FIELD OF INVENTION

The present invention relates to oral pharmaceutical compositions comprising mesalamine or its pharmaceutically acceptable salts, and mixtures thereof.

More particularly, the present invention is related to delayed controlled release pharmaceutical composition comprising mesalamine or its pharmaceutically acceptable salts, and mixtures thereof, wherein the composition comprises rate-controlling hydrophilic and/or hydrophobic substances in the core matrix of the composition.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Mesalamine or Mesalazine (Formula I) is chemically known as 2- hydroxy-5-aminobenzoic acid or 5-aminosalicylic acid (5-ASA), which is a well- known locally acting anti-inflammatory agent used in the treatment of ulcerative colitis and Crohn's disease.

Mesalamine have been approved in the United States and other countries and is available in various dosage forms for oral administration. For example, ASACOL™ (mesalamine delayed immediate release tablets 400mg; Procter & Gamble), PENTASA^"^ (mesalamine extended release capsules 250mg «& 500mg;
Shire Inc.), LIALDA™ (mesalamine delayed controlled release tablets 1200mg; Shire Inc.) are the conmiercially available versions of this drug.

LIALDA™ is based on its Multi Matrix (MMX™) technology. The technology allows die delivery of active pharmaceutical ingredients into the lumen of the colon through tablets in a delayed and controlled extent with the effect that the active pharmaceutical ingredients can be {^plied to the full length of the colon. The technology involves complex manufacturing process and equipments; as well as specialized ingredients in order to achieve the desired results.

U.S. Patent No. 6,773,720 discloses controlled release oral pharmaceutical compositions containmg mesalamine, comprising: a) an inner lipophilic matrix consisting of substances with melting point below 90°C in which the active ingredient is at least partially inglobated; b) an outer hydrophilic matrix in which the lipophilic matrix is dispersed; c) optionally other excipients.

U.S. Patent Application Publication No. 2006/0159749 discloses controlled release and taste-masking compositions containing mesalamine incorporated in a three-component matrix structure, i.e. a structure formed by successive amphiphilic, lipophilic or inert matrices and finally incorporated or dispersed in hydrophilic matrices.

It has been surprisingly found that delayed controlled release of mesalamine yielding desired in-vitro release profiles matching with the commercially available LIALDA™ can be obtained by the use of rate controlling hydrophilic and/or hydrophobic substances in the core matrix of the composition, thereby avoiding the need of complex and costly Muki Matrix (MMX™) technology, thus enabling ease and cost-effectiveness in manufacturing such composition.

SUMMARY AND OBJECTIVE OF THE INVENTION

The present invention relates to oral pharmaceutical compositions comprising mesalamine or its pharmaceutically acceptable salts, and mixtures thereof; processes for preparing such compositions and their uses.

More particularly, the invention is related to delayed controlled release pharmaceutical compositions for oral administration comprising mesalamine or its pharmaceutically acceptable salts, and mixtures thereof, wherein the composition comprises rate-controlling hydrophilic and/or hydrophobic substances in the core matrix of the composition.

An aspect of the invention provides for a mesalamine composition that is essentially devoid of the lipophilic substances, especially in the core matrix of the composition.

Further aspect of the invention provides for pharmaceutical compositions of mesalamine wherein the mesalamine is admixed with rate-controlling hydrophilic substances and optionally other excipients, granulated, compressed into tablets, and optionally coated with an enteric polymer.

Another aspect of the invention provides for the pharmaceutical compositions of mesalamine wherein the mesalamine is admixed with rate- controlling hydrophobic substances and optionally other excipients, granulated, compressed into tablets, and optionally coated with an enteric polymer.

Another aspect of the invention provides for the pharmaceutical compositions of mesalamine wherein the mesalamine is admixed and granulated with rate-controlling hydrophilic substances and optionally other excipients and further embedded in a hydrophobic matrix, compressed into tablets, and optionally coated with an enteric polymer.

