Delayed release drug formulation

Abstract

Delayed release of a drug to the colon is achieved from a delayed release formulation comprising a core and a coating for the core. The core comprises a drug and the coating comprises an inner layer and an outer layer. The outer layer comprises a mixture of a first polymeric material which is susceptible to attack by colonic bacteria, and a second polymeric material which has a pH threshold at about pH 5 or above. The inner layer comprises a third polymeric material which is soluble in intestinal fluid or gastrointestinal fluid, said third polymeric material being selected from an at least partially neutralized polycarboxylic acid and a non-ionic polymer. In embodiments in which the third polymeric material is a non-ionic polymer, the inner layer comprises at least one of a buffer agent and a base. Advantages of formulations according to the present invention include accelerated release of the drug when exposed to colonic conditions and reduction or elimination of a food and/or alcohol effect on drug release after administration.

Claims

1. A delayed release drug formulation for oral administration to deliver a drug to the colon of a subject, said formulation comprising: a core and a coating for the core, the core comprising a drug and the coating comprising an outer layer and an inner layer, wherein the outer layer comprises a mixture of a first polymeric material which is susceptible to attack by colonic bacteria and a second polymeric material which has a pH threshold at about pH 6 or above, wherein the inner layer comprises a third polymeric material which is soluble in intestinal fluid or gastrointestinal fluid, said third polymeric material being a polycarboxylic acid polymer selected from the group consisting of polymethacrylate; cellulose acetate phthalate (CAP); polyvinyl acetate phthalate (PVAP); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose acetate succinate (HPMC-AS); xanthan gum; and shellac, wherein said polycarboxylic acid polymer is at least partially neutralized such that at least 90% of the carboxylic acid groups are in the form of carboxylate anions, and wherein the at least partially neutralized polycarboxylic acid polymer is the sole film-forming polymer in the inner layer.

2. The formulation of claim 1, wherein said polycarboxylic acid polymer is fully neutralized.

3. The formulation of claim 1, wherein said second polymeric material is based on the same polycarboxylic acid polymer as said third polymeric material, and the third polymeric material has a higher degree of neutralization than the second polymeric material.

4. The formulation of claim 1, wherein said third polymeric material is an at least partially neutralized co-polymer of (meth)acrylic acid and a (meth)acrylic acid C.sub.1-4 alkyl ester.

5. The formulation of claim 1, wherein said third polymeric material is a fully neutralized co-polymer of (meth)acrylic acid and (meth)acrylic acid methyl ester.

6. The formulation of claim 1, wherein the second polymeric material is a blend of at least two different polymers having a pH threshold of about pH 5 and above.

7. The formulation of claim 6, wherein the at least two different polymers in the blend are different polymethacrylate polymers.

8. The formulation of claim 6, wherein there are two different polymers in the blend in a weight ratio from about 40:60 to about 60:40.

9. The formulation of claim 1, wherein the first and second polymeric materials are present the outer layer in a weight ratio of up to about 60:40.

10. The formulation of claim 1, wherein the first and second polymeric materials are present in the outer layer in a weight ratio from about 25:75 to about 35:65.

11. The formulation of claim 1, wherein the first and second polymeric materials are present in the outer layer in a weight ratio from about 40:60 to about 60:40.

12. A method of producing the delayed release drug formulation for oral administration to deliver a drug to the colon as claimed in claim 1, said method comprising: forming the core comprising the drug; coating the core with an inner coating preparation comprising the third polymeric material in a solvent system to form an inner coated core; and coating the inner coated core with an outer coating preparation comprising the first polymeric material and the second polymeric material to form an outer coated core.

13. The method of claim 12, wherein the solvent system of the inner coating preparation is aqueous.

14. The method of claim 12, wherein said third polymeric material is said polycarboxylic acid polymer that is at least partially neutralized, said method comprising dispersing a polycarboxylic acid polymer in a solvent, optionally with the buffer agent, and adding the base to at least partially neutralize the polycarboxylic acid polymer to form the inner coating preparation.

15. The method of claim 14, wherein the amount of base added is at least sufficient to neutralize at least 10% of the carboxylic acid groups in the polycarboxylic acid polymer.

16. The method of claim 14, wherein the amount of base added is more than sufficient to fully neutralize the polycarboxylic acid polymer.

17. The method of claim 12, wherein said third polymeric material is said non-ionic polymer, the pH of the inner coating preparation being adjusted prior to coating to be at least 0.5 pH units higher than the pH threshold of the second polymeric material.

18. The method of claim 12, wherein the pH of the inner coating preparation is adjusted to be from about pH 7.5 to about pH 10.

19. The method of claim 12, wherein the base is selected from the group consisting of hydroxide bases, alkali metal bicarbonates, alkali metal carbonates, alkali metal phosphates, alkali metal citrates, or physiologically tolerated amines.

20. The method of claim 12, wherein the base is a hydroxide.

21. The method of claim 12, wherein the base is sodium hydroxide.

22. The formulation of claim 6, wherein there are two different polymers in the blend in a weight ratio of about 50:50.

23. The formulation of claim 1, wherein the first and second polymeric materials are present in the outer layer in a weight ratio of about 30:70.

24. The formulation of claim 1, wherein the first and second polymeric materials are present in the outer layer in a weight ratio of about 50:50.

25. The formulation of claim 1, wherein said inner layer further comprises at least one additive selected from the group consisting of a buffer agent, which is a non-polymeric organic acid or an inorganic salt, and a base, which is a non-polymeric base.

26. The formulation of claim 25, wherein the inner layer comprises the buffer agent and the base.

27. The formulation of claim 25, wherein the inner layer comprises a buffer agent and wherein the buffer agent is selected from the group consisting of a carboxylic acid having from 1 to 16 carbon atoms, an alkali metal salt, an alkali earth metal salt, an ammonium salt and a soluble metal salt.

28. The formulation of claim 25, wherein the inner layer comprises a buffer agent and wherein the buffer agent is a phosphate salt.

29. The formulation of claim 25, wherein the inner layer comprises a buffer agent and wherein the buffer agent is potassium dihydrogen phosphate.

30. The formulation of claim 25, wherein the inner layer comprises a buffer agent and wherein the buffer agent is present in the inner layer an amount from about 0.1 wt % to about 20 wt % based on the dry weight of the third polymeric material.

31. The formulation of claim 25, wherein the inner layer comprises a base and wherein the base is selected from the group consisting of hydroxide base, alkali metal bicarbonate, alkali metal carbonate, alkali metal phosphate, alkali metal citrate, and physiologically tolerated amine.

