METHOD OF PRODUCING A DELAYED RELEASE DRUG FORMULATION

Abstract

A method produces a coatable core for a delayed release drug formulation for oral administration, to deliver a drug to the colon. The method involves forming a core containing a drug. An outer layer coating preparation is formed by combining a first aqueous preparation of an enzymatically degradable polymer, which is degradable by colonic bacterial enzymes; a second aqueous preparation of a film-forming enteric polymer having a pH threshold of about pH 6 or above; and an organic anti-tack agent. The core is then coated with the outer layer coating preparation to form an outer layer coated core.

Claims

1: A method of producing a delayed release drug formulation for oral administration to deliver a drug to the colon, said method comprising: forming a core comprising a drug; combining a first aqueous preparation of an enzymatically degradable polymer which is degradable by colonic bacterial enzymes; a second aqueous preparation of a film forming enteric polymer having a pH threshold of about pH 6 or above; and an organic anti-tack agent, to form an outer layer coating preparation; and coating the core with the outer layer coating preparation to form an outer layer coated core.

2: The method as claimed in claim 1, wherein the second aqueous preparation is formed by suspending the enteric polymer in water under stirring to form a suspension, and partially neutralising the suspension with a base.

3: The method as claimed in claim 2, wherein the base is added to the suspension in an amount sufficient to neutralise from about 10% to about 30% of carboxylic acid groups in the enteric polymer.

4: The method as claimed in claim 2, wherein the suspension is partially neutralised using aqueous ammonia.

5: The method as claimed in claim 4, wherein the aqueous ammonia has a concentration from about 0.5 N to about 2 N.

6: The method as claimed claim 1, wherein the organic anti-tack agent is in the form of an aqueous dispersion.

7: The method as claimed in claim 6, wherein the aqueous dispersion comprises a surfactant.

8: The method as claimed in claim 7, wherein the surfactant is non-ionic.

9: The method as claimed in claim 7, wherein the surfactant is hydrophilic.

10: The method as claimed in claim 1, wherein the organic anti-tack agent is glyceryl monostearate (GMS) or stearic acid.

11: The method as claimed in claim 1, wherein the core is pre-coated with an isolation layer comprising a film-forming non-ionic polymer that is soluble in gastrointestinal fluid, an inner layer comprising a polymeric material which is soluble in intestinal or gastrointestinal fluid, or both the isolation layer and the inner layer; wherein said polymeric material is selected from the group consisting of a polycarboxylic acid polymer that is at least partially neutralised, and a non-ionic polymer, provided that, where said polymeric material is a non-ionic polymer, said inner layer comprises at least one additive selected from a buffer agent and a base.

12: The method as claimed in claim 11, wherein the inner layer, when present, comprises a buffer agent and a base.

13: The method as claimed in claim 1, wherein the outer layer coating preparation comprises no more than about 5% v/v organic solvent.

14: A delayed release drug formulation for oral administration to deliver a drug to the colon, said formulation comprising: a core comprising a drug, and an outer coating layer for the core, the outer coating layer comprising a mixture of an enzymatically degradable polysaccharide which is degradable by colonic bacterial enzymes, a film-forming enteric polymer having a pH threshold at about pH 6 or above, and an organic anti-tack agent; wherein the outer coating layer comprises no more than about 5000 ppm residual free organic solvent; and/or wherein the outer coating layer comprises at least 10% by weight of at east one plasticizer based on the weight of the film-forming enteric polymer.

15: The delayed release drug formulation according to claim 14, comprising an inner layer located between said core and said outer coating layer, wherein said inner layer comprises a film-forming non-ionic polymer that is soluble in gastrointestinal fluid, a buffer agent, and a base.

16: The delayed release drug formulation according to claim 14, comprising an isolation layer located on the surface of the core, said isolation layer comprising a film-forming ionic polymer that is soluble in gastrointestinal fluid.

17: The method as claimed in claim 3, wherein the base is added to the suspension in an amount sufficient to neutralise from about 15% to 20% of carboxylic acid groups in the enteric polymer.

