SOLID ORAL PHARMACEUTICAL COMPOSITIONS FOR ADMINISTRATION OF MESALAZINE OR DERIVATIVES THEREOF

Abstract

The present invention relates to solid oral pharmaceutical compositions for chronotropic administration of mesalazine, the salts or derivatives thereof, consisting of a complex monolithic matrix core comprising at least one low/medium viscosity hydroxypropyl methylcellulose, at least one medium/high viscosity hydroxypropyl methylcellulose, one or more methacrylic polymers or copolymers and/or cellulose acetate phthalate and/or hydroxypropyl methylcellulose acetate succinate or shellac, and an outer coating of said core consisting of a layer comprising ethylcellulose, or of a gastroresistant layer or of a layer comprising ethylcellulose coated in turn with gastroresistant polymers.

Claims

1. A controlled-release solid oral pharmaceutical composition comprising a core containing mesalazine, the salts or analogues thereof, and an outer coating of said core, wherein: a) the core comprises: (i) a monolithic matrix containing mesalazine, the salts or an analogue thereof, at least one hydroxypropyl methylcellulose having a viscosity ranging between 3 and 5000 mPa.s 2% in H.sub.2O at 20° C., at least one hydroxypropyl methylcellulose having a viscosity ranging between 135000 and 280000 mPa.s 2% in H.sub.2O at 20° C., at least one or more methacrylic polymers/copolymers and/or shellac, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, or (ii) a monolithic matrix as defined above adjacent to an immediate-release layer comprising mesalazine or an analogue thereof; b) the outer coating comprises a layer comprising ethylcellulose or a gastroresistant layer or a layer comprising ethylcellulose which in turn is coated with gastroresistant polymers.

2. A composition as claimed in claim 1 wherein the core comprises a monolithic matrix as defined in claim 1, point (i).

3. A composition as claimed in claim 1 wherein the core comprises a monolithic matrix as defined in claim 1, adjacent to an immediate-release layer comprising mesalazine or an analogue thereof.

4. A composition as claimed in claim 1 wherein the outer coating comprises a layer comprising ethylcellulose.

5. A composition as claimed in claim 1 wherein the outer coating comprises a layer comprising ethylcellulose coated with gastroresistant polymers.

6. A composition as claimed in claim 1 wherein the outer coating comprises a gastroresistant layer.

7. A composition as claimed in claim 1 wherein the acrylic/methacrylic polymers or copolymers are selected from pH-independent methacrylic ester copolymers, pH-independent ammonium alkyl methacrylate copolymers; amino alkyl methacrylate copolymers soluble up to pH 5.0, methacrylic acid copolymers soluble at pH≥5.5, methacrylic acid copolymers soluble at pH 6.0-7.0; and pH-dependent methacrylic acid copolymers soluble at pH≥7.0.

8. A composition as claimed in claim 1 wherein the monolithic matrix comprises shellac.

9. A composition as claimed in claim 1 wherein the gastroresistant coating comprises pH-dependent methacrylic acid copolymers soluble at pH≥5.5; pH-dependent methacrylic acid copolymers soluble at pH 6.0-7.0; pH-dependent methacrylic acid copolymers soluble at pH≥7.0; shellac; cellulose acetate phthalate; or cellulose succinate.

10. A composition as claimed in claim 1 wherein the hydroxypropyl methylcellulose having a viscosity ranging between 3 and 5000 mPa.s 2% in H.sub.2O at 20° C. constitutes 1 to 20% of the weight of the core, the hydroxypropyl methylcellulose having a viscosity ranging between 135000 and 280000 mPa.s 2% in H.sub.2O at 20° C. constitutes 1 to 20% of the weight of the matrix, and the methacrylic polymer/copolymer constitutes 0.1 to 2% of the weight of the core.

11. A composition as claimed in claim 1 wherein ethylcellulose is present in percentages ranging from 1 to 20% of the weight of the core.

