Delayed release drug formulation

Abstract

In a delayed release formulation comprising a core containing a drug and a delayed release coating for providing intestinal release, release of the drug in the colon is accelerated by including an isolation layer between the core and the delayed release coating. The delayed release coating comprises an inner layer and an outer layer. The outer layer comprises a pH dependently soluble polymeric material which has a pH threshold at about pH 5 or above. The inner layer comprises a soluble polymeric material which is soluble in intestinal fluid or gastrointestinal fluid, said soluble polymeric material being selected from the group consisting of a polycarboxylic acid polymer that is at least partially neutralised, and a non-ionic polymer, provided that, where said soluble polymeric material is a non-ionic polymer, said inner layer comprises at least one additive selected from a buffer agent and a base.

Claims

1. A dosage form, comprising: a delayed release drug formulation for oral administration to a subject in need thereof, said formulation comprising: a core comprising said drug; an isolation layer comprising at least one non-ionic polymer, said isolation layer coating said core; and an outer coating for providing intestinal release of said drug, said outer coating comprising an outer layer and an inner layer, wherein said outer layer comprises a pH dependently soluble polymeric material which has a pH threshold at about pH 5 or above, wherein the inner layer comprises (i) a soluble polymeric material which is a non-ionic polymer soluble in intestinal fluid or gastrointestinal fluid selected from the group consisting of methylcellulose (MC); hydroxypropyl cellulose (HPC); hydroxypropyl methylcellulose (HPMC); poly(ethylene oxide)-graft-polyvinyl alcohol; polyvinylpyrrolidone (PVP); and polyvinyl alcohol (PVA), (ii) a base wherein said base is a hydroxide base, and (iii) a buffer agent wherein said buffer agent is a phosphate salt and is present in the inner layer in a total amount from about 10 wt % to about 30 wt % based on a dry weight of the soluble polymeric material which is the non-ionic polymer of the inner layer, wherein the inner layer is disposed between the isolation layer and the outer layer, and wherein a composition of the isolation layer and a composition of the inner layer are different.

2. The dosage form of claim 1, wherein intestinal release of said drug from said delayed release drug formulation is accelerated compared to an equivalent formulation without said isolation layer.

3. The dosage form of claim 1, for use in accelerating drug release in the colon of said subject.

4. The dosage form of claim 3, wherein lag time (T.sub.lag) in vitro in Krebs buffer at pH 7.4 after 2 h at 0.1M HCl is reduced by at least 10 %.

5. The dosage form of claim 3, wherein lag time (T.sub.lag) in vitro in Krebs buffer at pH 7.4 after 2 h at 0.1M HCl is reduced by at least 10 minutes.

6. The dosage form of claim 1, for use in accelerating drug release in the small intestine of said subject.

7. The dosage form of claim 1, for use in accelerating drug release in the proximal small intestine of said subject.

8. The dosage form of claim 1, wherein the isolation layer has a coating amount from about 1 mg polymer/cm.sup.2 to about 5 mg polymer/cm.sup.2.

9. The dosage form of claim 1, wherein the isolation layer has a thickness from about 5 μm to about 100 μm.

10. The dosage form of claim 1, wherein said at least one non-ionic polymer of the isolation layer is selected from the group consisting of methylcellulose (MC); hydroxypropyl cellulose (HPC); hydroxypropyl methylcellulose (HPMC); poly(ethylene oxide)-graft-polyvinyl alcohol; polyvinylpyrrolidone (PVP); and polyvinyl alcohol (PVA).

11. The dosage form of claim 1, wherein said at least one non-ionic polymer of the isolation layer is hydroxypropyl methylcellulose (HPMC).

12. The dosage form of claim 1, wherein said at least one non-ionic polymer of the isolation layer is polyvinyl alcohol (PVA).

13. The dosage form of claim 1, wherein said at least one non-ionic polymer of the isolation layer is the only film-forming polymeric material in the isolation layer.

14. A dosage form, comprising: a delayed release drug formulation for oral administration to deliver a drug to the intestine of a subject in need thereof, said formulation comprising: a core comprising said drug; an isolation layer comprising a non-ionic polymer, said isolation layer coating said core, said isolation layer for use in accelerating drug release in the intestine of said subject; and an outer coating for providing intestinal release of said drug, said outer coating comprising an outer layer and an inner layer, wherein the outer layer comprises a film-forming polymeric material consisting of a pH dependently soluble polymeric material which has a pH threshold at about pH 5 or above, wherein the inner layer comprises (i) a soluble polymeric material which is a non-ionic polymer soluble in intestinal fluid or gastrointestinal fluid, (ii) a base wherein said base is a hydroxide base, and (iii) a buffer agent wherein said buffer agent is a phosphate salt and is present in the inner layer in a total amount from about 10 wt % to about 30 wt % based on a dry weight of the soluble polymeric material which is the non-ionic polymer of the inner layer, wherein the inner layer is disposed between the isolation layer and the outer layer, and wherein a composition of the isolation layer and a composition of the inner layer are different.

