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 release pharmaceutical compositions comprising mesalamine or its pharmaceutically acceptable salts, and mixtures thereof, wherein said compositions comprise a single enteric coating layer coated over the core, where in said coating minimizes the impact or negative effects of coating fractures, especially for larger or heavier unit dosage forms.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Mesalamine or Mesalazine (Structure I) is chemically known as 2- hydroxy-5-aminobenzoic acid or 5-aminosalicylic acid (5-AS A), 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 release tablets 400mg & 800mg; Procter & Gamble), PENT ASA™ (mesalamine extended release capsules 250mg & 500mg; Shire Inc.), LIALDA™ (mesalamine delayed controlled release tablets 1200mg; Shire Inc.) are the commercially available versions of this drug.

High dose dosage forms such as that of mesalamine tend to have higher tablet core weight in the range of 0.7-1.5 g, which are subjected to critical process of enteric coating in order to ensure that the drug is delivered in the gastrointestinal tract at the exact site and in precise amount. Hence in such cases, the enteric coating layer forms an integral and important part of such specialized dosage form, so as to ensure the success of drug delivery at the specific site in the gastrointestinal tract.

In view of the above facts, there always exists the problem or possibility of coating fractures that may occur during processing, manufacturing, packaging, transportation or even during shelf-life storage of said oral unit dosage form. Coating fractures can cause unreliable or inconsistent delivery or release of the drug to the desired site in the gastrointestinal tract. These fractures may also be associated with premature rupture or release of the unit dosage forms. Moreover, these coating fractures are especially problematic for larger than average size unit dosage forms or heavier unit dosage forms as in this particular case of mesalamine.

US 5,171,580 discloses pharmaceutical preparations containing an active ingredient to be released in the lower part of the gastrointestinal tract, the large intestine and especially the colon, consisting of a core with the active, the core being coated with three protective layers at different solubilities, to release the active ingredient especially in the colon, achieved with the three protection layers, as well as the benefits of having a selective effect in the colon.

US 5,686,105 discloses colonic delivery of therapeutic agents wherein the dosage form comprises a coating system with at least one inner coating layer and one outer coating layer. The inner coating layer is an enteric polymer that begins to dissolve in an aqueous media at a pH between about 5 to about 6,3, and the outer coating layer is an enteric polymer that begins to dissolve in an aqueous media at a pH between about 6.8 to about 7.2.

US 5,482,718 discloses a tablet comprising three parts; (1) an enteric coating to prevent penetration of gastric fluid into the delivery system, thereby preventing any drug release in the stomach; (2) an erodible polymer layer which is exposed and gradually erodes during transit through the upper intestinal tract, and (3) a core, which is a conventional tablet or beadlet containing an active ingredient(s), which readily disintegrates and subsequently releases the drug to the target site, the colon, after erosion of the erodible polymer layer. The erodible polymer layer prevents drug release in the upper portion of the intestinal tract for 4-6 hours after gastric emptying, representing the amount of time needed for the delivery system to reach the colon.

WO 98/27967 discloses a tablet comprising three parts: a) an inner core containing a biologically active ingredient and conventional excipients, b) an enteric coating, which prevents gastric fluid to enter into the core thereby preventing drug release in the stomach, but being soluble in the intestinal fluid (pH > 5), and c) an outer coating consisting of one or more polymer(s).

The prior arts cited above disclose the use of more than one coating layer over the core tablet in order to achieve the drug release in the desired region of the gastrointestinal tract. Further none of them addresses the problem of coating fractures that may occur during processing, manufacturing, packaging, transportation or even during shelf-life storage of said oral unit dosage.

However, US 6,893,662 addressed the above problem of coating fractures in larger than average size unit dosage forms or heavier unit dosage forms and discloses a pharmaceutical composition in a solid unit dosage form comprising an inner enteric coating layer and an outer enteric coating layer; wherein the inner coating layer is not the same as the outer coating layer; and further the inner coating layer and the outer coating layer do not contain any drug.

