CONTROLLED RELEASE DOSAGE FORMS OF 5-AMINOSALICYLIC ACID AND PROCESS THEREOF

Abstract

Accordingly, the invention provides controlled release minitablets of 5-ASA with high drug load and less net weight for easier administration. In another aspect of the present invention, the process of preparation of 5-ASA or its prodrugs/derivatives as coated minitablets, wherein the minitablets are prepared by wet granulation of 5-Aminosalicylic acid or its prodrugs/derivatives and at least one pharmaceutical retarding agent either at intra granular or extragranular stage and at least one pharmaceutical excipient or carrier of other categories for tableting. Then, the granules are size controlled through milling with size in the range of 100 microns to 700 microns. Further the granules are compressed using single tip or multi-tip punch and die to get the required size and shape and used as minitablets in sachets for administering with water/soft foods or encapsulated in capsules for whole administration.

Claims

1. A controlled release composition comprising: a. a core minitablet comprising: i) 5-ASA or its pharmaceutically acceptable salt, solvate, and/or ester thereof having a weight percentage in a range of 80%-90% w/w with respect to the weight of the core mini tablet; and b. a coating layer comprising: i) hydrophobic cellulose to the weight gain of 0.5% to 1% w/w; or ii) hydrophobic cellulose and hydrophilic polymer mixture, coated to weight gain of 2%-10% w/w to the weight of the core minitablet, such that the total weight of the controlled release composition is in the range of 595-650 mg.

2. The controlled release composition as claimed in claim 1, wherein ratio of the hydrophobic cellulose to hydrophilic polymers is in the range of 1:9 to 4:6.

3. The controlled release composition as claimed in claim 1, wherein ratio of the hydrophobic cellulose to hydrophilic polymers is 1:3.

4. The controlled release composition as claimed in claim 1, wherein ratio of the hydrophobic cellulose to hydrophilic polymers is 4:6.

5. The controlled release composition as claimed in claim 1, wherein ratio of the hydrophobic cellulose to hydrophilic polymers is 1:4.

6. The controlled release composition as claimed in claim 1, wherein the core minitablet further comprises: binder(s) having a weight percentage in a range of 1%-10% with respect to the core minitablet; diluent(s) having a weight percentage in the range of 0.5%-20% with respect to the core minitablet, disintegrant(s) having a weight percentage in a range of 1%-10% with respect to the core minitablet, lubricant(s) having a weight percentage in a range of 1%-5% with respect to the core minitablet, glidant(s) having a weight percentage in a range of 1%-5% with respect to the core minitablet, and retarding agent(s) having a weight percentage in the range of 4-18% with respect to the core minitablet.

7. The coating layer composition in claim 1, wherein the hydrophobic cellulose is in the range of 0.5-1%

8. The controlled release composition as claimed in claim 6, wherein the diluents are selected from a group consisting of lactose, lactose monohydrate, starch, hydrolysed starch, partially hydrolysed starch, stearic acid, microcrystalline cellulose, calcium phosphates, mannitol and/or any co-processed excipients of above; wherein the binder are selected from a group consisting of polyvinyl pyrrolidine, hydroxypropyl cellulose, hypromellose, acacia, starch, starch derivatives and gelatin; the disintegrant(s) is selected from a group consisting of crospovidone, sodium starch glycolate, starch, hydrolysed starch, partially hydrolysed starch, croscarmellose sodium, the lubricant(s) are selected from a group consisting of magnesium stearate, calcium stearate, stearic acid, glyceryl dibehenate, glyceryl stearate, other glyceride derivatives, low MW polyethylene glycols, the glidant(s) are selected from the group consisting of colloidal silicon dioxide, silicon dioxide and talc, and the retarding agent(s) are selected from a group consisting of ethyl cellulose, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl dibehenate, glyceryl distearate, stearic acid and any stearic acid or fatty acid derivatives thereof.

9. The coating layer composition as claimed in claim 1, wherein the hydrophobic cellulose is ethyl cellulose.

10. The controlled release composition as claimed in claim 1, wherein the core is optionally coated with a coating solution comprising seal coating polymers to bring about 0.3%-5% weight gain to the core minitablet.

11. The controlled release composition as claimed in claim 1, wherein the controlled release layer is coated on the core minitablet or a seal coated surface.