18: The method as claimed in claim 5, wherein the aqueous ammonia has a concentration of about 1 N.

Description

EXAMPLES

[0144] Preferred embodiments of the present invention will now be described with reference to the drawings, in which:—

[0145] FIG. 1 is a graph comparing drug release as a function of time from coated 5-ASA capsules according to Examples 1, Example 2, Comparative Example 1 and Comparative Example 2, when exposed to 0.1M HCl for 2 hours (data not shown) and then Krebs's buffer (pH 7.4) for 10 hours;

[0146] FIG. 2 is a graph comparing drug release as a function of time from coated 5-ASA capsules according to Example 1, Example 2 and Comparative Example 1, when exposed to 0.1N HCl for 2 hours (data not shown) and then Sørensen's buffer (pH 6.8) for about 18 hours (a) with α-amylase and (b) without α-amylase.

[0147] FIG. 3 is a graph comparing drug release as a function of time from coated 5-ASA capsules according to Comparative Example 2, when exposed to 0.1N HCl for 2 hours (data not shown) and then Sørensen's buffer (pH 6.8) for about 18 hours (a) with α-amylase and (b) without α-amylase.

[0148] FIG. 4 is a graph comparing drug release as a function of time from coated 1600 mg 5-ASA tablets according to Example 3 and Comparative Example 5, when exposed to 0.1M HCl for 2 hours and then Hank's buffer (pH 6.8) for 10 hours;

[0149] FIG. 5 is a graph comparing drug release as a function of time from coated 1600 mg 5-ASA tablets according to Example 3 and Comparative Example 5, when exposed to 0.1M HCl for 2 hours and then Krebs's buffer (pH 7.4) for 10 hours;

MATERIALS

[0150] 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%, talc, 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. Syloid 244 FP was received from Grace, Discovery Sciences, Belgium and Aerosil 300 from Evonik GmbH, Darmstadt, Germany. HPMC (Pharmacoat 603) was purchased from Shin-Etsu and hydroxypropyl methylcellulose (HPMC, Methocel E3 or Methocel E5) was purchased from Colorcon. Glyceryl monostearate (GMS) was purchased from Cognis. (Polyethylene glycol (PEG) was purchased from Aldrich. Iron oxide red and iron oxide yellow (Sicovit) were purchased from BASF. HPMC capsules were purchased from Qualicaps. Gelatin was purchased from Gelita. Ammonia solution (25%) was purchased from VWR International LTD, Poole, UK.

[0151] Preparation of Gelatin Banded Capsule Cores

[0152] 5-ASA granules were prepared by mixing 5-ASA with an aqueous solution of HPMC in a high shear granulator at 550 rpm. The granules were passed through a 6.34 mm sieve (Comil) before drying at 45° C. The dry granules were then sieved through a 1.6 mm conical mill.

[0153] Capsules of size 00 were filled with 550 mg to 630 mg of the dry 5-ASA granules and the capsules were banded with a 21.8% gelatin solution and dried at room temperature.

[0154] Preparation of Tablet Cores

[0155] Oblong shaped 1600 mg cores were prepared according to the following method. The amount of each component per tablet core is: 160 mg mesalazine, 32 mg hypromellose, 178 mg microcrystalline cellulose, 54 mg sodium starch glycolate, 2 mg colloidal silicon dioxide and 1 mg magnesium stearate.

[0156] Mesalazine (8 kg) and an aqueous solution containing HPMC (160 g, Pharmacoat® 603) were granulated in a high speed mixer granulator. The wet granules were passed through a 9.4 mm sieve (Comil) before drying in a fluid bed dryer at an inlet air temperature of about 80° C. until the product temperature reached 42° C. The dry granules were sieved using a 1.6 mm grater sieve.