15. The dosage form of claim 14, wherein said core is acidic.

16. The dosage form of claim 14, wherein said drug, or any other component in the core, comprises at least one acidic group.

17. The dosage form of claim 14, wherein said drug is an anti-inflammatory agent.

18. The dosage form of claim 14, wherein said drug is 5ASA.

19. The dosage form of claim 14, wherein the buffer agent is potassium dihydrogen phosphate.

20. The dosage form of claim 14, wherein the base is sodium hydroxide.

21. The dosage form of claim 14, wherein the pH dependently soluble polymeric material of the outer layer is a blend of at least two different polymers having a pH threshold of about pH 5 and above.

22. The dosage form of claim 21, wherein the polymers in the blend are different polymethacrylate polymers.

23. The dosage form of claim 21, wherein there are two different polymers in the blend in a ratio from about 40:60 to about 60:40.

24. The dosage form of claim 14, wherein said pH dependently soluble polymeric material is present in the outer layer as the sole film forming polymeric material.

25. The dosage form of claim 14, wherein said pH dependently soluble polymeric material is present in the outer layer in admixture with a digestible polymeric material which is susceptible to attack by colonic bacteria.

26. The dosage form of claim 25, wherein said digestible polymeric material and said pH dependently soluble polymeric material are present in the outer layer in a ratio of up to about 60:40.

27. The dosage form of claim 25, wherein said digestible polymeric material and said pH dependently soluble polymeric material are present in the outer layer in a ratio from about 25:75 to about 35:65.

28. The dosage form of claim 25, wherein said digestible polymeric material and said pH dependently soluble polymeric material are present in the outer layer in a ratio from about 40:60 to about 60:40.

29. The dosage form of claim 14, wherein release of said drug in the intestine is accelerated.

30. A method, comprising: accelerating drug release in an intestine of a subject in need thereof by administering to the subject a delayed release drug formulation, said formulation comprising: a core comprising said drug; an isolation layer comprising a non-ionic polymer, said isolation layer coating said core; and an outer coating for providing intestinal release of said drug, said outer coating comprising an outer layer and an inner layer, wherein the outer layer comprises a pH dependently soluble polymeric material which has a pH threshold at about pH 5 or above, wherein the inner layer comprises (i) a soluble polymeric material which is a non-ionic polymer soluble in intestinal fluid or gastrointestinal fluid selected from the group consisting of methylcellulose (MC); hydroxypropyl cellulose (HPC); hydroxypropyl methylcellulose (HPMC); poly(ethylene oxide)-graft-polyvinyl alcohol; polyvinylpyrrolidone (PVP); and polyvinyl alcohol (PVA), (ii) a base, and (iii) a buffer agent, wherein said buffer agent is a phosphate salt and is present in the inner layer in a total amount from about 10 wt % to about 30 wt % based on a dry weight of the soluble polymeric material which is the non-ionic polymer of the inner layer, wherein the inner layer is disposed between the isolation layer and the outer layer, and wherein a composition of the isolation layer and a composition of the inner layer are different.

31. A method of producing a delayed release drug formulation for oral administration, comprising: obtaining a core comprising said drug; coating said core with an isolation layer to produce an isolated core, the isolation layer comprising a non-ionic polymer; and coating said isolated core with an outer coating for providing intestinal release of said drug, said outer coating comprising an outer layer and an inner layer, wherein the outer layer comprises a pH dependently soluble polymeric material which has a pH threshold at about pH 5 or above, wherein the inner layer comprises (i) a soluble polymeric material which is a non-ionic polymer soluble in intestinal fluid or gastrointestinal fluid selected from the group consisting of methylcellulose (MC); hydroxypropyl cellulose (HPC); hydroxypropyl methylcellulose (HPMC); poly(ethylene oxide)-graft-polyvinyl alcohol; polyvinylpyrrolidone (PVP); and polyvinyl alcohol (PVA), (ii) a base, and (iii) a buffer agent, wherein said buffer agent is a phosphate salt and is present in the inner layer in a total amount from about 10 wt % to about 30 wt % based on a dry weight of the soluble polymeric material which is the non-ionic polymer of the inner layer, wherein the inner layer is disposed between the isolation layer and the outer layer, and wherein a composition of the isolation layer and a composition of the inner layer are different, wherein said formulation provides accelerated release of a drug in an intestine of a subject in need thereof.

