COLONIC DRUG DELIVERY FORMULATION

Abstract

A delayed release drug formulation contains a core containing a drug and a delayed release coating for intestinal release, where release of the drug in the colon is not hindered by the absence of an alkaline middle layer between the core and the outer layer. The delayed release coating contains an outer coating, and optionally, an isolation layer. The outer coating contains a mixture of an enzymatically degradable polysaccharide which is degradable by colonic enzymes selected from the group of starch, amylose, amylopectin, chitosan, chondroitin sulfate, cyclodextrin, dextran, ptallulan, carrageenan, scleroglucan, curdulan, and levan and a film-forming enteric polymer having a pH threshold at about pH 6 or above. The enzymatically degradable polysaccharide and the enteric polymer are present in the outer coating in a ratio of more than 60:40.

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 comprising a drug and optionally, an isolation layer; and an outer coating for the core, the outer coating comprising a mixture of an enzymatically degradable polysaccharide which is susceptible to attack by colonic enzymes selected from the group consisting of starch, amylose, amylopectin, chitosan, chondroitin sulfate, cyclodextrin, dextran, pullulan, carrageenan, scleroglucan, chitin, curdulan, and. levan; and a film-forming enteric polymer having a pH threshold at about pH 6 or above, wherein the enzymatically degradable polysaccharide and the enteric polymer are present in the outer coating in a ratio of more than 60:40; and wherein the outer coating is in direct contact with the surface of the uncoated core or, if present, the isolation layer.

2. The delayed release drug formulation as claimed in claim 1, wherein the enzymatically degradable polysaccharide and the enteric polymer are present in the outer coating in a ratio of about 65:35 to about 90:10.

3. A The delayed release drug formulation as claimed in claim 1, wherein the enteric polymer is present in the outer coating in an amount from about 4 mg/cm.sup.2 to about 6 mg/cm.sup.2, based on the dry weight of the enteric polymer.

4. The delayed release drug formulation as claimed in claim 1, wherein the core comprises an isolation layer.

5. The delayed release drug formulation as claimed in claim 4, wherein the isolation layer comprises a film-forming non-ionic polymer.

6. The delayed release drug formulation as claimed in claim 5, wherein the non-ionic polymer is a non-ionic cellulose-based polymer.

7. 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 and, optionally, the isolation layer, and coating the core directly with an outer coating preparation comprising the enzymatically degradable polysaccharide which is susceptible to attack by colonic enzymes selected from the group consisting of starch, amylose, amylopectin, chitosan, chondroitin sulfate, cyclodextrin, dextran, carrageenan, scleroglucan, chitin, curdulan, and levan; and the film-forming enteric polymer having a pH threshold at about pH 6 or above in a solvent, to form an outer coated core, wherein the enzymatically degradable polysaccharide and the enteric polymer are present in the outer layer in a ratio of more than 60:40.

8. The method as claimed in claim 7, comprising initially coating the core with an isolation layer coating preparation comprising a film-forming non-ionic polymer in a solvent, to form an isolated core for coating with the outer coating preparation.

9. The method as claimed in claim 8, wherein the non-ionic polymer is a non-ionic cellulose-based polymer.

10. The method as claimed in claim 7, wherein the enzymatically degradable polysaccharide and the enteric polymer are present in the outer coating preparation in a ratio of about 65:35 to about 90;10.

11. The method as claimed in claim 7, wherein the core is coated with the outer coating preparation until the enteric polymer is coated on to the core in an amount from about 4 m.sup.2/cm.sup.2 to about 6 mg/cm.sup.2, based on the dry weight of the enteric polymer.

12. The delayed release drug formulation as claimed in claim 2, wherein the enzymatically degradable polysaccharide and the enteric polymer are present in the outer coating in a ratio of about 75:25.

13. The delayed release drug formulation as claimed in claim 3, wherein the enteric polymer is present in the outer coating in an amount of about 5 mg/cm', based on the dry weight of the enteric polymer.

14. The method as claimed in claim 10, wherein the enzymatically degradable polysaccharide and the enteric polymer are present in the outer coating preparation in a ratio of about 75:25.

15. The method as claimed in claim 11, wherein the core is coated with the outer coating preparation until the enteric polymer is coated on to the core in an amount of about 5 mg/cm.sup.2, based on the dry weight of the enteric polymer.