32. The formulation of claim 25, wherein the inner layer comprises a base and wherein the base is a hydroxide base.

33. The formulation of claim 25, wherein the inner layer comprises a base and wherein the base is sodium hydroxide.

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 as a function of time from 400 mg 5ASA tablets coated with (a) a single layer of Eudragit S alone (Comparative Example 1), (b) a single layer of a 30:70 mixture of starch and Eudragit S (Comparative Example 2), (c) an inner layer of fully neutralised Eudragit S and an outer layer of Eudragit S (Comparative Example 3), or (d) an inner layer of fully neutralised Eudragit S and an outer layer of a 30:70 mixture of starch and Eudragit S (Example 1), when exposed to 0.1N HCl for 2 hours and then Kreb's buffer (pH 7.4) for 8 hours;

(3) FIG. 2 is a graph comparing drug release as a function of time from 400 mg 5ASA tablets coated with (a) a single layer of a 30:70 mixture of starch and Eudragit S (Comparative Example 2), (b) an inner layer of fully neutralised Eudragit S and an outer layer of Eudragit S (Comparative Example 3), or (c) an inner layer of fully neutralised Eudragit S and an outer layer a 30:70 mixture of starch and Eudragit S (Example 1), when exposed to faecal slurry at pH 6.8 for 24 hours;

(4) FIG. 3 is a graph comparing drug release as a function of time from 400 mg 5ASA tablets coated with (a) an inner layer of fully neutralised Eudragit S and an outer layer of Eudragit S (Comparative Example 3), and (b) an inner layer of fully neutralised Eudragit S and an outer layer of a 30:70 mixture of starch and Eudragit S (Example 1), when exposed to faecal slurry at pH 6.5 for 24 hours;

(5) FIG. 4 is a graph depicting drug release as a function of time from 400 mg 5ASA tablets coated with an inner layer of fully neutralised Eudragit S and an outer layer of a 30:70 mixture of starch and Eudragit S (Example 1), when exposed to Hanks buffer at pH 6.8;

(6) FIG. 5 is a graph comparing drug release as a function of time from 1200 mg 5ASA tablets coated with (a) an inner layer of fully neutralised Eudragit L30D-55 and an outer layer of a 30:70 mixture of starch and Eudragit S (Example 2) and (b) an inner layer of Eudragit L30D-55 (not neutralised) and an outer layer of a 30:70 mixture of starch and Eudragit S (Comparative Example 4), when exposed to 0.1N HCl for 2 hours and then Kreb's buffer (pH 7) for 10 hours;

(7) FIG. 6 is a graph comparing drug release as a function of time from tablets of Example 2 and Comparative Example 4, when exposed to faecal slurry at pH 6.5 for 24 hours;

(8) FIG. 7 is a graph comparing drug release as a function of time from 1200 mg 5ASA tablets coated with (a) an inner layer of neutralized Eudragit L30D-55 and an outer layer of a 3:1 mixture of guar gum and Eudragit L30D-55 (Example 3) and (b) an inner layer of Eudragit L30D-55 (not-neutralized) and an outer layer of a 3:1 mixture of guar gum and Eudragit L30D-55 (Comparative Example 5) when exposed to 0.1N HCl for 2 hours and then Krebs buffer (pH 7.4) for 10 hours;

(9) FIG. 8 is a graph comparing drug release as a function of time from tablets of Example 3 and Comparative Example 5 when exposed to 0.1N HCl for 2 hours and then Hanks buffer (pH 6.8) for 10 hours;

(10) FIG. 9 is a graph comparing drug release as a function of time from tablets of Example 3 and Comparative Example 5 when exposed to faecal slurry at pH 6.5 for 24 hours;

(11) FIG. 10 is a graph comparing drug release, as a function of time from 1200 mg 5ASA tablets coated with (a) an isolation layer of polyvinyl alcohol (Opadry II 85F), an inner layer of polyvinyl alcohol (Opadry II 85F) adjusted to pH 8 and 20% buffer salt, and an outer layer of a blend of Eudragit S/Eudragit FS in a 70:30 mixture with starch (Example 4) and (b) an isolation layer made of polyvinyl alcohol (Opadry II 85F) and an outer layer made of a blend of Eudragit S/Eudragit FS in a 70:30 mixture with starch (Comparative Example 6) when exposed to 0.1N HCl for 2 hours and then Krebs buffer (pH 7.4) for 10 hours;

(12) FIG. 11 is a graph comparing drug release 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 starch:Eudragit S applied from a semi organic coating preparation (Example 5) when exposed to FeSSGF at pH 5 for 4 hours (fed state), and then to Hanks buffer at pH 6.8 for 10 hours (only the Hanks buffer stage is presented);

(13) FIG. 12 is a graph comparing drug release as a function of time from 1200 mg 5ASA tablets coated with an isolation layer of HPMC and an outer layer of 30:70 starch: Eudragit S applied from a semi organic coating preparation (Comparative Example 7) when exposed to (a) 0.1N HCl for 2 hours (fasted state) or (b) FeSSGF at pH 5 for 4 hours (fed state), and then to Hanks buffer at pH 6.8 for 10 hours (only the Hanks buffer stage is presented);

(14) FIG. 13 is a graph comparing drug release as a function of time from 1200 mg 5ASA tablets coated with an isolation layer of HPMC and an outer layer of 30:70 starch: Eudragit S applied from an aqueous coating preparation (Comparative Example 8) when exposed to (a) 0.1N HCl for 2 hours (fasted state) or (b) FeSSGF at pH 5 for 4 hours (fed state), and then to Hanks buffer at pH 6.8 for 10 hours (only the Hanks buffer stage is presented);

(15) FIG. 14 is a graph comparing drug release 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 50:50 starch: Eudragit S applied from a semi organic coating preparation (Example 6) when exposed to (a) 0.1N HCl for 2 hours (fasted state) or (b) FeSSGF at pH 5 for 4 hours (fed state), and then to Hanks buffer at pH 6.8 for 10 hours (only the Hanks buffer stage is presented);

(16) FIG. 15 is a graph comparing drug release 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 30:70 starch: Eudragit S applied from a semi organic coating preparation (Example 7) when exposed to (a) 0.1N HCl for 2 hours (fasted state) or (b) FeSSGF at pH 5 for 4 hours (fed state), and then to Hanks buffer at pH 6.8 for 10 hours (only the Hanks buffer stage is presented);

(17) FIG. 16 is a graph comparing drug release as a function of time from 400 mg 5ASA tablets coated with an inner layer of neutralized Eudragit S and an outer layer of 30:70 starch: Eudragit S applied from a semi organic coating preparation (Example 1) when exposed to (a) 0.1N HCl for 2 hours (fasted state) or (b) FeSSGF at pH 5 for 4 hours (fed state), and then to Hanks buffer at pH 6.8 for 10 hours (only the Hanks buffer stage is presented); and

MATERIALS

(18) 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. Polyvinylpyrolidon (PVP) was purchased from ISP Global Technologies, Kln, Germany. Magnesium stearate was purchased from Peter Greven GmbH, Bad Mnstereifel, 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.

(19) Preparation of 400 mg 5ASA Tablet Cores

(20) Oblong shaped 400 mg 5ASA tablet cores with dimensions 14.55.7 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).