Description

EXAMPLES

(1) Preferred embodiments of the present invention will now be described with reference to the drawings, in which:—

(2) FIG. 1 is a graph comparing drug release in 0.1N HCl (2 hours) followed by Krebs buffer pH 7.4 as a function of time, from 400 mg 5ASA tablets, coated with (a) an isolation layer of HPMC, an inner layer of neutralized Eudragit S and an outer layer of Eudragit® S (Example 1), (b) coated with an inner layer of neutralized Eudragit S and an outer layer of Eudragit® S (Comparative Example 1) and (c) coated with a single layer of Eudragit S (Comparative Example 2);

(3) FIG. 2 is a graph comparing drug release in 0.1N HCl (2 h) followed by Krebs buffer pH 7.4 as a function of time from 400 mg 5ASA tablets coated with an isolation layer of HPMC, an inner layer of neutralized Eudragit® S and an outer layer of Eudragit® S (Example 1) after storage at 40° C./75% RH for (a) 0 days, (b) 15 days and (c) 45 days;

(4) FIG. 3 is a graph comparing drug release in 0.1N HCl (2 h) followed by Krebs buffer pH 7.4 as a function of time from 400 mg 5ASA tablets coated with an inner layer of neutralized Eudragit® S and an outer layer of Eudragit® S (Comparative Example 1) after storage at 40° C./75% RH for (a) 0 days, (b) 15 days and (c) 45 days;

(5) FIG. 4 is a graph comparing drug release in 0.1N HCl (2 h) followed by Krebs buffer pH 7.4 as a function of time from 800 mg 5ASA tablets coated with (a) an isolation layer of HPMC, an inner layer of neutralized Eudragit® S and an outer layer of 30:70 mixture of starch:Eudragit® S (Example 2), (b) an isolation layer of PVA (Opadry AMB), an inner layer of neutralized Eudragit® S and an outer layer of 30:70 mixture of starch:Eudragit® S (Example 3), (c) an inner layer of neutralized Eudragit® S and an outer layer of 30:70 mixture of starch:Eudragit® S (Comparative Example 3), (d) an isolation layer of HPMC and an outer layer of 30:70 mixture of starch:Eudragit® S (Comparative Example 4), (e) an outer layer of 30:70 mixture of starch:Eudragit® S (Comparative Example 5);

(6) FIG. 5 is a graph comparing drug release in 0.1N HCl (2 h) followed by Krebs buffer pH 7.4 as a function of time from 1200 mg 5ASA tablets coated with an isolation layer of HPMC, an inner layer of neutralized Eudragit® S and an outer layer of 30:70 mixture of starch:Eudragit® S, wherein the isolation layer has a thickness of (a) 1 mg/cm.sup.2 (Comparative Example 6) (b) 3 mg/cm.sup.2 (Example 4), or (c) 5 mg/cm.sup.2 (Comparative Example 7);

(7) FIG. 6 is a graph comparing drug release in 0.1N HCl (2 h) followed by Krebs buffer pH 7.4 as a function of time from 800 mg 5ASA tablets coated with an inner layer of neutralized Eudragit® S and an outer layer of 30:70 mixture of starch:Eudragit® S (Comparative Example 3) before storage (Initial) and after storage in a closed HDPE bottle at 40° C./75% RH for 1 month and 3 months;

(8) FIG. 7 is a graph comparing drug release in 0.1N HCl (2 h) followed by Krebs buffer pH 7.4 as a function of time from 800 mg 5ASA tablets coated with an isolation layer of HPMC, an inner layer of neutralized Eudragit® S and an outer layer of 30:70 mixture of starch:Eudragit® S (Example 2) before storage (Initial) and after storage in a closed HDPE bottle at 40° C./75% RH for 1 month and 3 months;

(9) FIG. 8 is a graph comparing drug release in 0.1N HCl (2 h) followed by Krebs buffer pH 7.4 as a function of time from 800 mg 5ASA tablets coated with an isolation layer of HPMC, an inner layer of neutralized Eudragit® S and an outer layer of 50:50 mixture of starch:Eudragit® S (Example 5) before storage (Initial) and after storage in a closed HDPE bottle at 40° C./75% RH for 1 month and 3 months;

(10) FIG. 9 is a graph depicting drug release in 0.1N HCl (2 h) followed by Krebs buffer pH 7.4 as a function of time from 800 mg 5ASA tablets coated with an inner layer of neutralized Eudragit® S and an outer layer of 30:70 mixture of starch:Eudragit® S (Comparative Example 3) before storage (Initial) and after storage in an open HDPE bottle at 25° C./60% RH for 1 month and for 3 months;

(11) FIG. 10 is a graph depicting drug release in 0.1N HCl (2 h) followed by Krebs buffer pH 7.4 as a function of time from 800 mg 5ASA tablets coated with an isolation layer of HPMC, an inner layer of neutralized Eudragit® S and an outer layer of 30:70 mixture of starch:Eudragit® S (Example 2) before storage (Initial) and after storage in an open HDPE bottle at 25° C./60% RH for 1 month and 3 months;

(12) FIG. 11 is a graph comparing drug release in 0.1N HCl (2 h) followed by Krebs buffer pH 7.4 as a function of time from 800 mg 5ASA tablets coated with an isolation layer of HPMC, an inner layer of neutralized Eudragit® S and an outer layer of 50:50 mixture of starch:Eudragit® S (Example 5) before storage (Initial) and after storage in an open HDPE bottle at 25° C./60% RH for 1 month and 3 months.