12. A method of preparing the controlled release, the method comprising: (a) mixing/granulating 5-ASA or premixed 5-ASA and retarding agent along with a pharmaceutically acceptable binder solution prepared in suitable solvents (e.g. water or ethanol or Isopropyl alcohol or mixture of two or more Solvent) to obtain a first mixture; b) drying the first mixture to a temperature range of 40-70° C. to obtain a dried mixture; c) passing the granules through mill and/or sifter of mesh range between mesh size #16 and mesh #60, wherein the granules have a size in the range of 100 microns to 700 microns; d) mixing the granules obtained in step c) with other diluents, retarding agents, glidants and lubricants to obtain free flowing granule of 5-ASA; e) compressing the granules obtained in step d) using single tip or multi-tip (of about 16 tips) and die to obtain the core minitablet of claim 1; and f) coating the core minitablet with a coating solution comprising: i) hydrophobic cellulose to the weight gain of 0.5% to 1%; or ii) hydrophobic cellulose and hydrophilic polymer mixture, coated to weight gain of 2%-10% to the total weight of the core minitablet, such that the total weight of the controlled release composition is in the range of 595-650 mg.

13. A method to improve patient compliance comprising administering to a patient in need thereof the composition of claim 1.

Description

DETAILED DESCRIPTION OF INVENTION

[0020] The embodiments herein and the various features and advantageous details thereof are explained more fully with reference to the non-limiting embodiments that are illustrated in the accompanying drawings and detailed in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. Also, the various embodiments described herein are not necessarily mutually exclusive, as some embodiments can be combined with one or more other embodiments to form new embodiments. The term “or” as used herein, refers to a non-exclusive or, unless otherwise indicated. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein can be practiced and to further enable those skilled in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.

[0021] Conventional dosage forms of 5-ASA or its or its pharmaceutically acceptable salt, solvate, and/or ester thereof are larger in size due to its dosage levels. Till today, the market available dosage form of 5-ASA in tablet forms are more than 18 mm in its largest dimension, and have a net weight greater than 800 mg. 5-ASA or its prodrug/derivatives in capsule forms are in the size range of 19 mm to 25 mm in its largest dimension. Also, these drugs are administered as multiple units at a time according to the clinical requirement or severity in fewer available capsules (treatment or maintenance for ulcerative colitis) due to its high dose or dosage level. Moreover, marketed products have excess excipients added either as inert diluent or startup sugar or other pharmaceutical acceptable startup beads (or spheres) or more percentage of coating layering affects the final dosage size of the product i.e. the encapsulating gelatin shells or capsule size. Moreover, this in turn generates a fear for administering the bigger size dosage forms. In order to circumvent the bigger size, the object of the present invention is to provide unique combination of composition and the process for the preparation of controlled release minitablets to reduce the net weight thereby the size of the final dosage form its encapsulating, e.g. capsules.

[0022] The controlled released composition comprising: a) a core minitablet comprising: i) 5-ASA or a pharmaceutically acceptable salt, solvate, and/or ester thereof having a weight percentage in a range of 80%-90% w/w with respect to the core weight of the core mini tablet; and b) a coating layer comprising: i) hydrophobic cellulose to the weight gain of 0.5% to 1%; or ii) hydrophobic cellulose and hydrophilic polymer mixture, coated to weight gain of 2%-10% to the total weight of the core minitablet, such that the total weight of the controlled release composition is in the range of 595-650 mg. In another embodiment, the hydrophobic cellulose is in the range of 0.5-1%. The net weight of the controlled release composition of the present invention is much lower compared to the conventionally available drug formulations of mesalamine available in the market, thereby minimizing swallowing difficulties, and improve patient compliance and overcome the challenges associated with medication regimens of larger dose and dosage forms.

[0023] In another embodiment of the present invention, the controlled released composition comprising: a) a core minitablet comprising: i) 5-ASA or a pharmaceutically acceptable salt, solvate, and/or ester thereof having a weight percentage in a range of 80%-90% w/w with respect to the core weight of the core mini tablet; and b) a coating layer comprising: i) hydrophobic cellulose to the weight gain of 0.5% to 1%; or ii) hydrophobic cellulose and hydrophilic polymer mixture, coated to weight gain of 2%-10% to the total weight of the core minitablet, and wherein ratio of the hydrophobic cellulose to the hydrophilic polymer mixture is in the range of 1:9 to 4:6, such that the total weight of the controlled release composition is in the range of 595-650 mg. In another embodiment, the ratio of the hydrophobic cellulose to the hydrophilic polymer mixture is 1:3. In another embodiment, the ratio of the hydrophobic cellulose to the hydrophilic polymer mixture is 4:6. In another embodiment, the ratio of the hydrophobic cellulose to the hydrophilic polymer mixture is 1:4.