(21) The obtained tablet cores were coated as discussed below in Examples 1, 8 and 9, and in Comparative Examples 1 to 3 and 9.

(22) Preparation of 1200 mg 5ASA Tablet Cores

(23) Oblong-shaped 1200 mg 5ASA tablet cores (having dimensions 2110 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.

(24) The obtained tablet cores were coated as discussed below in Examples 2 to 7 and 10, and in Comparative Examples 4 to 7.

Example 1 (Inner Layer of Neutralised Eudragit S/Outer Layer of 70:30 Mixture of Eudragit S and Starch)

(25) Inner Layer

(26) The inner coating layer was applied using an aqueous preparation of Eudragit S 100, where the pH is adjusted to pH 8. The composition of the inner layer also includes 50% of triethyl citrate (based on dry polymer weight), 10% potassium dihydrogen phosphate (based on dry polymer weight), 10% glyceryl monostearate (GMS; 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. Potassium dihydrogen phosphate and triethyl citrate were dissolved in distilled water, followed by dispersion of the Eudragit S 100 under mechanical agitation. The pH of the dispersion was then adjusted to pH 8 with 1M NaOH and left mixing for 1 hour.

(27) A GMS dispersion 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. The dispersion was then heated to 75 C. for 15 minutes under strong magnetic stirring in order to form an emulsion. The emulsion was cooled at room temperature and under stirring.

(28) The GMS dispersion was added to the neutralised Eudragit S 100 solution and the final preparation was coated on to 400 mg 5ASA tablet cores, using a fluid bed spray coating machine until the coating amount reached 5 mg polymer/cm.sup.2. The total solids content of the coating solution is 10%. The coating parameters were as follows: spraying rate 20 ml/min/kg tablets, atomizing pressure 0.2 bar and inlet air temperature 40 C.

(29) Outer Layer

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

(31) 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 % solids content of the cooled preparation was calculated based on the final weight of the dispersion (considering the evaporation during heating).

(32) 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. 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 hours and 20% triethyl citrate (based on total polymer weight) and 5% glyceryl monostearate (GMS, based on total polymer weight) were added and mixed for further 2 hours.

(33) The GMS was added in the form of a dispersion 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 at room temperature and under stirring.

(34) The final preparation was coated on to 5ASA tablet cores, previously coated with the inner coating layer, using a fluid bed spray coating machine until a coating having 7 mg total polymer/cm.sup.2 was obtained. The spray coating parameters were as follows: spraying rate 14 ml/min/kg tablets, atomizing pressure 0.2 bar and inlet air temperature 40 C.

Example 2 (Isolation Layer/Inner Layer of Neutralised Eudragit L30D-55/Outer Layer of 70:30 Mixture of Eudragit S and Starch)

(35) Isolation Layer

(36) An isolation layer was used containing a mixture of HPMC and 20% polyethylene glycol 6000 (PEG 6000), based on dry polymer weight.

(37) The HPMC was dissolved in water under magnetic stirring and then the PEG 6000 was added to form a coating preparation. The coating preparation was sprayed onto the 1200 mg 5ASA cores, using a pan-coating machine to achieve a coating amount of 3 mg polymer/cm.sup.2 to form isolation layer coated tablets.

(38) The coating parameters were as follows: Spray rate 3.1 g/min per kg tablet cores; atomizing pressure 0.7 bar; inlet air volume 19 m.sup.3/h per kg tablet cores; and product temperature 35 C.

(39) Inner Layer

(40) The inner layer was applied from an aqueous coating preparation of Eudragit L30D-55, where the pH had been adjusted to pH 8. The composition of the inner layer also included 20% TEC (based on dry polymer weight), 1% potassium dihydrogen phosphate (based on dry polymer weight) and 50% talc (based on dry polymer weight). The pH was adjusted using 1M NaOH until pH 8 is obtained.

(41) Potassium dihydrogen phosphate and TEC were dissolved in distilled water for 15 minutes, after which an Eudragit L30D-55 dispersion was added under mechanical agitation and mixed for 15 minutes. The pH was then adjusted to pH 8 with 1M NaOH and the solution was left stirring for 1 hour. Talc was then added to the solution and mixing continued for a further 30 minutes to form the inner coating preparation. The inner coating preparation was coated onto the isolation layer coated tablets, using a pan-coating machine until the coating amount reached 5 mg polymer/cm.sup.2 to form inner layer coated tablets. The total solids content of the inner coating preparation was 10% (by weight).

(42) As used herein, the total solids content of a suspension, dispersion or other preparation is the total weight of solids used to form the preparation as a proportion of the total weight of the preparation (solids and solvent). The skilled reader would appreciate that dissolution of a portion of the solids into the solvent does not affect the total solids content of the preparation.

(43) The coating parameters were as follows: Spray rate 6.75 g/min per kg tablet cores; atomizing pressure 0.6 bar; inlet air volume 75 m.sup.3/h per kg tablet cores; and product temperature 31 C.

(44) Outer Layer

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

(46) 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 under reflux and then cooled under stirring overnight.

(47) The aqueous Eudragit S 100 solution was prepared by dispersing Eudragit S 100 in water under high speed stirring followed by partial (15-20%) neutralization with 1N ammonia solution (obtained by dilution of 25% ammonia solution).

(48) The aqueous Eudragit S 100 solution was added to the starch dispersion to obtain a ratio of starch:Eudragit S of 30:70. The mixture was stirred for 1 hour and 60% TEC (based on Eudragit S polymer weight), 50% talc (based on Eudragit S polymer weight), 13.18% iron oxide red (based on Eudragit S polymer weight) and 2.27% iron oxide yellow (based on Eudragit S polymer weight) were added and mixed for further 30 minutes.

(49) The final preparation was sprayed onto inner layer coated tablets, in a pan-coating machine until 7.14 mg total polymer/cm.sup.2 was obtained to produce the coated tablets of Example 2.

(50) The coating parameters were as follows: Spray rate 6.175 g/min per kg tablet cores; atomizing pressure 0.4 bar; inlet air volume 100 m.sup.3/h per kg tablet cores; and product temperature 35 C.

Example 3 (Isolation Layer/Inner Layer of Neutralised Eudragit L30D-55/Outer Layer of 1:3 Mixture of Eudragit L30D-55 and Guar Gum)

(51) Isolation Layer

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

(53) The HPMC polymer was dissolved in water under magnetic stirring and then PEG 6000 was added to form an isolation layer coating preparation. The coating preparation was sprayed onto 1200 mg 5ASA tablet cores, using a pan-coating machine to achieve a coating amount of 3 mg polymer/cm.sup.2 to form isolation layer coated tablets.

(54) The coating parameters were as follows: Spray rate 2.7 g/min. per kg tablet cores; atomizing pressure 0.7 bar; inlet air volume 16 m.sup.3/h per kg tablet cores; and product temperature 35 C.