[0157] The dry granules were blended with microcrystalline cellulose (Avicel® pH 102) and sodium starch glycolate (Explotab®) in an 80 L drum for about 20 minutes at 28 rpm. Magnesium stearate and colloidal silicon dioxide (Aerosil® 200) were both individually pre-blended with about 500 g of the of the mixture of mesalazine granules, microcrystalline cellulose and sodium starch glycolate and passed through a 1 mm sieve before adding to the remainder of the mixture. The mixture was blended for about 5 minutes at 28 rpm to form a final compression blend.

[0158] Compression of the final compression blend was performed using a Fette P1200 tableting machine combined with an external lubrication system (PKB). Magnesium stearate was sprayed onto the punches of the tableting machine at a dose of 400 g/h.

[0159] The obtained capsules and tablet cores were coated as discussed below in Examples 1 to 3 and Comparative Examples 1 to 9.

Example 1 (5-ASA Capsule Cores Coated with Single Layer of a 70:30 Mixture of Eudragit® S 100 and High Amylose Starch; Aqueous Coating Preparation Containing 5% GMS and Polysorbate 80)

[0160] The coating was applied from a mixture of an aqueous starch dispersion (first aqueous preparation) and an aqueous Eudragit® S 100 dispersion (second aqueous preparation).

[0161] The aqueous starch dispersion was prepared by dispersing maize starch into butan-1-ol, followed by water, under magnetic stirring. The ratio of maize starch:butan-1-ol:water was 1:1:12.5. The resulting dispersion was heated to boiling and then cooled under stirring overnight.

[0162] The aqueous Eudragit® S 100 dispersion 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).

[0163] The aqueous Eudragit® S 100 dispersion was added dropwise to the starch dispersion to obtain a ratio of Eudragit® S 100:starch of 70:30. The mixture was stirred for 1 hour and 60% TEC (based on Eudragit® S 100 polymer weight) and 5% glyceryl monostearate (GMS, based on Eudragit® S 100 polymer weight) were added and mixed for further 1 hour. An aqueous suspension of 13.18% iron oxide red (based on Eudragit® S 100 polymer weight) and 2.27% iron oxide yellow (based on Eudragit® S 100 polymer weight) was added and the mixture was mixed for further 10 minutes to form an outer layer coating preparation.

[0164] 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.

[0165] The pigment suspension was formed by suspending red and yellow iron oxide pigments in water for 10 minutes under homogenization.

[0166] The outer layer coating preparation was sprayed on to the gelatin banded 5-ASA capsule cores using a pan coater, until a coating amount of 5 mg/cm.sup.2 of Eudragit® S 100 was obtained.

[0167] The spray coating parameters were as follows: spraying rate 2.5-3.4 g/min; spray pressure 0.4 bar; pattern pressure 0.4 bar; air flow 40 m.sup.3/h; inlet air temperature 54-60° C.; outlet air temperature 41.4-42.5° C.; product temperature 29.5-41° C.; drum speed 10-14 rpm.

Example 2 (5-ASA Capsule Cores Coated with a Single Layer of a 50:50 Mixture of Eudragit® S 100 and High Amylose Starch; Aqueous Coating Preparation Containing 10% GMS and Polysorbate 80)

[0168] The coating was applied from a mixture of an aqueous starch dispersion (first aqueous preparation) and an aqueous Eudragit® S 100 dispersion (second aqueous preparation) using the same method as described for Example 1 with 10% GMS (based on Eudragit® S 100 polymer weight).

[0169] The aqueous Eudragit® S 100 dispersion was added dropwise to the starch dispersion to obtain a ratio of Eudragit® S 100:starch of 50:50.

[0170] The outer layer coating preparation was sprayed on to the gelatin banded 5-ASA capsule cores using a pan coater, until a coating amount of 5 mg/cm.sup.2 of Eudragit® S 100 was obtained.

[0171] The spray coating parameters were as described for Example 1.

Example 3 (1600 mg 5-ASA Tablet Cores Coated with an HMPC Isolation Layer and an Outer Layer of a 70:30 Mixture of Eudragit® S 100 and High Amylose Starch; Aqueous Coating Preparation Containing 5% GMS, Based on Eudragit S® 100 and Polysorbate)

[0172] Isolation Layer

[0173] The isolation layer was applied from an aqueous mixture of HPMC and 20% PEG 6000.