[0024] In another embodiment of the present invention, the core minitablet further comprises binder(s) having a weight percentage in a range of 1%-10% with respect to the core minitablet; diluent(s) having a weight percentage in the range of 0.5%-20% with respect to the core minitablet, optionally disintegrant(s) having a weight percentage in a range of 1%-10% with respect to the core minitablet, lubricant(s) having a weight percentage in a range of 1%-5% with respect to the core minitablet, glidant(s) having a weight percentage in a range of 1%-5% with respect to the core minitablet, and retarding agent(s) having a weight percentage in the range of 4-18% with respect to the core minitablet.

[0025] In another embodiment of the present invention, the core minitablet comprising: 5-ASA or its pharmaceutically acceptable salt, solvate, and/or ester thereof having a weight percentage in a range of 80%-90% w/w with respect to the core weight of the core mini tablet; binder(s) having a weight percentage in a range of 1%-10% with respect to the core minitablet, wherein the binders are selected from a group consisting of polyvinyl pyrrolidine, hydroxypropyl cellulose, hypromellose, acacia, starch, starch derivatives and gelatin; the diluent(s) having a weight percentage in the range of 0.5%-20% with respect to the core minitablet, wherein the diluents are selected from a group consisting of lactose, lactose monohydrate, starch, hydrolysed starch, partially hydrolysed starch, stearic acid, microcrystalline cellulose, calcium phosphates, mannitol and/or any co-processed excipients of above; the disintegrant(s) having a weight percentage in a range of 1%-10% with respect to the core minitablet selected from a group consisting of crospovidone, sodium starch glycolate, starch, hydrolysed starch, partially hydrolysed starch, croscarmellose sodium; lubricant(s) having a weight percentage in a range of 1%-5% with respect to the core minitablet selected from a group consisting of magnesium stearate, calcium stearate, stearic acid, glyceryl dibehenate, glyceryl stearate, other glyceride derivatives, low MW polyethylene glycols; the glidant(s) having a weight percentage in a range of 1%-5% with respect to the core minitablet selected from the group consisting of colloidal silicon dioxide, silicon dioxide and talc; and retarding agent(s) having a weight percentage in the range of 4-18% with respect to the core minitablet selected from a group consisting of ethyl cellulose, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl dibehenate, glyceryl distearate, stearic acid and any stearic acid or fatty acid derivatives thereof.

[0026] In another embodiment of the present invention, the controlled release composition is optionally coated with a coating solution comprising seal coating polymers to bring about 0.3%-5% weight gain to the core minitablet. In another embodiment, the controlled release layer is coated on the core minitablet or a seal coated surface.

[0027] In another embodiment of the present invention, a method of preparing the pharmaceutical composition of claim 1, comprising: (a) granulating 5-ASA or a pharmaceutically acceptable salt, ester, and/or solvate thereof along with binders, retarding agents, and lubricants in a sequential manner to obtain the core minitablet; and (b) coating the core mini tablet with a coating layer comprising hydrophobic cellulose or mixture of hydrophobic cellulose and hydrophilic polymers.

[0028] In another embodiment of the present invention, the process to prepare the controlled release composition comprising: i) 5-ASA or a pharmaceutically acceptable salt, solvate, and/or ester thereof having a weight percentage in a range of 80%-90% w/w with respect to the core weight of the core mini tablet; and b) a coating layer comprising: i) hydrophobic cellulose to the weight gain of 0.5% to 1%; or ii) hydrophobic cellulose and hydrophilic polymer mixture, coated to weight gain of 2%-10% to the total weight of the core minitablet, such that the total weight of the controlled release composition is in the range of 595-650 mg, the method comprising: (a) mixing/granulating 5-ASA or premixed 5-ASA and retarding agent along with a pharmaceutically acceptable binder solution prepared in suitable solvents (e.g. water or ethanol or Isopropyl alcohol or mixture of two or more Solvent) to obtain a first mixture; b) drying the first mixture to a temperature range of 40-70° C. to obtain a dried mixture; c) passing the granules through mill and/or sifter of mesh range between mesh size #16 and mesh #60, wherein the granules have a size below 700 microns; d) mixing the granules obtained in step c) with other diluents, retarding agents, glidants and lubricants to obtain free flowing granule of 5-ASA; e) compressing the granules obtained in step d) using single tip or multi-tip (of about 16 tips) and die to obtain the core minitablet of claim 1; and f) coating the core minitablet with a coating solution comprising: i) hydrophobic cellulose to the weight gain of 0.5% to 1%; or ii) hydrophobic cellulose and hydrophilic polymer mixture, coated to weight gain of 2%-10% to the total weight of the core minitablet, such that the total weight of the controlled release composition is in the range of 595-650 mg.

