WO2015071812A1

WO2015071812A1 - Solid oral modified-release composition comprising budesonide or salt thereof

Info

Publication number: WO2015071812A1
Application number: PCT/IB2014/065914
Authority: WO
Inventors: Ajmal Shareef; Ananda Haranath UPPALA; Rahul Sudhakar Dabre; Girish Kumar Jain
Original assignee: Wockhardt Limited
Priority date: 2013-11-18
Filing date: 2014-11-10
Publication date: 2015-05-21

Abstract

The present invention relates to solid oral modified-release composition comprising budesonide or a pharmaceutically acceptable salt thereof. In particular, the present invention relates to solid oral modified-release composition comprising matrix of budesonide or a pharmaceutically acceptable salt thereof with one or more amphiphilic excipients and one or more hydrophilic excipients comprising polymers having low viscosity and one or more lipophilic or amphiphilic excipients. The invention further relates to a process of preparing such composition and method of treating ulcerative colitis using such composition.

Description

SOLID ORAL MODIFIED-RELEASE COMPOSITION COMPRISING

BUDESONIDE OR SALT THEREOF

Field of the Invention

The present invention relates to solid oral modified-release composition comprising budesonide or a pharmaceutically acceptable salt thereof. By legitimate selection of hydrophilic excipients and lipophilic or amphiphilic excipients in the matrix composition, it is possible to achieve compositions which exhibit desired release profile of budesonide. There is also provided a process of preparing such composition and method of treating ulcerative colitis using such composition.

Background of the Invention

The present invention relates to solid oral modified-release composition comprising budesonide or a pharmaceutically acceptable salt thereof. In particular, the present invention relates to solid oral modified-release composition comprising matrix of budesonide or a pharmaceutically acceptable salt thereof with one or more hydrophilic excipients comprising polymers having low viscosity and one or more lipophilic or amphiphilic excipients. The invention further relates to a process of preparing such composition and method of treating ulcerative colitis using such composition.

Budesonide, a synthetic corticosteroid, is designated chemically as (RS)- 1 1 p, 16a, 17,21 tetrahydroxypregna-1 ,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde.

Budesonide is provided as a mixture of two epimers (22R and 22S). Budesonide is having a molecular formula of C25H34O6 and has a molecular weight of 430.5 with the following structural formula:

Budesonide is a white to off-white, tasteless, odorless powder that is practically insoluble in water, sparingly soluble in alcohol, and freely soluble in chloroform.

Ulcerative colitis is a form of inflammatory bowel disease (IBD), a disease of the colon (large intestine) that includes characteristic ulcers, or open sores. The disease may be triggered in a susceptible person by environmental factors.

Treatment for ulcerative colitis depends on extent of involvement and disease severity. The ultimate goal of the treatment is to induce remission initially with medications, followed by the administration of maintenance medications to prevent a relapse of the disease.

Budesonide has a high topical glucocorticosteroid (GCS) activity and substantial first-pass elimination. Budesonide is currently marketed in US under brand name Uceris™ by Santarus and the formulation contains budesonide in an extended release tablet core. The tablet core is enteric coated to protect dissolution in gastric juice which delays budesonide release until exposure to a pH >7 in the small intestine. Upon disintegration of the coating, the core matrix provides extended release of budesonide in a time dependent manner.

U.S. Patent Nos. 7,410,651 ; 7,431 ,943; 8,293,273 & RE43,799 discloses controlled release and taste masking compositions containing budesonide as active ingredient incorporated in a three-component matrix structure, i.e. a structure formed by successive amphiphilic, lipophilic and hydrophilic matrices. U.S. Patent No. 4,608,248 discloses a process for the timed control of the release of active substance from a retarded release composition by the addition of a hydrophilic polymer. The patent further discloses that the rate of release of active substance increases with increasing polymer viscosity.

Budesonide is a type of medicament which is topically active in the gastrointestinal tract. When preparing sustained-, controlled-release dosage forms of such medicaments, it is important to avoid initial "burst release", facilitate extended release over the colonic length and ensure complete release of budesonide.

Prior art teaches attaining the said objective by using the combination of three matrices viz. successive amphiphilic, lipophilic and hydrophilic matrices. Such compositions are characterized by the absence of "burst release" of budesonide present superficially on the matrix by quick solubilization. The amphiphilic excipient present in the matrix compensates the lack of affinity of the aqueous solvent with the lipophilic excipients and further contributes to desired controlled release of budesonide.