MATERIALS

(13) 5-aminosalicylic acid (mesalazine EP) was purchased from Cambrex Karlskoga AB, Karlskoga, Sweden. Lactose (Tablettose 80) was purchased from Meggle, Hamburg, Germany. Sodium starch glycolate (Explotab™) was purchased from JRS Pharma, Rosenberg, Germany. Talc was purchased from Luzenac Deutschland GmbH, Dusseldorf, Germany. Polyvinylpyrrolidone (PVP) was purchased from ISP Global Technologies, Köln, Germany. Magnesium stearate was purchased from Peter Greven GmbH, Bad Münstereifel, Germany. Eudragit® S 100, Eudragit® L 30 D-55 and Eudragit® FS 30 D were all purchased from Evonik GmbH, Darmstadt, Germany. Maize starch (NI-460 and Eurylon VI or 6) was purchased from Roquette, Lestrem, France. Polysorbate 80, butan-1-ol and sodium hydroxide were all purchased from Sigma-Aldrich, Buchs, Switzerland. Potassium dihydrogen phosphate, glyceryl monostearate (GMS), triethyl citrate (TEC) and ammonia solution (25%) were all purchased from VWR International LTD, Poole, UK.

(14) Preparation of 400 mg 5ASA Tablet Cores

(15) Oblong shaped 400 mg 5ASA tablet cores with dimensions 14.5×5.7 mm were prepared by fluid bed granulation followed by blending and compression. Each tablet contained 76.9 wt % 5ASA (400 mg; drug); 14.7 wt % lactose (filler); 1.7 wt % PVP (binder); 3.5 wt % sodium starch glycolate (disintegrant); and 2 wt % talc and 1.2 wt % magnesium stearate (lubricants).

(16) The obtained tablet cores were coated as discussed below in Examples 1 & 2 and in Comparative Examples 1 to 5.

(17) Preparation of 800 mg 5ASA Tablet Cores

(18) Oblong shaped 800 mg tablets with dimensions 8×17 mm were prepared by granulation followed by blending and compression. Each tablet contained 800 mg 5ASA (drug) and additional excipients, including lactose (filler); PVP (binder); sodium starch glycolate (disintegrant); and talc and magnesium stearate (lubricants).

(19) The obtained tablet cores were coated as discussed below in Examples 8 to 11 and in Comparative Examples 7 to 11.

(20) Preparation of 1200 mg 5ASA Tablet Cores

(21) Oblong-shaped 1200 mg 5ASA tablet cores (having dimensions 21×10 mm) were prepared by wet granulation. Each tablet contained 85.7 wt % 5ASA (1200 mg), 9.2 wt % microcrystalline cellulose, 1.7 wt % HPMC, 2.9 wt % sodium starch glycolate, and 0.5 wt % magnesium stearate.

(22) The obtained tablet cores were coated as discussed below in Examples 3 to 7 and in Comparative Example 6.

Example 1

(23) (400 mg 5ASA tablets with isolation layer of HPMC/inner layer of neutralised Eudragit® S/outer layer of Eudragit® S)

(24) Isolation Layer

(25) The isolation layer was formed from a mixture of HPMC and 10% triethyl citrate (TEC), based on dry polymer weight.

(26) The HPMC was dissolved in water under magnetic stirring and then TEC was added to form a coating preparation. The coating preparation was sprayed onto 400 mg 5ASA cores using a fluid bed spray coating machine to achieve a coating amount of 3 mg polymer/cm.sup.2.

(27) The coating parameters were as follows: spray rate 3.1 g/min/kg tablet cores, atomizing pressure 0.2 bar, and inlet air temperature 40° C.

(28) Inner Layer

(29) The inner layer was applied to the isolation layer coated tablets from an aqueous preparation of Eudragit® S 100, where the pH was adjusted to pH 8. The composition of the inner layer also included 50% of triethyl citrate (based on dry polymer weight), 10% potassium dihydrogen phosphate (based on dry polymer weight), 10% glyceryl monostearate (based on dry polymer weight) and 40% polysorbate 80 (based on GMS weight). The pH was adjusted using 1M NaOH until the pH 8 was obtained.

(30) Potassium dihydrogen phosphate and triethyl citrate were dissolved in distilled water, after which a dispersion of Eudragit® S 100 was added under mechanical agitation. The pH was then adjusted to pH 8 with 1M NaOH and the solution was left mixing for 1 hour.

(31) A GMS emulsion was prepared at a concentration of 10% w/w. Polysorbate 80 (40% based on GMS weight) was dissolved in distilled water followed by dispersion of GMS. This preparation was then heated to 75° C. for 15 minutes under strong magnetic stirring in order to form the emulsion. The emulsion was cooled to room temperature under stirring.