[0174] The HPMC was dissolved in water under magnetic stirring and then the PEG 600 was added to form an isolation layer coating preparation. The isolation layer coating preparation was sprayed on to the 5-ASA tablet cores using a pan coater, until the coating amount of HPMC reached 3 mg/cm.sup.2, to form isolation layer coated tablet cores.

[0175] Outer Layer

[0176] The outer layer coating was applied from a mixture of an aqueous starch dispersion (first aqueous preparation) and an aqueous Eudragit® S 100 dispersion (second aqueous preparation) prepared according to Example 1.

[0177] The outer layer coating preparation was sprayed on to the isolation layer coated 5-ASA tablet cores using a pan coater, until a coating amount of 5 mg/cm.sup.2 of Eudragit® S 100 was obtained.

[0178] The spray coating parameters were as follows: spraying rate 2.0-2.8 g/min; spray pressure 0.4 bar; pattern pressure 0.5 bar; air flow 40 m.sup.3/h; inlet air temperature 52-60° C.; outlet air temperature 40.0-45.0° C.; product temperature 32.0-36.0° C.; drum speed 10-12 rpm.

Comparative Example 1 (5-ASA Capsule Cores Coated with a Single Layer of a 70:30 Mixture of Eudragit® S 100 and High Amylose Starch; “Semi-Organic” Coating Preparation Containing 5% GMS, Based on Eudragit® S 100 and Polysorbate)

[0179] The coating was applied from a mixture of an aqueous starch dispersion and an organic Eudragit® S 100 solution.

[0180] 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 1:2:25. The resulting dispersion was heated to boiling and then cooled under stirring overnight.

[0181] The organic Eudragit® S 100 solution was prepared by dissolving Eudragit® S 100 in 96% ethanol under high speed stirring.

[0182] The starch dispersion was added dropwise to the Eudragit® S 100 solution to obtain a ratio of Eudragit® S 100:starch: of 70:30. The mixture was stirred for 1 hour and 29% TEC (based on Eudragit® S 100 polymer weight) and 5% glyceryl monostearate (GMS, based on Eudragit® S 100 polymer weight) were added and mixed for further 1 hour. A suspension of 13.18% iron oxide red (based on Eudragit® S polymer weight) and 2.27% iron oxide yellow (based on Eudragit® S 100 polymer weight) in ethanol was added and the mixture was mixed for further 10 minutes to form an outer layer coating preparation.

[0183] The GMS was added in the form of an emulsion as prepared in Example 1.

[0184] The outer layer coating preparation was sprayed on to the gelatin banded 5-ASA capsule cores using a pan coater, until a coating amount of 5 mg/cm.sup.2 of Eudragit® S 100 was obtained.

[0185] The spray coating parameters were as described for Example 1.

Comparative Example 2 (5-ASA Capsule Cores Coated with Single Layer of a 70:30 Mixture of Eudragit® S 100 and High Amylose Starch; Aqueous Coating Preparation Containing 50% Talc)

[0186] The coating was applied from a mixture of an aqueous starch dispersion and an aqueous Eudragit® S 100 dispersion using the same method as described for Example 1, with talc (50% based on total Eudragit® S 100 polymer weight) as the anti-tack agent instead of GMS.

[0187] The talc was added in the form an aqueous suspension with the red and yellow iron oxide pigments.

[0188] The outer layer coating preparation was sprayed on to the isolation layer coated 5-ASA capsules using a pan coater, until a coating amount of 5 mg/cm.sup.2 of Eudragit® S 100 was obtained.

[0189] The spray coating parameters were as described for Example 1.

Comparative Example 3 (1600 mg 5-ASA Tablet Cores Coated with a HPMC Isolation Layer and an Outer Layer of a 70:30 Mixture of Eudragit® S 100 and High Amylose Starch; “Semi-Organic” Coating Preparation Containing 5% GMS and Polysorbate)

[0190] Isolation Layer

[0191] The isolation layer was prepared and applied to the 5-ASA tablet cores according to Example 3.