[0029] A method to improve patient compliance comprising administering to a patient in need thereof the composition comprising: i) 5-ASA or a pharmaceutically acceptable salt, solvate, and/or ester thereof having a weight percentage in a range of 80%-90% w/w with respect to the core weight of the core mini tablet; and b) a coating layer comprising: i) hydrophobic cellulose to the weight gain of 0.5% to 1%; or ii) hydrophobic cellulose and hydrophilic polymer mixture, coated to weight gain of 2%-10% to the total weight of the core minitablet, such that the total weight of the controlled release composition is in the range of 595-650 mg.

[0030] In another aspect of the present invention, the composition to controlled release minitablets of 5-ASA or its prodrugs/derivatives comprising: a core minitablet and coating, wherein the core further comprises: i) any one 5-ASA drug or its pharmaceutically acceptable salt, solvate, and/or ester thereof, having a weight percentage in the range of 80%-90% w/w with respect to the core minitablet, ii) diluent(s) having a weight percentage of 0.5%-20% w/w with respect to the weight of the core minitablet, iii) binder(s) having a percentage of 1%-10% w/w with respect to the core minitablet, iv) release retarding agent(s) having a weight percentage of 4%-18% w/w with respect to the total weight of the core minitablet, wherein the retarding agent may be used in intragranular or extragranular or in both stages (either similar agents or mix match), v) lubricant(s) or glidant(s) or both having a weight percentage of 0.5%-5% w/w with respect to the weight of core minitablet. The coating layer further comprises i) functional coating of ethyl cellulose coating mixture or admixture of ethyl cellulose and immediate release coating agents to the weight gain of 0.3% to 10% to the weight of core minitablet ii) optionally one seal coating to the weight gain of 0.3%-5% w/w to the weight of core minitablet, wherein the coating solution is prepared from any pharmaceutically known conventional seal coat polymers.

[0031] In another aspect of present invention, the composition of coating or coating solution is mixture of ethyl cellulose and pharmaceutically known film coating material or water-soluble excipients dispersed or dissolved in solid ratio between 10:90 and 40:60 on total solid weight of coating material used.

[0032] In another aspect of present invention, the dissolution profile can be achieved using minitablets of either single mixture coating ratio or by combination of two or more different ratio.

[0033] In another aspect of present invention, the dissolution profile can be achieved using minitablets of similar size/shape or mixture of different sizes/shapes.

[0034] In another aspect of present invention, the dissolution profile can be achieved using similar or different size controlled release minitablets, wherein the minitablets are of similar release mechanism of same composition or different composition.

[0035] In another aspect of present invention, the minitablets can be encapsulated in capsules for whole administration or by opening and dispersing in water or by opening and spreading the minitablets in apple sauce or any soft foods.

[0036] In another aspect of present invention, the minitablets can be packed in sachets, wherein minitablets are to be administered by dispersing in water or by opening and spreading the minitablets in apple sauce or any soft foods.

[0037] In another aspect of present invention, the minitablets can be packed in multiple unit dose containers, wherein minitablets of respective unit dose prescribed are to be dispensed and taken either qualitatively (in a tablespoon or teaspoon) or quantitatively (in a volumetric device). The unit dose minitablets can be administered by dispersing in water or by opening and spreading the minitablets in apple sauce or any soft foods.

[0038] In another aspect of present invention, the minitablets can be suspended in syrup base, wherein suspension is to be administered by volume after shaking either qualitatively (in a tablespoon or teaspoon) or quantitatively (in a volumetric device).