Another aspect of the invention provides for the pharmaceutical compositions of mesalamine wherein the mesalamine is admixed and granulated with rate-controlling hydrophobic substances and optionally other excipients and further embedded in a hydrophilic matrix, compressed into tablets and optionally coated with an enteric polymer.
Further aspect of the invention provides for pharmaceutical compositions of mesalamine wherein the release of mesalamine is in a delayed manner, or in a prolonged or extended manner or in a controlled manner or combination of delayed and controlled manner.
Further aspect of the invention provides for pharmaceutical compositions of mesalamine wherein the in vitro dissolution release profile matches with the commercially available LIALDA™.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to oral pharmaceutical compositions comprising mesalamine or its pharmaceutically acceptable salts, and mixtures thereof; processes for preparing such compositions and their uses.
More particularly, the present invention relates to oral phamaceutical compositions for delayed controlled release comprising mesalamine or its pharmaceutically acceptable salts, wherein the core matrix of the composition comprises rate-controlling hydrophilic and/or hydrophobic substances and optionally other pharmaceutically acceptable excipients, and further being devoid of lipophilic substances in the matrix core.
An embodiment of the invention provides for the delayed controlled release composition of mesalamine wherein the unit dose comprises mesalamine from about more than 800 mg in combination with rate-controlling hydrophilic and/or hydrophobic substances and optionally other pharmaceutical excipients, compressed into tablets and optionally coated with enteric polymers.
In context of the present invention, terms like "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for mesalamine and its pharmaceutically acceptable salts, and mixtures thereof
The terms "mesalamine" or "mesalazine" or "S-aminosalicylic acid" or "5-ASA" relate to the active ingredient.
The term "delayed controlled release" refers to the in vitro release of mesalamine wherein no drug is released in the initial acid phase for about 2 hours and buffer stage (pH 6.4 ± 0.4) for about 1 hour followed by programmed or controlled release in buffer stage (pH 7.2) for about 4-12hrs.
The term "matrix" or "core matrix" as used herein refers to homogeneous intimate admixture or dispersion of the active substance within the rate- controlling hydrophilic and/or hydrophobic substances, optionally along with other pharmaceutically acceptable excipients; further being devoid of, or free from lipophilic substances. The core can be a particle, a granule, a pellet, a bead, a mini-tablet, a tablet and the like.
The term "lipophilic substances" as used herein and which are excluded from the scope of the present invention comprises substances selected from unsaturated and/or hydrogenated fatty acids, salts, esters or amides thereof, fatty acids mono-, di- or triglycerides, waxes, ceramides, cholesterol derivatives or mixtures tfiereof having melting point within the range of 40°C to 90°C. It also includes Ce-Cao alcohols or Cg-Cao fatty acids or esters of fatty acids with glycerol or sorbitol or other polyalcohols with carbon atom chain not higher than six. It further includes polar lipids of type I or II or glycols partially etherified with Cp C4 alkyl chains.
The term "hydrophilic" refers to the general meaning of being having a property of likeness or affinity of a substance towards water or the like solvent system and mixtures thereof.
The term "hydrophobic" refers to the general meaning of being having a property of non-affinity of a substance towards water or like solvent system and mixtures tiiereof
In an embodiment of the invention, mesalamine is admixed and granulated with rate-controlling hydrophilic substances and optionally other excipients, compressed into tablets, and optionally coated with an enteric polymer.
The rate-controlling hydrophilic substances according to tiie invention include both non-polymeric and polymeric substances and their mixtures thereof Non-limiting examples include cellulose and cellulose derivatives like hydroxypropyl methylcellulose(HPMC), hydroxypropyl cellulose (HPC), cellulose carboxymethyl ethers and their salts, polyvinyl acetate (homopolymer); propylene glycol alginate; polyvinylpyrrolidone (PVP); polyvinylpyrrolidone/vinyl acetate (PVPA^A) copolymer; polyalkylene polyols like polyethylene glycols; gelatin and gelatin derivatives; alginates; carbomers; polycarbophils; carrageenans; pectins; chitosans; cyclodextrins; natural and synthetic gums containing galactomannans like xanthan gum, tragacanth, acacia.
agar, guar gum, and the like. Other substances which demonstrate similar characteristics are also included within the scope of the present invention.
In an another embodiment of the invention, mesalamine is admixed and granulated with rate-controlling hydrophobic substances and optionally other excipients, compressed into tablets, and optionally coated with an enteric polymer.
The rate-controlling hydrophobic substances according to the invention include both non-polymeric and polymeric substmices and their mixtures thereof Non-limiting examples include cellulose and cellulose derivatives like methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, cellulose acetate and their salts, stearic acid and their salts; cross-linked vinyl pyrrolidone polymers (commercially available under the name "crospovidone"), polymethacrylic acid based polymers and copolymers sold under the trade name of EUDRAGIT™ (including Eudragit™ L30D, Eudragit™ NE SOD, Eudragit™ RL and Eudragit™ RS), aliphatic polyesters, shellac, zein and the like. Any other substance which demonstrates similar characteristics, are also included within the scope of the present invention.
In an another embodiment of the invention, mesalamine is admixed and granulated with rate-controlling hydrophilic substances and optionally other excipients and further embedded in a hydrophobic matrix, compressed into tablets, and optionally coated with an enteric polymer.
In a further embodiment of the invention, mesalamine is admixed and granulated with rate-controlling hydrophobic substances and optionally other excipients and further embedded in a hydrophilic matrix, compressed into tablets and optionally coated with an enteric polymer.