But the above prior art again teaches the use of more than one coating layer in order to address the problem of coating fractures as disclosed above. Multiple coating layers over the core dosage form has the inherent problems, for example, the requirement of higher quantity of coating materials per dosage form; increased process time; increased exposure of active ingredient to more solvents and temperature during coating and subsequent drying process, thus subjecting the sensitive drugs to harsh conditions; increased residual solvents in the final dosage form and lastly increased manufacturing costs.

It has been surprisingly found that the above problem or possibility of coating fractures that may occur during processing, manufacturing, packaging, transportation or even during shelf-life storage of oral unit dosage which are larger than average size or heavier unit dosage forms can be addressed by the use of a single enteric coating layer over the core dosage form, thus minimizing or eliminating any coating fractures that can occur and further ensuring consistent delivery or release of the active agent to the desired site in the gastrointestinal tract.

This and other such needs are addressed by the present invention.

SUMMARY AND OBJECTIVE OF THE INVENTION

The present invention relates to oral pharmaceutical composition comprising mesalamine or its pharmaceutically acceptable salts, and mixtures thereof; processes for preparing such compositions and their uses-More particularly, the present invention is related to delayed release pharmaceutical compositions for oral administration comprising mesalamine or its pharmaceutically acceptable salts, and mixtures thereof, wherein said compositions comprise a single enteric coating layer coated over the core, wherein said coating layer minimizes the possibility or negative effects of coating fractures, especially for larger or heavier unit dosage forms.

An aspect of the present invention provides for mesalamine compositions that are essentially devoid of multiple enteric coating layers, especially over the core of the dosage form.

Further aspect of the present invention provides for pharmaceutical compositions of mesalamine wherein the rupture of the dosage form during the processing, manufacturing, packaging, transportation or even during shelf-life storage of said oral unit dosage form are prevented.

Another aspect of the present invention provides for the process of preparing pharmaceutical compositions of mesalamine wherein said compositions comprises a single enteric coating layer coated over the core wherein said coating layer minimizes the impact or negative effects of coating fractures, especially for larger or heavier unit dosage forms.

Further aspect of the present 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 combination of delayed and extended manner.

Further aspect of the present invention provides for the pharmaceutical compositions of mesalamine wherein the in vitro dissolution release profile matches with the commercially available ASACOL" 800mg.

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.

An embodiment of the invention provides for the delayed release composition of mesalamine wherein the unit dose comprises mesalamine from about more than 500 mg in combination with other pharmaceutically acceptable recipients, compressed into tablets and coated with a single enteric coating layer wherein the coating layer minimizes the impact or negative effects of coating fractures that may occur during processing, manufacturing, packaging, transportation or even during shelf-life storage of said oral unit dosage form.

In the context of the present invention, the terms "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for mesalamine.

The terms "mesalamine" or "mesalazine" or "5-aminosalicylic acid" or "5- ASA" all relate to above active ingredient.

The term "core" or "core matrix" as used herein refers to a particle, a granule, a pellet, a bead, a mini-tablet, a tablet and the like.

The "larger" or "heavier" unit dosage forms according to the invention are those, wherein the weight of the core or core matrix is atleast 800mg. More preferably the weight of the core or core matrix is in the range of 850mg – ll00mg.

The enteric coating layer employed herein, is one which is applied directly onto the core by using conventional process known to one skilled in the art. The enteric coating layer can also be employed over an optional seal coat layer by using conventional process known in the art.

According to the present invention the weight of the orally administrable delayed release composition comprising more than about 500mg of mesalamine ranges between 1000 to 1700mg; and preferably between about 1100 mg to about 1600mg.

Other pharmaceutically acceptable recipients which can be used in the 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 cros-povidone, 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.

The tablets according to this invention are prepared by forming a table tlike matrix in which the active ingredient in combination with other pharmaceutically acceptable excipients are granulated suitably, compressing said 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 techniques such 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, 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 other 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. The granulates are then compressed in conventional manner, using lubricants, glidants, etc., as required.