Description

EXAMPLE 1

[0046] 1.2 Kg of mesalazine is loaded into a granulator with 105 g of hydroxypropyl methylcellulose (HPMC K4M), 54 g of hydroxypropyl methylcellulose (HPMC K100M), 2 g of polymethacrylate L100 and 2 g of polymethacrylate S100. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained; 10 g of magnesium stearate, 8 g of talc and 8 g of colloidal silicon dioxide are then added in sequence. The mixture is then homogenised for at least 15 minutes. This mixture is then compressed to obtain a tablet weighing 1472 mg. The resulting tablets are film-coated with a gastroresistant solution/suspension based on 36 g of polymethacrylate L100, 36 g of polymethacrylate S100, 8 g of talc, 3 g of titanium dioxide and 1 g of triethyl citrate, to obtain a tablet with a mean weight of 1556 mg.

[0047] When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release below 1%; when subjected to the dissolution test at pH≥6.4 they exhibit the following release profile: not more than 1% after 1 hour, at pH 7.2 not more than 30% after 1 hour, and not more than 35% after 2 hours; the value must be >80% after 6 hours; and 100% after 10 hours.

EXAMPLE 2

[0048] 1.2 Kg of mesalazine is loaded into a granulator, and wet-granulated with an aqueous solution containing 83 g of PVP. The resulting granulate is dried, and then placed in a mixer with 106 g of hydroxypropyl methylcellulose (HPMC K4M), 53 g of hydroxypropyl methylcellulose (HPMC K100M) and 4 g of polymethacrylate L100-55. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained; 10 g of magnesium stearate, 8 g of talc and 8 g of colloidal silicon dioxide are then added in sequence. The mixture is then homogenised for at least 15 minutes. This mixture is then compressed to obtain a tablet weighing 1472 mg. The resulting tablets are film-coated with a solution/suspension of 27 g of ethylcellulose, 4 g of talc and 0.5 g of triethyl citrate. This is followed by a gastroresistant coating containing 45 g of polymethacrylate L100-55, 4 g of talc, 3 g of titanium dioxide and 0.5 g of triethyl citrate, to obtain a tablet with a mean weight of 1556 mg.

[0049] When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release below 1%; when subjected to the dissolution test at pH≥6.4 they exhibit the following release profile: not more than 1% after 1 hour, at pH 7.2 not more than 1% after 1 hour, and not more than 10% after 2 hours; not more than 30% after 6 hours; less than 50% after 8 hours; less than 80% after 10 hours; and 100% after 18 hours.

EXAMPLE 3

[0050] 1.2 Kg of mesalazine is loaded into a granulator with 15 g of hydroxypropyl methylcellulose (HPMC K 1001v), 35 g of hydroxypropyl methylcellulose (HPMC K100M), 2 g of polymethacrylate L100, 2 g of polymethacrylate S100 and 1 g of shellac. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained; 10 g of magnesium stearate, 8 g of talc and 8 g of colloidal silicon dioxide are then added in sequence. The mixture is then homogenised for at least 15 minutes. This mixture is then compressed to obtain a tablet weighing 1281 mg. The resulting tablets are then film-coated with a solution/suspension of 27 g of ethylcellulose, 8 g of talc, 3 g of titanium dioxide and 1 g of triethyl citrate, to obtain a tablet with a mean weight of 1320 mg.

[0051] When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release below 1%; when subjected to the dissolution test at pH≥6.4 they exhibit the following release profile: not more than 1% after 1 hour, at pH 7.2 not more than 5% after 1 hour, and not more than 10% after 2 hours; not more than 50% after 6 hours; less than 70% after 8 hours; less than 90% after 10 hours; and 100% after 18 hours.