(32) The GMS emulsion was added to the neutralised Eudragit® S solution to form an inner layer coating preparation which was coated onto the isolation layer coated tablets using a fluid bed spray coating machine until the coating amount reached 5 mg polymer/cm.sup.2 to form inner layer coated tablets.

(33) The coating parameters were as follows: spraying rate 20 ml/min/kg tablets, atomizing pressure 0.2 bar and inlet air temperature 40° C.

(34) Outer Layer

(35) The outer coating layer was applied from an organic solution of Eudragit® S 100. The coating solution contains 20% triethyl citrate (based on dry polymer weight), 10% glyceryl monostearate (based on dry polymer weight) and 40% polysorbate 80 (based on GMS weight).

(36) Triethyl citrate was dissolved in 96% ethanol followed by Eudragit® S 100 under mechanical stirring and mixing was continued for 1 hour.

(37) A GMS emulsion was prepared at a concentration of 10% w/w. Polysorbate 80 (40% based on GMS weight) was dissolved in distilled water followed by dispersion of the GMS. This dispersion was then heated to 75° C. for 15 minutes under strong magnetic stirring in order to form the emulsion. The emulsion was cooled to room temperature under stirring.

(38) The GMS preparation was added to the Eudragit® S 100 solution and the final coating solution was coated on to the inner layer coated tablets using a fluid bed spray coating machine to achieve a coating amount of 5 mg Eudragit® S polymer/cm.sup.2.

(39) The coating parameters were as follows: spraying rate 16 ml/min/kg tablets, atomizing pressure 0.2 bar and inlet air temperature 40° C.

Example 2

(40) (800 mg 5ASA tablets with isolation layer of HPMC/inner layer of neutralised Eudragit® S/outer layer of 30:70 mixture of starch:Eudragit® S)

(41) Isolation Layer

(42) The isolation layer was formed from a mixture of HPMC and 20% PEG 6000 (based on dry polymer weight).

(43) The polymer was dissolved in water under magnetic stirring and then the PEG 6000 was added. The final preparation was sprayed onto 800 mg 5ASA cores using a perforated pan coater to achieve a coating amount of 3 mg polymer/cm.sup.2 to form isolation layer coated tablets. The coating parameters were as follows: spray rate 2.4 g/min/kg tablet cores, atomizing pressure 0.7 bar, and inlet air volume 15 m.sup.3/h/Kg tablets and product temperature 34° C.

(44) Inner Layer

(45) The inner layer was applied using an aqueous preparation of Eudragit® S 100, where the pH was adjusted to pH 8. The composition of the middle layer also includes 70% triethyl citrate (based on dry polymer weight), 1% potassium dihydrogen phosphate (based on dry polymer weight), 10% glyceryl monostearate (based on dry polymer weight) and 40% polysorbate 80 (based on GMS weight). The pH was adjusted using 1M NaOH until the pH 8 is obtained.

(46) Potassium dihydrogen phosphate and triethyl citrate were dissolved in distilled water, followed by dispersion of the Eudragit® S 100 under mechanical agitation. The pH was then adjusted to pH 8 with 1M NaOH and left mixing for 1 h.

(47) A GMS emulsion was prepared at a concentration of 10% w/w. Polysorbate 80 (40% based on GMS weight) was dissolved in distilled water followed by dispersion of GMS. This preparation was then heated to 75° C. for 15 minutes under strong magnetic stirring in order to form an emulsion. The emulsion was cooled to room temperature under stirring.

(48) The GMS emulsion was added to the neutralised Eudragit® S solution and the final preparation was coated onto isolation layer coated tablets using a perforated pan coater until the coating amount reached 5 mg polymer/cm.sup.2 to produce inner layer coated tablets. The total solids content of the coating solution was 10%. The coating parameters were as follows: spraying rate 3.1 g/min/kg tablets, atomizing pressure 0.6 bar, inlet air volume 15 m3/h/Kg tablets and product temperature 26.5° C.

(49) Outer Layer

(50) The outer layer was applied using a mixture of an aqueous starch dispersion and an organic Eudragit® S 100 solution. The aqueous starch dispersion was prepared by dispersing maize starch into butan-1-ol, followed by water, under magnetic stirring. The ratio of maize starch:butan-1-ol:water was 1:2:22. The resulting dispersion was heated to boiling and then cooled under stirring overnight. The organic Eudragit® S 100 solution was prepared by dissolving Eudragit® S 100 in 96% ethanol under high speed stirring. The final solution contained about 6% polymer solids.

(51) The starch dispersion was added dropwise to the Eudragit® S 100 solution to obtain a ratio of starch:Eudragit® S of 30:70. The mixture was mixed for 2 h, 20% triethyl citrate (based on total polymer weight) and 5% glyceryl monostearate (GMS, based on total polymer weight) were added and mixing was continued for a further 2 h.