(55) Inner Layer

(56) The inner layer is applied from an aqueous preparation of Eudragit L30D-55, where the pH is adjusted to pH 8. The composition of the inner layer also includes 20% TEC (based on dry polymer weight), 1% potassium dihydrogen phosphate (based on dry polymer weight), and 50% talc (based on dry polymer weight). The pH is adjusted using 1M NaOH until pH 8 is obtained.

(57) Potassium dihydrogen phosphate and TEC were dissolved in distilled water with stirring for 15 minutes, after which Eudragit L30D-55 dispersion was added under mechanical agitation and mixed for 15 minutes. The pH was then adjusted to pH 8 with 1M NaOH and the solution was left mixing for 1 hour. Talc was then added and mixing was continued for a further 30 minutes to form the inner layer coating preparation. The inner layer coating preparation was coated onto the isolation layer coated tablets using a pan-coating machine until the coating amount reached 5 mg polymer/cm.sup.2 to form inner layer coated tablets. The total solids content of the final preparation is 10%.

(58) The coating parameters were as follows: Spray rate 2.7 g/min. per kg tablet cores; atomizing pressure 0.6 bar; inlet air volume 30 m.sup.3/h per kg tablet cores; and product temperature 31 C.

(59) Outer Layer

(60) The outer layer is applied from a mixture of Eudragit L30D-55 and guar gum.

(61) Eudragit L30D-55 was dissolved in isopropanol. Guar gum was dispersed with talc in a mixture of water and isopropanol (50:50) for 15 minutes followed by homogenization for 5 minutes. The Eudragit L30D-55 solution was then added to the guar gum dispersion and the resultant mixture was stirred for 20 minutes to form the outer layer coating preparation. The coating preparation was sprayed onto inner layer coated tablets, in a pan-coating machine until the coating amount reached 9.71 total polymer/cm.sup.2 (weight ratio of 1:3 of the dry substances). The coated tablets were dried at 40 C. for 2 hours to form the tablets of Example 3.

(62) The coating parameters were as follows: Spray rate 8.0 g/min per kg tablet cores; atomizing pressure 0.6 bar; inlet air volume 75 m.sup.3/h per kg tablet cores; and product temperature 29 C.

Example 4 (Isolation Layer/Inner Layer of PVA with Buffer and Base/Outer Layer of a 70:30 Mixture of Eudragit S & FS Blend (50:50) and Starch)

(63) Isolation Layer

(64) The isolation layer is composed of polyvinyl alcohol or PVA (Opadry 85F).

(65) The polymer was suspended in water under magnetic stirring to achieve a concentration of 10% solids of the final weight of the dispersion to form an isolation layer coating preparation.

(66) The coating preparation was sprayed onto 1200 mg 5ASA tablet cores, using a pan-coating machine to achieve a coating amount of 2%, based on the weight of the uncoated tablets to form isolation layer coated tablets.

(67) The coating parameters were as follows: Spray rate 6.45 g/min per kg tablets; atomizing pressure 0.6 bar; inlet air volume 62.5 m.sup.3/h per kg tablet cores; and product temperature 40 C.

(68) Inner Layer

(69) The inner layer is composed of polyvinyl alcohol (Opadry 85F) and 20% potassium dihydrogen phosphate (based on Opadry 85F).

(70) Potassium dihydrogen phosphate was dissolved in water under magnetic stirring and then the polyvinyl alcohol (Opadry 85F) was added to form a suspension. The pH of the suspension was then adjusted to pH 8 with 1M NaOH and the mixture was left stirring for 1 hour to form an inner layer coating preparation. The coating preparation was sprayed onto isolation layer coated tablets using a pan-coating machine until the coating amount reached 2%, based on the weight of the uncoated tablets, to form inner layer coated tablets.

(71) The coating parameters were as follows: Spray rate 8.2 g/min per kg tablet cores; atomizing pressure 0.7 bar; inlet air volume 62.5 m.sup.3/h per kg tablet cores; and product temperature 40 C.

(72) Outer Layer

(73) The outer layer formulation is applied from a mixture of an aqueous starch dispersion and an aqueous dispersion of a 50:50 blend (based on dry polymer) of Eudragit S 100 and Eudragit FS 30D.

(74) The aqueous starch dispersion was prepared by dispersing maize starch (Eurylon 6) into butan-1-ol under magnetic stirring. Water was added while stirring was continued. The ratio of maize starch:butan-1-ol:water was 1:2:22. The resulting dispersion was heated to boiling under reflux and then cooled under stirring overnight.

(75) An aqueous dispersion of Eudragit S 100 was prepared by dispersing Eudragit S 100 in water under high speed stirring followed by partial (15-20%) neutralization with 1N ammonia (formed by dilution of 25% ammonia solution) TEC was added to the dispersion and mixed for 30 minutes. Eudragit FS 30D was added to form a 50:50 blend with the Eudragit S 100 and mixing was continued for a further 30 minutes.

(76) The starch dispersion was added into the dispersion of the Eudragit S 100/Eudragit FS 30D blend and the mixture was stirred for a further 30 minutes. The mixture contained a ratio of starch:Eudragit S 100/Eudragit FS 30D blend of 30:70.

(77) A suspension of 50% talc (based on Eudragit polymer weight), 13.18% iron oxide red (based on Eudragit polymer weight) and 2.27% iron oxide yellow (based on Eudragit polymer weight) in water was formed under high shear homogenization and this suspension was added to the starch/Eudragit blend mixture and mixing was continued for a further 30 minutes to form an outer layer coating preparation.

(78) The coating preparation was sprayed onto inner layer coated tablets in a pan-coating machine until 5.2 mg Eudragit polymer blend/cm.sup.2 was obtained to form the tablets of Example 4.

(79) The coating parameters were as follows: Spray rate 8.5 g/min per kg tablet cores; atomizing pressure 0.7 bar; inlet air volume 62.5 m.sup.3/h per kg tablet cores; and product temperature 41 C.

Example 5 (Isolation Layer/Inner Layer of Neutralised Eudragit S/Outer Layer of 70:30 Mixture of Eudragit S and Starch)

(80) Isolation Layer

(81) The isolation layer was formed as in Example 3 although 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.

(82) Inner Layer

(83) The inner coating layer was formed as in Example 1 with the exceptions that the composition of the inner layer included 70% (not 50%) of triethyl citrate (based on dry polymer weight) and 1% (not 10%) potassium dihydrogen phosphate (based on dry polymer weight), that the coating preparation was coated onto the isolation layer coated 1200 mg tablets using a perforated pan coater machine, and that the coating parameters were as follows: spraying rate 2.9 g/min/kg tablets, atomizing pressure 0.6 bar, inlet air volume was 16.3 m.sup.3/h/kg tablets and the product temperature was 33 C.