The enteric polymers used according to the invention are one which provide protection to the composition against drug release in the stomach and enable controlled release in the intestine. The dosage form according to the present invention can reach the colon, without being exposed to the variations in gastric pH, by coating them with a pH-dependent polymer, insoluble in acidic pH but soluble in neutral or alkaline pH. The polymers most currently used for this purpose are derivatives of methacrylic acid, for example commercially available Eudragit™ L, Eudragit™ S and their combinations thereof However other polymer or substances which demonstrate similar characteristics, are also included within the scope of the present invention.
The enteric-coat may also further comprise a plasticizer, a surfactant, anti- foaming agent, anti-tacking agent and optionally a pigment.
Other pharmaceutically acceptable excipients which can optionally be used in preparation of the particles, granules, pellets, beads, mini-tablets, tablets or final dosage form according to the invention may include, but are not limited to diluents such as microcrystalline cellulose (MCC), silicified MCC, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like; binders such as PVP, cellulose derivatives such as hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, carboxy methyl cellulose sodium, starch and the likes; disintegrants such as crospovidone, sodium starch glycolate, starch and its derivatives, low- substituted hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose and the like; glidant and lubricants such as colloidal silicon dioxide, talc, stearic acid and its salts and the like; plasticizers such as diethylphthalate, triacetin, tributyl sebacate, or polyethylene glycol and the like; anti-foaming agents such as dimethicone, simethicone and the like; surfactants such as sodium dodecyl sulfate, and the like; anti-tacking agents such as talc, fumed silica, magnesium stearate and the like; pigments such as titanium dioxide, edible lake pigments and the like.
According to the invention the weight of the orally administrable controlled release composition comprising more than about 800mg of mesalamine ranges between 1200 to ISOOmg; and preferably between about 1300mg to about 1700mg.
The controlled release composition according to this invention, are prepared by forming a tablet-like matrix in which the active ingredient is dispersed along with or within the rate-controlling hydrophilic and/or hydrophobic substances and their mixtures thereof, granulating them suitably, compressing the granulates and other optional excipients into tablets and then coating this matrix tablet with an enteric coat. Optionally a sub/seal coat can also be applied between the core matrix tablet and the enteric coating layer.
To form the tablet matrix or core, granulation technique ^ch as dry granulation or wet granulation is employed. In dry granulation, the ingredients are blended in dry form, made denser by slugging or compaction and reduced to granules by grinding or milling, using suitable equipments. The ground particles or granules are then compressed into tablet form in conventional manner using lubricants, glidants, etc., which can take any of the conventional shapes, e.g., round, elongated, oval, etc. A tablet press fitted with suitably sized punches and dies is used to form the tablet core.
The wet granulation technique can also be used. According to this procedure, the dry active ingredient, rate-controlling hydrophilic and/or hydrophobic substances and other diluents are blended, for example, in a
planetary mixer or a rapid mixer granulator. The powders are wetted with a granulating liquid like water, isopropyl alcohol or acetone or dichloromethane and otiier hydro-alcoholic solvents such as isopropyl alcohol-water mixture. Binders may be included in the granulating liquid. The moist mass is granulated, e.g., by forcing through a screen of suitable mesh size, dried, and, if desired, the particles further reduced in size. Granules obtained are then compressed in conventional manner, using lubricants, glidants, etc., as required.
The enteric film forming polymers are applied by spraying a system containing them on the core by conventional film coating techniques. The enteric polymers are dissolved in a solvent or mixture of solvents in which both types are soluble or form a solvent system. Such solvents include alcohols like methyl alcohol, ethyl alcohol or isopropyl alcohol, ketones like acetone, methyl ethyl ketone, chlorinated hydrocarbons like methylene chloride, dichloroediane, 1,1,1- trichloroethane, etc. The coating composition may optionally further include plasticizers, surfactants, anti-tacking agents, anti-foaming agents and pigments.
Conventional coating machines, for example, pan coaters, rotary drum- type coaters, Wurster-type fluidizing coaters and fluidizing coaters may be employed in the method of the invention.
In a further embodiment of the invention, release of mesalamine from the composition according to the invention is in a delayed manner, or in a prolonged or extended manner or in a controlled manner or combination of delayed and controlled manner.
The composition according to the present invention has an in vitro release profile of mesalamine wherein no drug is released in the initial acid phase (O.IN HCl) for about 2 hours when tested using the USP Dissolution Apparatus Type II at 100 rpm; and no drug is fiirttier released in the buffer stage I (pH 6.4 ± 0.4 phosphate buffer) for about 1 hour, when tested using the USP Dissolution Apparatus Type II at 100 rpm; followed by programmed or controlled release in buffer stage II (pH 7.2 phosphate buffer) for about 4-12hrs. The programmed or controlled release of the present composition ensures uniform delivery of the drug in the colon preferably for about 6-lOhrs.
Further embodiment of the invention provides for pharmaceutical composition of mesalamine wherein the in vitro dissolution release profile matches with the commercially available LIALDA™.
The compositions according of the present invention can be used for the treatment of Crohn's disease, ulcerative colitis, inflammatory bowel disease and any other such disease conditions.
Following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof It is to be understood that the examples given are by way of illustration only and are not intended to limit the scope of the invention in any manner.