(52) 13.18% iron oxide red (based on Eudragit® polymer weight) and 2.27% iron oxide yellow (based on Eudragit® polymer weight) were suspended in ethanol under high shear homogenization and this suspension was added into the starch and Eudragit® mixture and mixed for a further 30 minutes.

(53) The GMS was added in the form of an emulsion prepared at a concentration of 5% w/w. Polysorbate 80 (40% based on GMS weight) was dissolved in distilled water followed by dispersion of the GMS. This dispersion was then heated to 75° C. for 15 minutes under strong magnetic stirring in order to form an emulsion. The emulsion was cooled to room temperature under stirring.

(54) The final preparation was coated onto the inner layer coated tablets using a perforated pan coater machine until a coating having 5 mg Eudragit® polymer/cm.sup.2 was obtained. The spray coating parameters were as follows: spraying rate 8.0 g/min/kg tablets, atomizing pressure 0.4 bar, inlet air volume 100 m.sup.3/h/Kg tablets and product temperature 34.5° C.

Example 3

(55) (800 mg 5ASA tablets with isolation layer of PVA/inner layer of neutralised Eudragit® S/outer layer of a 30:70 mixture of starch/Eudragit® S)

(56) Isolation Layer

(57) The isolation layer was formed using Opadry® AMB (a polyvinyl alcohol-based product).

(58) The polymer was dissolved in water under magnetic stirring and mixed for 45 minutes. The final preparation was sprayed onto 800 mg 5ASA cores using a pan-coating machine to achieve a coating amount of 3.61 mg Opadry®/cm.sup.2. The coating parameters were as follows: spray rate 7.0 g/min/kg tablet cores, atomizing pressure 0.6 bar, inlet air volume 75 m.sup.3/h per kg tablet cores and product temperature 42° C.

(59) Inner Layer

(60) The inner layer was prepared according to Example 2.

(61) Outer Layer

(62) The outer layer was prepared according to Example 2

Example 4

(63) (1200 mg 5ASA tablets with isolation layer of HPMC (3 mg/cm.sup.2)/inner layer of neutralised Eudragit® S/outer layer of 30:70 mixture of starch:Eudragit® S)

(64) Isolation Layer

(65) The isolation layer was prepared according to Example 2. The final preparation was sprayed onto 1200 mg 5ASA cores using a perforated pan-coating machine to achieve a coating amount of 3 mg polymer/cm.sup.2 to form isolation layer coated tablets. The coating parameters were as follows: spray rate 2.33 g/min. per kg tablet cores, atomizing pressure 0.7 bar, inlet air volume 16.3 m.sup.3/h per kg tablet cores and product temperature 33° C.

(66) Inner Layer

(67) The inner coating was prepared according to Example 2. The final preparation was coated on to the isolation layer coated tablets using a perforated pan coater machine until the coating amount reached 5 mg polymer/cm.sup.2. The total solids content of the coating solution is approximately 10%.

(68) The coating parameters were as follows: spraying rate 2.9 g/min/kg tablets, atomizing pressure 0.6 bar, and inlet air volume 16.3 m.sup.3/h/kg tablets and product temperature 33° C.

(69) Outer Layer

(70) The outer layer was prepared according to Example 2. The final preparation was coated onto inner layer coated tablets using a perforated pan coater machine until a coating having 5 mg Eudragit® S polymer/cm.sup.2 was obtained. The spray coating parameters were as follows: spraying rate 3.1 g/min/kg tablets, atomizing pressure 0.4 bar, inlet air volume 21.7 m.sup.3/h/kg tablets and product temperature 34° C.

Example 5

(71) (800 mg 5ASA tablets with isolation layer of HPMC/inner layer of neutralised Eudragit® S/outer layer of a 50:50 mixture of starch/Eudragit® S)

(72) Isolation Layer

(73) The isolation layer was prepared according to Example 2.

(74) Inner Layer

(75) The inner layer was prepared according to Example 2

(76) Outer Layer

(77) The outer layer was applied from a mixture of an aqueous starch dispersion and an organic Eudragit® S 100 solution.

(78) The aqueous starch dispersion was prepared by dispersing maize starch into butan-1-ol, followed by water, under magnetic stirring. The ratio of maize starch:butan-1-ol:water was 1:1:9.53. The resulting dispersion was heated to boiling and then cooled under stirring overnight. The % solids content of the cooled preparation was calculated based on the final weight of the dispersion (considering the evaporation during heating).

(79) The organic Eudragit® S 100 solution was prepared by dissolving Eudragit® S 100 in 96% ethanol under high speed stirring. The final solution contained about 6% polymer solids.

(80) The starch dispersion was added dropwise to the Eudragit® S 100 solution to obtain a ratio of starch:Eudragit® S of 50:50. The mixture was mixed for 2 h, 20% triethyl citrate (based on total polymer weight) and 5% glyceryl monostearate (GMS, based on total polymer weight) were added and mixing continued for a further 2 h.

