FIELD OF THE INVENTION
The present invention relates to novel controlled release pharmaceutical compositions comprising at least one active agent(s), at least one hydrophilic component and at least one water insoluble component, optionally with at least one pH dependent polymer and/or other pharmaceutically acceptable excipient(s), wherein the said composition releases the active agent(s) gradually along the intestinal region of the gastro-intestinal tract for an extended time period. The present invention also describes process for preparation of such compositions and method of using such compositions. Preferably, the compositions of the present invention provide site specific controlled release of the active agent(s) characterized by the release of active agent(s) at the desired site where the therapeutic activity of active agent(s) is required.
BACKGROUND OF THE INVENTION
Controlled release pharmaceutical compositions and dosage forms are designed to improve the delivery profile of the active agents administered to humans. A controlled release composition is typically used to improve the effects of administered substances by optimizing the kinetics of delivery, thereby increasing bioavailability, convenience, and patient compliance. Oral drug delivery to the colon has attracted significant attention during the past 20 years. Colon targeting is recognized to have several therapeutic advantages, such as the oral delivery of drugs that are destroyed by the stomach acid and/or metabolized by pancreatic enzymes. Sustained colonic release of drugs can be useful in the treatment of nocturnal asthma, angina and arthritis. Local treatment of colonic pathologies, such as ulcerative colitis, colorectal cancer and Crohn's disease, is more effective with the delivery of drugs to the affected area. Likewise, colonic delivery of vermicides and colonic diagnostic agents requires smaller doses.
Targeting of drugs to the colon through oral administration of drugs is attractive and important for two reasons: 1) large bowel diseases, such as ulcerative colitis or Crohn's Disease, can be treated locally, thus avoiding enema dosage forms and minimizing systemic absorption; and 2) drugs that may be absorbed in the colon but which are degraded in the upper digestive tract (e.g., protein and peptide drugs), can be made available orally, since the colonic site minimizes the exposure of these compounds to the multitude of degradative digestive and proteolytic enzymes present in the upper digestive tract. Even though it would be expected that the absorption of most drugs from the colon is slower than from the small intestine, this is balanced by the longer residence time (17-72 hours) in the colon.

Ulcerative colitis is a chronic inflammatory disease of unknown etiology afflicting only the large bowel and, except when very severe, limited to the bowel mucosa. The course of the disease may be continuous or relapsing, mild or severe; it is curable by total colectomy which may be needed for acute severe disease or chronic unremitting disease. Most patients with ulcerative colitis are managed medically rather than surgically. Crohn's disease is also a chronic inflammatory disease of unknown etiology but, unlike ulcerative colitis, it can affect any part of the bowel. Although lesions may start superficially, the inflammatory process extends through the bowel wall to the draining lymph nodes. As with ulcerative colitis, the course of the disease may be continuous or relapsing, mild or severe but, unlike ulcerative colitis it is not curable by resection of the involved segment of bowel, most patients with Crohn's disease come to surgery at some time, but subsequent relapse is common and continuous medical treatment is usual.
For treatment of acute attacks of inflammatory bowel disease (IBD), glucocorticosteroids such as budesonide, prednisone or prednisolone acetate are almost invariably used and given by mouth for the average acute attack or relapse, or locally, by enema. The use of oral budesonide in the treatment of small bowel Crohn's disease in its active phase has been described (Wolman SL: Use of oral budesonide in a patient with small bowel Crohn's disease and previous pseudotumor cerebra secondary to steroids. Scand. J. Gastroenterol. 24, Supplement 158:146-147).
Budesonide (16a, 17-butylidenedioxy-lb,21-dihydroxy-l,4-pregnadiene-3,20-dione) is a highly active corticosteroid which has been shown to be extremely effective for the treatment of inflammatory processes of the middle and lower intestinal tract. Thus, budesonide in oral slow-release form has brought about remission of active Crohn's disease and has few side effects on adrenocortical function (cf. the pilot study in "Der Kassenarzt, 13, pages 34 to 37, 1993"). A review of the pharmacological properties and the therapeutic efficacy of budesonide for asthma and rhinitis are given in "Drugs 44 (3), 375-407, 1992". The absorption of budesonide is low and it is subject to extensive first-pass metabolism. Since inflammatory processes often affect relatively large sections of the intestinal tract, there is a demand for a pharmaceutical form which spreads reproducibly over wide areas of the intestine and, moreover, releases the active substance only there. US patent no. 3929768 describes a novel steroid which is known as Budesonide possessing anti-inflammatory activity.
PCT Publication No. WO03090693 discloses a colon-specific drug delivery system comprising a core comprising a pharmaceutically active agent, a solid particulate interpolymer complex of a cationic polymeric glucosamine or its derivatives and an anionic, cross-linked polyacrylic acid or