Brief Manufacturing process:
1. Mesalamine, dicalcium phosphate, and stearic acid were milled separately throu^ Quadra co-mill fitted with suitable screen.
2. Preparation of binder solution: Eudragit L30D was diluted with sufficient quantity of purified water.
3. Mesalamine and dicalcium phosphate were mixed in a blender.
4. Blend from step 3 was granulated with binder solution of step 2.
5. Wet mass obtained from the step 4 was milled using suitable screen.
6. The granules were dried in rapid dryer at 60°C to get LOD below 3.0% at 105°C.
7. The dried granules were sifted through mechanical sifter fitted with mesh #20.
8. Sifted granules of step 7 were lubricated along with the stearic acid (initially sifted through # 40 mesh).
9. Compression: Lubricated blend of step 8 was compressed using suitable tooling.

Brief Manufacturing process:
1. Mesalamine, sodium carboxy methyl cellulose and stearic acid were milled separately through Quadra co-mill fitted with suitable screen.
2. Preparation of binder solution: Eudragit L30D was diluted with sufficient quantity of purified water.
3. Mesalamine and sodium CMC were mixed in a blender.
4. Blend from step 3 was granulated with above binder solution of step 2.
5. Wet mass obtained from the step 4 was milled using suitable screen.
6. The granules were dried in rsq)id dryer at 60° C to get LOD below 3.0% at 105°C
7. The dried granules were sifted through mechanical sifter fitted with mesh #20.
8. Sifted granules of step 7 were lubricated along with the stearic acid (initially sifted through # 40 mesh).
9. Compression: Lubricated blend of step 8 was compressed using suitable tooling.