The core can optionally be coated with a sub/seal coat, which provides a smoothing coat in order to have uniform surface to coat the enteric polymer layer. The seal coat comprises polymers such as cellulose derivatives such as one which is commercially available as Opadry®.

The enteric polymers used in the context of the invention are those which provide protection to the dosage form against drug release in the stomach and enable delayed release in the intestine and further prevent or minimizes the impact or negative effects of coating fractures, especially for larger or heavier unit dosage forms. The tablets 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 polymethacrylates, anionic polymethacrylates, poly(methacrylic acid, methyl methacrylate) 1:1, mixtures of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacryIic acid, methyl methacrylate) 1:1, poly(methyl acrylate, methyl methacrylate, methacrylic acid); cellulose acetate phthalate, cellulose acetate trimelliate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate phthalate, poly(methacrylic acid, ethyl acrylate) 1:1, and compatible mixtures thereof However other polymer or substances which demonstrate similar characteristics, are also included within 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.

Plasticizers are selected from among 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.

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. Such solvents include alcohols like methyl alcohol, ethyl alcohol or isopropyl alcohol, ketones like acetone, methyl ethyl ketone, chlorinated hydrocarbons like methylene chloride, dichloroethane, 1,1,1- trichloroethane, etc. The coating composition may optionally further include plasticizers, surfactants, anti-tacking agents, anti-foaming agents and pigments.

The enteric coating layer coated over the core is of sufficient thickness so as to avoid the rupturing, as well as to deliver the drug at its required site. Preferably the thickness of enteric coating layer is at least 60 µm, More preferably, the thickness of said enteric coating layer is in the range of 70-180µm.

Conventional coating machines, for example, pan coaters, rotary drum- type coaters, Wurster-type fluidizing coaters and fluidizing coaters may be employed in said method of the invention.

In a further embodiment of the invention, release of mesalamine according to the present invention is in a delayed manner, or in a prolonged or extended manner or in a combination of delayed and extended 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 ftirther released in the buffer stage I (pH 6.0 phosphate buffer) for about 1 hour, when tested using the USP Dissolution Apparatus Type II at 100 rpm; followed by programmed release in buffer stage II (pH 7.2 phosphate buffer) for about 2hrs.

Further embodiment of the invention provides for the pharmaceutical composition of mesalamine wherein the in vitro dissolution release profile matches with the commercially available ASACOL™ 800mg.
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.

The 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 are given by way of illustration only and are not intended to limit the scope of the invention in any manner,

Compositions:

S. Ingredients Exl Ex2 Ex3 Exl eTs e76
No.


Intra-granular

L [Mesalamine 800.00 800.00 800.00 800.00 800.00 800.00
2. Lactose monohydrate 85.00 85.00 85.00 85.00 85.00 85.00
3. Povidone 30.00 30.00 30.00 30.00 30.00 30.00
4. Sodmon starch glycolate 25.00 25.00 25.00 25.00 25.00
Extra-granular
5. Sodium starch glycolate 25.00 25.00 25.00 25.00 25.00 25.00
6. Colloidal Silicon dioxide 20.00 20.00 20.00 20.00 20.00 20.00
7. Magnesium Stearate 15.00 15.00 15.00 15.00 15.00 15.00
Core weight 1000.00 1000.00 1000.00 1000.00 1000.00 1000.00
Sub-coat
8. Opadry ® Clear 30.00 30.00 30.00 -- -- --
Enteric Coat
9. Eudragit® S-100 28.00 28.00 --- 28.00 28.00 ---
10. Eudragit® FS30D 28.00 --- 28.00 28.00 -- 28.00
11. HPMC AS-HF --- 28.00 28.00 -- 28.00 28.00
12. Di-butyl phthalate 7.00 7.00 7.00 7.00 7.00 7.00
13. Iron oxide red 0.35 0.35 0.35 0.35 0.35 0.35
14 . Talc 7.65 7.65 7.65 7.65 7.65 7.65
15. Isopropyl alcohol q.s. q.s. q.s. q.s. q.s. q.s.
16. Purified Water q.s. q.s q.s. q.s. q.s. 28.00
Total Tablet Weight 1100.00 1100.00 1100.00 1100.00 1100.00 1100.00