(81) 13.18% iron oxide red (based on Eudragit® polymer weight) and 2.27% iron oxide yellow (based on Eudragit® polymer weight) were suspended in ethanol under high shear homogenization and this suspension was added into the starch and Eudragit mixture and mixing continued for a further 30 minutes.

(82) The GMS was added in the form of an emulsion prepared at a concentration of 5% w/w. Polysorbate 80 (40% based on GMS weight) was dissolved in distilled water followed by dispersion of the GMS. This dispersion was then heated to 75° C. for 15 minutes under strong magnetic stirring in order to form an emulsion. The emulsion was cooled to room temperature under stirring. The final preparation was coated onto the inner layer coated tablets using a perforated pan coater until a coating having 5 mg Eudragit® S polymer/cm.sup.2 was obtained. The spray coating parameters were as follows: spraying rate 8.0 g/min/kg tablets, atomizing pressure 0.4 bar, inlet air volume 100 m.sup.3/h/kg tablets and product temperature 35.5° C.

Comparative Example 1

(83) (400 mg 5ASA tablets with inner layer of neutralised Eudragit® S/outer layer of Eudragit® S)

(84) Inner Layer

(85) The inner layer was prepared according to Example 1.

(86) Outer Layer

(87) The outer layer was prepared according to Example 1

Comparative Example 2

(88) (400 mg 5ASA tablets with a single layer of Eudragit® S)

(89) The single layer of Eudragit S was prepared according to Example 1 and applied directly on 400 mg 5ASA tablet cores (without isolation and without inner layer).

Comparative Example 3

(90) (800 mg 5ASA tablets with inner layer of neutralised Eudragit® S/outer layer of a 30:70 mixture of starch:Eudragit® S)

(91) Inner Layer

(92) The inner layer was prepared according to Example 2.

(93) Outer Layer

(94) The outer layer was prepared according to Example 2.

Comparative Example 4

(95) (800 mg 5ASA tablets with isolation layer of HPMC/outer layer of a 30:70 mixture of starch:Eudragit® S)

(96) Isolation Layer

(97) The isolation layer was prepared according to Example 2

(98) Outer Layer

(99) The outer layer was prepared according to Example 2

Comparative Example 5

(100) (800 mg 5ASA tablets with a single layer of a 30:70 mixture of starch/Eudragit® S)

(101) The single layer of a 30:70 mixture of starch/Eudragit® S was prepared according to Example 2, and applied directly on 800 mg 5ASA tablet cores (without isolation layer and without inner layer).

Comparative Example 6

(102) (1200 mg 5ASA tablets with isolation layer of HPMC (1 mg/cm.sup.2)/inner layer of neutralised Eudragit® S/outer layer of 30:70 mixture of starch:Eudragit® S)

(103) Isolation Layer

(104) The isolation layer was applied from a mixture of HPMC and 20% polyethylene glycol 6000 (PEG 6000), based on dry polymer weight.

(105) The HPMC polymer was dissolved in water under magnetic stirring and then PEG 6000 was added. The final preparation was sprayed onto 1200 mg 5-ASA cores using a perforated pan-coating machine to achieve a coating amount of 1 mg polymer/cm.sup.2 to form isolation layer coated tablets.

(106) The coating parameters were as follows: spray rate 9.75 g/min. per kg tablet cores, atomizing pressure 0.7 bar, inlet air volume 75 m.sup.3/h/kg tablets and product temperature 32° C.

(107) Inner Layer

(108) The inner layer was prepared according to Example 4

(109) Outer Layer

(110) The outer layer was prepared according to Example 4.

Comparative Example 7

(111) (1200 mg 5ASA tablets with isolation layer of HPMC (5 mg/cm.sup.2)/inner layer of neutralised Eudragit® S/outer layer of 30:70 mixture of starch:Eudragit® S)

(112) Isolation Layer

(113) The isolation layer was formed from a mixture of HPMC and 20% polyethylene glycol 6000 (PEG 6000), based on dry polymer weight.

(114) The HPMC polymer was dissolved in water under magnetic stirring and then PEG 6000 was added. The final preparation was sprayed onto 1200 mg 5ASA cores using a pan-coating machine to achieve a coating amount of 5 mg polymer/cm.sup.2 to form isolation layer coated tablets.

(115) Inner Layer

(116) The inner layer was prepared according to Example 4.

(117) Outer Layer

(118) The outer layer was prepared according to Example 4.

(119) The coating parameters were as follows: spray rate 5.75 g/min. per kg tablet cores, atomizing pressure 0.7 bar, inlet air volume 75 m.sup.3/h per kg tablet cores and product temperature 32° C.

