COLONIC DRUG DELIVERY FORMULATION

Abstract

A delayed release drug formulation for oral administration delivers a drug to the colon of a subject. The formulation includes a core containing a drug and a coating for the core. The coating contains an outer layer and an inner layer. The outer layer contains a film-forming enteric polymer having a pH threshold at about pH 6 or above, and the inner layer contains a film-forming non-ionic polymer that is soluble in intestinal or gastrointestinal fluid and a buffer agent in an amount from more than 20 wt % to about 60 wt % based on the dry weight of the non-ionic polymer.

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 film-forming enteric polymer having a pH threshold at about pH 6 or above, and wherein the inner layer comprises a first film-forming non-ionic polymer that is soluble in intestinal or gastrointestinal fluid, and a buffer agent in an amount of more than about 20 wt % to about 60 wt %, based on the dry weight of the first non-ionic polymer.

2. The delayed release drug formulation as claimed in claim 1, wherein the first non-ionic polymer is a non-ionic cellulose-based polymer.

3. The delayed release drug formulation as claimed in claim 1, wherein the first non-ionic polymer is hydroxypropyl methylcellulose (HPMC).

4. The delayed release drug formulation as claimed in claim 1, wherein the first non-ionic polymer is a non-ionic acrylate polymer or a polyvinyl-based polymer.

5. The delayed release drug formulation as claimed in claim 1, wherein the first non-ionic polymer is present in the inner layer in an amount from about 2 mg/cm.sup.2 to about 5 mg/cm.sup.2, based on the dry weight of the first non-ionic polymer.

6. The delayed release drug formulation as claimed in claim 1, wherein the buffer agent is present in the inner layer in an amount of more than 20 wt % to about 50 wt %, based on the dry weight of the first non-ionic polymer in the inner layer.

7. The delayed release drug formulation as claimed in claim 1, 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.

8. The delayed release drug formulation as claimed in claim 1, wherein the buffer agent is a phosphate salt.

9. The delayed release drug formulation as claimed in claim 1, wherein the buffer agent is combined with a base.

10. The delayed release drug formulation as claimed in claim 9, wherein the base is selected from the group consisting of hydroxide bases, alkali metal bicarbonates, alkali metal carbonates, alkali metal phosphates, alkali metal citrates, and physiologically tolerated amines.

11. The delayed release drug formulation as claimed in claim 9, wherein the base is a hydroxide base.

12. The delayed release drug formulation as claimed in claim 1, wherein the outer layer comprises a mixture of the enteric polymer and an enzymatically degradable polymer that is degraded by colonic enzymes.

13. The delayed release drug formulation as claimed in claim 12, wherein the enzymatically degradable polymer and the enteric polymer are present in the outer coating in a ratio of more than 10:90.

14. The delayed release drug formulation as claimed in claim 12, wherein the enteric polymer is present in the outer layer in an amount from about 3 to 10 mg/cm.sup.2, based on the dry weight of the enteric polymer.

15. The delayed release drug formulation as claimed in claim 1, comprising an isolation layer between the core and the coating.

16. The delayed release drug formulation as claimed in claim 15, wherein the isolation layer comprises a second film-forming non-ionic polymer.

17. A method of producing the delayed release drug formulation for oral administration to deliver the drug to the colon as claimed in claim 1, said method comprising: forming the core comprising the drug; dissolving the first film-forming non-ionic polymer that is soluble in intestinal or gastrointestinal fluid in an aqueous solvent with the buffer agent in the amount of more than about 20 wt % to about 60 wt %, based on the dry weight of the first non-ionic polymer, to form an inner layer coating preparation having a pH of greater than pH 7; coating the core using the inner layer coating preparation to form an inner layer coated core; and coating the inner layer coated core with an outer layer coating preparation comprising the film-forming enteric polymer having a pH threshold of about pH 6 or above in a solvent system, to form an outer coated core.

18. The method as claimed in claim 17, wherein the method comprises adding base to the inner layer coating preparation in an amount sufficient to raise the pH to the required level.

19. The method as claimed in claim 18, wherein the amount of base added to the inner layer coating preparation is sufficient to raise the pH of the inner layer coating preparation to be in a range from about pH 7.5 to about pH 10.

20. The method as claimed in claim 18, wherein the base is selected from the group consisting of hydroxide bases, alkali metal bicarbonates, alkali metal carbonates, alkali metal phosphates, alkali metal citrates, and physiologically tolerated amines.