EXAMPLE 4

[0052] 1.2 Kg of mesalazine is loaded into a granulator and wet-granulated with an aqueous solution containing 83 g of PVP. The resulting granulate is dried, and then placed in a mixer with 35 g of hydroxypropyl methylcellulose (HPMC K4M), 15 g of hydroxypropyl methylcellulose (HPMC K100M) and 4 g of polymethacrylate L100-55. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained; 10 g of magnesium stearate, 8 g of talc and 8 g of colloidal silicon dioxide are then added in sequence. The mixture is then homogenised for at least 15 minutes. This mixture is then compressed to obtain a tablet weighing 1363 mg. The resulting tablets are then film-coated with a solution/suspension of 27 g of ethylcellulose, 8 g of talc, 3 g of titanium dioxide and 1 g of triethyl citrate, to obtain a tablet with a mean weight of 1402 mg.

[0053] When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release below 1%; when subjected to the dissolution test at pH≥6.4 they exhibit the following release profile: not more than 1% after 1 hour, at pH 7.2 not more than 3% after 1 hour, and not more than 5% after 2 hours; not more than 45% after 6 hours; less than 70% after 8 hours; less than 90% after 10 hours; and 100% after 18 hours.

EXAMPLE 5

[0054] 1.2 Kg of mesalazine is loaded into a granulator with 50 g of lactose monohydrate, 50 g of mannitol, 15 g of hydroxypropyl methylcellulose (HPMC K 1001v), 35 g of hydroxypropyl methylcellulose (HPMC K100M), 2 g of polymethacrylate RL100, 2 g of polymethacrylate RS100 and 1 g of shellac. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained; 10 g of magnesium stearate, 8 g of talc and 8 g of colloidal silicon dioxide are then added in sequence. The mixture is then homogenised for at least 15 minutes. This mixture is then compressed to obtain a tablet weighing 1380 mg. The resulting tablets are then film-coated with a solution/suspension of 27 g of ethylcellulose, 8 g of talc, 3 g of titanium dioxide and 1 g of triethyl citrate, to obtain a tablet with a mean weight of 1420 mg.

[0055] When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release below 1%; when subjected to the dissolution test at pH≥6.4 they exhibit the following release profile: not more than 1% after 1 hour, at pH 7.2 not more than 5% after 1 hour, and not more than 15% after 2 hours; not more than 55% after 6 hours; less than 70% after 8 hours; less than 90% after 10 hours; and 100% after 18 hours.

EXAMPLE 6

[0056] 960 g of mesalazine is loaded into a granulator with 25 g of lactose and 25 g of microcrystalline cellulose, and wet-granulated with an aqueous solution containing 40 g of PVP. 15 g of hydroxypropyl methylcellulose (HPMC K 1001v), 35 g of hydroxypropyl methylcellulose (HPMC K15M), 1 g of polymethacrylate RL 100 and 1 g of polymethacrylate RS 100 are added in sequence to the resulting granulate after drying. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained. 4 g of talc, 4 g of colloidal silicon dioxide and 5 g of magnesium stearate are then added in sequence. The mixture is then homogenised for at least 15 minutes. This mixture will form part of the first, controlled-release layer of the tablet. 240 g of mesalazine is loaded into a second granulator. 25 g of microcrystalline cellulose, 25 g of lactose monohydrate, 20 g of crospovidone, 20 g of croscarmellose, 1 g of magnesium stearate and 1 g of talc are added and homogeneously mixed. The mixture is then homogenised for at least 20 minutes. This mixture will form part of the second, immediate-release layer of the tablet. The two separate mixtures are then compressed to obtain a double-layer tablet weighing 1407 mg. The resulting tablets are then film-coated with a solution/suspension of 27 g of ethylcellulose, 8 g of talc, 3 g of titanium dioxide and 2 g of triethyl citrate, to obtain a tablet with a mean weight of 1487 mg.

[0057] When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release below 1%; when subjected to the dissolution test at pH≥6.4 they exhibit the following release profile: not more than 1% after 1 hour, at pH 7.2 not more than 15% after 1 hour, and not more than 25% after 2 hours; not more than 55% after 6 hours; less than 75% after 8 hours; less than 90% after 10 hours; and 100% after 18 hours.