[0192] Outer Layer

[0193] The outer layer coating was applied from a mixture of an aqueous starch dispersion and an organic Eudragit® S 100 solution as described for Comparative Example 1.

[0194] The outer layer coating preparation was sprayed on to the isolation layer coated 5-ASA tablet cores using a pan coater, until a coating amount of 5 mg/cm.sup.2 of Eudragit® S 100 was obtained.

[0195] The spray coating parameters were as described for Example 3.

Comparative Example 4 (1600 mg 5-ASA Tablet Cores Coated with a HPMC Isolation Layer and an Outer Layer of a 70:30 Mixture of Eudragit® S 100 and High Amylose Starch; “Semi-Organic” Coating Preparation Containing 50% Talc)

[0196] The outer layer coating was applied from a mixture of an aqueous starch dispersion and an organic Eudragit® S 100 solution using the same method as described for Comparative Example 1, with talc (50% based on Eudragit® S 100 polymer weight) as the anti-tack agent instead of GMS.

[0197] The talc was added as an ethanolic suspension with the red and yellow iron oxide pigments.

[0198] The outer layer coating preparation was sprayed on to isolation layer coated 5-ASA tablet cores previously using a pan coater, until a coating amount of 5 mg/cm.sup.2 of Eudragit® S 100 was obtained.

[0199] The spray coating parameters were as described for Example 3.

Comparative Example 5 (1600 mg 5-ASA Tablet Cores Coated with a HPMC Isolation Layer and an Outer Layer of a 70:30 Mixture of Eudragit® S 100 and High Amylose Starch; “Aqueous” Coating Preparation Containing 50% Talc)

[0200] Isolation Layer

[0201] The isolation layer was prepared and applied to the 5-ASA tablet cores according to Example 3.

[0202] Outer Layer

[0203] The outer layer coating was applied from a mixture of an aqueous starch dispersion and an aqueous Eudragit® S 100 dispersion as described for Comparative Example 2.

[0204] The outer layer coating preparation was sprayed on to the isolation layer coated 5-ASA tablet cores using a pan coater, until a coating amount of 5 mg/cm.sup.2 of Eudragit® S 100 was obtained.

[0205] The spray coating parameters were as described for Example 1.

Comparative Example 6 (1600 mg 5-ASA Tablet Cores Coated with a HPMC Isolation Layer and an Outer Layer of a 70:30 Mixture of Eudragit® S 100 and High Amylose Starch; “Aqueous” Coating Preparation Containing 5% Talc)

[0206] Isolation Layer

[0207] The isolation layer was prepared and applied to the 5-ASA tablet cores according to Example 3.

[0208] Outer Layer

[0209] The outer layer coating was applied from a mixture of an aqueous starch dispersion and an aqueous Eudragit® S 100 dispersion as described for Comparative Example 2 with talc (5% based on Eudragit® S 100 polymer weight) as the anti-tack agent.

[0210] The outer layer coating preparation was sprayed on to the isolation layer coated 5-ASA tablet cores using a pan coater, until a coating amount of 5 mg/cm.sup.2 of Eudragit® S 100 was obtained.

[0211] The spray coating parameters were as described for Example 1.

Comparative Example 7 (1600 mg 5-ASA Tablet Cores Coated with a HPMC Isolation Layer and an Outer Layer of a 70:30 Mixture of Eudragit® S 100 and High Amylose Starch; “Aqueous” Coating Preparation Containing 5% Talc and Polysorbate 80)

[0212] Isolation Layer

[0213] The isolation layer was prepared and applied to the 5-ASA tablet cores according to Example 3.

[0214] Outer Layer

[0215] The outer layer coating was applied from a mixture of an aqueous starch dispersion and an aqueous Eudragit® S 100 dispersion using the same method as described for Comparative Example 2, with talc (5% based on total Eudragit® S 100 solid content) as the anti-tack agent.