21. The method as claimed in claim 18, wherein the base is a hydroxide base.

22. The method as claimed in claim 17, wherein the first non-ionic polymer is a non-ionic cellulose-based polymer.

23. The method as claimed in claim 22, wherein the first non-ionic polymer is hydroxypropyl methylcellulose (HPMC).

24. The method as claimed in claim 17, wherein the core is coated with the inner layer coating preparation until the first non-ionic polymer is coated on to the core in an amount from about 2 to about 5 mg/cm.sup.2, based on the dry weight of the first non-ionic polymer.

25. The method as claimed in claim 17, wherein the buffer agent is present in the inner layer coating preparation in an amount of more than about 20 to about 50 wt %, based on the dry weight of the first non-ionic polymer.

26. The method as claimed in claim 17, 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.

27. The method as claimed in claim 17, wherein the buffer agent is a phosphate salt.

28. The method as claimed in claim 17, wherein the outer layer coating preparation comprises a mixture of the enteric polymer and an enzymatically degradable polymer that is susceptible to attack by colonic enzymes.

29. The method as claimed in claim 28, wherein the enzymatically degradable polymer and the enteric polymer are present in the outer layer coating preparation in a ratio of more than 10:90.

30. The method as claimed in claim 28, wherein the inner coated core is coated with the outer layer coating preparation until the enteric polymer is coated on to the inner coated core in an amount from about 3 to 10 mg/cm.sup.2, based on the dry weight of the enteric polymer.

31. The method as claimed in claim 17, comprising initially coating the core with an isolation layer coating preparation comprising a second, film-forming non-ionic polymer in a solvent to form an isolated core for coating with the inner layer coating preparation.

32. The method as claimed in claim 31, the second non-ionic polymer of the isolation layer coating preparation is the same as the first non-ionic polymer of the inner layer coating preparation.

Description

EXAMPLES

[0150] A number of preferred embodiments of the present invention will now be described with reference to the drawings, in which:

[0151] FIG. 1 is a graph comparing drug release as a function of time from coated 5-ASA tablets according to Comparative Example 1, when exposed to (a) FaSSGF for 2 hours and then Kreb's buffer (pH 7.4) for 10 hours; and (b) FeSSGF for 4 hours then Krebs buffer (pH 7.4) for 10 hours. Only data in pH 7.4 Krebs buffer is represented;

[0152] FIG. 2 is a graph comparing drug release as a function of time from coated 5-ASA tablets according to according to Comparative Examples 2 and 3 and Examples 1 to 3 when exposed to FaSSGF for 2 hours and then Kreb's buffer (pH 7.4) for 10 hours. Only data in pH 7.4 Krebs buffer is represented;

[0153] FIG. 3 is a graph comparing drug release as a function of time from coated 5-ASA tablets according to according to Comparative Example 3, when exposed to (a) FaSSGF for 2 hours and then Kreb's buffer (pH 7.4) for 10 hours; and (b) FeSSGF for 4 hours then Krebs buffer (pH 7.4) for 10 hours. Only data in pH 7.4 Krebs buffer is represented;

[0154] FIG. 4 is a graph comparing drug release as a function of time from coated 5-ASA tablets according to Example 1, when exposed to (a) FaSSGF for 2 hours then Krebs buffer (pH 7.4) for 10 hours; and (b) FeSSGF for 4 hours then Krebs buffer (pH 7.4) for 10 hours. Only data in pH 7.4 Krebs buffer is represented;

[0155] FIG. 5 is a graph comparing drug release as a function of time from coated 5-ASA tablets according to Example 2, when exposed to (a) FaSSGF for 2 hours then Krebs buffer (pH 7.4) for 10 hours; and (b) FeSSGF for 4 hours then Krebs buffer (pH 7.4) for 10 hours. Only data in pH 7.4 Krebs buffer is represented;

[0156] FIG. 6 is a graph comparing drug release as a function of time from coated 5-ASA tablets according to Example 3, when exposed to (a) FaSSGF for 2 hours then Krebs buffer (pH 7.4) for 10 hours; and (b) FeSSGF for 4 hours then Krebs buffer (pH 7.4) for 10 hours. Only data in pH 7.4 Krebs buffer is represented;