There still exists an enduring need to develop alternative formulations of budesonide that employ limited excipients and provide desired release of budesonide or a pharmaceutically acceptable salt thereof from the formulation.

The inventors of present inventions have surprisingly found that it is possible to provide the similar in-vitro release profile of budesonide or a pharmaceutically acceptable salt thereof as compared to currently marketed preparation of budesonide i.e. Uceris^® which utilizes three matrix system namely lipophilic, amphiphilic and hydrophilic, by avoiding use of either lipophilic or amphiphilic excipients, and by legitimate selection of hydrophilic and other excipients. The inventors of the present invention have surprisingly found that by avoiding use of either amphiphilic or lipophilic excipients, and using hydrophilic excipients having low viscosity, it may be possible to provide a formulation that exhibits desired release profile of budesonide or a pharmaceutically acceptable salt thereof, particularly across the length of colon.

Further, the inventors of the present invention have also found that such formulation of budesonide or a pharmaceutically acceptable salt thereof can impart taste masking properties to the formulation and exhibit excellent storage stability.

Generally, the non-disintegrating formulations that are intended for delivery of medicaments to colon are marred by incomplete release of medicament due to the physiological characteristics of colon.

The compositions of the present invention are designed to avoid initial "burst release", facilitate extended release and ensure complete release of budesonide. The present invention avoids "burst release" of budesonide by dispersing amphiphilic or lipophilic matrix comprising budesonide or a pharmaceutically acceptable salt thereof into matrix of hydrophilic excipients. The composition also utilizes polymers having low viscosity in a manner so as to extend the release of budesonide over a period of time and yet, may ensure its complete release.

Without binding to any particular theory, the inventors of the present invention believe that, excipients, preferably polymers having low viscosity are particularly suitable for controlling the release of budesonide across the length of colon in a desired manner over an extended period of time. Summary of the Invention

In one general aspect, there is provided a solid oral modified-release composition comprising a core, said core comprising: (a) budesonide or a pharmaceutically acceptable salt thereof; (b) hydrophilic matrix comprising one or more hydrophilic excipients having viscosity less than 500 cps; said core further comprising: (i) amphiphilic matrix comprising one or more amphiphilic excipients, or (ii) lipophilic matrix comprising one or more lipophilic excipients.

In another general aspect, there is provided a solid oral modified-release composition comprising amphiphilic matrix comprising one or more amphiphilic excipients is devoid of lipophilic excipients.

In another general aspect, there is provided a solid oral modified-release composition comprising lipophilic matrix comprising one or more lipophilic excipients is devoid of amphiphilic excipients.

In another general aspect, the core is coated with one or more coating comprising one or more rate-controlling excipients, preferably polymers having pH dependent solubility comprising methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate, methyl methacrylate-methacrylic acid copolymers or combination thereof.

In another general aspect, there is provided a solid oral modified-release composition comprising budesonide or a pharmaceutically acceptable salt thereof, one or more amphiphilic or lipophilic excipients and one or more hydrophilic excipients having viscosity less than 500 cps, preferably, less than 300 cps. In another general aspect, there is provided a solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof, wherein polymers having low viscosity are low viscosity hydrogels having viscosity less than 500 cps.

In another general aspect, low viscosity polymers are selected from a group comprising low viscosity grades (less than 500 cps) of cellulosic polymers, such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, powdered cellulose such as microcrystalline cellulose, cellulose acetate, sodium carboxymethyl cellulose, calcium salt of carboxymethyl cellulose, and ethylcellulose. Preferably, combination of different grades of hydroxypropyl cellulose having viscosity less than 500 cps may be used.

Specifically, the amphiphilic matrix consists of excipients selected from polar lipids of type I or II (lecithin, phosphatidylcholine, phosphatidylethanolainine), ceramides, glycol alkyl ethers such as diethylene glycol monomethyl ether (Transcutol) or glycols partially etherified with Ci-C₄ alkyl chains or mixtures thereof.

Specifically, the lipophilic matrix consists of of at least one excipient having melting point within the range of 40 to 90°C and selected from unsaturated alcohols; hydrogenated alcohols; fatty acids or salts, esters or amides thereof; fatty acids mono-, di-or triglycerids; polyethoxylated derivatives fatty acids, waxes; ceramides; cholesterol derivatives or a mixture thereof.