its derivatives; and a pH-dependent coating surrounding at least a portion of the core, the pH-dependent coating being insoluble in gastric fluid and intestinal fluid below pH 6.0 but soluble in the colonic intestinal environment. GB patent No. 1219026 describes a pharmaceutical dosage form for oral administration comprising an active drug and a resin embedding individual particles of said drug in such a manner that said drug remains substantially protected by said resin while the particles travel through the stomach and small intestines of the patient and that the drug is substantially completely exposed at the time the particles reach the large intestines.
PCT Publication No. WO8300435 discloses an orally administrate pharmaceutical composition for selectively administering a pharmacologically active agent to the large intestine comprising a solid oral dosage form containing said agent and coated with an anionic polymer which is insoluble in gastric juice and in intestinal juice below pH 7 but soluble in colonic intestinal juice, said coating being sufficiently thick that the oral dosage form remains intact until it reaches the colon.
US Patent No. 5811388 pertains to a pharmaceutical tablet having an inner composition optionally coated by a pharmaceutically-acceptable coating, which inner composition of the tablet comprises about 0.01% by weight to about 10.0% by weight of a drug useful for treating a lower GI tract disorder; about 40-98% by weight of a hydrocolloid gum obtainable from higher plants; and about 2-50% by weight to of a pharmaceutically acceptable excipient; wherein the components of the inner composition are distributed so that the drug is concentrated in an active core with the gum and excipient surrounding the active core. EP patent No. 0453001 discloses a pharmaceutical composition for the targeted controlled release of an active principle within the intestine, said active principle being formulated in multiparticle multidose form, each particle thereof being covered with at least two membranes, one of which is soluble at a pH equal to or greater than 5.5, the other of said membranes being insoluble at said pH but permeable to the intestinal fluids.
EP patent No. 629398 discloses a pharmaceutical preparation to provide a controlled release of a medicinal compound at a targeted site in the intestinal tract, which comprises a medicinal compound-containing phase and an enteric coating phase provided around the medicinal compound-containing phase, said medicinal compound-containing phase releasing the medicinal compound quickly after a predetermined lag-time after the dissolution of the enteric coating phase. US Publication No. 2004162263 describes a composition, comprising a water-soluble, acid-labile drug enteric-coated with an enteric coating material that dissolves at pH above 5.2.
Several attempts to provide dosage forms for delivery of active agent to a specific site,

particularly to the colon, have been described previously. However, there still exists a need to develop effective delivery system, preferably those which can provide the active agent specifically at the desired site of action in a controlled release manner for extended periods of time, and which are easy to formulate.
SUMMARY OF THE INVENTION
It is an objective of the present invention to provide a novel controlled release pharmaceutical composition comprising at least one active agent(s), at least one hydrophilic component in an amount not less than about 10% by weight of the composition and at least one water insoluble component in an amount not less than about 5% by weight of the composition, optionally with at least one pH dependent polymer and/or other pharmaceutically acceptable excipient(s), wherein the said composition releases the active agent(s) gradually along the intestinal region of the gastro-intestinal tract for an extended time period.
It is an objective of the present invention to provide a novel controlled release pharmaceutical composition, wherein the composition is in the form of a multiparticulate dosage form which when administered in vivo, disintegrates into a plurality of particles that spreads in a wide area of the gastro-intestinal tract thus avoiding or at least reducing problems of irritation of the mucosa due to a high concentration of the active agent, and improving absorption of the active agent.
It is also an objective of the present invention to provide a novel controlled release pharmaceutical composition, wherein the pH dependent polymer is used to form a coating on the particles comprising the dosage form which are in the form of powder, granules, extrudes, pellets or spheroids or the dosage form such that the said coating dissolves when the coated particles reach the suitable pH environment particularly in the intestinal region of gastro-intestinal tract.
It is an objective of the present invention to provide novel controlled release pharmaceutical composition comprising at least one active agent(s), at least one hydrophilic component in an amount not less than about 10% preferably not less than about 35% by weight of the composition, at least one water insoluble component in an amount not less than about 5% by weight of the composition, optionally with at least one pH dependent polymer and/or other pharmaceutically acceptable excipient(s).
It is also an objective of the present invention to provide a novel controlled release pharmaceutical composition comprising at least one active agent(s), at least one hydrophilic

component in an amount not less than about 10% by weight of the composition, at least one water insoluble component in an amount not less than about 5% by weight of the composition, at least one pH dependent polymer, optionally with at least one surfactant(s) and/or other pharmaceutically acceptable excipient(s), wherein the said composition releases the active agent(s) gradually along intestinal region of gastro-intestinal tract for an extended time period.
It is also an objective of the present invention to provide novel controlled release pharmaceutical composition comprising at least one active agent(s), preferably glucocorticoids, more preferably budesonide or its salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, derivatives or mixtures thereof as active agent, either alone or in combination with other active agent(s), at least one hydrophilic component and at least one water insoluble component, optionally with at least one pH dependent polymer and/or other pharmaceutically acceptable excipient(s).
It is another objective of the present invention to provide process for preparation of such
composition which comprises of the following steps:
i) mixing the active agent(s) with hydrophilic component(s), water insoluble component(s)
and optionally a pH dependent polymer(s),
ii) optionally adding one or more other pharmaceutically acceptable excipient(s), and iii) formulating the mixture into a suitable dosage form.
It is a further objective of the present invention to provide process for the preparation of such
novel composition which comprises of the following steps:
i) dispersing the active agent(s) in a suitable solvent,
ii) mixing the hydrophilic component(s) and water insoluble component(s),
iii) granulating the mixture of step (ii) with the dispersion of step (i),
iv) optionally adding one or more other pharmaceutically acceptable excipient(s),
v) formulating the mixture of step (iv) into a suitable dosage form, and
vi) optionally coating the dosage form of step (v) with pH dependent polymer(s).
It is a still further objective of the present invention to provide process for the preparation of
such novel composition which comprises of the following steps:
i) preparing an aqueous solution of surfactant(s),
ii) dispersing the active agent(s) in the material of step (i),
iii) mixing the hydrophilic component(s) and water insoluble component(s), optionally with