MATERIALS

[0157] Eudragit® S 100, was purchased from Evonik GmbH, Darmstadt, Germany. Maize starch (Eurylon® 6) was purchased from Roquette, Lestrem, France. Polysorbate 80 (Tween® 80), butan-1-ol, triethyl citrate (TEC), ethanol 95%, butanol, potassium phosphate monobasic (KH.sub.2PO.sub.4), sodium diphosphate dibasic dihydrate (Na.sub.2HPO.sub.4.2H.sub.2O), and sodium hydroxide were all purchased from Sigma-Aldrich, Buchs, Switzerland. HPMC (Pharmacoat® 603) was purchased from Shin-Etsu. Opadry® AMB was purchased from Colorcon. Glyceryl monostearate (GMS) was purchased from Cognis. Polyethylene glycol (PEG 6000) was purchased from Aldrich. Iron oxide red and iron oxide yellow (Sicovit) were purchased from BASF.

[0158] Tablet Cores

[0159] Tablet cores containing 800 mg 5-ASA (Examples 1 to 3 and Comparative Examples 2 and 3 and 1200 mg 5-ASA (Comparative Example 1) were provided.

[0160] The tablet cores of Comparative Examples 1 to 3 and Example 1 were coated with an isolation layer of hydroxypropyl methylcellulose (HPMC) whereas the tablet cores of Examples 2 and 3 were coated with an isolation layer of Opadry® AMB, a polyvinyl alcohol (PVA)-based coating material.

[0161] Preparation of Coated Tablet Cores

[0162] COMPARATIVE EXAMPLES 1 and 2 (5-ASA tablet cores coated with an HPMC isolation layer/inner layer of neutralized Eudragit® S 100 with buffer and base/outer layer of a 50:50 (Comparative Example 1) or 70:30 (Comparative Example 2) mixture of Eudragit® S 100 and high amylose starch)

[0163] Isolation Layer

[0164] The isolation layer was applied from an aqueous mixture of HPMC and 20% PEG 6000 in the following amounts:

TABLE-US-00001 TABLE 1 Component mg/cm.sup.2 HPMC 3 PEG 6000 0.6

[0165] The HPMC was dissolved in water under magnetic stirring and then the PEG 6000 was added to form an isolation layer coating preparation.

[0166] The isolation layer coating preparation was sprayed on to the 5-ASA cores using a pan coater having a 0.8 L drum on a batch size of 400 g until the coating amount of HPMC reached 3 mg polymer/cm.sup.2 to form isolation layer coated cores. The spray coating parameters were as follows:

TABLE-US-00002 TABLE 2 Drum speed (rpm) 10-15 Nozzle diameter (mm) 0.8 Spray rate (g/min) .sup. 3-5.2 Spray pressure (bar) 0.7 Pattern pressure (bar) 1.0 Air flow (m.sup.3/h) 30   Inlet air temperature (° C.) 65-70 Outlet air temperature (° C.) 40-43 Product temperature (° C.) 33-34

[0167] Inner Layer

[0168] The inner layer was applied from an aqueous preparation of Eudragit® S 100, where the pH was adjusted to pH 8. The composition of the inner layer also included 70% TEC (based on dry polymer weight), 1% KH.sub.2PO.sub.4 (based on dry polymer weight), 10% GMS (based on dry polymer weight) and 40% polysorbate 80 (based on GMS weight). The pH was adjusted using 1M NaOH until pH 8 was obtained.

TABLE-US-00003 TABLE 3 Comparative Comparative Example 1 Example 2 mg/cm.sup.2 Eudragit ® S 5 5 KH.sub.2PO.sub.4 0.05 0.05 Glyceryl monostearate 0.5 0.5 Polysorbate 80 0.2 0.2 Triethyl citrate 3.5 3.5 1M NaOH As required to reach pH 8

[0169] The inner layer coating preparation was prepared by dissolving the required amounts of KH.sub.2PO.sub.4 and TEC 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 mixed for 1 h to form a neutralised Eudragit® S solution.

[0170] 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.