[0039] The foregoing description of the specific embodiments will so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.

EXAMPLES

[0040] The disclosure will now be illustrated with working examples, which is intended to illustrate the working of disclosure not intended to take restrictively to imply any limitations on the scope of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to any one of the ordinary skilled in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of disclosed methods and compositions, the exemplary methods, devices and materials are described herein. It is to be understood that this disclosure is not limited to particular methods, and experimental conditions described, as such methods and conditions may apply.

Example 1

[0041] Controlled release compositions: Various controlled release compositions, herewith referred to as compositions, from A1-A13 were prepared by mixing 5-ASA with other excipients like binders, diluents, retarding agents, glidants, lubricants in different w/w ratios. Further each of these compositions (A1-A11) were coated with various coating solutions and the effect of coating solutions on the dissolution profiles of these controlled release compositions are studied, and the results are provided under from Table 2 to 4. Compositions A12 and A13 are used as reference (devoid of any coating solution).

TABLE-US-00003 TABLE 2 A1 A2 A3 A4 Ingredients (w/w %) (w/w %) (w/w %) (w/w %) 5-ASA (active 81.3 84 87 86.8 ingredient) Glyceryl dibehenate 9.8 6.7 3.5 8.7 (retarding agent)-Intra Granular Polyvinylpyrrolidone 0 6.7 7 0 (binder) Gelatin (binder) 6.5 0 0 2.6 Glyceryl dibehenate 1.6 1.7 1.7 0 (retarding agent and lubricant) Stearic acid 0 0 0 1 (retarding agent and lubricant) Colloidal 0.8 0.9 0.8 0.9 silicon dioxide (glidant) Water (Solvent) q.s q.s q.s q.s Ethyl alcohol 0 0 0 0 (Solvent) Total weight of 615 595 575 576 minitablets (mg) Coating 4.8% 3.0% 4.2% 0.75% weight weight weight weight gain of gain of gain of gain surelease: surelease: surelease: of diluted opadry II opadry II opadry II surelease (40:60) to (25:75) to (25:75) to (2%) the core the core the core solution weight weight weight to and the core cured weight

TABLE-US-00004 TABLE 3 A5(w/ A6(w/ A7 (w/ A8 (w/ Ingredients w %) w %) w %) w %) 5-ASA (active 84 80.1 87 89.3 ingredient) Glyceryl dibehenate 6.7 14.5 — — (retarding agent)-Intra Granular Stearic acid (retarding 3.7 agent)-Intra Granular Polyvinylpyrrolidone 6.7 2.4 7 0 (binder) Gelatin (binder) 0 0 0 2.7 Glyceryl dibehenate 1.7 0 0 5.4 (retarding agent and lubricant) Stearic acid (retarding 0 2 1.7 agent and lubricant) Magnesium Stearate 1.8 Colloidal 0.9 1 0.8 0.8 silicon dioxide (glidant) Water (solvent) q.s q.s — q.s Ethyl alcohol 0 0 q.s 0 (solvent) Total weight of 595 624 575 560 minitablets (mg) Coating 5% weight 1% weight 3.25% 1.5% gain of gain of weight weight gain surelease: aquarius gain of of diluted opadry II to the surelease: surelease (50:50) core opadry II (1%) to the weight (25:75) to solution to core the core the core weight weight weight

TABLE-US-00005 TABLE 4 A10 A11 A12 A13 A9 (w/w (w/ (w/ (w/ (w/ Ingredients %) w %) w %) w %) w %) 5-ASA (active 84 84 80 94.34 84 ingredient) Glyceryl dibehenate 6.7 6.7 9.6 0 6.7 (retarding agent) Polyvinylpyrrolidone 6.7 6.7 6.4 0 6.7 (binder) Gelatin (binder) 0 0 0 2.83 0 Glyceryl dibehenate 1.7 1.7 3.2 0 1.7 (retarding agent) Stearic acid 0 0 0 1.89 0 (retarding agent and lubricant) Colloidal silicon 0.9 0.9 0.8 0.94 0.9 dioxide (glidant) Water (solvent) q.s q.s q.s q.s q.s Ethyl alcohol 0 0 0 0 0 (solvent) Total weight of 595 595 625 530 595 minitablets (mg) Coating 8% 12% 2% No No weight weight weight coating coating gain of gain of gain of (imme- surelease: surelease: surelease: diate opadry II opadry II HPMC release) (20:80) to (20:80) to (40:60) to the core the core the core weight weight weight