In another general aspect, there is provided a solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof, wherein the composition comprises one or more sugars incorporated or dispersed in either an amphiphilic or lipophilic matrix. In another general aspect, the sugar comprises lactose, sucrose, maltose, dextrose, mannose, galactose, more preferably lactose.

In another general aspect, lactose may be present in form of anhydrate, monohydrate, hemihydrate or dihydrate or combination thereof.

In another general aspect, the core comprises less than 16% w/w, preferably in the range of about 16% to about 5% of sugar by weight of the core.

In another general aspect, the ratio of budesonide or a pharmaceutically acceptable salt thereof to sugar is in the range of 1 :5 to 1 :1 , preferably, in ratio of about 1 :5.

In another general aspect, sugar is dispersed or incorporated partly in a hydrophilic matrix and partly either in a lipophilic or an amphiphilic matrix.

In another general aspect, there is provided a solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof, wherein amphiphilic or lipophilic matrix is incorporated or dispersed in a hydrophilic matrix comprising one or more hydrophilic excipients to form a double matrix core.

In another general aspect, the double matrix core may be in the form of granules, pellets, beads, minitablets and tablets.

In another general aspect, there is provided a solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof; wherein the aforesaid double matrix structure of the composition imparts taste masking properties to the composition. In another general aspect, there is provided a solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof; wherein the amount of amphiphilic or lipophilic excipients ranges from about 0.1 % w/w to about 30% w/w of the composition. Preferably, the amount of said excipients range from about 1 % w/w to about 10% w/w of the composition.

In another general aspect, there is provided a solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof comprising hydrophilic matrix, either amphiphilic or lipophilic matrix and one or more sugars.

In another general aspect, there is provided a solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof; wherein the amount of hydrophilic excipients ranges from about 30% w/w to about 95% w/w of the composition. Preferably, the amount of hydrophilic excipients ranges from about 70% w/w to about 95% w/w of the composition.

In another general aspect, there is provided a solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof; wherein the ratio of the amount of budesonide or a pharmaceutically acceptable salt thereof to amphiphilic or lipophilic excipients ranges from about 1 :0.5 to about 1 :10 by weight.

In another general aspect, there is provided a solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof; wherein the ratio of the amount of budesonide or salt thereof to hydrophilic excipients ranges from about 1 :5 to about 1 :40 by weight.

In another general aspect, there is provided a solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof; wherein the ratio of the amount of amphiphilic or lipophilic excipients to hydrophilic excipients ranges from about 2:1 to about 1 :80 by weight.

In another general aspect, there is provided a solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof; wherein budesonide or a pharmaceutically acceptable salt thereof is released in any of the following amounts, when measured in in-vitro dissolution test using USP type II apparatus at 75 rpm:

a) not more than 5% of budesonide or a pharmaceutically acceptable salt thereof is released within 2 hours when the release is measured at pH 1 in 0.1 N HCI, b) not more than 5% of budesonide or a pharmaceutically acceptable salt thereof is released within 2 hours when the release is measured at pH 6.4 in phosphate buffer

c) at least 10% of budesonide or a pharmaceutically acceptable salt thereof is released within 2 hours when the release is measured at pH 7.2 in phosphate buffer,

d) at least 25% of budesonide or a pharmaceutically acceptable salt thereof is released within 4 hours when the release is measured at pH 7.2 in a phosphate buffer, or

e) at least 70% of budesonide or a pharmaceutically acceptable salt thereof is released within 8 hours when the release is measured at pH 7.2 in phosphate buffer.

In another general aspect, budesonide is released completely from the composition after 16 hours in in-vitro dissolution test.

In another general aspect, there is provided a solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof; wherein the composition may exhibit in-vitro drug release profile that is equivalent to marketed budesonide formulation (Uceris^®). In another general aspect, the solid oral modified-release composition comprises one or more pharmaceutically acceptable excipients comprising fillers, glidants, alkalizers, lubricants, anti-adherents, disintegrants, flavours, colours, preservatives, sweeteners, and binders.

In another general aspect, the solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof is in the form of tablets, pellets, capsules, granules or pellets filled in capsule, tablet in capsule, multilayer tablet, a bilayer tablet, a tri-layer tablet, or said dosage forms filled in a capsule. Preferably, the composition is in the form of a tablet.