one or more other pharmaceutically acceptable excipient(s), iv) granulating the mixture of step (iii) with the dispersion of step (ii), v) optionally adding one or more other pharmaceutically acceptable excipient(s), vi) formulating the mixture of step (v) into suitable particles such as powder, granules,
extrudes, pellets or spheroids,
vii) coating the particles of step (vi) with pH dependent polymer(s), and viii) formulating the coated particles of step (vii) into a suitable dosage form.
It is yet another objective of the present invention to provide a method of using such composition which comprises administering to a subject in need thereof an effective amount of the composition.
The novel controlled release pharmaceutical compositions of the present invention provide the active agent(s) specifically at the desired site of action and also provide controlled release of the active agent(s) for extended periods of time. The compositions are easy to formulate. Preferably the compositions provide therapeutic concentrations of active agent(s) at the specific site of the gastro-intestinal tract, particularly the colon.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel controlled release pharmaceutical composition comprising at least one active agent(s), at least one hydrophilic component in an amount not less than about 10% by weight of the composition and at least one water insoluble component in an amount not less than about 5% by weight of the composition, optionally with at least one pH dependent polymer and/or other pharmaceutically acceptable excipient(s), wherein the said composition releases the active agent(s) gradually along the intestinal region of the gastrointestinal tract for an extended time period.
In an embodiment, the composition is in the form of a multiparticulate dosage form which when administered in vivo, disintegrates into a plurality of particles that spreads in a wide area of the gastro-intestinal tract thus avoiding or at least reducing problems of irritation of the mucosa due to a high concentration of the active agent, and improving absorption of the active agent.
In another embodiment, the controlled release pharmaceutical composition comprises a pH dependent polymer, wherein the pH dependent polymer is used to coat the dosage form composition such that the said coating dissolves when the coated particles reach the suitable pH environment

particularly in the intestinal region of the gastro-intestinal tract. The intestinal region of the gastrointestinal tract (GIT) is particularly the region of the gastro-intestinal tract beyond the stomach also referred to as the upper-GIT and lower-GIT and includes the large and the small intestines.
In another embodiment of the present invention, the hydrophilic component is present in an amount not less than about 10% preferably not less than about 35% by weight of the composition. In an embodiment, the hydrophilic component is either a non-polymeric or a polymeric material. In a preferred embodiment, the hydrophilic component is a non-polymeric material.
In another embodiment, the present invention provides a novel controlled release pharmaceutical composition comprising at least one active agent(s), at least one hydrophilic component in an amount not less than about 10% by weight of the composition, at least one water insoluble component in an amount not less than about 5% by weight of the composition, at least one pH dependent polymer, optionally with at least one surfactant(s) and/or other pharmaceutically acceptable excipient(s), wherein the said composition releases the active agent(s) gradually along the intestinal region of the gastro-intestinal tract for an extended time period.
The active agent of the present invention is selected from but not limited to a group comprising active agent(s) such as penicillin G, calcitonin, heparin, ferritin, sucralfate, mebeverine hydrochloride, acarbose, dimethicone, simethicone, immunoglobulin, anthelmintics, anti-protozoals, local and general action intestinal anti-infectants and antifungal drugs, drugs having aminosalicylic acid functional groups, anti-inflammatory and antiphlogistic drugs having a local action in the intestine, corticosteroids such as glucocorticoids for local treatment of chronic intestinal inflammation or irritation, and peppermint oil, and mixtures thereof.
Preferably, the active agent used in the present invention is preferably glucocorticoid, more preferably budesonide or its salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, derivatives, or mixtures thereof. In another embodiment, the active agent of the present invention is selected from but not limited to a group comprising hydrocortisone (and pharmaceutically acceptable salts or esters such as the acetate, cypionate, sodium phosphate, sodium succinate, butyrate, valerate, or the like), beclomethasone, beclomethasone dipropionate, betamethasone (and its pharmaceutically acceptable salts or esters such as the benzoate, dipropionate, sodium phosphate, acetate, valerate, or the like), budesonide, cortisone, cortisone acetate, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, flunisolide, methylprednisone, methylprednisone acetate, methylprednisone sodium succinate,

paramethasone acetate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebutatc, prcdnisone, triaincinolone, triamcinolone acetinide, triamcinolone diacetate, triamcinolone hexacetonide, alclometasone dipropioante, amcinonide, clobetasol propionate, clocortolone pivalate, desonide, desoximetasone, diflorasone diacetate, fluocinolone acetonide, fluocinonide, fluorometholone, flurandrenolide, halcinonide, medrysone, mometasone, fluticasone, tixocortol pivalate, prednisolone metasulfobenzoate, and pharmaceutically acceptable salts, hydrates, polymorphs, esters, and derivatives thereof, used either alone or in combination thereof.
The hydrophilic component useful in the present invention may be a water soluble component or at least a water miscible component with appreciable aqueous solubility. In a preferred embodiment of the present invention, the hydrophilic component is a water soluble component. Preferably the hydrophilic component is selected from a group comprising non-polymeric components but not limited polyethylene glycols, mannitol, sorbitol, cyclodextrin, succinic acid, lactose, sucrose and the like, or mixtures thereof.
In an embodiment of the present invention, the hydrophilic component is selected from a group comprising polymeric components but not limited to hydrolysed polyvinyl acetate, copolymers of ethyl acrylate with methacrylate and methacrylic acid, copolymers of maleic acid with unsaturated hydrocarbons and mixed polymerisation products of the said polymers, polysaccharide gums, both natural and modified (semi-synthetic), cellulose derivatives such as hydroxyalkyl alkyl celluloses such as hydroxypropyl methyl cellulose (HPMC, Methocel® K15M), vinylpyrrolidones, vinyl acetates, polyvinylimidazoles, polyvinylpyridine N-oxides, polyethylene glycols (PEG® 1500, Lutrol® E 1500), copolymers of ethylene oxide with propylene oxide (Poloxamer 407, Poloxamer 188, Poloxamer 407), gelatin, polyvinylpyrrolidones (PVP, Kollidon® 12 PF, Kollidon® 17 PF), terpolymers of caprolactam/vinylpyrrolidone/dimethylaminoethyl methacrylates, copolymers of styrene and acrylic acid, polycarboxylic acids, polyacrylamides, polyvinyl alcohols (PVA, Mowiol® 40-88), dextran, dextrin, and the like or mixtures thereof. Preferably the hydrophilic component is a non-polymeric component, more preferably a saccharide such as lactose. Preferably the lactose is present in an amount not less than about 15% by weight of the composition, more preferably about 20-50% w/w of the composition.
In an embodiment of the present invention, the water insoluble component is selected from but not limited to group comprising cellulose derivatives such as microcrystalline cellulose, ethylcellulose, butylcellulose; acrylic polymers such as polyacrylamide, polyacrylic dextrin,