Example 2

[0042] General process of preparing the controlled release compositions. The process steps include firstly mixing/granulating 5-ASA or 5-ASA and retarding agents by any of the granulation techniques known in the art (wet, dry or hot melt granulation) using a pharmaceutically acceptable binder to obtain a first mixture granule. The first mixture thus obtained was dried to a temperature range of 40-70° C. to obtain a dried mixture. The dried mixture were further passed through mill and/or sifter of mesh range between mesh size #16 and mesh #60 to obtain the granules of a size below 700 microns. Further, the milled granules was mixed with other excipients like diluents, retarding agents, glidants and lubricants to obtain final blend of 5-ASA. The final blend were compressed using single tip or multi-tip (of about 16) punch(s) and die to obtain the core minitablet of claim 1; and f) coating the core minitablet with a coating solution comprising: i) hydrophobic cellulose to the weight gain of 0.5% to 1%; or ii) hydrophobic cellulose and hydrophilic polymer mixture, coated to weight gain of 2%-10% to the total weight of the core minitablet, such that the total weight of the controlled release composition is in the range of 595-650 mg. The controlled release dosage forms are further cured (if required) and were analyzed for their drug release kinetics.

[0043] Process of preparation of A1: Minitablets of 2.5 mm was compressed and coated with surerelease:opadry II (40:60) as per the formula provided in Table 2. For this purpose, dry mix of mesalamine (also referred to as 5-ASA) with glyceryl dibehenate was carried out, followed by wet granulation in granulator using gelatin dissolved in water as binder, dried milled and then extra granulated with other excipients and lubricated. The coating is performed to achieve the target weight gain.

[0044] Process of preparation of A2: Minitablets of 2.5 mm was compressed and coated with surerelease:opadry II (25:75) as per the formula provided in Table 2. For this purpose, dry mix of mesalamine with glyceryl Dibehenate was carried out, followed by wet granulation in granulator using Polyvinylpyrrolidone dissolved in water as binder, dried, milled and then lubricated with respective lubricants. The coating is performed to achieve the target weight gain.

[0045] Process of preparation of A3: Minitablets of 2.0 mm was compressed and coated with surelease: opadry II as per the formula provided in Table 2. For this purpose, dry mix of mesalamine and glyceryl dibehenate was carried out, followed by wet granulation in granulator using polyvinylpyrrolidone as binder by dissolving in water, dried, milled and then mixed with glyceryl dibehenate and then with respective lubricants. The coating is performed to achieve the target weight gain and then cured.

[0046] Process of preparation of A4: Minitablets of 2.0 mm was compressed and coated with diluted surelease solution (2% w/w) as per the formula provided in Table 2. For this purpose, mesalamine granulation was carried out, by wet granulation in granulator using gelatin as binder by dissolving in water, dried, milled and then mixed with glyceryl dibehenate and then with respective lubricants. The coating is performed to achieve the target weight gain.

[0047] Process of preparation of A5: Minitablets of 2.0 mm was compressed and coated with Surelease: Opadry II (50:50) as per the formula provided in Table 3. For this purpose, dry mix of glyceryl dibehenate and mesalamine granulation was carried out, followed by wet granulation in granulator using polyvinylpyrrolidone dissolved in water as binder, dried, milled and then mixed with glyceryl dibehenate and then with respective lubricants. The coating is performed to achieve the target weight gain.

[0048] Process of preparation of A6: Minitablets of 2.0 mm was compressed and coated with Aquarius control ECD film coating solution as per the formula provided in Table 3. For this purpose, mesalamine along with glyceryl dibehenate was granulated by wet granulation in granulator using polyvinylpyrrolidone dissolved in water as binder, dried, milled and then mixed with stearic acid and then colloidal silicon dioxide. The coating is performed to achieve the target weight gain.

[0049] Process of preparation of A7: Minitablets of 2.5 mm was compressed and coated with sure release: Opadry II (25:75) as per the formula provided in Table 3. For this purpose, dry mix of mesalamine with stearic acid, followed by wet granulation in granulator using Polyvinylpyrrolidone as binder by dissolving in suitable organic solvent, dried and then lubricated with respective extragranular excipients and lubricants. The coating is performed to achieve the target weight gain.