[0216] The talc was added in the form an aqueous dispersion with Polysorbate 80 (40% based on talc weight).

[0217] The outer layer coating preparation was sprayed on to the isolation layer coated 5-ASA tablet cores using a pan coater, until a coating amount of 5 mg/cm.sup.2 of Eudragit® S 100 was obtained.

[0218] The spray coating parameters were as described for Example 1.

Comparative Example 8 (1600 mg 5-ASA Tablet Cores Coated with a HPMC Isolation Layer and an Outer Layer of a 70:30 Mixture of Eudragit® S 100 and High Amylose Starch; “Aqueous” Coating Preparation Containing 5% Colloidal Silicon Dioxide)

[0219] Isolation Layer

[0220] The isolation layer was prepared and applied to the 5-ASA tablet cores according to Example 3.

[0221] Outer Layer

[0222] The outer layer coating was applied from a mixture of an aqueous starch dispersion and an aqueous Eudragit® S 100 dispersion as described for Comparative Example 2 with 5% colloidal silicon dioxide (Aerosil® 300) as the anti-tack agent.

[0223] The colloidal silica (Aerosil® 300) was added in the form a dispersion. Aerosil 300 (5%, based on total Eudragit® S 100 polymer weight) was homogenized in water for 10 minutes and then added to the mixture of the aqueous starch dispersion and the aqueous Eudragit® S 100 dispersion.

[0224] The outer layer coating preparation was sprayed on to the isolation layer coated 5-ASA tablet cores using a pan coater, until a coating amount of 5 mg/cm.sup.2 of Eudragit® S 100 was obtained.

[0225] The spray coating parameters were as described for Example 1.

Comparative Example 9 (1600 mg 5-ASA Tablet Cores Coated with a HPMC Isolation and an Outer Layer of a 70:30 Mixture of Eudragit® S 100 and High Amylose Starch; “Aqueous” Coating Preparation Containing 5% Colloidal Silicon Dioxide)

[0226] Isolation Layer

[0227] The isolation layer was prepared and applied to the 5-ASA tablet cores according to Example 3.

[0228] Outer Layer

[0229] The outer layer coating was applied from a mixture of an aqueous starch dispersion and an aqueous Eudragit® S 100 dispersion as described for Comparative Example 2 with 5% colloidal silicon dioxide (Syloid 244 FP) as the anti-tack agent.

[0230] The colloidal silica (Syloid 244 FP) was added in the form a dispersion. Syloid 244 FP (5%, based on total Eudragit® S 100 polymer weight) was homogenized in water for 10 minutes and then added to the mixture of the aqueous starch dispersion and the aqueous Eudragit® S 100 dispersion.

[0231] The outer layer coating preparation was applied to the isolation layer coated 5-ASA tablet cores using a pan coater, until a coating amount of 5 mg/cm.sup.2 of Eudragit® S 100 was obtained.

[0232] The spray coating parameters were as described for Example 3.

[0233] Acid Resistance Test

[0234] Acid resistance testing was performed using a disintegration apparatus and basked rack assembly. 6 coated tablets or capsules were tested in 0.1 M HCl for 2 hours at 37° C. Tablets and capsules were considered acid resistant if no visible cracks or deformation of the coating was observed.

[0235] Acid resistance of coated tablets was also determined after mechanical stress. 6 tablets were subjected to 100 rotations (25 rpm/4 minutes) in a friability tester, prior to being tested in 0.1 M HCl for 2 hours at 37° C.

[0236] Drug Release Test #1—Simulated Fasted State then Dissolution in Hanks Buffer at pH 6.8

[0237] 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. To simulate the “fasted” state, capsules/tablets were first tested in 0.1 M HCl for 2 hours followed by 10 hours in Hanks buffer (pH 6.8).

[0238] The pH of the buffer was stabilized at 6.8±0.05 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).

[0239] Drug Release Test #2—Simulated Fasted State then Dissolution in Krebs Buffer at pH 7.4

[0240] 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.

