth gum, locust bean gum, guar gum, sodium carboxymethyl cellulose, methyl cellulose, beeswax, carnauba wax, cetyl alcohol, hydrogenated vegetable oils, and the mixtures thereof.

5. A pharmaceutical composition according to claim 3, wherein hydrophilic polymer is selected from the group comprising carbohydrates like celluloses their derivatives such as ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose; gums like xanthan gum, guar gum, locust bean gum; alginates; carbomer; poly vinylacetatae, polyvinylalcohol, povidone/polyethylene oxide, acrylic and methacrylic acid copolymers and mixtures thereof.

6. A pharmaceutical composition according to claim 3, wherein hydrophobic release component is selected from the group comprising beeswax; fatty acids; long chain fatty alcohols, such as cetyl alcohol, myristyl alcohol, stearyl alcohol; glycerides such as glyceryl esters of fatty acids like glyceryl monostearate, glyceryl distearate, glyceryl esters of hydrogenated castor oil, mineral oil, hydrogenated vegetable oil, acetylated glycerides; ethyl cellulose, stearic acid, paraffin, camauba wax, talc; stearate salts such as calcium, magnesium, zinc and mixtures thereof.

7. A novel modified release pharmaceutical composition as in claim 1 , wherein 5-Amino salicylic acid or a pharmaceutically acceptable salt or enantiomer or polymorph or metabolites are selected from the group consisting of Mesalamine, Balsalazide, Olsalazine, sulfasalazine.

8. A modified release pharmaceutical composition according to claim 1 or 2 , wherein the increase in residence time of mesalamine formulation in the gastrointestinal tract is achieved by bioadhesion.

9. A modified release pharmaceutical composition according to claim 1 or 2 wherein bioadhesion is provided for a period ranging from about 0.5 hours to about 36 hours.

10. A modified release pharmaceutical composition according to claim 1 or 2 is a once- daily dosage form comprising 200 to 2400mg of Mesalamine or a pharmaceutically acceptable salt or enantiomer or polymorph or metabolites or a pharmaceutically acceptable salt or enantiomer or polymorph or metabolites

11. A modified release pharmaceutical composition according to claim 1 or 2 is administered to increase patient compliance for treatment of ulcerative colitis, irritable bowel syndrome, peptic ulcer disease and gastric dyspepsia.

12. A novel modified release pharmaceutical composition according claim 1 or 2 wherein increase in residence time in gastrointestinal tract is achieved by bioadhesion and/or by delaying expulsion from gastrointestinal tract.

13. A novel colon targeted modified release matrix formulation, which comprises a therapeutically effective amount of mesalamine or a pharmaceutically acceptable salt or enantiomer or polymorph thereof, optionally one or more hydrophilic or hydrophobic release controlling agent(s) and pharmaceutical acceptable excipient(s) thereof, wherein the composition is coated with coating comprises anionic copolymer of methacrylic acid and methacrylic acid ester soluble in gastric juice and in intestinal juice, which release maximum amount of the drug over the period of about 10 to about 36 hours in the colon, wherein the composition is formulated to increase the residence time in the colon.

14. A method for treating ulcerative colitis or Crohn's disease of the colon comprising orally administering the composition of claim 1 , wherein there is sustained release of mesalamine for a period more than about 10 hours.

15. A novel colon targeted modified release matrix formulation, comprises a therapeutically effective amount of 5-Amino salicylic acid or a pharmaceutically acceptable salt or enantiomer or polymorph or metabolites thereof, and a pharmaceutical acceptable excipients, wherein the composition exhibits a dissolution profile for the test:

4 hours: More than about 25% of drug is released.

8 hours: More than about 55% of drug is released.

12 hours: More than about 75% of drug is released.

16 hours: More than about 90% of drug is released.

16. A novel colon targeted modified release matrix formulation, which comprises a therapeutically effective amount of Balsalazide or prodrug or a pharmaceutically acceptable salt or enantiomer or polymorph thereof, optionally one or more hydrophilic or hydrophobic release controlling agent(s) and pharmaceutical acceptable excipient(s) thereof, wherein the composition is coated with coating comprises anionic copolymer of methacrylic acid and methacrylic acid ester soluble in gastric juice and in intestinal juice, which release maximum amount in the colon, wherein the composition is formulated to increase the residence time in the colon.