In another general aspect, there is provided a process of preparing the solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof, which process comprises steps of:

a) preparing a core comprising budesonide or a pharmaceutically acceptable salt thereof, one or more amphiphilic excipients and one or more pharmaceutical excipients other than lipophilic excipients to form a amphiphilic matrix;

b) incorporating or dispersing amphiphilic matrix of step (a) in one or more hydrophilic excipients having viscosity less than 500 cps to form a double matrix core; and

c) formulating the double matrix core of step (b) into a solid oral composition intended for oral administration.

a) preparing a core comprising budesonide or a pharmaceutically acceptable salt thereof, one or more lipophilic excipients and one or more pharmaceutical excipients other than amphiphilic excipients to form a lipophilic matrix; b) incorporating or dispersing amphiphilic matrix of step (a) in one or more hydrophilic excipients having viscosity less than 500 cps to form a double matrix core; and

In another general aspect, there is provided a process comprising steps of:

a) preparing a core comprising budesonide or a pharmaceutically acceptable salt thereof, one or more amphiphilic or lipophilic excipients, one or more hydrophilic excipients having viscosity less than 500 cps and one or more pharmaceutical excipients to form a lipophilic or amphiphilic matrix;

b) incorporating or dispersing amphiphilic matrix of step (a) in one or more hydrophilic excipients to form a double matrix core; and

a) preparing a core by granulating budesonide or a pharmaceutically acceptable salt thereof with sugar in an amount more than 18% w/w of the core, one or more amphiphilic or lipophilic excipients and one or more pharmaceutical excipients to form a lipophilic or amphiphilic matrix in the form of granules;

b) incorporating or dispersing granules of step (a) in one or more hydrophilic excipients comprising polymers having viscosity less than 500 cps to form a double matrix core;

c) compressing the double matrix core of step (b) to form a tablet, and

d) coating the tablet of step (c) with one or more coatings comprising one or more rate-controlling polymers having pH dependent solubility. In another general aspect, the granulation step is carried out in a rapid mixer granulator or fluidized bed processor.

In another general aspect, the solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof retains at least 90% by weight of the total content of budesonide when stored at 40°C and 75% relative humidity over a period of at least 3 months.

In another general aspect, there is provided a method of treating ulcerative colitis or Chrohn's disease in a patient in need thereof, which method comprises of administering the solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof in accordance with the present invention.

Detailed Description of the Invention

The term "budesonide" as used throughout the specification refers to not only budesonide per se, but also its other a pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.

Suitable pharmacologically acceptable salts of budesonide are in particular water-soluble and water -insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4- hydroxybenzoyl)-benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 1 -hydroxys- naphthoic acid, the acids being employed in salt preparation - depending on whether it is a mono- or polybasic acid and depending on which salt is desired -in an equimolar quantitative ratio or one differing therefrom.

The term "double matrix core" as used herein refers to structure wherein two matrices differing in their properties are incorporated or dispersed in each other so as to form a physically defined structure. This core may be present in the form of granules, pellets, beads, minitablets and tablets. Preferably, the composition comprises of mixture of one or more forms of double matrix core viz. granules, pellets, beads, minitablets or tablets.

The term "hydrophilic excipients" as used throughout the specification refers to any excipient having a good affinity towards aqueous fluids.

The term "amphiphilic excipients" as used throughout the specification refers to any excipient comprising a molecule that has both a hydrophobic portion and a lipophobic portion and that has good affinity towards both aqueous and nonaqueous fluids.

The term "lipophilic excipients" as used throughout the specification refers to any excipient having a poor affinity towards aqueous fluids.

The term "matrix" as used herein can be described as a macroscopically homogeneous structure in all its volume. The term "amphiphilic matrix" as used herein can be described as a "matrix" of at least one amphiphilic excipient and a "hydrophilic matrix" as used herein can be described as a "matrix" of at least one hydrophilic excipient.

The term "modified release" as used herein means release, which is not immediate release and is taken to encompass controlled release, sustained release, prolonged release, timed release, retarded release, extended release and delayed release. The term "modified release dosage form" as used herein can be described as dosage forms whose drug-release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release dosage form. Modified release solid oral dosage forms include both delayed and extended release drug products.

The term "viscosity" as used herein can be described as viscosity of the 1 % w/w aqueous solution of hydrophilic excipient, polymer or hydrogel as measured by standard instruments such as Brookfield viscometer.

The solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof can be prepared without using lipophilic excipients or lipophilic matrix. Typically, the composition comprises of amphiphilic and hydrophilic matrices wherein budesonide or a pharmaceutically acceptable salt thereof is dispersed in amphiphilic matrix and that amphiphilic matrix in turn is dispersed in hydrophilic matrix.