Description

EXAMPLES

[0135] A number of preferred embodiments of the present invention will now be described with reference to the drawings, in which:

[0136] FIG. 1 is a graph comparing drug release as a function of time from coated 5-ASA tablets according to Example 1, Example 2, Example 3 and Comparative Example 1, when exposed to 0.1M HCI for 2 hours and then Krebs buffer (pH 7.4) for 8 hours;

[0137] FIG. 2 is a graph comparing drug release as a function of time from coated 5-ASA tablets according to Example 2, when exposed to 0.1N HCI for 2 hours and then Sorensen's buffer (pH 6.8), (a) with a-amylase and (b) without a-amylase.

MATERIALS

[0138] 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, triethylcitrate (TEC), ethanol 95%, potassium phosphate monobasic (KH.sub.2PO.sub.4), sodium diphosphate dibasic dihydrate (Na.sub.2HPO.sub.4.circle-solid.2H.sub.2O), and sodium hydroxide were all purchased from Sigma-Aldrich, Buchs, Switzerland. Hydroxypropyl methylcellulose (HPMC, Pharmacoat® 603) was purchased from Shin-Etsu. Polyethylene glycol 6000 (PEG 6000) was purchased from Fluka. Glyceryl monostearate (GMS) was purchased from Cognis. Iron oxide red and iron oxide yellow (Sicovit) were purchased from BASF.

[0139] Tablet Cores

[0140] Tablet cores containing 5-ASA were provided. For Example 1, cores of 800 mg were used. For Example 2, cores of 1200 mg were used. For Example 3 and Comparative Example 1, cores of 1600 mg were used.

[0141] The tablet cores for Example 1-3 and Comparative Example 1 were coated with an isolation layer comprising HPMC and polyethylene glycol 6000 (PEG 6000).

[0142] Preparation of Coated Tablet Cores

Examples 1, 2 and 3

(HPMC Isolation Layer/Outer Coating of a 25:75 Mixture of Eudragit® S 100 and high amylose starch)

[0143] Isolation Layer

[0144] The isolation layer was applied from an aqueous mixture of HPMC and 20% PEG 6000 (based on dry polymer weight) in the following amounts:

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

[0145] The HPMC was dissolved in water under magnetic stirring and then the PEG 6000 was added to form an isolation layer coating preparation. The isolation layer coating preparation was sprayed onto the 5-ASA cores using a perforated pan coater 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 Nozzle diameter (mm) 1.0 Spray rate (g/min) 3 Spray pressure (bar) 0.7 Pattern pressure (bar) 1.0 Air flow (m.sup.3/h) 40 Inlet air temperature (° C.) 58-65 Outlet air temperature (° C.) 40-42

[0146] Outer Coating

[0147] The isolation layer coated tablet cores were coated with an outer coating formed of 25%

[0148] Eudragit® S 100 and 75% high amylose starch.

[0149] 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-00003 TABLE 3 Component mg/cm.sup.2 Starch 17.15 GMS 1.0 Polysorbate 80 0.4 Iron Oxide yellow 0.11 Iron Oxide red 0.66 Eudragit ® S 100 5 Triethyl citrate 4

[0150] 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.

[0151] The Eudragit® S 100 solution was prepared by dispersing Eudragit® S 100 in 96% ethanol under high speed stirring.

[0152] 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 25:75. 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.

[0153] 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.

[0154] The pigment suspension was formed by suspending red and yellow iron oxide pigments in 96% ethanol for 10 minutes under homogenization.

[0155] The final outer coating preparation was sprayed onto the isolation layer coated cores using a perforated pan coater until the coating amount of Eudragit® S 100 reached 5 mg polymer/cm.sup.2. The spray coating parameters were as follows:

TABLE-US-00004 TABLE 4 Drum speed (rpm) 12-14 Nozzle diameter (mm) 1.0 Spray rate (g/min) 4.0-5.1 Spray pressure (bar) 0.4 Pattern pressure (bar) 0.5 Air flow (m.sup.3/h) 40   Inlet air temperature (° C.) 57-60 Outlet air temperature (° C.) 40-41

[0156] COMPARATIVE EXAMPLE 1 (HPMC isolation layer/inner layer of partially neutralized Eudragit® S 100/outer coating of a 25:75 mixture of Eudragit® S 100 and high amylose starch)

[0157] Isolation Layer

[0158] The isolation layer was prepared and applied according to Examples 1, 2 and 3.

[0159] Inner Layer

[0160] The inner layer was applied from an aqueous preparation of methacrylic acid-methyl methacrylate copolymer, ratio 1:2 (Eudragit® S 100), where the pH was adjusted to pH 8. The composition of the inner layer also included 70% triethyl citrate (based on dry polymer weight), 10% GMS (based on dry polymer weight), 40% Polysorbate 80 (based on GMS weight), and 1% KH.sub.2PO.sub.4 buffer agent (based on dry polymer weight).