[0241] To simulate the “fasted” state, tablets/capsules were first tested in 0.1 M HCl for 2 hours followed by 10 hours in Krebs buffer (pH 7.4).

[0242] Drug Release Test #3—Simulated Fasted State then Dissolution in Sørenson Buffer at pH 6.8

[0243] 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. The coated capsules/tablets were tested in Sørenson buffer at pH 6.8 (35.4 mM KH.sub.2PO.sub.4+35.6 mM NaH.sub.2PO.sub.4).

[0244] To simulate the “fasted” state, capsules/tablets were first tested in 0.1 M HCl for 2 hours using a disintegration apparatus followed by 18 hours in Sørenson buffer (pH 6.8).

[0245] Drug Release Test #4—Simulated Fasted State then Dissolution in Sørenson Buffer at pH 6.8 with 50 U/mL α-Amylase (Effect of α-Amylase Triggered Release).

[0246] 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. The coated capsules/tablets were tested in Sørenson buffer at pH 6.8 (35.4 mM KH.sub.2PO.sub.4+35.6 mM NaH.sub.2PO.sub.4) containing 50 U (units)/ml α-amylase derived from B. licheniformis.

[0247] To simulate the “fasted” state, capsules/tablets were first tested in 0.1 M HCl for 2 hours using a disintegration apparatus followed by 18 hours in Sørenson buffer (pH 6.8).

[0248] Results

[0249] Coated Capsules

[0250] The results presented in FIGS. 1 to 3 demonstrate that the coated capsules prepared according to the method of the present invention have improved dissolution properties when compared to the coated capsules of the Comparative Examples.

[0251] In gastric simulated fluid, all coated capsules tested were robust for at least 2 hours, independent of the coating composition. In addition, in aqueous solution at pH 6.8 (data not shown), no release of 5-ASA was observed from any of the capsules tested in the 10 hours that the capsules were exposed to simulated conditions of the small intestine (drug release test #1, Hank's buffer, pH 6.8). Notably, the preparation of the outer coating using an aqueous coating preparation resulted in coated capsules which were resistant to simulated small intestinal conditions, independent of the starch ratio (Example 1 and 2) and independent of the anti-tack agent used, i.e. GMS (Example 1 and Example 2) and talc (Comparative Example 2).

[0252] However, it should be noted that once the capsules were exposed to pH 7.4 (drug release test #2, FIG. 1), initial release of 5-ASA from coated capsules prepared according to the method of the present invention occurred earlier than for Comparative Example 1 capsules (which were prepared using a conventional “semi-organic” coating preparation). Notably, increasing the starch content of the coating did not significantly change the dissolution profile under these conditions (FIG. 1, compare Examples 1 and 2). Replacing GMS with talc as the anti-tack agent resulted in a delay in the initial release of 5-ASA (FIG. 1, compare Example 1 and Comparative Example 2).

[0253] Enzymatic Digestion

[0254] In aqueous solution at pH 6.8, enzymatic triggered release was observed for the coated capsules of Examples 1 and 2 (drug release tests #3 and #4, FIG. 2). Specifically, initial release of 5-ASA was observed when α-amylase was present in the buffer solution at pH 6.8. This is consistent with WO2013/164315A in which it was found 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. This result also demonstrates that the presence of colonic enzymes in the surrounding medium is necessary to achieve significant release of the active under these conditions, thereby efficiently preventing premature drug release.

[0255] Increasing the starch content of the coating did not significantly change the dissolution profile under these conditions.

[0256] In contrast, whilst enzymatic triggered release was observed for the capsules of Comparative Example 1 (which were prepared using a conventional “semi-organic” outer coating preparation), the release was triggered later than for the coated capsules of Examples 1 and 2 according to the present invention. Without being bound by any particular theory, the Inventors believe that this may be explained by a tighter film structure when the coating is prepared from a “semi-organic” coating preparation.