Physical observations of Coating rupture time;

The tablets coated with the above enteric coating compositions are subjected to physical observation in the following dissolution conditions (which simulates various physiological pH and residence time as suggested by Office of Generic Drug - Dissolution recommendation for Mesalamine Delayed Release Tablets) to observe the rupture time of coating layer, thereby giving a measure of the effect of the composition to prevent the impact or negative effects of coating fractures, especially for larger or heavier unit dosage forms. The results below shows that the single enteric coating composition according to the invention provides similar or comparable results, when compared with the commercially available Asacol ™ 800mg which comprises multiple enteric coating layer.

Condition 1: O.IN HCl (900ml, 100rpm, USP II) followed by pH 6.0 Phosphate Buffer (900 ml, 50 rpm, USP II)
Medium Time Observation
(mins) Asacol ™ Ex 1 Ex 2 Ex3 Ex4 Ex5 Ex 6
800mg
O.IN HCl 60 No No No No No No No
120 rupture rupture rupture rupture rupture rupture rupture
pH 6.0 60 No No No No No No No
Phosphate 120 rupture rupture rupture rupture rupture rupture rupture
Buffer 150
Condition 2: O.IN HCl (900ml, lOOrpm, USP II) followed by pH 6.5 Phosphate Buffer (900 ml, 50 rpm, USP II)
Medium Time Observation
(mins) Asacol ™ Ex 1 Ex 2 Ex 3 Ex 4 Ex5 Ex 6
800mg
O.IN HCl 60 No No No No No No No
120 rupture rupture rupture rupture rupture rupture rupture
pH 6.0 60 No No No No No No No
Phosphate 120 rupture rupture rupture rupture rupture rupture rupture
Buffer 150

Condition 3: O.IN HCl (900ml, 100rpm, USP II) followed by pH 6.8 Phosphate Buffer (900 ml, 50 rpm, USP II)
Medium Time Observation
(mins) Asacol™ Ex 1 Ex 2 Ex 3 Ex 4 Ex 5 Ex 6
800mg
O.IN HCl 60 No No No No No No No
120 rupture rupture rupture rupture rupture rupture rupture
pH 6.8 60 No No No No No No No
Phosphate 120 rupture rupture rupture rupture rupture rupture rupture Buffer 150

Condition 4: O.IN HCl (900ml, 100rpm, USP II) followed by pH 7.2 Phosphate Buffer (900 ml, 50 rpm, USP II)
Medium Time Observation
(rains) Asacol™ Ex 1 Ex2 Ex 3 Ex 4 Ex 5 Ex 6
800mg
O.IN HCl 60 No No No No No No No
120 rupture rupture rupture rupture rupture rupture rupture
pH 7.2 15 No No No No No No No
Phosphate rupture rupture rupture rupture rupture rupture
Buffer 30 Rupture Rupture Rupture Rupture Rupture Rupture
Note: Observation was not continued upto 150mins in pH 7.2 Phosphate buffer due to rupture at 30mins Condition 5: O.IN HCl (900ml,100rpm, USP II) followed by pH7.5 Phosphate Buffer (900 ml, 50 rpm, USP II)

Medium Time Observation
(mins) Asacol™ Ex 1 Ex 2 Ex 3 Ex 4 Ex 5 Ex 6 SOOmg
O.IN HCl 60 No No No No No No No
120 rupture rupture rupture rupture rupture rupture rupture
pH7.5 10 No No No No No No No
Phosphate rupture rupture rupture rupture rupture rupture
Buffer 20 Rupture Rupture Rupture Rupture Rupture Rupture
Note: Observation was not continued upto 150mins in pH 7,5 Phosphate buffer due to rupture at 20mins

Dissolution 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 6,0 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 1.5hrs; USP II method; 50 rpm.