EXAMPLE 7

[0058] 1.2 Kg of mesalazine is loaded into a granulator with 50 g of hydroxypropyl methylcellulose (HPMC K4M), 25 g of hydroxypropyl methylcellulose (HPMC K100M), 2 g of polymethacrylate L 100, 2 g of polymethacrylate S100 and 1 g of shellac. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained; 10 g of magnesium stearate, 8 g of talc and 8 g of colloidal silicon dioxide are then added in sequence. The mixture is then homogenised for at least 15 minutes. This mixture is then compressed to obtain a tablet weighing 1306 mg. The resulting tablets are then film-coated with a gastroresistant solution/suspension based on 80 g of shellac, 2 g of hydroxypropyl methylcellulose E 5 Premium, 8 g of talc, 3 g of titanium dioxide and 1 g of triethyl citrate to obtain a mini-tablet with a mean weight of 1390 mg.

[0059] When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release below 1%; when subjected to the dissolution test at pH≥6.4 they exhibit the following release profile: not more than 1% after 1 hour, at pH 7.2 not more than 30% after 1 hour, and not more than 35% after 2 hours; the value must be >80% after 6 hours; and 100% after 10 hours.

EXAMPLE 8

[0060] 750 g of mesalazine is loaded into a granulator and wet-granulated with an aqueous solution containing 50 g of PVP. After drying, 65 g of hydroxypropyl methylcellulose (HPMC K4M), 33 g of hydroxypropyl methylcellulose (HPMC K100M), 2.5 g of polymethacrylate L 100 and 2.5 g of polymethacrylate S 100 are added to the resulting granulate. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained. 5 g of talc, 5 g of colloidal silicon dioxide and 7 g of magnesium stearate are then added in sequence. The mixture is then homogenised for at least 15 minutes. The mixture is then compressed to obtain a mini-tablet weighing 92 mg. The resulting mini-tablets are then film-coated with a gastroresistant solution of 33 g of polymethacrylate L 100, 33 g of polymethacrylate S100, 35 g of talc, 12 g of titanium dioxide and 7 g of triethyl citrate, to obtain a mini-tablet with a mean weight of 104 mg. When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release ≤1%; when subjected to the dissolution test at pH≥6.4, the tablets exhibit a release not exceeding 1% after 60 minutes; when subjected to the dissolution test at pH≥7.2 they exhibit the following release profile: not more than 30% after 60 minutes; not more than 35% after 120 minutes, not less than 80% after 360 minutes; the value must be 100% after 18 hours.

EXAMPLE 9

[0061] 750 g of mesalazine is loaded into a granulator and wet-granulated with an aqueous solution containing 50 g of PVP. After drying, 65 g of hydroxypropyl methylcellulose (HPMC K 4M), 33 g of hydroxypropyl methylcellulose (HPMC K 100M) and 5 g of polymethacrylate L 100-55 are added to the resulting granulate. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained. 5 g of talc, 5 g of colloidal silicon dioxide and 7 g of magnesium stearate are then added in sequence. The mixture is then homogenised for at least 15 minutes. The mixture is then compressed to obtain a mini-tablet weighing 92 mg. The mini-tablets thus obtained are then film-coated with a solution/suspension of 60 g of ethylcellulose and 3.5 g of triethyl citrate; then further film-coated with a gastroresistant solution of 66 g of polymethacrylate L 100-55, 35 g of talc, 12 g of titanium dioxide and 3.5 g of triethyl citrate to obtain a mini-tablet with a mean weight of 110 mg.

[0062] When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release ≤1%; when subjected to the dissolution test at pH≥6.4, the tablets exhibit a release not exceeding 1% after 60 minutes; when subjected to the dissolution test at pH≥7.2 they exhibit the following release profile: not more than 5% after 60 minutes; not more than 10% after 120 minutes, and not less than 20% after 360 minutes; the value must be 100% after 18 hours.