[0050] Process of preparation of A8: Minitablets of 2.0 mm was compressed and coated with diluted surelease solution (1% w/w) as per the formula provided in Table 3. For this purpose, mesalamine granulation was carried out, by wet granulation in granulator using gelatin as binder by dissolving in water, dried, milled and then mixed with glyceryl dibehenate and then with respective lubricants. The coating is performed to achieve the target weight gain.

[0051] Process of preparation of A9: Minitablets of 2.0 mm was compressed and coated with Surelease: Opadry II (20:80) as per the formula provided in Table 4. For this purpose, mesalamine and glyceryl dibehenate premixed and granulation was carried out, by wet granulation in granulator using Polyvinylpyrrolidone as binder by dissolving in water, dried and then mixed with glyceryl dibehenate and then with respective lubricants. The coating is performed to achieve the target weight gain.

[0052] Process of preparation of A10: Minitablets of 2.0 mm was compressed and coated with Surelease: Opadry II (20:80) as per the formula provided in Table 4. For this purpose, mesalamine and glyceryl dibehenate premixed and granulation was carried out, by wet granulation in granulator using polyvinylpyrrolidone as binder by dissolving in water, dried and then mixed with glyceryl dibehenate and then with respective lubricants. The coating is performed to achieve the target weight gain.

[0053] Process of preparation of A11: Dry mix of Mesalamine with Glyceryl dibehenate was carried out, followed by wet granulation in granulator using polyvinylpyrrolidone as binder by dissolving in water, dried and then lubricated with extragranular excipients and respective lubricants. The coating is performed to achieve the target weight gain.

[0054] Process of preparation of A12—Core without retarding agents (immediate release): Mesalamine was granulated by wet granulation in granulator using gelatin as binder by dissolving in water, dried and then lubricated.

[0055] Process of preparation of A13—Core with retarding agent: Minitablets of 2.0 mm was compressed as per the formula below. For this purpose, mesalamine and glyceryl dibehenate premixed and granulation was carried out, by wet granulation in granulator using polyvinylpyrrolidone as binder by dissolving in water, dried and then mixed with glyceryl dibehenate and then with respective lubricants.

Example 3—Dissolution Testing of Tablets

[0056]

TABLE-US-00006 In vitro dissolution study conditions Strength of Dosage form 500 mg Apparatus USP 2 (Paddles) Speed 100 rpm Media 0.1N HCL and Buffers at pH values 4.5 and 7.5 Volume 900 mL Temperature 37° C. Sampling Time 1, 2, 4, 6, 8 and 12 hours

Results and Discussion

[0057] The percentage release of mesalamine at 0.1 pH at various time intervals is herewith provided in Table 5.

TABLE-US-00007 TABLE 5 Time (h) A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 A11 A12 A13 1 32 35 35 30 4 35 41 20 39 33 35 99 50 2 51 55 54 52 8 62 69 39 61 54 53 100 74 4 75 76 80 85 12 85 90 81 77 80 98 6 100 90 91 102 103 102 96 89 93 8 99 99 99 99 101 12
From table 5 (A1-A11) it can be inferred that A1 to A11 met the dissolution criteria in 0.1N HCl except for A5 and A8.

[0058] The A5, coated for weight gain of 5% with mixture of ethyl cellulose dispersion and Opadry II at ratio of 50:50 w/w of total solids (i.e., hydrophobic cellulose to hydrophilic polymers) failed to meet the dissolution criteria compared to A2 which had same core composition.

[0059] Similarly, A8 Coated for weight gain of 1.5% with ethyl cellulose coating dispersion (hydrophobic cellulose) retarded the release and it doesn't meet the criteria of reference dissolution limits of 0.1N HCL established in table 1.

[0060] The percentage release of mesalamine at 4.5 pH at various time intervals is herewith provided in Table 6.