[0171] The GMS emulsion was added to the neutralised Eudragit® S solution and the final inner layer coating was sprayed onto isolation layer coated tablets using a perforated pan coater until the coating amount of Eudragit® S 100 reached 5 mg polymer/cm.sup.2 to produce inner layer coated cores. The spray coating parameters were as follows:

TABLE-US-00004 TABLE 4 Comparative Comparative Example 1 Example 2 Drum speed (rpm) 12-16 12 Nozzle diameter (mm) 0.8 0.8 Spray rate (g/min) 3.1 6.8-7.2 Spray pressure (bar) 0.4 0.7 Pattern pressure (bar) 0.5 1.0 Air flow (m.sup.3/h) 30   30 Inlet air temperature (° C.) 58-65 70 Outlet air temperature (° C.) 37.6-38.0 34.1-37.8 Product temperature (° C.) 24.5-25.5 25.5-31.5

[0172] Outer Layer

[0173] The inner layer coated tablet cores were coated with an outer coating formed of 50% Eudragit® S 100 and 50% high amylose starch (Comparative Example 1) or with an outer layer formed of 70% Eudragit® S 100 and 30% high amylose starch (Comparative Example 2).

[0174] The outer layer coating was applied from a mixture of an aqueous starch dispersion and an ethanolic Eudragit® S 100 solution in the following amounts (based on Eudragit® S 100 dry polymer weight):

TABLE-US-00005 TABLE 5 Comparative Comparative Example 1 Example 2 mg/cm.sup.2 Starch (raw) 5.71 2.45 Glyceryl monostearate 0.5 0.36 Polysorbate 80 0.2 0.14 Iron Oxide yellow 0.11 0.11 Iron Oxide red 0.66 0.66 Eudragit ® S 100 5 5.00 Triethyl citrate 2 2

[0175] The aqueous starch dispersion was prepared by dispersing high amylose maize starch, (Eurylon® 6 also known as Amylo N-400) into butan-1-ol, followed by water, under magnetic stirring. The resulting dispersion was heated to boiling and then cooled under stirring overnight.

[0176] The Eudragit® S 100 solution was prepared by dispersing Eudragit® S 100 in 96% ethanol under high speed stirring.

[0177] The aqueous starch dispersion was added dropwise to the Eudragit® S 100 solution under stirring to obtain a ratio of Eudragit® S 100:starch of 50:50 (Comparative Example 1) or 70:30 (Comparative Example 2). The mixture was stirred for 1 hour and triethyl citrate and a GMS emulsion (previously prepared with Polysorbate 80) were added and mixed for further 30 minutes. A suspension of iron oxide red and iron oxide yellow was added and the mixture was stirred for a further 10 minutes.

[0178] The GMS emulsion was prepared at a concentration of 5% w/w. Polysorbate 80 (Tween®, 40% based on GMS weight) was dissolved in distilled water followed by dispersion of the GMS. The dispersion was heated at 75° C. for 15 minutes under strong magnetic stirring in order to form an emulsion. The emulsion was cooled at room temperature under stirring. The pigment suspension was formed by suspending red and yellow iron oxide pigments in 96% ethanol for 10 minutes under homogenization.

[0179] The final outer layer coating preparation was sprayed on to the inner layer coated cores using the same pan coater as used to apply the isolation layer having a 0.8 L drum on a batch size of 400 g until the coating amount of Eudragit® S 100 reached 5 mg polymer/cm.sup.2. The spray coating parameters were as follows:

TABLE-US-00006 TABLE 6 Comparative Comparative Example 1 Example 2 Drum speed (rpm) 12 12 Nozzle diameter (mm) 1.0 0.8 Spray rate (g/min) 2.95 3.2 Spray pressure (bar) 0.4 0.4 Pattern pressure (bar) 0.5 0.5 Air flow (m.sup.3/h) 40 40 Inlet air temperature (° C.) 53-55 52-55 Outlet air temperature (° C.) 40.5-41.6 40.9-42.6 Product temperature (° C.) 34.5-36.5 34.5-36.5

[0180] COMPARATIVE EXAMPLE 3 and EXAMPLE 1 (5-ASA tablet cores coated with a HPMC isolation layer/inner layer of HPMC with 10 wt % buffer salt (Comparative Example 3) or 30 wt % buffer salt (Example 1) and a base/outer layer of a 70:30 mixture of Eudragit® S 100 and high amylose starch).

[0181] The isolation layer was applied as described for Comparative Example 1 and 2.

[0182] The inner layer was applied from a mixture of HPMC, 20% PEG 6000 (based on HPMC dry weight), and a KH.sub.2PO.sub.4 buffer agent in the following amounts:

TABLE-US-00007 TABLE 7 Comparative Example 1 Example 1 mg/cm.sup.2 HPMC 3 KH.sub.2PO.sub.4 0.3 0.9 PEG 6000 0.6 1M NaOH As required to reach pH 8

[0183] The inner layer coating preparation was prepared by dissolving the required amount of KH.sub.2PO.sub.4 and PEG 6000 in water under magnetic stirring. The HPMC was added slowly and allowed to stir until complete dissolution was observed. The pH of the solution was adjusted to pH 8 by adding aliquots of 1M NaOH.