EXAMPLE 10

[0063] 250 g of mesalazine is loaded into a granulator and wet-granulated with an aqueous solution containing 10 g of PVP. After drying, 5 g of hydroxypropyl methylcellulose (HPMC K 4M), 3 g of hydroxypropyl methylcellulose (HPMC K 100M), 2.5 g of polymethacrylate L 100 and 2.5 g of polymethacrylate S100 are added to the resulting granulate. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained. 5 g of talc, 5 g of colloidal silicon dioxide and 7 g of magnesium stearate are then added in sequence. The mixture is then homogenised for at least 15 minutes. The mixture is then compressed to obtain a mini-tablet weighing 28.1 mg. The resulting mini-tablets are film-coated with a solution/suspension of 25 g of ethylcellulose, 7 g of triethyl citrate, 1 g of talc and 1 g of titanium dioxide to obtain a mini-tablet with a mean weight of 31.5 mg.

[0064] When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release <1%; when subjected to the dissolution test at pH≥6.4, the tablets exhibit a release not exceeding 1% after 1 hour; when subjected to the dissolution test at pH≥7.2 they exhibit the following release profile: not more than 5% after 1 hour; not more than 10% after 2 hours, not more than 70% after 6 hours; the value must be ≥80% after 8 hours; and must reach 100% after 18 hours.

EXAMPLE 11

[0065] 250 g of mesalazine is loaded into a granulator and wet-granulated with an aqueous solution containing 10 g of PVP. After drying, 4 g of hydroxypropyl methylcellulose (HPMC K 4M), 2 g of hydroxypropyl methylcellulose (HPMC K 100M) and 5 g of polymethacrylate L 100-55 are added to the resulting granulate. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained. 5 g of talc, 5 g of colloidal silicon dioxide and 7 g of magnesium stearate are then added in sequence. The mixture is then homogenised for at least 15 minutes. The mixture is then compressed to obtain a mini-tablet weighing 22.9 mg. The resulting mini-tablets are film-coated with a solution/suspension of 25 g of ethylcellulose, 7 g of triethyl citrate, 1 g of talc and 1 g of titanium dioxide to obtain a mini-tablet with a mean weight of 26.3 mg.

[0066] When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release ≤1%; when subjected to the dissolution test at pH≥6.4, the tablets exhibit a release not exceeding 1% after 1 hour; when subjected to the dissolution test at pH≥7.2 they exhibit the following release profile: not more than 5% after 1 hour; not more than 15% after 2 hours, not more than 75% after 6 hours; the value must be ≥80% after 8 hours; and must reach 100% after 18 hours.

EXAMPLE 12

[0067] 187.5 g of mesalazine is loaded into a granulator and wet-granulated with an aqueous solution containing 12.99 g of PVP. After drying, 16.7 g of hydroxypropyl methylcellulose (HPMC K 4M), 8.35 g of hydroxypropyl methylcellulose (HPMC K 100M), 0.53 g of polymethacrylate L 100 and 0.53 g of polymethacrylate S100 are added to the resulting granulate. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained. 1.25 g of talc, 1.26 g of colloidal silicon dioxide and 1.89 g of magnesium stearate are then added in sequence. The mixture is then homogenised for at least 15 minutes. The mixture is then compressed to obtain a mini-tablet weighing 23.1 mg. The resulting mini-tablets are film-coated with a gastroresistant solution/suspension of 23.76 g of polymethacrylate L 100, 23.76 g of polymethacrylate S 100, 2.3 g of triethyl citrate, 35.56 g of talc, 14.25 g of titanium dioxide and 2.84 g of iron oxide to obtain a mini-tablet with a mean weight of 35.5 mg.

[0068] When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release <1%; when subjected to the dissolution test at pH≥6.4, the tablets exhibit a release not exceeding 1% after 1 hour; when subjected to the dissolution test at pH≥7.2 they exhibit the following release profile: not more than 20% after 1 hour; not more than 30% after 2 hours, and not less than 80% after 6 hours; the value must be ≥90% after 8 hours; and must reach 100% after 18 hours.