[0257] The Inventors have also observed that replacing GMS with talc as the anti-tack agent results in a higher variability in coating dissolution and eliminates the enzymatic triggered release from the capsules thereby compromising the drug release mechanism when the pH is below the pH at which the enteric polymer dissolves (FIG. 3, Comparative Example 2). Therefore, coatings comprising GMS as the anti-tack agent are superior to those containing talc as the anti-tack agent. In addition, since talc is a less effective anti-tack agent than GMS, it is necessary to use it in in higher quantities than GMS (50 wt % talc based on Eudragit® S 100 versus 10 wt % GMS). This means that the amount of excipients in the coating is significantly higher, which could potentially hinder amylase accessibility to the starch embedded in the film matrix.

[0258] Coated Tablets

[0259] The coatings were applied to the 1600 mg 5-ASA tablets coated with a HPMC isolation layer without any processing difficulties. The results presented in Table 1 and FIGS. 4 and 5 demonstrate that the coated tablets prepared according to the method of the present invention have improved gastric resistance as well as gastric resistance after mechanical impact (Example 3) and improved dissolution properties when compared to the coated tablets of the Comparative Examples.

[0260] In gastric simulated fluid (0.1 M HCl for 2 hours), the coated tablets of both Example 3 and Comparative Example 3 (both of which use GMS as the anti-tack agent) were robust for at least 2 hours. Thus, the use GMS as the anti-tack agent in the outer coating layer produces coated tablets which are gastric resistant, independent of whether an aqueous or a semi-organic coating preparation is used to prepare the outer layer.

[0261] Coated tablets of Comparative Example 5 to Comparative Example 9 (all of which use inorganic anti-tack agents) were not sufficiently robust in simulated gastric fluid leading to premature release of 5-ASA.

[0262] In addition, the coated tablets of Example 3 demonstrated 100% acid resistance even after mechanical impact. In contrast, the coated tablets of Comparative Examples 5 to 9 demonstrated very poor acid resistance after mechanical impact.

TABLE-US-00001 TABLE 1 Acid Anti-tack agent Outer layer Acid resistance Quantity coating resistance after mechanical Examples Type (%) preparation (%) impact (%) Example 3 GMS 5 Aqueous 100 100 Comparative GMS 5 Semi-organic 100 100 Example 3 Comparative Talc 50 Semi-organic 83.33 83.33 Example 4 Comparative Talc 50 Aqueous 83.33 33.33 Example 5 Comparative Talc 5 Aqueous 33.33 16.67 Example 6 Comparative Talc 5 Aqueous 33.33 0.00 Example 7 Comparative Aerosil ® 5 Aqueous 0 0 Example 8 300 Comparative Syloid 244 5 Aqueous 0 0 Example 9 FP

[0263] When the coated tablets were tested in vitro for drug release in pH 6.8 Hanks buffer to simulate the conditions of the proximal small intestine, after exposure to simulated gastric conditions (drug release test #1), higher resistance to dissolution was observed for the coated tablets of Example 3 comprising 5% GMS in the outer coating than for the tablets of Comparative Example 5 comprising talc in the outer coating (FIG. 4). In particular, release of 5-ASA from the tablets of Example 3 was well below 5% after 10 hours whereas the coated tablets of Comparative Example 5 showed around 30% release of 5-ASA after 10 hours.

[0264] Additionally, upon exposure to pH 7.4 Krebs buffer (drug release test #2) to simulate the conditions of the ileo-colonic region, rapid pH triggered release of 5-ASA was observed for the coated tablets of Example 3 containing 5% GMS (FIG. 5) in the outer coating, indicating that once the pH trigger of the enteric polymer is reached (pH above 7), rapid coating dissolution and drug release occurs. Replacing GMS with talc as the anti-tack agent (Comparative Example 5) resulted in a delay in the initial release of 5-ASA, slower dissolution of the coating and therefore slower release of 5-ASA (FIG. 5).

[0265] Thus, it can be seen that the combination of an organic anti-tack agent and an aqueous outer coating preparation produces delayed release formulations that are superior to comparative formulations.

[0266] 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.