[0184] The inner layer coating preparation was sprayed on to the isolation layer coated cores using the same pan coater as for the isolation layer until the coating amount of HPMC reached 3 mg polymer/cm.sup.2 to form inner layer coated cores. The spray coating parameters were as follows:

TABLE-US-00008 TABLE 8 Comparative Example 3 and Example 1 Drum speed (rpm) 10-12 Nozzle diameter (mm) 0.8 Spray rate (g/min) 2.5 Spray pressure (bar) 0.6 Pattern pressure (bar) 0.8 Air flow (m.sup.3/h) 30   Inlet air temperature (° C.) 62-70 Outlet air temperature (° C.) 40.6-40.9 Product temperature (° C.) 30.5-31.sup. 

[0185] Outer Layer

[0186] The inner layer coated tablet cores were coated with an outer coating formed of 30% Eudragit® S 100 and 70% high amylose starch.

[0187] The outer coating was applied from a mixture of an aqueous starch dispersion and an ethanolic Eudragit® S 100 solution in the following amounts (based on Eudragit® S 100 dry polymer weight):

TABLE-US-00009 TABLE 9 Comparative Example 3 and Example 1 mg/cm.sup.2 Starch (raw) 2.45 Glyceryl monostearate 0.36 Polysorbate 80 0.14 Iron Oxide yellow 0.11 Iron Oxide red 0.66 Eudragit ® S 100 5 Triethyl citrate 1.43

[0188] The aqueous starch dispersion was prepared by dispersing high amylose maize starch, (Eurylon® 6 also known as Amylo N-400) into butan-1-ol, followed by water, under magnetic stirring. The resulting dispersion was heated to boiling and then cooled under stirring overnight.

[0189] The Eudragit® S 100 solution was prepared by dispersing Eudragit® S 100 in 96% ethanol under high speed stirring.

[0190] The aqueous starch dispersion was added dropwise to the Eudragit® S 100 solution under stirring to obtain a ratio of Eudragit® S 100:starch of 30:70 (Example 1 and 2) or 50:50 (Example 3). The mixture was stirred for 1 hour and triethyl citrate and a GMS emulsion (previously prepared with Polysorbate 80) were added and mixed for further 30 minutes. A suspension of iron oxide red and iron oxide yellow was added and the mixture was stirred for a further 10 minutes.

[0191] The GMS emulsion was prepared at a concentration of 5% w/w. Polysorbate 80 (Tween®, 40% based on GMS weight) was dissolved in distilled water followed by dispersion of the GMS. The dispersion was heated at 75° C. for 15 minutes under strong magnetic stirring in order to form an emulsion. The emulsion was cooled at room temperature under stirring.

[0192] The pigment suspension was formed by suspending red and yellow iron oxide pigments in 96% ethanol for 10 minutes under homogenization.

[0193] The final outer layer coating preparation was sprayed on to the inner layer coated cores using the same pan coater as used to apply the isolation layer having a 0.8 L drum on a batch size of 400 g until the coating amount of Eudragit® S 100 reached 5 mg polymer/cm.sup.2. The spray coating parameters were as follows:

TABLE-US-00010 TABLE 10 Drum speed (rpm) 12 Nozzle diameter (mm) 0.8 Spray rate (g/min) 3.8 Spray pressure (bar) 0.4 Pattern pressure (bar) 0.5 Air flow (m.sup.3/h) 40 Inlet air temperature (° C.) 55-57 Outlet air temperature (° C.) 41-43 Product temperature (° C.) 32.5-33  

[0194] EXAMPLE 2 and EXAMPLE 3 (5-ASA tablet cores coated with a PVA-based isolation layer/inner layer of HPMC with a buffer and a base/outer layer of a 30:70 mixture of Eudragit® S 100 and high amylose starch)

[0195] Isolation Layer

[0196] The isolation layer was applied from an aqueous dispersion of Opadry® AMB at 3.1 mg/cm.sup.2 (total solids).