(84) Outer Layer

(85) The outer coating layer was formed as in Example 1 with the exceptions that 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 homogenisation and this suspension was added into the starch and Eudragit mixture and the resultant mixed for the further 30 minutes prior to the addition of the GMS, that the coating preparation was applied onto the inner layer coated 1200 mg 5ASA tablets using a perforated pan coater machine, and that the spray coating parameters were as follows: spraying rate 3.1 g/min/kg tablets, atomising pressure 0.4 bar, inlet air volume 21.7 m.sup.3/h/kg tablets and product temperature 34 C.

Example 6 (Isolation Layer/Inner Layer of Neutralised Eudragit S/Outer Layer of 50:50 Mixture of Eudragit S and Starch)

(86) Isolation Layer

(87) The isolation layer was formed on 1200 mg 5ASA tablets cores as described in Example 3.

(88) Inner Layer

(89) The inner layer was formed on isolation layer coated 1200 mg 5ASA tablet cores as described in Example 5.

(90) Outer Layer

(91) The outer coating layer was formed on inner layer coated 5ASA tablet cores as described in Example 5 with the exceptions that the ratio of maize starch:butan-1-ol:water was 1:1:9.5, that the starch:Eudragit S ratio was 50:50, and that the spray parameters were as follows: spraying rate 7.4 g/min/kg tablets, atomising pressure 0.4 bar, inlet air volume 40 m.sup.3/h/kg tablets and product temperature 34 C.

Example 7 (Isolation Layer/Inner Layer of Neutralised Eudragit S/Outer Layer of 70:30 Mixture of Eudragit S and Starch)

(92) Isolation Layer

(93) The isolation layer was applied to 400 mg 5ASA tablet cores using the procedure described in Example 3 with the exceptions that a fluid bed spray coater was used and the coating parameters were as follows: spraying rate 3.1 g/min/kg tablets, atomising pressure 0.2 bar, and inlet air temperature 40 C.

(94) Inner Layer

(95) The inner coating layer was applied in the same manner as described in Example 1 with the exception that the composition of the inner layer included 70% (not 50%) of triethyl citrate (based on dry polymer weight) and 1% (not 10%) potassium dihydrogen phosphate (based on dry polymer weight). In addition, the inner coating layer preparation was coated on to the isolation layer coated 400 mg 5ASA tablet cores.

(96) Outer Layer

(97) The outer coating layer was formed as in Example 1 with the exceptions that 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 homogenisation and this suspension was added into the starch and Eudragit mixture and the resultant mixed for the further 30 minutes prior to the addition of the GMS, and that the outer coating layer preparation was coated on to the inner layer coated 400 mg 5ASA tablet cores. The coating parameters were as follows: spraying rate 11 ml/min/kg tablets, atomising pressure 0.2 bar, and inlet air temperature 40 C.

Comparative Example 1 (Single-Layer Coating of Eudragit S)

(98) The coating layer containing Eudragit S 100 was applied as an organic coating composition. The coating composition contained 20% triethyl citrate (based on dry polymer weight), 10% glyceryl monostearate (based on dry polymer weight) and 40% polysorbate 80 (based on GMS weight). Briefly, triethyl citrate was dissolved in 96% ethanol followed by Eudragit S 100 under mechanical stirring and mixing continued for 1 hour.

(99) The GMS was added in the form of a dispersion 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 at room temperature and under stirring.

(100) The GMS dispersion was added to the organic Eudragit S solution and the final coating solution was coated on to the 5ASA tablet cores, using a fluid bed spray coating machine to achieve a coating amount of 5 mg polymer/cm.sup.2. The coating parameters were as follows: spraying rate 16 ml/min/kg tablets, atomizing pressure 0.2 bar and inlet air temperature 40 C.

Comparative Example 2 (Single-Layer Coating of a 70:30 Mixture of Eudragit S and Starch)

(101) The coating layer composition contains 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 % solids content of the cooled preparation was calculated based on the final weight of the dispersion (considering the evaporation during heating).

(102) The organic Eudragit S solution was prepared by dissolution of Eudragit S 100 in 96% ethanol under high speed stirring. The final solution contained about 6% polymer solids. 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 hours and 20% triethyl citrate (based on total polymer weight) and 5% glyceryl monostearate (based on total polymer weight) were added and the mixture was mixed for further 2 hours.

(103) The GMS was added in the form of a dispersion prepared at a concentration of 5% 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 at room temperature and under stirring.

(104) The final preparation was coated on to the 5ASA tablet cores in a fluid bed spray coating machine until a 7 mg Eudragit S polymer/cm.sup.2 was obtained. The spray coating parameters were as follows: spraying rate 14 ml/min/kg tablets, atomizing pressure 0.2 bar and inlet air temperature 40 C.

Comparative Example 3 (Inner Layer of Neutralised Eudragit S/Outer Layer of Eudragit S)

(105) Inner Layer

(106) The inner coating layer is composed by an aqueous preparation of Eudragit S 100, where the pH is adjusted to pH 8. The composition of the inner layer also includes 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 is obtained. 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 hour.

(107) A GMS dispersion 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 at room temperature and under stirring.

(108) The GMS dispersion was added to the neutralised Eudragit S solution and the final preparation was coated on to 5ASA tablet cores, using a fluid bed spray coating machine until the coating amount reached 5 mg polymer/cm.sup.2. The total solids content of the coating solution is 10%. The coating parameters were as follows: spraying rate 20 ml/min/kg tablets, atomizing pressure 0.2 bar and inlet air temperature 40 C.

(109) Outer Layer

(110) The outer coating layer is composed of Eudragit S 100, applied as an organic solution. 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). Briefly, triethyl citrate was dissolved in 96% ethanol followed by Eudragit S 100 under mechanical stirring and mixing continued for 1 hour.

(111) A GMS dispersion 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 an emulsion. The emulsion was cooled at room temperature and under stirring.

(112) The GMS preparation was added to the Eudragit S 100 solution and the final coating solution was coated on to 5ASA tablet cores, previously coated with the inner coating layer, using a fluid bed spray coating machine to achieve a coating amount of 5 mg Eudragit S polymer/cm.sup.2. The coating parameters were as follows: spraying rate 16 ml/min/kg tablets, atomizing pressure 0.2 bar and inlet air temperature 40 C.

Comparative Example 4 (Isolation Layer/Inner Layer of Eudragit L30D-55/Outer Layer of a 70:30 Mixture of Eudragit S/Starch)

(113) Isolation Layer

(114) The isolation layer is formed from a mixture of HPMC and 20% polyethylene glycol 6000 (PEG6000), based on dry polymer weight.

(115) The polymer was dissolved in water under magnetic stirring and then PEG6000 was added to form the isolation layer coating preparation. The coating preparation was sprayed onto 1200 mg 5ASA tablet cores, using a pan-coating machine to achieve a coating amount of 3 mg polymer/cm.sup.2 to form isolation layer coated tablets.