Medium Time Acceptance % Drug release
(mins) Limit for Asacol™ Ex 1 Ex 2 Ex 3 Ex 4 Ex 5 Ex 6 SQOmg
O.IN HCl 120 NMT1% Nil Nil Nil Nil Nil Nil Nil
pH 6.0 60 NMT1% Nil Nil m Nil Nil Nil Nil Phosphate Buffer
pH 7.2 90 NLT 80% Above Above Above Above Above Above Above Phosphate 80% 80% 80% 80% 80% 80% 80% Buffer

WE CLAIM:

1. A pharmaceutical composition in a solid unit dosage form for oral administration consisting essentially of:

i. a core comprising 5-amino salicylic acid and optionally other pharmaceutically acceptable excipients; and

ii. a single enteric coating layer coated over said core;

wherein the total weight of said core is atleast 800mg.

2. The pharmaceutical composition of claim 1, wherein said core is optionally coated with a sub-coat or a seal-coat layer.

3. The pharmaceutical composition of claim 1, wherein said enteric coating layer comprises pH-dependent polymers selected from a group consisting of methacrylic acid copolymers, ammonio methacrylate co-polymers, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, alginic acid, and sodium alginate or mixtures thereof

4. The pharmaceutical composition of claim 3, wherein said enteric coating layer comprises pH-dependent polymers selected from a group consisting of poly(methacrylic acid, methyl methacrylate) 1:2, poly(methacrylic acid, methyl methacrylate) 1:1, anionic polymethacrylates, mixtures of poly (methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methaciylate) 1:1, polyvinyl acetate phthalate, poly(methacrylic acid, ethyl acrylate) 1:1, co-polymer based on methyl acrylate, methyl methacrylate and methacrylic acid, hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate or mixtures thereof

5. A pharmaceutical composition in a solid unit dosage form for oral administration consisting essentially of:

i. a core comprising 5-amino salicylic acid and optionally other pharmaceutically acceptable excipients selected among diluents, binders, disintegrants, glidants, lubricants; and

ii. a single enteric coating layer coated over said core, wherein said enteric coating layer comprises poly(methacrylic acid, methyl methacrylate) 1:2, co-polymer based on methyl acrylate, methyl methacrylate and methacrylic acid, hydroxypropylmethyl cellulose acetate succinate or mixtures thereof;

wherein the total weight of said core is atleast 800mg.

6. The pharmaceutical composition of claim 5, wherein said diluents are selected among lactose, cellulose, dicalcium phosphate, sugar alcohol, or mixtures thereof; binders are selected among povidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelatin, starch, or mixtures thereof; disintegrants are selected among sodium starch glycolate, crospovidone, croscarmellose sodium, pregelatinized starch, low- substituted hydroxypropyl cellulose, or mixtures thereof; glidants and lubricants are selected among silicon dioxide, talc, magnesium stearate, stearic acid, sodium starch fumarate, or mixtures thereof

7. The pharmaceutical composition of claim 5, wherein said enteric coating layer further comprises plasticizers selected among triethyl citrate, dibutyl sebacate, dibutyl phthalate, polyethylene glycol, propylene glycol, or mixtures thereof; anti-tacking agents such as talc, fumed silica, magnesium stearate or mixtures thereof; pigments selected among titanium dioxide, edible lake pigments; or mixtures thereof.

8. The pharmaceutical composition of claim 1, wherein said single enteric coating layer has a thickness of atleast 60µm.

9. The pharmaceutical composition of claim 1, wherein said solid unit dosage form is a compressed tablet.

10. The pharmaceutical composition of claim 9, wherein the total weight of coated tablet including said single enteric coating layer ranges from about 1000 mg to about 1700 mg.