TABLE-US-00008 TABLE 6 Time (h) A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 A11 A12 A13 1 6 8 7 5 2 7 10 5 9 8 7 32 14 2 12 13 12 10 3 11 16 7 18 12 12 59 24 4 20 24 21 20 5 27 27 28 24 21 91 39 6 30 32 27 29 37 34 38 31 30 100 46 8 40 38 35 38 — 40 45 37 38 60 12 59 50 46 56 67 59 55 55 56 85
From table 6 (A1-A11) it can be inferred that following trials failed to release drug in pH 4.5 as per the dissolution limits in Table 1 [0061] a. A3 coated with weight gain of 4.2% with mixture of ethylcellulose dispersion and Opadry II at ratio of 1:3 w/w of total solids (i.e., hydrophobic cellulose to hydrophilic polymers) has completely failed to release drug due to curing process. [0062] b. A5 coated for weight gain of 5% with mixture of ethyl cellulose dispersion and Opadry II at ratio of 1:1 w/w of total solids (i.e. hydrophobic cellulose to hydrophilic polymers) [0063] c. A6 Coated with weight gain of 1% w/w with ethyl cellulose dispersion (hydrophobic cellulose) has failed to control the release in pH 4.5 at end time points. [0064] d. A8 Coated with weight gain of 1.5% w/w with ethyl cellulose dispersion (hydrophobic cellulose) has retarded the release in pH 4.5. [0065] e. A10 coated for weight gain of 12% w/w with mixture of ethyl cellulose dispersion and Opadry II at ratio of 2:4 w/w of total solids (i.e. hydrophobic cellulose to hydrophilic polymers) has failed to match the dissolution limits.

[0066] The percentage release of mesalamine at 7.5 pH at various time intervals is herewith provided in Table 7.

TABLE-US-00009 TABLE 7 T (h) A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 A11 A12 A13 1 18 23 21 16 3 22 39 12 27 25 18 81 28 2 37 39 38 31 9 38 60 20 54 37 38 100 48 4 76 63 74 67 12 69 85 80 66 76 72 6 97 81 93 85 86 88 93 78 89 85 8 99 95 95 97 84 94 100 12 100 100 92 100

[0067] From table 7 it can be inferred that, A5 coated for weight gain of 5% with mixture of ethyl cellulose dispersion and Opadry II at ratio of 1:1 w/w of total solids (i.e., hydrophobic cellulose to hydrophilic polymers) and A8 Coated for weight gain of 1.5% with ethyl cellulose dispersion (hydrophobic cellulose) retarded the release and it doesn't meet the criteria of reference dissolution limits of pH 7.5 established in table 1 similar as that of 0.1N HCl.

[0068] Further, from a combined reading of Table 5-table 7 it can be concluded that, the coating hydrophobic cellulose above 1% completely retards the release and failed to meet the dissolution criteria set in Table 1. Similarly, the mixture of hydrophobic cellulose and hydrophilic polymers coating fails to meet the dissolution criteria at weight gain 12% w/w to the core weight. From the results, we can infer that not all compositions pass the dissolution criteria. It appears that the weight ratios of the weight ratio of hydrophobic cellulose and hydrophilic polymer mixture (ethyl cellulose to Opadry) in desired weight percentage plays a critical role in release of the active ingredient 5-ASA. Those compositions where the weight ratio of the was beyond the hydrophobic cellulose and hydrophilic polymer mixture (ethyl cellulose to Opadry) the claimed ranges i.e., 1:9 to 4:6, and where the weight gain was beyond the claimed range (2%-10% to the total weight of minitablet), such compositions failed to meet the dissolution criteria. The mixture composition also retards the drug release on curing coated minitablets.

Advantages of the Present Disclosure:

[0069] The present disclosure provides a pharmaceutical composition and process for preparing high drug load of 5-ASA as controlled release minitablets using a pharmaceutically acceptable diluent or carrier for oral administration. The pharmaceutical composition comprises the minitablets as core, and a coating layer; the core tablet comprising: i) 5-ASA or its pharmaceutically acceptable salt, solvate, and/or ester thereof having a weight percentage in a range of 80%-90% w/w with respect to the core weight of the core mini tablet; and a coating layer comprising: i) hydrophobic cellulose to the weight gain of 0.5% to 1%; or ii) hydrophobic cellulose and hydrophilic polymer mixture, coated to weight gain of 2%-10% to the total weight of the core minitablet, such that the total weight of the controlled release composition is in the range of 595-650 mg. The composition of the present disclosure is a mini-tablet formulation with high drug load and functional coating, so that single dosage unit encapsulating the multiple minitablets can be administered in size smaller than the currently available product size of 00 EL, thereby enhancing the swallowability of the dosage unit. Further, the ease of swallowing the dosage unit ensures patient compliance, thereby overcoming the drawbacks of the prior art.