In an embodiment, a solid oral modified-release composition comprising a core, said core comprising: (a) budesonide or a pharmaceutically acceptable salt thereof; (b) hydrophilic matrix comprising one or more hydrophilic excipients having viscosity less than 500 cps; said core further comprising: (i) amphiphilic matrix comprising one or more amphiphilic excipients, or (ii) lipophilic matrix comprising one or more lipophilic excipients.

In another embodiment, the solid oral modified-release composition comprising amphiphilic matrix comprising one or more amphiphilic excipients is devoid of lipophilic excipients. In another embodiment, the solid oral modified-release composition comprising lipophilic matrix comprising one or more lipophilic excipients is devoid of amphiphilic excipients.

In another embodiment, the amphiphilic or lipophilic matrix is incorporated or dispersed in a hydrophilic matrix comprising one or more hydrophilic excipients to form a double matrix core.

The double matrix core may be in the form of granules, pellets, beads, minitablets and tablets and may also be present in the form of mixture of granules or pellets or beads or pellets or minitablets or tablets. A typical double matrix core is formed by granulating budesonide or salt thereof with one or more amphiphilic excipients, one or more hydrophilic excipients and optionally, other pharmaceutical excipients, mixing the granules with one or more hydrophilic excipients and then compressing the resulting blend to form double matrix core.

The double matrix core may be present in the form of a tablet and preferably, that tablet is coated with one or more coatings comprising one or more rate- controlling excipients, preferably polymers having pH dependent solubility.

Hydrophilic excipient comprises one or more hydrophilic excipients having viscosity less than 500 cps. Hydrophilic excipient may comprise one or more polymers having viscosity than 500 cps.

The amount of hydrophilic excipients in the composition may range from about 30% w/w to about 95% w/w of the composition. Preferably, the amount of hydrophilic excipients ranges from about 70% w/w to about 95% w/w of the composition. In another embodiment, the ratio of the amount of budesonide or a pharmaceutically acceptable salt thereof to amphiphilic or lipophilic excipients in the composition is ranges from about 1 :0.5 to about 1 :10 by weight.

In another embodiment, the ratio of the amount of budesonide or pharmaceutically acceptable salt thereof to hydrophilic excipients in the composition is in the range of about 1 :5 to about 1 :40 by weight.

In another embodiment, the ratio of the amount of amphiphilic or lipophilic excipients to hydrophilic excipients in the composition is in the range of about 2:1 to about 1 :80 by weight.

The solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof in accordance with the present invention may impart budesonide taste masking properties to the composition.

In another embodiment, the solid oral modified-release composition comprises- a) about 0.1 % w/w to about 60% w/w of budesonide or a pharmaceutically acceptable salt thereof;

b) about 1 % w/w to about 30% w/w amphiphilic or lipophilic excipient;

c) about 30% w/w to about 95% w/w hydrophilic excipient;

d) about 1 % w/w to about 30% w/w of filler, and

e) about 0.01 % w/w to about 20% w/w of lubricant.

The solid oral modified-release composition may comprise one or more sugars as hydrophilic excipient.

Suitable sugar for use in the composition comprises lactose, sucrose, maltose, dextrose, mannose, galactose, more preferably lactose. Lactose may be present in form of anhydrate, monohydrate, hemihydrate or dihydrate or combination thereof. Sugar may be incorporated or dispersed in an amphiphilic or lipophilic matrix. It is important to use sugar in an appropriate amount, too less of it may lead to incomplete release and too much of it may lead to of uneven and immediate release of budesonide or a pharmaceutically acceptable salt thereof. Sugar may be dispersed or incorporated partly in a amphiphilic matrix and partly in a hydrophilic matrix and may be present in form of anhydrate, monohydrate, hemihydrate or dihydrate or combination thereof.

In another embodiment, the solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof, wherein sugar is used in an amount less than 16%, preferably, in the range of about 16% to about 5% by weight of the core.

In another embodiment, the ratio of amount of budesonide or a pharmaceutically acceptable salt thereof to sugar in the composition is in the range of 1 :5 to 1 :1 , preferably, in the ratio of about 1 :5.