EXAMPLE 13

[0069] 187.5 g of mesalazine is loaded into a granulator and wet-granulated with an aqueous solution containing 12.99 g of PVP. After drying, 16.7 g of hydroxypropyl methylcellulose (HPMC K 4M), 8.35 g of hydroxypropyl methylcellulose (HPMC K 100M), 0.53 g of polymethacrylate L 100 and 0.53 g of polymethacrylate S100 are added to the resulting granulate. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained. 1.25 g of talc, 1.26 g of colloidal silicon dioxide and 1.89 g of magnesium stearate are then added in sequence. The mixture is then homogenised for at least 15 minutes. The mixture is then compressed to obtain a mini-tablet weighing 23.1 mg. The resulting mini-tablets are film-coated with a solution/suspension of 16.28 g of ethylcellulose, 4.07 g of triethyl citrate, 2.21 g of titanium dioxide and 0.44 g of iron oxide to obtain a mini-tablet with a mean weight of 25.4 mg.

[0070] When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release ≤1%; when subjected to the dissolution test at pH≥6.4, the tablets exhibit a release not exceeding 1% after 1 hour; when subjected to the dissolution test at pH≥7.2 they exhibit the following release profile: not more than 10% after 1 hour; not more than 20% after 2 hours, not more than 70% after 6 hours; the value must be ≥80% after 8 hours; and must reach 100% after 18 hours.

EXAMPLE 14

[0071] 750 g of mesalazine is loaded into a granulator and wet-granulated with an aqueous solution containing 50 g of PVP. After drying, 65 g of hydroxypropyl methylcellulose (HPMC K 4M), 33 g of hydroxypropyl methylcellulose (HPMC K 100M), 2 g of polymethacrylate RL 100, 2 g of polymethacrylate RS 100 and 1 g of shellac are added to the resulting granulate. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained. 5 g of talc, 5 g of colloidal silicon dioxide and 7 g of magnesium stearate are then added in sequence. The mixture is then homogenised for at least 15 minutes. The mixture is then compressed to obtain a mini-tablet weighing 92 mg. The resulting mini-tablets are then film-coated with a gastroresistant solution/suspension of 60 g of shellac, 10 g of hydroxypropyl methylcellulose E 5 Premium, 35 g of talc, 12 g of titanium dioxide and 7 g of triethyl citrate to obtain a mini-tablet with a mean weight of 104 mg.

[0072] When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release ≤1%; when subjected to the dissolution test at pH≥6.4, the tablets exhibit a release not exceeding 1% after 60 minutes; when subjected to the dissolution test at pH≥7.2 they exhibit the following release profile: not more than 25% after 60 minutes; not more than 40% after 120 minutes, not less than 80% after 360 minutes; the value must be 100% after 18 hours.

EXAMPLE 15

[0073] 750 g of mesalazine is loaded into a granulator and wet-granulated with an aqueous solution containing 50 g of PVP. After drying, 33 g of hydroxypropyl methylcellulose (HPMC K 100 1v), 65 g of hydroxypropyl methylcellulose (HPMC K 100M), 2.5 g of polymethacrylate L 100 and 2.5 g of polymethacrylate S100 are added to the resulting granulate. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained. 5 g of talc, 5 g of colloidal silicon dioxide and 7 g of magnesium stearate are then added in sequence. The mixture is then homogenised for at least 15 minutes. The mixture is then compressed to obtain a mini-tablet weighing 92 mg. The resulting mini-tablets are then film-coated with a gastroresistant solution of 33 g of polymethacrylate L 100, 33 g of polymethacrylate S 100, 30 g of talc, 10 g of titanium dioxide and 4 g of triethyl citrate, to obtain a mini-tablet with a mean weight of 103 mg.

[0074] When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release ≤1%; when subjected to the dissolution test at pH≥6.4, the tablets exhibit a release not exceeding 1% after 60 minutes; when subjected to the dissolution test at pH≥7.2 they exhibit the following release profile: not more than 35% after 60 minutes; not more than 45% after 120 minutes, not less than 85% after 360 minutes; the value must be 100% after 18 hours.

[0075] Table 1 below summarises the qualitative and quantitative compositions of Examples 1-15.