(116) The coating parameters were as follows: Spray rate 2.7 g/min. per kg tablet cores; atomizing pressure 0.7 bar; inlet air volume 16 m.sup.3/h per kg tablet cores; and product temperature 35 C.

(117) Inner Layer

(118) The inner layer is made from a standard (non-neutralised) aqueous preparation of Eudragit L30D-55. The composition of the inner layer also includes 20% TEC (based on dry polymer weight) and 50% talc (based on dry polymer weight).

(119) Eudragit L30D-55 was diluted in distilled water and then TEC and a talc suspension were added and mixed for 1 hour to form the inner layer coating preparation. The coating preparation was coated onto isolation layer coated tablets using a pan-coating machine until the coating amount reached 5 mg polymer/cm.sup.2 to form inner layer coated tablets. The total solids content of the final preparation is 10%.

(120) The coating parameters were as follows: Spray rate 6.125 g/min per kg tablet cores; atomizing pressure 0.6 bar; inlet air volume 100 m.sup.3/h per kg tablet cores; and product temperature 33 C.

(121) Outer Layer

(122) The outer layer is made from a mixture of aqueous starch dispersion and an aqueous Eudragit S 100 re-dispersion.

(123) 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 under reflux and then cooled under stirring overnight.

(124) The aqueous Eudragit S re-dispersion was prepared by dispersing Eudragit S 100 in water under high speed stirring followed by partial (15-20%) neutralization with 1N ammonia (obtained by dilution of 25% ammonia solution).

(125) The aqueous Eudragit S re-dispersion was added to the starch dispersion to obtain a ratio of starch:Eudragit S of 30:70. The mixture was stirred for 1 hour and 60% TEC (based on Eudragit S polymer weight), 50% talc (based on Eudragit S polymer weight), 13.18% iron oxide red (based on Eudragit S polymer weight) and 2.27% iron oxide yellow (based on Eudragit S polymer weight) were added and the mixture was stirred for a further 30 minutes to form an outer layer coating preparation. The outer layer coating preparation was sprayed onto inner layer coated tablets, in a pan-coating machine until 7.14 mg total polymer/cm.sup.2 was obtained to produce the tablets of Comparative Example 4.

(126) The coating parameters were as follows: Spray rate 10.0 g/min; atomizing pressure 0.4 bar; inlet air volume 100 m.sup.3/h per kg tablet cores; and product temperature 35 C.

Comparative Example 5 (Isolation Layer/Inner Layer of Eudragit L30D-55/Outer Layer of a 1:3 Mixture of Eudragit L30D-55/Guar Gum)

(127) Isolation Layer

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

(129) The HPMC polymer was dissolved in water under magnetic stirring and then PEG 6000 was added to form the isolation layer coating preparation. The coating preparation was sprayed onto 1200 mg 5ASA tablet cores using a pan-coating machine to achieve a coating amount of 3 mg polymer/cm.sup.2 to form isolation layer coated tablets.

(130) The coating parameters were as follows: Spray rate 2.7 g/min per kg tablet cores; atomizing pressure 0.7 bar; inlet air volume 16 m.sup.3/h per kg tablet cores; and product temperature 35 C.

(131) Inner Layer

(132) The inner layer was applied from a standard (non-neutralised) aqueous preparation of Eudragit L30D-55. The composition of the inner layer also included 20% TEC (based on dry polymer weight) and 50% talc (based on dry polymer weight).

(133) Eudragit L30D-55 was diluted in distilled water and then TEC and talc were added to form a mixture which was stirred for 1 hour to form an inner layer coating preparation. The coating preparation was coated onto isolation layer coated tablets using a pan-coating machine until the coating amount reached 5 mg polymer/cm.sup.2 to form inner layer coated tablets. The total solids content of the final preparation is 10% based on the final weight of the suspension.

(134) The coating parameters were as follows: Spray rate 2.45 g/min per kg tablet cores; atomizing pressure 0.6 bar; inlet air volume 25 m.sup.3/h per kg tablet cores; and product temperature 33 C.

(135) Outer Layer

(136) The outer layer contains a mixture of Eudragit L30D-55 and guar gum.

(137) Eudragit L30D-55 was dissolved in isopropanol, and guar gum was dispersed with talc in a mixture of water and isopropanol (50.50) for 15 minutes followed by homogenization for 5 minutes. The Eudragit L30D-55 solution was then added to the guar gum dispersion and stirred for 20 minutes to form an outer layer coating preparation. The coating preparation was sprayed onto inner layer coated tablets in a pan-coating machine until 9.71 total polymer/cm.sup.2 (weight ratio of 1:3 of the dry substances) was obtained. The coated tablets were dried at 40 C. for 2 hours to form the tablets of Comparative Example 5.

(138) The coating parameters were as follows: Spray rate 8.0 g/min per kg tablet cores; atomizing pressure 0.6 bar; inlet air volume 75 m.sup.3/h per kg tablet cores; and product temperature 29 C.

Comparative Example 6 (Isolation Layer/Outer Layer of a 70:30 Mixture of Eudragit S & FS Blend (50:50) and Starch)

(139) Isolation Layer

(140) The isolation layer was composed of polyvinyl alcohol (Opadry 85F).

(141) The polyvinyl alcohol (Opadry 85F) was suspended in water under magnetic stirring to achieve a concentration of 10% solids based on the final weight of the suspension to form an isolation layer coating preparation.

(142) The coating preparation was sprayed onto 1200 mg 5ASA tablet cores using a pan-coating machine to achieve a coating amount of 2%, based on the weight of the uncoated tablets, to form isolation layer coated tablets.

(143) The coating parameters were as follows: Spray rate 6.45 g/min per kg tablets; atomizing pressure 0.6 bar; inlet air volume 62.5 m.sup.3/h per kg tablet cores; and product temperature 40 C.

(144) Outer Layer

(145) The outer layer formulation is applied from a mixture of an aqueous starch dispersion and an aqueous dispersion of a 50:50 blend (based on dry polymer) of Eudragit S 100 and Eudragit FS 30D.

(146) The aqueous starch dispersion was prepared by dispersing maize starch (Eurylon 6) into butan-1-ol under magnetic stirring. Water was added while stirring was continued. The ratio of maize starch:butan-1-ol:water was 1:2:22. The resulting dispersion was heated to boiling under reflux and then cooled under stirring overnight.

(147) An aqueous dispersion of Eudragit S 100 was prepared by dispersing Eudragit S 100 in water under high speed stirring followed by partial (15-20%) neutralization with 1N ammonia (formed by dilution of 25% ammonia solution) TEC was added to the dispersion and mixed for 30 minutes. Eudragit FS 30D was added to form a 50:50 blend with the Eudragit S 100 and mixing was continued for a further 30 minutes.