In another embodiment, the solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof, wherein budesonide or a pharmaceutically acceptable salt thereof is released in any of the following amounts, when measured in in-vitro dissolution test using USP type II apparatus at 75 rpm:

c) at least 10% of budesonide or a pharmaceutically acceptable salt thereof is released within 2 hours when the release is measured at pH 7.2 in phosphate buffer, d) at least 25% of budesonide or a pharmaceutically acceptable salt thereof is released within 4 hours when the release is measured at pH 7.2 in a phosphate buffer, or

e) at least 70% of budesonide or a pharmaceutically acceptable salt thereof is released within 8 hours when the release is measured at pH 7.2 in phosphate buffer..

In another embodiment, there is provided a solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof; wherein the composition may exhibit in-vitro drug release profile that is equivalent to marketed budesonide formulation (Uceris^®). Preferably, budesonide is released completely from the composition after 8 hours in in-vitro dissolution test.

The solid oral modified-release composition of budesonide may be prepared by various methods known in the art.

Typically, budesonide, polymers, and other excipients are combined and wet granulated using a granulating fluid. However, other methods of forming granules such as slugging and roller compaction can also be used to manufacture matrix granules. Granules can be made in any granulating device such as mixers, high shear granulators, and fluid bed granulators. Granules can be dried in appropriate drying equipment such as fluid bed dryers, ovens etc. Granules can also be air-dried. Dried granules can be milled using appropriate milling device to achieve a particular particle size distribution. Granules can be blended with other excipients and tableted on a tablet press.

In another embodiment, the process of preparing the solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof comprises steps of: a) preparing a matrix comprising budesonide or a pharmaceutically acceptable salt thereof, one or more lipophilic or amphiphilic excipients to form a lipophilic or amphiphilic matrix;

b) incorporating or dispersing said lipophilic or amphiphilic matrix of step (a) in one or more hydrophilic excipients having viscosity less than 500 cps to form a double matrix core; and

In another embodiment, the process comprising steps of:

a) preparing a matrix comprising budesonide or a pharmaceutically acceptable salt thereof, one or more amphiphilic excipients and one or more excipients other than lipophilic excipients to form an amphiphilic matrix;

b) incorporating or dispersing said amphiphilic matrix of step (a) in one or more hydrophilic excipients having viscosity less than 500 cps to form a double matrix core; and

In another embodiment, the process comprising steps of:

a) preparing a matrix comprising budesonide or a pharmaceutically acceptable salt thereof, one or more lipophilic excipients and one or more excipients other than amphiphilic excipients to form a lipophilic matrix;

b) incorporating or dispersing said lipophilic matrix of step (a) in one or more hydrophilic excipients having viscosity less than 500 cps to form a double matrix core; and

In another embodiment, the process comprising steps of: a) preparing a core by granulating budesonide or a pharmaceutically acceptable salt thereof with sugar in an amount more than 18% w/w of the core, one or more amphiphilic excipients and one or more pharmaceutical excipients other than lipophilic excipients to form a amphiphilic matrix in the form of granules;

c) compressing the double matrix core of step (b) to form a tablet, and

d) coating the tablet of step (c) with one or more coatings comprising one or more rate-controlling polymers having pH dependent solubility.

In another embodiment, the process comprising steps of:

a) preparing a core by granulating budesonide or a pharmaceutically acceptable salt thereof with sugar in an amount more than 18% w/w of the core, one or more lipophilic excipients and one or more pharmaceutical excipients other than amphiphilic excipients to form a lipophilic matrix in the form of granules;

c) compressing the double matrix core of step (b) to form a tablet, and

The solid oral modified-release composition may be in the form of tablets, pellets, capsules, granules or pellets filled in capsule, tablet in capsule, multilayer tablet, a bilayer tablet, a tri-layer tablet, or said dosage forms filled in capsule. Preferably, the composition is in the form of a tablet.

The solid oral modified-release composition of budesonide or a pharmaceutically acceptable salt thereof may retain at least 90% by weight of the total content of budesonide when stored at 40°C and 75% relative humidity over a period of at least 3 months.

The solid oral modified-release composition may additionally comprises one or more pharmaceutically acceptable excipients selected from one or more binders, fillers, filler-binders, disintegrants, glidants, antiadherents, sweeteners, flavouring and colouring agents.

Examples of the rate-controlling excipients including polymers having pH dependent solubility used for coating comprising methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate, methyl methacrylate-methacrylic acid copolymers or combination thereof.

Examples of the hydrophilic/amphiphilic lubricants/glidants suitable for use in the solid oral modified-release composition of the present invention may be selected from one or more of polyethylene glycol, propylene glycol, talc, siliconised talc, micronised talc. Preferable lubricant/glidants is sodium stearyl fumarate.