TABLE-US-00001 TABLE 1 Active ingredient Mesalazine Mesalazine Mesalazine Mesalazine Mesalazine Mesalazine Mesalazine F1 F2 F3 F4 F5 F6 F7 Ingredients of MR core 1200 1200 1200 1200 1200 960 1200 Lactose 50 25 monohydrate Microcrystalline 50 25 cellulose HPMC 100 lv 15 15 15 HPMC K4 M 105 106 35 50 HPMC K15 M 35 35 HPMC K100 M 54 53 35 15 25 Eudragit L100/55 4 4 Eudragit L 100 2 2 2 Eudragit S 100 2 2 2 Shellac 1 1 Eudragit RL 100 2 1 Eudragit RS 100 2 1 Talc 8 8 8 8 8 4 8 Hydrated coll. 8 8 8 8 8 4 8 silicon dioxide PVP 83 83 40 Mg stearate 10 10 10 10 10 5 10 1472 1472 1281 1363 1380 1075 1306 Ingredients of IR core 240 Lactose 25 monohydrate Microcrystalline 25 cellulose Crosslinked PVP 20 Croscarmellose 20 (AcDisol) Talc 1 Mg stearate 1 Total 332 Film-coating ingredients Talc 8 8 8 8 8 8 8 Eudragit L100/55 45 Eudragit L 100 36 Eudragit S 100 36 Shellac 80 Ethylcellulose 27 27 27 27 27 Titanium dioxide 3 3 3 3 3 3 3 Triethyl citrate 1 1 1 1 2 2 1 HPMC 5 premium 2 Total 84 84 39 39 40 40 84 Grand total 1556 1556 1320 1402 1420 1487 1390

TABLE-US-00002 TABLE 2 Active ingredient of Mini-tablets Active ingredient Mesalazine* Mesalazine* Mesalazine** Mesalazine*** Mesalazine**** Mesalazine**** Mesalazine* Mesalazine* F8 F9 F10 F11 F12 F13 F14 F15 Ingredients of MR MiniCore 75 75 25 20 18.75 18.75 75 75 HPMC 100 lv 3.3 HPMC K4 M 6.5 6.5 0.5 0.4 1.670 1.670 6.5 HPMC K15 M 6.5 HPMC K100 M 3.3 3.3 0.3 0.2 0.835 0.835 3.3 Eudragit L100/55 0.5 0.5 Eudragit L100 0.25 0.25 0.053 0.053 0.25 Eudragit S100 0.25 0.25 0.053 0.053 0.25 Shellac 0.1 Eudragit RL 0.2 100 Eudragit RS 0.2 100 PVP 5 5 0.1 0.1 1.299 1.299 5 5 Talc 0.5 0.5 0.5 0.5 0.125 0.125 0.5 0.5 Mg stearate 0.7 0.7 0.7 0.7 0.189 0.189 0.7 0.7 Silicon dioxide 0.5 0.5 0.5 0.5 0.126 0.126 0.5 0.5 92 92 28.1 22.9 23.10 23.10 92 92 Film-coating ingredients Talc 3.5 3.5 0.1 0.1 3.563 3.5 3 Eudragit L100/55 6.6 Eudragit L 100 3.3 2.376 3.3 Eudragit S 100 3.3 2.376 3.3 Shellac 6 HPMC E 5 P 1 Ethylcellulose 6 2.5 2.5 1.628 Titanium 1.2 1.2 0.1 0.1 1.425 0.221 1.2 1 dioxide Triethyl citrate 0.7 0.7 0.7 0.7 2.376 0.407 0.7 0.4 Iron dioxide 0.284 0.044 Total 12 18 3.4 3.4 12.4 2.3 12 11 Grand total 104 110 31.5 26.3 35.5 25.4 105 103 Mesalazine* 16 mini-tablets 4 mm = 1200 mg Mesalazine** 48 mini-tablets 3 mm = 1200 mg Mesalazine*** 60 mini-tablets 3 mm = 1200 mg Mesalazine**** 64 mini-tablets 3 mm = 1200 mg