(120) Drug Release Test—Effect of pH Alone

(121) In vitro dissolution studies were performed on a USP type II apparatus using a paddle speed of 50 rpm and a media temperature of 37±0.5° C. Tablets were first tested in 0.1 M HCl for 2 h followed by 8 h in Krebs buffer (pH 7.4). The pH of the buffer was stabilized at 7.4±0.05 by continuously sparring with 5% CO.sub.2/95% O.sub.2. Absorbance measurements were taken at 5 minute intervals, with an absorbance wavelength of 301 nm in HCl and 330 nm in Krebs buffer. The composition per litre of Krebs buffer is 0.16 g of KH.sub.2PO.sub.4, 6.9 g of NaCl, 0.35 g KCl, 0.29 g MgSO.sub.4.7H.sub.2O, 0.376 g CaCl.sub.2.2H.sub.2O and 2.1 g NaHCO.sub.3. Only the measurements taken at 30 or 60 minute intervals are depicted in the figures.

(122) Storage

(123) Drug release was tested before storage (Initial) and after storage under different conditions at the 1 month and 3 month points. The storage conditions exemplified herein are (i) open HDPE bottles at 25° C./60% RH (relative humidity); (ii) closed HDPE bottles at 25° C./60% RH; (iii) open HDPE bottle at 40° C./75% RH; and (iv) closed HDPE bottles 40° C./75% RH.

(124) Results

(125) The results depicted in FIG. 1 clearly indicate that initial drug release is quicker (i.e. T.sub.lag is reduced) from 400 mg 5ASA tablets coated with an isolation layer of HPMC, an inner layer of neutralized Eudragit S and an outer layer of Eudragit S (Example 1) than if the isolation layer is absent (Comparative Example 1) or both the isolation layer and the inner layer are absent (Comparative Example 2).

(126) The results depicted in FIGS. 2 to 3 indicate that the drug release is substantially unaffected after storage (at 40° C./75% RH) after 45 days from tablets coated with an HPMC isolation layer, an inner layer of neutralized Eudragit S and outer layer of Eudragit S (Example 1) when compared to equivalent tablets without the isolation layer (Comparative Example 1). Clearly, the use of an HPMC isolation layer improves the stability of the tablets during storage.

(127) The results depicted in FIG. 5 indicate that initial release drug release is quicker from 1200 mg 5ASA tablets coated with an isolation layer of HPMC, an inner layer of neutralized Eudragit S and an outer layer of a 30:70 mixture of starch:Eudragit S when the isolation layer has a thickness of 3 mg polymer/cm.sup.2 (Example 4) than if the isolation layer has a thickness of 1 mg polymer/cm.sup.2 (Comparative Example 6) or 5 mg polymer/cm.sup.2 (Comparative Example 7)) although it should be noted that initial release is accelerated in each of these cases.

(128) Turning to FIGS. 4 to 11, the results indicate that presence of an isolation layer made of HPMC (Example 2) leads to a faster drug release compared to tablets coated only with an inner layer of neutralized Eudragit S and an outer layer of a 30:70 mixture of starch:Eudragit S (Comparative Example 3). Furthermore, in the absence of the middle layer (Comparative Example 4), the isolation layer contributes to a later drug release when compared to a single layer of 30:70 mixture of starch:Eudragit S (Comparative Example 5). This result demonstrates that improved drug release is not inevitable if an isolation layer is present between the core and the alkaline inner layer.

(129) Moreover, when using an isolation layer of PVA, the contribution to drug release acceleration was actually higher than the one given by the inner layer alone (Example 3, Comparative Example 3 and Comparative Example 9). In the absence of isolation layer (Comparative Example 3), after 1 month storage at 40° C./75% RH, the drug release was delayed even if stored in closed HDPE bottles. However, the presence of an HPMC isolation layer (Example 2) avoided the delay in drug release after 1 month at 40° C./75% RH for the tablets stored in closed HDPE bottles. The same observations are also valid when the outer layer has a 50:50 mixture of starch and Eudragit S (Example 5).

(130) At 25° C./60% RH, even in open conditions, there is no significant change in drug release if an isolation layer is present (Example 2 and Example 5), whereas in the absence of the isolation layer (Comparative Example 3), tablets stored openly show a delayed release after 1 month.

(131) It can be seen therefore that the delayed release formulation according to the present invention is significantly superior to comparative formulations.

(132) Whilst the invention has been described with reference to a preferred embodiment, it will be appreciated that various modifications are possible within the spirit or scope of the invention as defined in the following claims.

(133) In this specification, unless expressly otherwise indicated, the word ‘or’ is used in the sense of an operator that returns a true value when either or both of the stated conditions is met, as opposed to the operator ‘exclusive or’ which requires that only one of the conditions is met. The word ‘comprising’ is used in the sense of ‘including’ rather than in to mean ‘consisting of’. All prior teachings acknowledged above are hereby incorporated by reference. No acknowledgement of any prior published document herein should be taken to be an admission or representation that the teaching thereof was common general knowledge in Australia or elsewhere at the date hereof.