polyalkylcyanoacrylates, polymethylmethacrylates and methacrylic resins; polyvinyl acetate; polyvinyl chloride; polyethylene; and the like; and mixtures thereof. Preferably the water insoluble component is microcrystalline cellulose and is present in an amount not less than about 5% w/w by weight of the composition, most preferably about 10-60% w/w of the composition. In another embodiment, the water insoluble polymer is present in an amount not less than about 5% by weight of the composition.
In another embodiment, the composition additionally comprises at least one pH dependent polymer present in an amount not less than about 10% by weight of the composition. In an embodiment of the present invention, the pH dependent polymer is selected from but not limited to group comprising copolymers of acrylate polymers with amino substituents, acrylic acid esters, polyacrylamides, phthalate derivatives (i.e., compounds with covalently attached phthalate moieties) such as acid phthalates of carbohydrates, amylose acetate phthalate, cellulose acetate phthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropyl cellulose phthalate, hydroxypropyl ethylcellulose phthalate, hydroxypropyl methylcellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, sodium cellulose acetate phthalate, starch acid phthalate, styrene maleic acid dibutyl phthalate copolymer, styrene-maleic acid polyvinyl acetate phthalate copolymer, styrene and maleic acid copolymers, formalized gelatin, gluten, shellac, salol, keratin, ammoniated shellac, benzophenyl salicylate, cellulose acetate trimellitate, cellulose acetate blended with shellac, hydroxypropyl methylcellulose acetate succinate, oxidized cellulose, polyacrylic acid derivatives such as acrylic acid and acrylic ester copolymers, methacrylic acid and esters, cationic polymer with a dimethylaminoethyl ammonium group, anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid thereof such as poly(methacrylic acid, methyl methacrylate) 1:1 (e.g. Eudragit® L100), poly(methyacrylic acid, ethyl acrylate) 1:1 (e.g. Eudragit® L100-55, Eudragit® L30D-55), poly(methacrylic acid, methyl methacrylate) 1:2 (e.g. Eudragit® S100, Eudragit® S12.5P, Eudragit® FS30D), vinyl acetate and crotonic acid copolymers and the like; and mixtures thereof. Preferably the pH dependent polymer is an acrylic acid or methacrylic acid copolymer. Preferably the pH dependent polymer is present in an amount not less than about 2% w/w of the composition, more preferably about 10-60% w/w of the composition.
The compositions of the present invention may be produced as coated or uncoated dosage form. In another embodiment, the pH dependent polymer, when present in the composition of the present invention, is preferably used to form a coating on the particles comprising the dosage

form, or the dosage form of the present invention. Preferably the coating is done on the particles which are in the form of powder, granules, extrudes, pellets or spheroids. Different coating polymers were evaluated in vitro for enteric properties and targeting suitability to the colon by the inventors of the present invention. To guarantee desired colonic delivery, the polymer must dissolve from pH above about 5-6 and allow an immediate or controlled release of the active agent at the site of action. The inventors have now found that preferably the acrylic/methacrylic acid polymers or copolymers such as Eudragit® FS30D or Eudragit® L30D-55 having a pH of about 2.5 showed good enteric properties, dissolved in pH above about 5-6, and also provided a controlled release of active agent for an extended period of time at desired site i.e. the colon.
In yet another embodiment, the pH dependent polymer is formulated into a coating solution or dispersion comprising additionally a plasticizer such as triethyl citrate or polyethylene glycol, optionally a surfactant such as sodium lauryl sulphate or polysorbate 80 and/or a colorant such as red iron oxide and/or a lubricant such as talc in purified water or a hydro-alcoholic or a non-aqueous solvent system. The said coating solution or dispersion is used to coat the dosage form by conventional techniques known to the art. It might be appreciated that the term 'coating' as stated herein refers to the formation of a film on the surface of either multiple particulates such as in the form of powder, granules, extrudes, pellets or spheroids comprising the active agent(s) or an intact dosage form such as a tablet or a capsule depending on the type of dosage form intended to be prepared and/or the active agent(s) used. In another aspect, the coating composition comprises a part of the same active agent used in the core or a different active agent if desired. In an aspect, the composition of the present invention can also be prepared by coating an inert core such as non-pariel seeds with a coating material comprising the active agent alongwith suitable coating aids known to the art, followed by formulating the coated particles into a suitable dosage form, and optionally coating the dosage form by a coating material comprising at least one pH dependent polymer.
In a preferred embodiment of the present invention, the ratio of the hydrophilic component and the water insoluble component is about 1:50 to 50:1, preferably about 1:10 to 10:1 by weight of the composition. In another embodiment of the present invention, the composition additionally comprises of a surfactant, the surfactant being selected from but not limited to group comprising polyethylene glycols; polyoxyethylene-polyoxypropylene block copolymers known as 'poloxamer'; polyglycerin fatty acid ester such as decaglyceryl monolaurate and decaglyceryl monomyristate; sorbitan fatty acid ester such as sorbitan monostearate; polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan monooleate(Tween®); polyethylene glycol fatty