(148) The starch dispersion was added into the dispersion of the Eudragit S 100/Eudragit FS 30D blend and the mixture was stirred for a further 30 minutes. The mixture contained a ratio of starch:Eudragit S 100/Eudragit FS 30D blend of 30:70.

(149) A suspension of 50% talc (based on Eudragit polymer weight), 13.18% iron oxide red (based on Eudragit polymer weight) and 2.27% iron oxide yellow (based on Eudragit polymer weight) in water was formed under high shear homogenization and this suspension was added to the starch/Eudragit blend mixture and mixing was continued for a further 30 minutes to form an outer layer coating preparation.

(150) The coating preparation was sprayed onto isolation layer coated tablets in a pan-coating machine until 5.2 mg Eudragit polymer blend/cm.sup.2 was obtained to form the tablets of Example 4.

(151) The coating parameters were as follows: Spray rate 8.5 g/min per kg tablet cores; atomizing pressure 0.7 bar; inlet air volume 62.5 m.sup.3/h per kg tablet cores; and product temperature 41 C.

Comparative Example 7 (Isolation Layer/Outer Layer of 30:70 Starch:Eudragit S)

(152) Isolation Layer

(153) Isolation layer coated 1200 mg 5ASA tablet cores were prepared as in Comparative Example 4.

(154) Outer Layer

(155) The outer coating layer was applied to the inner coated tablet cores from a mixture of aqueous starch dispersion and an organic Eudragit S 100 solution.

(156) 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 % solids content of the cooled preparation was calculated based on the final weight of the dispersion (considering the evaporation during heating).

(157) 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. The starch dispersion was added dropwise to the Eudragit S 100 solution to obtain a ratio of starch:Eudragit S of 30:70.

(158) The mixture was mixed for 2 hours and 20% triethyl citrate (based on total polymer weight) and 5% glyceryl monostearate (GMS, based on total polymer weight) were added and mixed for further 2 hours. 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 further 30 minutes.

(159) 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 at room temperature and under stirring. The final preparation was coated onto the isolation layer coated tablet cores 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.

Comparative Example 8 (Isolation Layer/Outer Layer of 30:70 Starch:Eudragit S)

(160) Isolation layer coated 1200 mg 5ASA tablet cores were prepared as in Comparative Example 4.

(161) Outer Layer

(162) The outer layer is applied from a mixture of an aqueous starch dispersion and an aqueous Eudragit S 100 re-dispersion.

(163) The aqueous starch dispersion was prepared as described in Example 1.

(164) The aqueous Eudragit S re-dispersion was prepared by dispersing Eudragit S 100 in water under high speed stirring followed by partial neutralisation with 1N NH.sub.3 obtained by dilution of 25% ammonia.

(165) The aqueous Eudragit S re-dispersion was added to the starch dispersion to obtain a ratio of starch to Eudragit S of 30:70. This was mixed for 1 hour and 60% TEC (based on Eudragit S polymer weight), 50% talc (based on Eudragit S polymer weight), 13.18% iron oxide red (based on Eudragit S polymer weight) and 2.27% iron oxide yellow (based on Eudragit S polymer weight) were added and mixed for a further 30 minutes to form the outer layer coating preparation.

(166) The outer layer coating preparation was sprayed on to inner layer coated 1200 mg 5ASA tablet cores in a pan coating machine until 7.14 mg total polymer/cm.sup.2 was obtained. The coating parameters were as follows: spray rate 6.175 g/min.Math.kg tablet cores, atomising pressure 0.4 bar, inlet air volume 100 m.sup.3/h/kg tablet cores and product temperature 35 C.

(167) Drug Release Test #1Effect of pH Alone

(168) In vitro dissolution studies were performed on a USP type II apparatus using a paddle speed of 50 rpm and a media temperature of 370.5 C. Tablets were first tested in 0.1 M HCl for 2 hours followed by 8 or 10 hours in Krebs buffer (pH 7.4). The pH of the buffer was stabilized at 7.40.05 by continuously sparging 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 liter 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 15 minute intervals are depicted in FIG. 1.

(169) Drug Release Test #2Faecal Slurry at pH 6.8

(170) The fermentation assays used to test the formulations were based on the method described by Hughes et al. (In vitro fermentation of oat and barley derived beta-glucans by human faecal microbiota FEMS Microbiol. Ecol.; 2008; 64(3); pp 482 to 493).

(171) The basal medium used to allow bacterial growth was prepared according to Hughes et al and mixed in a ratio of 1:1 with a faecal slurry, which was prepared by homogenizing fresh human faeces (3 different donors) in phosphate buffered saline (pH 6.8) at a concentration of 40% w/w. The final concentration of the prepared faecal slurry (diluted with basal medium) was 20% w/w. The donors had not received antibiotic treatment for at least three months before carrying out the studies using the slurry.

(172) Tablets were tested in 210 ml of faecal slurry adjusted to the required pH and under continuous stirring. The tests were carried out in an anaerobic chamber (at 37 C. and 70% RH). The samples were analysed for 5ASA content by HPLC with a UV detector.

(173) Drug Release Test #3Faecal Slurry at pH 6.5

(174) As for Drug Release Test #2 but the pH of the faecal slurry was maintained at pH 6.5.

(175) Drug Release Test #4Dissolution in Hanks Buffer pH 6.8

(176) In vitro dissolution studies were performed on a USP type II apparatus using a paddle speed of 50 rpm and a media temperature of 370.5 C. Tablets were first tested in 0.1 M HCl for 2 hours followed by 8 or 10 hours in Hanks buffer (pH 6.8). The pH of the buffer was stabilized at 6.80.05 by continuously sparging 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 Hanks buffer pH 6.8. The composition per liter of Hanks buffer is 0.06 g of KH.sub.2PO.sub.4, 0.06 g Na.sub.2HPO.sub.4.2H.sub.2O, 8.0 g NaCl, 0.4 g KCl, 0.2 g MgSO.sub.4.7H.sub.2O, 0.139 g CaCl.sub.2.2H.sub.2O and 0.350 g NaHCO.sub.3.

(177) Drug Release Test #5Simulated Fed/Fasted State then Hanks Buffer pH 6.8

(178) In vitro dissolution studies were performed on a USP type II apparatus using a paddle speed of 50 rpm and a media temperature of 370.5 C. When simulating the fasted state, the studies were carried out in the manner described for Drug Release Test #4.

(179) When simulating the fed state, the tablets were first tested in Fed State Simulated Gastric Fluid (FeSSGF) at pH 5.0 for 4 h followed by 10 hours in Hanks buffer (pH 6.8). The FeSSGF was as described in Jantrid et al (2008) supra.

(180) Drug Release Test #540% Ethanol (v/v) in 0.1N HCl

(181) Coated tablets were tested in a disintegration apparatus using a hydro-alcoholic solution of 0.1N HCl (40% ethanol) for 2 hours. At the end of 2 hours, the morphology of the tablets was evaluated visually for presence of cracks and/or swelling.