Brief Manufacturing process'.
1. Mesalamine, crospovidone and stearic acid were milled separately through Quadra co-mill fitted with suitable screen.
2. Preparation of binder solution: HPMC was dissolved in purified water with continuous stirring to get clear solution.
3. Mesalamine was granulated with binder solution obtained from Step 2.
4. Wet mass obtained from the Step 3 was milled.
5. The granules were dried in rapid dryer at 60° C to get LOD below 3.0% at 105°C
6. The dried granules were sifted through mechanical sifter fitted with mesh #20.
7. Sifted granules of step 6 were mixed with crospovidone and then lubricated along with the stearic acid (initially sifted through # 40 mesh).
8. Compression: Lubricated blend of Step 7 was compressed using suitable tooling.

Brief Manufacturing process'.
1. Mesalamine, crospovidone and stearic acid were milled separately through Quadra co-mill fitted with suitable screen.
2. Preparation of binder solution: PVP K90 was dissolved in purified water with continuous stirring to get clear solution.
3. Mesalamine was granulated with the binder solution obtained from step 2.
4. Wet mass obtained from the step 3 was milled using suitable screen.
5. The granules were dried in rapid dryer at 60° C to get LOD below 3.0% at 105°C
6. The dried granules were sifted through mechanical sifter fitted with mesh #20.
7. Sifted granules of step 6 were mixed with crospovidone and then lubricated along with the stearic acid (initially sifted through # 40 mesh).
8. Compression: Lubricated blend of Step 7 was compressed using suitable tooling.

Brief Manufacturing process'.
1. Mesalamine, sodium carboxy methyl cellulose and stearic acid were milled separately through Quadra co-mill fitted with suitable screen.
2. Mesalamine and sodium carboxy methyl cellulose were mixed in a blender.
3. Blend from step 2 was granulated with purified water.
4. Wet mass obtained from the step 3 was milled using suitable screen.
5. The granules were dried in rapid dryer at 60° C to get LOD below 3.0% at 105°C.
6. The dried granules were sifted through mechanical sifter fitted with mesh #20.
7. Sifted granules of step 6 were lubricated along with the stearic acid (initially sifted through # 40 mesh).
8. Compression: Lubricated blend of step 7 was compressed using suitable tooling.
9. Coating: Coated the tablets of step 8 using above given coating composition.