[0197] Opadry® AMB is a fully formulated coating system based on polyvinyl alcohol (PVA). Opadry® AMB was diluted with purified water under magnetic stirring for 30 minutes to prepare a isolation layer coating preparation.

[0198] The isolation layer coating preparation was sprayed onto the 5-ASA cores using a pan coater having a 0.8 L drum on a batch size of 400 g until the coating amount of Opadry® AMB reached the target amount to form isolation layer coated cores. The spray coating parameters were the same as for Comparative Example 3 and Examples 1.

[0199] Inner Layer

[0200] The inner layer was applied from a mixture of HPMC, 20% PEG 6000 (based on HPMC dry weight), and a KH.sub.2PO.sub.4 buffer agent in the following amounts:

TABLE-US-00011 TABLE 11 Example 2 Example 3 mg/cm.sup.2 HPMC 3 KH.sub.2PO.sub.4 0.9 1.5 PEG 6000 0.6 1M NaOH As required to reach pH 8

[0201] The inner layer was prepared and applied to the isolation layer coated cores according to Comparative Example 3 and Example 1.

[0202] Outer Layer

[0203] The outer coating was prepared and applied according to Comparative Example 3 and Example 1.

[0204] Results

[0205] Drug Release Test #1—Simulated Fasted State then Krebs Buffer at pH 7.4

[0206] 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.

[0207] To simulate the “fasted” state, the tablets were first tested in 0.1 M HCI for 2 hours (FaSSGF) followed by 10 hours in Krebs buffer (pH 7.4).

[0208] Drug Release Test #2—Simulated Fed State then Krebs Buffer at pH 7.4

[0209] 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.

[0210] To simulate the “fed” state, the tablets were first tested in Fed State Simulated Gastric Fluid (FeSSGF) at pH 5.0 for 4 hours followed by 10 hours in Krebs buffer (pH 7.4). The FeSSGF was as described in Jantrid et al (2008) supra.

[0211] The results are shown in FIGS. 1 to 6.

[0212] The tablets according to Comparative Example 1 showed a delay in release in simulated fed state gastric conditions in comparison to fasted simulated gastric conditions (FIG. 1).

[0213] The tablets according to Examples 1 to 3 showed similar properties to the tablets of Comparative Example 2 after exposure to 0.1 N HCI for 2 hours. In particular, there was no release of 5-ASA 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 (drug release test #2), rapid release of 5-ASA was observed (FIG. 2). It should also be noted that an inner layer containing only 10 wt % buffer salt showed the slowest lagtime in simulated fasted state gastric conditions (Comparative Example 3, FIG. 2). The data in FIG. 2 also demonstrate that replacing the neutralized Eudragit® S 100 inner layer of Comparative Example 2 with an inner layer of HPMC containing more than 10 wt % buffer salt (Examples 1 to 3) was equally effective in promoting a fast drug release.

[0214] Tablets according to Examples 1 to 3 having an inner layer of HPMC and between 30 wt % and 50 wt % KH.sub.2PO.sub.4 buffer salt (based on dry polymer weight) showed no delay in release of 5-ASA in pH 7.4 Krebs buffer after exposure to simulated fed gastric fluid in comparison to release after exposure to fasted simulated gastric fluid (FIG. 4 to FIG. 6).

[0215] Tablets according to Comparative Example 3, having a middle layer of HPMC containing 10 wt % buffer salt (based on dry polymer weight) showed a slower dissolution rate in pH 7.4 Krebs buffer after pre-exposure to simulated fed gastric fluid (FIG. 3) in comparison to tablets according to Examples 1 to 3 having between 30 wt % and 50 wt % buffer salt in the inner layer (FIG. 4 to FIG. 6).

[0216] Without being bound by theory, it is thought that where the outer layer of the formulation is permeable to the gastric fluid, such as in fed state simulated gastric fluid (FeSSGF), thereby allowing access to the inner layer, modification of the inner layer can occur which can affect the drug release. The buffer salt content in the inner layer made from a neutral polymer, such as HPMC, can contribute to maintaining a high buffer capacity at the interface between the coating layer and the tablet core, decreasing or avoiding the impact of the fed state gastric fluid in delaying drug release in pH 7.4 Krebs buffer which resembles the luminal electrolyte composition of the distal small intestine.

[0217] It will be appreciated that the invention is not restricted to the details described above with reference to the preferred embodiments but that numerous modifications and variations can be made without departing from the scope of the invention as defined by the following claims.