(182) Results

(183) The results presented in FIGS. 1 to 4 demonstrate that the coated tablets according to the present invention are significantly superior to the tablets of the comparative examples. In this connection, an acceleration of drug release is observed for the tablets according to the present invention, both at a pH higher (pH 7.4) than the pH threshold (pH 7) of the second polymeric material and at a lower pH (pH 6.8 or pH 6.5) than the pH threshold, relative to the comparator tablets.

(184) In aqueous solution at pH 7.4 (drug release test #1; FIG. 1), there was no release of 5ASA from any of the tablets tested in the 2 hours that the tablets were exposed to simulated gastric conditions. However, it should be noted that, once the tablets were exposed to pH 7.4, initial release of 5ASA from Example 1 tablets occurred significantly earlier than from Comparative Example 1 (which is a conventional site-specific colonic release formulation) and from Comparative Example 2 (which is a site-specific colonic release formulation described in WO2007/122374). The profile of release of 5ASA from Example 1 closely followed that for Comparative Example 3. The similar release profiles may be explained by the similarities in the formulations themselves (Example 1 differing only in the presence of starch in the outer coating) and the absence of any colonic enzymes in the surrounding medium to digest the starch.

(185) In faecal slurry at pH 6.8 (drug release test #2; FIG. 2), initial release of 5ASA from the tablets of Example 1 occurred after about 1 hour, and complete release occurred in about 3 hours after initial release. In contrast, initial release from the tablets of both Comparative Examples 2 and 3 occurred after about 2 hours, with significant release from the tablets of Comparative Example 3 occurring only after 6 hours. In addition, while the tablets of Comparative Example 2 provided complete release after about 5 hours, the tablets of Comparative Example 3 provided less than 40% release over 24 hours. The results indicate that the presence of the inner soluble layer accelerates drug release under colonic conditions from tablets having an outer layer comprising a mixture of starch and Eudragit S. The results also indicate that, without the polysaccharide in the outer layer (Comparative Example 3), release under colonic conditions is not complete.

(186) In faecal slurry at pH 6.5 (drug release test #3; FIG. 3), initial release of 5ASA from the tablets of Example 1 occurred after about 2 hours, whereas initial release from the comparator tablets occurred only after about 8 hours. In addition, even though the pH of the surrounding medium was significantly below the pH threshold of Eudragit S, tablets according to Example 1 had release about 40% of the 5ASA after about 8 hours. In contrast, the tablets of Comparative Example 3 had released less than 10% of the 5ASA after 24 hours. These results indicate that the presence of starch in the outer layer enables release of a significant amount of the active when exposed to colonic enzymes even though the pH of the surrounding medium is well below the pH threshold of the second polymeric material.

(187) The skilled reader would appreciate that, even though the integrity of coating in Example 1 was compromised, not all of the active was released after 8 hours. The Inventors believe that this is because the test is in vitro. In vivo, the tablets would be subjected to mechanical pressure applied as a result of the motility of the colon and which should contribute to complete disintegration of the tablets.

(188) The Inventors have also observed that less than 10% of 5ASA is released from tablets of Example 1 when exposed to aqueous solution at pH 6.8 for 24 hours (see drug release test #4; FIG. 4). This result demonstrates the requirement for the presence of colonic enzymes in the surrounding medium to achieve significant release of the active from tablets according to the present invention and the resistance to the conditions of the small intestine, thereby efficiently preventing premature drug release.

(189) Accelerated drug release under colonic conditions is also observed for formulations of the present invention where the inner layer comprises neutralised Eudragit L30D-55 and the outer layer comprises a 30:70 mixture of starch/Eudragit S 100 when compared with equivalent formulations in which the inner layer has not been neutralised. As indicated in FIG. 5, no release is observed from either formulation when exposed to 0.1 M HCl for 2 hours. However, when exposed to Krebs buffer at pH 7.4, initial release from the formulation according to the present invention (Example 2) is observed after 30 minutes whereas initial release from the comparative formulation (Comparative Formulation 4) does not occur until about 150 minutes. Similar acceleration of initial release is observed when these formulations are exposed to faecal slurry at pH 6.5 with initial release from the tablets having the neutralised inner layer (Example 2) taking place after about 2 hours in contrast to about 4 hours for the tablets with the non-neutralised inner layer (Comparative Example 4) (FIG. 6).

(190) Formulations according to the present invention also demonstrate a clear advantage over the formulation exemplified in U.S. Pat. No. 5,422,121. In this regard, the Inventors reproduced as closely as possible the formulation of Example 2 of U.S. Pat. No. 5,422,121 in which a tablet core was coated first with an inner layer of Eudragit L30D and then with an outer layer of a 1:3 mixture of Eudragit L30D and guar gum (Comparative Example 5), and compared drug release over time in different conditions from this formulation with an equivalent formulation in which the Eudragit L30D of the inner layer was fully neutralised according to one embodiment of the present invention (Example 3). Under all of the colonic conditions tested, initial drug release was accelerated for the formulation having the neutralised inner layer (see FIGS. 7 to 9).

(191) Formulations having an inner layer comprising a non-ionic polymer, a base and a buffer agent also demonstrate accelerated initial drug release when compared with equivalent formulations in which the inner layer does not contain a base or a buffer agent. In this regard, the Inventors have demonstrated that initial release may be reduced from 4 hours to 3 hours when exposed to Krebs buffer in embodiments having an inner PVA polymer layer and an outer layer comprising a 70:30 mixture of Eudragit S/Eudragit FS (50:50) blend and starch, provided that the inner layer contains a base and a buffer agent (FIG. 10).

(192) Incomplete drug release was observed in some of the test runs after 10 hours at colonic conditions (see in particular FIGS. 8 and 9). The Inventors note that this observation may be explained by the fact that high dosage (1200 mg) tablets were tested in these runs and sink conditions could not be achieved with the low capacity buffers (Krebs and Hanks buffers) used, or with the limited volume (210 ml) of faecal slurry used.

(193) In contrast, the tablets of Examples 5 to 7 do not exhibit significant release prematurely when exposed to the simulated fed state conditions over the duration of the test (FIGS. 11, 14, 15). In addition, the tablets of Example 7 do not demonstrate a significant food effect when exposed to the simulated fed and fasted states over the duration of the tests (FIG. 15). In other words, not only do these tablets demonstrate less than 10% drug release by the end of the tests, but the release profiles in both the simulated fed and fasted states are either very similar (Example 7; FIG. 15) or almost identical (Example 6; FIG. 14).

(194) The results appear to support the conclusion a food effect associated with coated 5ASA tablets may be reduced or even eliminated by providing the tablets with a coating according to the present invention. In particular, the results appear to indicate that applying the outer coating using a semi organic coating preparation rather than an aqueous coating preparation can eliminate the food effect (Example 1; FIG. 16).

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

(196) 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.

(197) 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.