Examples of the lipophilic lubricants/glidants suitable for use in the solid oral pharmaceutical composition of the present invention may be selected from stearic acid and magnesium stearate. Preferable lubricant/glidants is magnesium stearate.

Examples of the fillers or filler-binder suitable for use in the solid oral pharmaceutical composition of the present invention may be selected from starches, such as maize starch, potato starch, rice starch, wheat starch, pregelatinized starch, fully pregelatinized starch, cellulose, such as microcrystalline cellulose or silicified microcrystalline cellulose, mannitol, erythritol, calcium salts, such as calcium hydrogen phosphate dihydrate, anhydrous dibasic calcium phosphate, sorbitol, xylitol, or mixtures thereof.

Examples of the binders suitable for use in the solid oral pharmaceutical composition of the present invention may be selected from one or more of polyvinyl pyrrolidone (povidone), copolymers of vinylpyrrolidone with other vinylderivatives (copovidone), hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates and starch.

The invention further provides a method of treating ulcerative colitis or Chrohn's disease in a human in need thereof, wherein method comprises of administering the solid oral pharmaceutical composition as described herein.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

The invention now will be described in particularity with the following illustrative examples; however, the scope of the present invention is not intended to be, and shall not be, limited to the exemplified embodiments below. Example 1 : Budesonide Tablets

Table 1

Titanium dioxide 4.5

Dehydrated ethanol q. s.

Total weight of coated Tablet (mg) 340

Process:

Intragranular materials were sifted through sieve and were mixed in rapid mixer granulator. Solution of soy lecithin was prepared in dehydrate ethanol. Then wet granulation of pre-sifted intragranular materials was done with alcoholic solution of soy lecithin. Granules were then dried and sifted through sieve. Extragranular materials were sifted through sieve separately. Lubrication of dried granules of intragranular and extragranular materials was carried out in double cone blender. The blend was then compressed to form the tablets. The tablets were then coated using mixture of methacrylic acid and methyl methacrylate copolymers (1 :1 ) and methacrylic acid and methyl methacrylate copolymers (1 :2) in ethanol.

Dissolution study: Composition of Example 1 and marketed formulation of Budesonide (Uceris^®) were subjected to dissolution study. Dissolution was carried out in 0.1 N HCI for 2 hrs followed by pH 6.4 phosphate buffer for 2hrs followed by 7.2 pH phosphate buffer, 900ml_, USP Type II (Paddle), 100 rpm. Drug release profile exhibited by the formulations is summarized in Table 2.

Table 2

Example 2: Budesonide Tablets

Table 3

Hydroxy propyl cellulose (Klucel GXF) 35

Lactose anhydrous 20

Colloidal silicon dioxide 2.5

Extraqranular Inqredients (Lubrication)

Sodium stearyl fumarate 4.5

Total weight of core Tablet 300

Coating

Methacrylic acid and methyl methacrylate

14

copolymers (1 :1 )

Methacrylic acid and methyl methacrylate

12

copolymers (1 :2)

Talc (micronized) 7.9

Triethyl citrate 1 .6

Titanium dioxide 4.5

Dehydrated ethanol q. s.

Total weight of coated Tablet 340

Process:

Intragranular materials were sifted through sieve and were mixed in rapid mixer granulator. Solution of hydroxypropyl cellulose was prepared in water. Then wet granulation of pre-sifted intragranular materials was done with hydroxy propyl cellulose solution. Granules were then dried and sifted through sieve. Extragranular materials were sifted through sieve separately. Lubrication of dried granules of intragranular and extragranular materials was carried out in double cone blender. The blend was then compressed to form the tablets. The tablets were then coated using mixture of methacrylic acid and methyl methacrylate copolymers (1 :1 ) and methacrylic acid and methyl methacrylate copolymers (1 :2) in ethanol. Dissolution study: Composition of Example 1 and marketed formulation of Budesonide (Uceris^®) were subjected to dissolution study. Dissolution was carried out in 0.1 N HCI for 2 hrs followed by pH 6.4 phosphate buffer for 2hrs followed by 7.2 pH phosphate buffer, 900ml_, USP type II apparatus (Paddle) 100 rpm. Drug release profile exhibited by the formulations is summarized in Table 2.