acid ester such as polyoxyethylene monostearate; polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether; polyoxyethylene castor oil and hardened castor oil such as polyoxyethylene hardened castor oil; sucrose ester of fatty acid such as sucrose state ester and sucrose palmitate ester and alkyl sulfate salt such as sodium lauryl sulfate and magnesium lauryl sulfate; sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, palmitoyl carnitine; and the like or mixtures thereof.
The pharmaceutically acceptable excipients of the present invention are selected from but not limited to a group comprising diluents, disintegrants, binders, anti-foaming agent, fillers, bulking agents, anti-adherants, anti-oxidants, buffering agents, colorants, flavoring agents, coating agents, plasticizers, organic solvents, stabilizers, preservatives, lubricants, glidants, chelating agents, and the like used either alone or in combination thereof. It will be appreciated that certain excipients used in the present composition can serve more than one purpose.
Suitable diluents include for example pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, saccharides, and/or mixtures thereof. Examples of diluents include microcrystalline celluloses such as Avicel® PH 101, Avicel® PH 102, Avicel® PH 112, Avicel® PH 200, Avicel® PH301 and Avicel® PH 302; lactose such as lactose monohydrate, lactose anhydrous and Pharmatose® DCL21, including anhydrous, monohydrate and spray dried forms; dibasic calcium phosphate such as Emcompress®; mannitol; Pearlitol® SD 200; starch; sorbitol; sucrose; glucose, or the like or mixtures thereof. Suitable anti-foaming agents include for example silicon emulsions or sorbitan sesquoleate. Suitable binders include for example starch, povidone, hydroxypropyl methylcellulose, pregelatinised starch, hydroxypropyl cellulose or mixtures thereof. Suitable plasticizers include for example triethyl citrate, cetyl alcohol, glycerol fatty acid ester, propylene glycol, polyethylene glycol, hydrogenated castor oil, hydrogenated rapeseed oil, and silicone oil.
Suitable lubricants are selected from but not limited to a group comprising colloidal silicon dioxide such as Aerosil® 200; talc; stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, hydrogenated vegetable oil and the like or mixtures thereof. Suitable disintegrants include for example crosslinked polyvinyl pyrrolidone, cornstarch, potato starch, maize starch and modified starches, croscarmellose sodium, sodium starch glycollate or mixtures thereof.
In a further embodiment, the compositions of the present invention comprising the pharmaceutically active agent(s) were subjected to in vitro dissolution study in a dissolution

media having a pH ranging from about 1 to about 9, preferably having a pH of about 4.5-8. About 0-40% of the active agent(s) was released within about 2 hours and greater than about 50% of the active agent(s) was released after about 8 hours of test. In a still further embodiment, the compositions of the present invention studied in healthy human volunteers are intended to achieve the peak plasma concentration (Cmax) in about 0.5-12 hours (Tmax), preferably in 1-10 hours. However, it might be emphasized that the selection of the in vitro dissolution study media, the parameters and apparatus is made in such a manner so as to provide a scientific rationale to the intended study and/or a logical correlation to the in vivo data as understood by a person skilled in art, and any modifications in such study either in vitro or in vivo is within the purview of the present invention.
The compositions of the present invention have various advantages. In an embodiment, the composition of the present invention is in the form of a multiparticulate dosage form. The multiparticulate dosage form compositions, when administered in vivo, disintegrates into a plurality of particles that spreads in a wide area of the gastro-intestinal tract thus avoiding or at least reducing problems of irritation of the mucosa due to a high concentration of the active agent, and improving absorption of the active agent. In a preferred embodiment, the present invention provides novel site specific controlled release compositions. The pH dependent polymer preferably used to coat the dosage form composition forms a membrane that dissolves when the coated particles reach suitable pH environment particularly in the intestine, releasing the active agent(s) in the intestine preferably the colon gradually thus prolonging its action.
In an embodiment of the present invention is provided a process for the preparation of such novel
composition which comprises of the following steps:
i) mixing the active agent(s) with hydrophilic component(s), water insoluble component(s)
and optionally a pH dependent polymer(s),
ii) optionally adding one or more other pharmaceutically acceptable excipient(s), and iii) formulating the mixture into a suitable dosage form.
In an embodiment of the present invention is provided a process for the preparation of such novel
composition which comprises of the following steps:
i) dispersing the active agent(s) in a suitable solvent,
ii) mixing the hydrophilic component(s) and water insoluble component(s),
iii) granulating the mixture of step (ii) with the dispersion of step (i),

iv) optionally adding one or more other pharmaceutically acceptable excipient(s),
v) formulating the mixture of step (iv) into a suitable dosage form, and
vi) optionally coating the dosage form of step (v) with pH dependent polymer(s).
In a further embodiment of the present invention is provided a process for the preparation of such
novel composition which comprises of the following steps:
i) preparing an aqueous solution of surfactant(s),
ii) dispersing the active agent(s) in the material of step (i),
iii) mixing the hydrophilic component(s) and water insoluble component(s), optionally with
one or more other pharmaceutically acceptable excipient(s), iv) granulating the mixture of step (iii) with the dispersion of step (ii), v) optionally adding one or more other pharmaceutically acceptable excipient(s), vi) formulating the mixture of step (v) into suitable particles such as powder, granules,
extrudes, pellets or spheroids, vii) coating the particles of step (vi) with a coating composition comprising a pH dependent
polymer(s), and viii) formulating the coated particles of step (vii) into a suitable dosage form.
In an embodiment, the dosage form compositions of the present invention provide a controlled release of the active agent(s) for extended periods of time. The release rate of the active agent(s) is primarily controlled by the amount of hydrophilic component(s) and water insoluble component(s) present in the composition. In a further embodiment, the present composition can be formulated by coating the blend comprising an active agent alongwith hydrophilic component and water insoluble component by a solution of pH dependent polymer in appropriate solvent. Optionally a non-functional coating can be done before functional coating.
In a further embodiment, the composition of the present invention is preferably in the form of solid dosage forms such as tablets, capsules, pellets, granules or the like, more preferably granules and pellets. The said dosage form can be prepared by either wet granulation, direct compression, or by dry compression (slugging). In a preferred embodiment of the present invention, the oral composition is prepared by wet granulation process. The granulation technique is either aqueous or non-aqueous. The non-aqueous solvent used is selected from a group comprising acetone, ethanol, isopropyl alcohol or methylene dichloride. In an embodiment, the compositions are in the form of compressed tablets, moulded tablets, mini-tablets, capsules, pellets, granules and products prepared by extrusion or film cast technique, and

the like. The tablets may be optionally coated with a nonfunctional coating to form a nonfunctional layer. The tablets/minitablets may be optionally filled into capsules.
In yet another embodiment of the present invention is provided a method of using such novel controlled release compositions which comprises administering to a subject in need thereof an effective amount of the composition. The compositions comprising budesonide as the active agent are useful for treating particularly inflammatory bowel diseases (IBD) such as Ulcerative colitis and Crohn's disease.
The examples given below serve to illustrate embodiments of the present invention. However they do not intend to limit the scope of present invention.