Brief Manufacturing process:
1. Preparation of binder solution 1: Sodium carboxy methyl cellulose was dispersed in purified water under stirring to get a clear solution. Eudragit L30DS5 is dispersed in the above solution under stirring.
2. Mesalamine and sodium starch glycolate were co-sifted using quadro-co- mill using appropriate screen and loaded into the rapid mixer granulator.
4. Wet mass obtained was dried in fluid bed drier at 60° C till LOD below 2% is attained.
5. Dried granules obtained were milled through quadro-co-mill usmg appropriate screen.
6. Preparation of binder solution 2: Sodium CMC was dispersed in the purified water under stirring to get a clear solution.
7. Methocel E15LV, Methocel E50LV, Aerosil 200 and sodium starch glycolate were sifted through vibratory sifter using appropriate screen.
8. Materials of step 7 along with granules from step 5 were loaded in the rapid mixer granulator and mixed for sufficient period of time.
9. Above mix was granulated with the binder solution 2 prepared from step 6.
10. Wet mass obtained was dried in fluid bed drier at 60° C till LOD below 2% is attained.
11. Dried granules obtained were milled through quadro-co-mill using appropriate screen.
12. Granules from step 11 were lubricated along with the stearic acid (initially sifted through appropriate screen).
13. Compression: Lubricated blend of step 12 was compressed using appropriate tooling.
14. Seal Coating: Tablets of step 13 were seal coated.
15. Enteric Coating: Seal coated tablets were coated with the coating composition mentioned in the above table.
16. Opadry coating: Enteric coated tablets were finally coated with Opadry Pink.

Dissotution study;

The compositions according to the present invention were tested for the in vitro release profile as laid down below:

Acid Stage: Media: 500 mL of O.IN HCl for initial 2hrs; USP II Method; 100 rpm

Followed by….

Buffer Stage I: Media: 900mL of pH 6.4 ± 0.4 phosphate buffer for next Ihr; USP II method; 100 rpm

Followed by....

Buffer Stage II: Media: 900mL of pH 7.2 phosphate buffer for next 8hrs; USP II method; 50 rpm.

WE CLAIM:

1. A delayed controlled release oral pharmaceutical composition containing an effective amount of mesalamine, wherein said composition essentially comprises:

a) a core matrix consisting of a rate-controlling hydrophilic or hydrophobic substance and optionally other pharmaceutically acceptable excipient;

b) optionally a seal/sub coat over said core matrix;

c) an enteric coat over said core matrix.

2. The delayed controlled release oral pharmaceutical composition according to claim 1, wherein said core matrix consists of particles, granules, pellets, mini-tablets and tablets.

3. The delayed controlled release oral pharmaceutical composition according to claim 1, wherein said rate-controlling hydrophilic substance is selected from a group consisting of: hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, carboxymethyl cellulose sodium, sodium polyacrylate, polyvinyl alcohol, polyethylene glycol, sodium alginate, and guar gum.

4. The delayed controlled release oral pharmaceutical composition according to claim 1, wherein said rate-controlling hydrophobic substance is selected from a group consisting of methyl cellulose, ethyl cellulose, cellulose acetate, stearic acid, methacrylate polymers, aliphatic polyesters, shellac and zein.

5. The delayed controlled release oral pharmaceutical composition according to claim 1, wherein said enteric coat comprises an enteric polymer selected from commercially available Eudragit™ L, Eudragit™ S and combinations thereof.

6. A delayed controlled release oral pharmaceutical composition in the form of tablet containing an effective amount of mesalamine, wherein said tablet is prepared by a process consisting essentially of:

a) admixing and granulating mesalamine with a rate-controlling hydrophilic or hydrophobic substance and optionally other pharmaceutically acceptable excipients to form a core matrix;

b) compressing said core matrix into a tablet;

c) optionally applying a seal/sub coat to said tablet; and

d) applying an enteric coating.

7. The delayed controlled release oral tablet according to claim 6, wherein mesalamine is present in a weight range of 800mg to 1200 mg and the final tablet weighs in the range of 1200mg to 1800g.

8. The delayed controlled release oral pharmaceutical composition according to claim 1 and 6, wherein other pharmaceutically acceptable excipients are selected from the group consisting of diluents, binders, disintegrants, glidants, lubricants, and stabilizers.

9. The delayed controlled release oral pharmaceutical composition according to claim 5, wherein the enteric coat further comprises a plasticizer, antifoaming agent, anti-tacking agent, pore-formers and pigments.

10. The delayed controlled release oral pharmaceutical composition according to any of the preceding claims, wherein the core matrix is devoid of any lipophilic substance.