Table 4

Claims

Claims:

1 . A solid oral modified-release composition comprising a core, said core comprising: (a) budesonide or a pharmaceutically acceptable salt thereof; (b) hydrophilic matrix comprising one or more hydrophilic excipients having viscosity less than 500 cps; said core further comprising: (i) amphiphilic matrix comprising one or more amphiphilic excipients, or (ii) lipophilic matrix comprising one or more lipophilic excipients.

2. The composition of claim 1 , wherein the amphiphilic matrix is devoid of lipophilic excipients.

3. The composition of claim 1 or 2, wherein the amphiphilic matrix consists of at least one excipient selected from polar lipids, ceramides, glycol alkyl ethers, glycols partially etherified with C1 -C4 alkyl chains or a mixture thereof.

4. The composition of claim 1 or 2, wherein the ratio of the amount of budesonide or a pharmaceutically acceptable salt thereof to the amphiphilic excipients ranges from about 1 :0.5 to about 1 :10 by weight.

5. The composition of claim 1 , wherein the lipophilic matrix is devoid of amphiphilic excipients.

6. The composition according to any one of the claims 1 or 5, wherein the lipophilic matrix consists of at least one excipient having melting point within the range of 40 to 90°C and selected from unsaturated alcohols; hydrogenated alcohols; fatty acids or salts, esters or amides thereof; fatty acids mono-, di-or triglycerids; polyethoxylated derivatives fatty acids, waxes; ceramides; cholesterol derivatives or a mixture thereof.

7. The composition of claim 1 or 5, wherein the ratio of the amount of budesonide or a pharmaceutically acceptable salt thereof to the lipophilic excipients ranges from about 1 :0.5 to about 1 :10 by weight.

8. The composition of claim 1 , wherein the ratio of the amount of budesonide or a pharmaceutically acceptable salt thereof to the hydrophilic excipients ranges from about 1 :5 to about 1 :40 by weight.

9. The composition of claim 1 , wherein the amount of amphiphilic or lipophilic excipients ranges from about 0.1 % w/w to about 30% w/w of the composition.

10. The composition of claim 1 , wherein the amount of hydrophilic excipients ranges from about 30% w/w to about 95% w/w of the composition.

1 1 .The composition of claim 1 , wherein the ratio of the amount of amphiphilic or lipophilic excipients to the hydrophilic excipients ranges from about 2:1 to about 1 :80 by weight.

12. The composition of claim 1 , further comprising one or more sugars.

13. The composition of claim 12, wherein the sugar is present in an amount which is less than 16% by weight of the core.

14. The composition of claim 12 or 13, wherein the ratio of budesonide or a pharmaceutically acceptable salt thereof to sugar ranges from about 1 :5 to about 1 :1 by weight.

15. The composition of claim 12, 13 or 14, wherein the sugar is at least one selected from lactose, sucrose, maltose, dextrose, mannose, galactose or mixture thereof.

16. The composition of any of the preceding claims 1 to 15, wherein said amphiphilic or lipophilic matrix is incorporated or dispersed in a hydrophilic matrix to form a double matrix core.

17. The composition of claim 16, wherein said double matrix core is capable of imparting taste masking to the composition.

18. The composition of claim 16, wherein said double matrix core is coated with one or more release-controlling excipients having pH dependent solubility.

19. The composition of claim 16, 17 or 18, wherein said double matrix core is in the form of granules, pellets, beads, minitablets, tablets or a combination thereof.

20. The composition of any of the preceding claims 1 to 19, wherein budesonide or a pharmaceutically acceptable salt thereof is released in any of the following amounts, when measured in in-vitro dissolution test using USP type II apparatus at 75 rpm:

a) not more than 5% of budesonide or a pharmaceutically acceptable salt thereof is released within 2 hours when the release is measured at pH 1 in 0.1 N HCI,

b) not more than 5% of budesonide or a pharmaceutically acceptable salt thereof is released within 2 hours when the release is measured at pH 6.4 in phosphate buffer

e) at least 70% of budesonide or a pharmaceutically acceptable salt thereof is released within 8 hours when the release is measured at pH 7.2 in phosphate buffer. The process of preparing solid oral modified-release composition of claim 1 , which process comprising:

a) preparing a matrix comprising budesonide or a pharmaceutically acceptable salt thereof, one or more lipophilic or amphiphilic excipients to form a lipophilic or amphiphilic matrix;

b) incorporating or dispersing said lipophilic or amphiphilic matrix in one or more hydrophilic excipients having viscosity less than 500 cps..