EXAMPLES
Example-1
mg/capsule
S. No. Ingredient
Core composition
1. Budesonide 3.0
2. Lactose 56.0
3. Polyoxyethylene sorbitan monostearate (TWEEN® 80) 1.0
4. Microcrystalline cellulose 27.0
5. Crospovidone 3.0
Coating Composition
7.0
2.0 0.5 0.01 q.s. (lost in processing)
6. Anionic copolymer based on methyl acrylate
(Eudragit® FS30D)
7. Talc
8. Triethyl citrate
9. Sorbitan sesquoleate
10. Purified Water
Procedure:
i) Clear solution of Polyoxyethylene sorbitan monostearate and Purified water was prepared.
ii) Budesonide was dispersed in the above solution.
iii) Lactose, Microcrystalline cellulose and Crospovidone were sifted and mixed together.
iv) The mixture in Step (iii) was granulated with the granulating fluid of Step (ii).
v) The wet mass of Step (iv) was passed through extruder using 0.5 mm extruding mesh.
vi) The extrude of Step (v) was spheroidized using 2.0 mm friction plate and was dried in rapid

dryer at 50°C for 30 minutes to get the granules.
vii) Talc, Sorbitan sesquoleate and Triethyl citrate were dispersed in water, viii) Aqueous dispersion of Anionic copolymer based on methyl acrylate was stirred and was
filtered through 0.5 mm mesh nylon cloth.
ix) Dispersions of Step (vii) and Step (viii) were mixed together and the mixture was stirred, x) The granules of Step (vi) were coated with the material of Step (ix) and were filled into hard
gelatin capsule.
ExatnpIe-2
S. No. Ingredient mg/tablet
Core composition
1. Budesonide 3.0
2. Cationic polymer with a dimethylaminoethyl 5.0
ammonium group (Eudragit® EPO)
3. Lactose 46.0
4. Sodium lauryl sulphate 1.0
5. Microcrystalline cellulose 24.5
6. Purified water q.s. (lost in processing)
Coating Composition
7. Anionic polymer of methacrylic acid with a 10.0
carboxylic group (Eudragit® L30D-55)
8. Talc 5.0
9. Polyethylene glycol 1.0

10. Purified water q.s. (lost in processing)
Lubrication
11. Magnesium stearate 0.5
Procedure:
i) Clear solution of Sodium lauryl sulphate and Purified water was formed.
ii) Budesonide, Lactose, Microcrystalline cellulose and Cationic polymer with a
dimethylaminoethyl ammonium group were mixed together iii) The mixture in Step (ii) was granulated with the granulating fluid of Step (i). iv) The wet mass of Step (iii) was passed through extruder using 0.5 mm extruding mesh, v) The extrude of Step (iv) was spheroidized using 2.0 mm friction plate and was dried in
rapid dryer at 50°C to obtain the granules.

vi) Talc and Polyethylene glycol were dispersed in water and stirred.
vii) Aqueous dispersion of Anionic polymer of methacrylic acid with a carboxylic group was
stirred and filtered through 0.5 mm mesh nylon cloth.
viii) Dispersions of Step (vi) and Step (vii) were mixed together with stirring, ix) The granules of Step (v) were coated with the mixture of Step (viii) and dried, x) Magnesium stearate sifted through mesh #40 was mixed with material of Step (ix). xi) The material of Step (x) was compressed into tablets.
Example-3
S. No. Ingredient mg/capsule
Core composition
1. Prednisone 2.5
2. Hydroxypropyl beta Cyclodextrin (HPpCD) 9.5
3. Polyvinylpyrrolidone (PVP K30) 1.0
4. Crospovidone 0.5
5. Mannitol 47.0
6. Microcrystalline cellulose 39.5
7. Purified water q.s. (lost in processing)
Coating Composition

8. Anionic copolymer based on methyl acrylate 10.0
(Eudragit®S100)
9. Talc 10.0
10. Triethyl citrate 0.4
11. Isopropyl alcohol (IPA) q.s. (lost in processing)
Procedure:
i) Clear solution of Polyvinylpyrrolidones and Purified water was formed.
ii) Prednisone was complexed with HPpCD by mixing both of them for 15 minutes.
iii) Prednisone-HPpCD complex, Lactose, Microcrystalline cellulose and Crospovidone were
mixed together
iv) The mixture of Step (iii) was granulated with the granulating fluid of Step (i). v) The wet mass of Step (iv) was passed through extruder using 0.5 mm extruding mesh, vi) The extrude of Step (v) was spheroidized using 2.0 mm friction plate and was dried in rapid
dryer to obtain granules.