[0161] The inner layer was applied by spray coating in the in the following amounts (based on Eudragit® S 100 dry polymer weight):

TABLE-US-00005 TABLE 5 Component mg/cm.sup.2 Eudragit ® S 100 5 KH.sub.2PO.sub.4 0.05 Triethyl citrate 3.5 Glyceryl monostearate 0.5 Polysorbate 80 0.2 1M NaOH As required to reach pH 8

[0162] KH.sub.2PO.sub.4 was dissolved in distilled water, followed by dispersion of the Eudragit® S 100. Thereafter, triethyl citrate and a GMS emulsion (previously prepared with Polysorbate 80) were added and mixed for further 30 minutes. The pH was then adjusted using 1M NaOH until pH 8 was obtained.

[0163] The final inner layer coating preparation was sprayed onto the isolation layer coated cores using a perforated pan coater until the amount of Eudragit® S 100 reached 5 mg polymer/cm.sup.2. The spray coating parameters were as follows:

TABLE-US-00006 TABLE 6 Drum speed (rpm) 10-12 Nozzle diameter (mm) 1.0 Spray rate (g/min) 4 Spray pressure (bar) 0.6 Pattern pressure (bar) 0.8 Air flow (m.sup.3/h) 40 Inlet air temperature (° C.) 60-65 Outlet air temperature (° C.) 39-40

[0164] Outer Coating

[0165] The outer coating was applied from a mixture of an aqueous starch dispersion and an aqueous Eudragit® S 100 solution. The outer coating preparation was formed as in

[0166] Examples 1, 2 and 3 and sprayed onto the inner layer coated cores until the amount of Eudragit® S 100 reached 5 mg polymer/cm.sup.2. The spray coating conditions were as used in Examples 1, 2 and 3.

[0167] Drug release test #1—Simulated fasted state then dissolution in Krebs Buffer at pH 7.4

[0168] 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, tablets were first tested in 0.1 M HCI for 2 hours followed by 8 hours in Krebs buffer (pH 7.4).

[0169] Drug release test #2—Simulated fasted state then dissolution in Sorenson buffer at pH 6.8 (without α-amylase)

[0170] 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 tablets were tested in Sorenson buffer at pH 6.8 (35.4 mM KH.sub.2PO.sub.4+35.6 mM NaH2PO4).

[0171] To simulate the “fasted” state, tablets were first tested in 0.1 M HCI for 2 hours followed by 10 hours in Sorenson buffer at pH 6.8.

[0172] Drug release test #3—Simulated fasted state then dissolution in Sorenson buffer at pH 6.8 (effect of α-amylase)

[0173] 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 tablets were tested in Sorenson buffer at pH 6.8 (35.4 mM KH.sub.2PO.sub.4+35.6 mM NaH2PO4) containing 50 U (units)/ml a-amylase derived from B. licheniformis.

[0174] To simulate the “fasted” state, tablets were first tested in 0.1 M HCI for 2 hours followed by 10 hours in Sorenson buffer at pH 6.8.

[0175] Results

[0176] The results presented in FIG. 1 demonstrate that the formulations according to Examples 1, 2 and 3 showed similar dissolution properties to those according to Comparative Example 1, independent of the core size used in each example. Specifically, upon exposure to pH 7.4 all tablets tested demonstrated a similar drug release profile, with lag times in the region of 130-160 minutes (drug release test #1, FIG. 1). This demonstrates that the absence of an alkaline inner layer in Examples 1, 2 and 3 does not have a negative effect on the release characteristics of the tablets.

[0177] It is surprising that the absence of the inner layer in Examples 1, 2 and 3 does not have an impact on the drug release profile when the outer coating has a high amount of polysaccharide since the inner layer was developed to provide drug release acceleration above the pH threshold of the enteric polymer. This is observed with lower ratios of polysaccharide to enteric polymer.

[0178] Enzymatic Digestion

[0179] In aqueous solution at pH 6.8, enzymatic triggered release is observed for tablets of Example 2 and 3 (drug release tests #2 and #3). Specifically, an earlier initial release of 5-ASA is observed when a-amylase is present in the buffer solution at pH 6.8. Interestingly, drug release from the single layer coated tablets of Examples 2 and 3 is significantly faster than the double layer coated tablets of Comparative Example 1 at pH 6.8, both with and without a-amylase (Table 7, FIG. 2).

TABLE-US-00007 TABLE 7 Lagtime in Sorensen Lagtime in Sorensen buffer pH 6.8 with buffer pH 6.8 without amylase (min) amylase (min) Example 2 60 120 Example 3 90 120 Comparative >600 530 Example 1

[0180] 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.