vii) Anionic copolymer based on methyl acrylate, Talc and Triethyl citrate were dispersed in
Isopropyl alcohol and stirred for 30 minutes, viii) 'I'he granules of Step (vi) were coated with the dispersion of Step (vii) and were filled into
hard gelatin capsule.
Example-4
S. No. Ingredient mg/tablet
1. Budesonide 3.0
2. Mannitol 100.0
3. Ethyl cellulose 95.0
4. Purified water q.s. (lost in processing)
Lubrication
5. Hydrogenated vegetable oil 2.5
6. Colloidal silicon dioxide 2.5
Procedure:
i) Budesonide, Mannitol and Ethyl cellulose were sifted and mixed together.
ii) The mixture in Step (i) was granulated with Purified water.
iii) The wet mass of Step (ii) was passed through sieve #12 mesh, dried and sifted through sieve
#20 mesh, iv) Hydrogenated vegetable oil and Colloidal silicon dioxide were sifted through sieve #40 and
mixed together with the material of Step (iii). v) The material of Step (iv) were compressed into tablets.
Example-5
S. No. Ingredient mg/tablet
1. 5-aminosalicylic acid (5-ASA) 400.0
2. Polyvinyl pyrrolidone 50.0
3. Poloxamer 5.0
4. Ethyl cellulose 95.0
5. Purified water q.s. (lost in processing)
Lubrication
6. Sodium stearyl fumarate 2.5
7. Colloidal silicon dioxide 2.5
Coating Composition

8. Methacrylate copolymer (Eudragit® L30D-55) 10.0
9. Talc 5.0
10. Red iron oxide 0.01
11. Triethyl citrate 0.4
12. Isopropyl alcohol q.s. (lost in processing)
Procedure:
i) Poloxamer was dissolved in Purified water to obtain a solution.
ii) 5-aminosalicylic acid was dispersed in the solution of Step (i) with stirring.
iii) Polyvinyl pyrrolidone and Ethyl cellulose were sifted and mixed together.
iv) The mixture of Step (iii) was granulated with the material of Step (ii).
v) The wet mass of Step (iv) was passed through sieve #12 mesh, dried and sifted through
sieve #20 mesh, vi) Sodium stearyl fumarate and Colloidal silicon dioxide were sifted through sieve #40 and
mixed together with the material of Step (v). vii) The material of Step (vi) was compressed into tablets, viii) Red iron oxide was sifted alongwith Talc through sieve #80 mesh and dispersed in part of
Isopropyl alcohol with stirring, ix) Methacrylate copolymer and Triethyl citrate were dispersed in Isopropyl alcohol and stirred
for 30 minutes.
x) The material of Step (viii) was added to the material of Step (ix) with stirring, xi) The tablets of Step (vii) were coated with the dispersion of Step (x) followed by drying.
Example-6
S. No. Ingredient nig/tablet
1. Indomethacin 25.0
2. Isopropyl myristate 5.0
3. Hydroxypropyl methylcellulose 55.0
4. Sodium starch glycolate 3.0
5. Ethyl cellulose 27.0
6. Calcium stearate 2.0
7. Purified water q.s. (lost in processing)
Procedure:
i) Isopropyl myristate was dispersed in Purified water followed by the addition of Indomethacin with stirring.

ii) Hydroxypropyl methylcellulose, Sodium starch glycolate and Ethyl cellulose were mixed, iii) The blend of Step (ii) was granulated by using dispersion of Step (i). iv) The wet mass of Step (iii) was dried and passed through # 30 sieve to obtain granules, v) The granules of Step (iv) were lubricated with calcium stearate (sifted through sieve #40 mesh) and compressed into tablets.
Example-7
S. No. Ingredient ing/capsule
Core composition
1. Sulfasalazine 500.0
2. Lactose 100.0
3. Polyoxyethylene sorbitan tnonooleate 5.0
4. Microcrystalline cellulose 92.0
5. Sodium starch glycolate 3.0
Coating Composition
6. Cellulose acetate phthalate 20.0
7. Talc 8.0
8. Triethyl citrate 2.0
9. Purified water q.s. (lost in processing)
Procedure:
i) Polyoxyethylene sorbitan monooleate was dispersed in Purified water.
ii) Sulfasalazine was dispersed in the above material of Step (i).
iii) Lactose, Microcrystalline cellulose and Sodium starch glycolate were mixed together.
iv) The mixture in Step (iii) was granulated with the granulating fluid of Step (ii).
v) The wet mass of Step (iv) was passed through extruder using 0.5 mm extruding mesh.
vi) The extrude of Step (v) was spheroidized and dried to obtain granules.
vii) Talc, Cellulose acetate phthalate and Triethyl citrate were dispersed in Purified water.
viii) The granules of Step (vi) were coated with the mixture of Step (vii) and dried.
ix) The material of Step (viii) was filled into hard gelatin capsules.

We ClAIMS
1. A novel controlled release pharmaceutical composition comprising at least one active
agent(s), at least one hydrophilic component in an amount not less than about 10% by
weight of the composition and at least one water insoluble component in an amount not less
than about 5% by weight of the composition, optionally at least one pH dependent polymer,
at least one surfactant(s) and/or other pharmaceutically acceptable excipient(s), wherein the
said composition releases the active agent(s) gradually along the intestinal region of the
gastro-intestinal tract for an extended time period.
2. A composition according to claim 1, wherein the composition is in the form of a
multiparticulate dosage form which when administered in vivo, disintegrates into a plurality
of particles that spreads in a wide area of the gastro-intestinal tract thus avoiding or at least
reducing problems of irritation of the mucosa due to a high concentration of the active
agent, and improving absorption of the active agent.
3. A composition according to claim 1, wherein the pH dependent polymer present in the
composition is used to form a coating on the particles comprising the dosage form which
are in the form of powder, granules, extrudes, pellets or spheroids, or the dosage form such
that the said coating dissolves when the coated particles reach the suitable pH environment
particularly in the intestinal region of the gastro-intestinal tract.
4. A composition according to claim 1, wherein the active agent is selected from a group
comprising penicillin G, calcitonin, heparin, ferritin, sucralfate, mebeverine hydrochloride,
acarbose, dimethicone, simethicone, immunoglobulin, anthelmintics, anti-protozoals, local
and general action intestinal anti-infectants and antifungal drugs, drugs having
aminosalicylic acid functional groups, anti-inflammatory and antiphlogistic drugs having a
local action in the intestine, corticosteroids such as glucocorticoids for local treatment of
chronic intestinal inflammation or irritation, and peppermint oil, or mixtures thereof.
5. A composition according to claim 4, wherein the glucocorticoid is selected from a group
comprising hydrocortisone; beclomethasone; beclomethasone dipropionate; betamethasone;
budesonide; cortisone; cortisone acetate; dexamethasone; dexamethasone acetate;
dexamethasone sodium phosphate; flunisolide; methylprednisone; methylprednisone
acetate; methylprednisone sodium succinate; paramethasone acetate; prednisolone;
prednisolone acetate; prednisolone sodium phosphate; prednisolone tebutate; prednisone;

triamcinolone; triamcinolone acetinide; triamcinolone diacetate, triamcinolone hexacetonide, alclometasone dipropioante, amcinonide, clobetasol propionate, clocortolone pivalate, desonide, desoximetasone, diflorasone diacetate, fluocinolone acetonide, fluocinonide, fluorometholone, flurandrenolide, halcinonide, medrysone, mometasone, fluticasone, tixocortol pivalate, prednisolone metasulfobenzoate, and pharmaceutically acceptable salts, hydrates, polymorphs, esters, and derivatives thereof used either alone or in combination thereof.
6. A composition according to claim 5, wherein the glucocorticoid is budesonide or its salts,
polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, derivatives or
mixtures thereof.
7. A composition according to claim 1, wherein the hydrophilic component is non-polymeric
selected from a group comprising polyethylene glycols, rnannitol, sorbitol, cyclodextrin,
succinic acid, saccharide such as lactose or sucrose, and mixtures thereof.
8. A composition according to claim 7, wherein the non-polymeric hydrophilic component is a
saccharide.
9. A composition according to claim 1, wherein the hydrophilic component is polymeric and
selected from a group comprising polyvinyl acetate, copolymers of ethyl acrylate with
methacrylate and methacrylic acid, copolymers of maleic acid with unsaturated
hydrocarbons and mixed polymerisation products of the said polymers, polysaccharide
gums, both natural and modified, cellulose derivatives, vinylpyrrolidones, vinyl acetates,
polyvinylimidazoles, polyvinylpyridine N-oxides, polyethylene glycols, copolymers of
ethylene oxide with propylene oxide, gelatin, poly vinylpyrrolidones, terpolymers of
caprolactam/vinylpyrrolidone/dimethylaminoethyl methacrylates, copolymers of styrene
and acrylic acid, polycarboxylic acids, polyacrylamides, polyvinyl alcohols, dextran,
dextrin, and mixtures thereof.
10. A composition according to claim 1, wherein the water insoluble component is a cellulose
derivative selected from a group comprising microcrystalline cellulose, ethylcellulose,
butylcellulose, acrylic polymers, polyacrylic dextrin, polyalkylcyanoacrylates,
polymethylmethacrylates, methacrylic resins, polyvinyl acetate, polyvinyl chloride,
polyethylene, and mixtures thereof.

11. A composition according to claim 10, wherein the water insoluble component is
microcrystalline cellulose.
12. A composition according to claim 1, wherein the pH dependent polymer is selected from a
group comprising copolymers of acrylate polymers with amino substituents, acrylic acid
esters, polyacrylamides, phthalate derivatives, styrene and maleic acid copolymers,
formalized gelatin, gluten, shellac, salol, keratin, ammoniated shellac, benzophenyl
salicylate, cellulose acetate trimellitate, cellulose acetate blended with shellac,
hydroxypropyl methylcellulose acetate succinate, oxidized cellulose, polyacrylic acid
derivatives, methacrylic acid and esters, cationic polymer with a dimethylaminoethyl
ammonium group, anionic copolymer based on methyl acrylate, methyl methacrylate and
methacrylic acid, vinyl acetate and crotonic acid copolymers; and mixtures thereof.
13. A composition according to claim 1, wherein the pharmaceutically acceptable excipients are
selected from a group comprising diluents, disintegrants, binders, anti-foaming agent,
fillers, bulking agents, anti-adherants, anti-oxidants, buffering agents, colorants, flavoring
agents, coating agents, plasticizers, organic solvents, stabilizers, preservatives, lubricants,
glidants, chelating agents, and the like used either alone or in combination thereof.
14. A process for the preparation of composition according to claim 1, which comprises of the
following steps:
i) dispersing the active agent(s) in a suitable solvent,
ii) mixing the hydrophilic component(s) and water insoluble component(s),
iii) granulating the mixture of step (ii) with the dispersion of step (i),
iv) optionally adding one or more other pharmaceutically acceptable excipient(s),
v) formulating the mixture of step (iv) into a suitable dosage form, and
vi) optionally coating the dosage form of step (v) with pH dependent polymer(s).
15. A process for the preparation of composition according to claim 1, which comprises of the
following steps:
i) preparing an aqueous solution of surfactant(s),
ii) dispersing the active agent(s) in the material of step (i),
iii) mixing the hydrophilic component(s) and water insoluble component(s), optionally
with one or more other pharmaceutically acceptable excipient(s), iv) granulating the mixture of step (iii) with the dispersion of step (ii),

v) optionally adding one or more other pharmaceutically acceptable excipient(s),
vi) formulating the mixture of step (v) into suitable particles such as powder, granules,
extrudes, pellets or spheroids, vii) coating the particles of step (vi) with a coating composition comprising a pH
dependent polymer(s), and viii) formulating the coated particles of step (vii) into a suitable dosage form.
16. The pharmaceutical composition and process for the preparation substantially as herein described and illustrated by the examples.