COATABLE CORE FOR A MODIFIED RELEASE DRUG FORMULATION
20220016040 · 2022-01-20
Assignee
Inventors
- Thomas Buser (Nuglar, CH)
- Yalcin Cetinkaya-Coskun (Rheinfelden, CH)
- Roberto Carlos Bravo González (Rheinfelden, CH)
Cpc classification
A61K31/196
HUMAN NECESSITIES
International classification
A61K9/28
HUMAN NECESSITIES
A61K31/196
HUMAN NECESSITIES
Abstract
A method produces a coatable core for a modified release drug formulation for oral administration. The coatable core has a high drug load of at least 70 wt % based on the total weight of the coatable core. The method involves the steps of granulating a composition containing a drug and at least one binder to form granules; blending the granules with a pharmacologically acceptable disintegrant and optionally, one or more additional pharmacologically acceptable excipients, to form a compression blend, wherein the disintegrant is present in an amount from about 0.5 wt % to about 5 wt %, based on the total weight of the coatable core; and compressing the compression blend using an external lubrication compression method to form a coatable core.
Claims
1: A method of producing a coatable core for a modified release drug formulation for oral administration, the coatable core having a high drug load of at least 70 wt % based on a total weight of the coatable core, the method comprising: granulating a composition comprising a drug and at least one binder to form granules; blending the granules with a pharmacologically acceptable disintegrant and optionally, one or more additional pharmacologically acceptable excipients, to form a compression blend, wherein the disintegrant is present in an amount from about 0.5 wt % to about 5 wt %, based on the total weight of the coatable core; and compressing the compression blend using an external lubrication compression method, to form a coatable core.
2: The method as claimed in claim 1, wherein said composition further comprises at least one granulation liquid, and wherein said method further comprises drying said granules to form dry granules.
3: The method as claimed in claim 2, wherein said granulation liquid is water.
4: The method as claimed in claim 1, wherein the coatable core has a drug load of from about 85 wt % to about 95 wt %, based on the total weight of the coatable core.
5: The method as claimed in claim 1, wherein the at least one binder is present in an amount of about 3 wt % or less, based on the total weight of the coatable core.
6: The method as claimed in claim 1, wherein the disintegrant is present in an amount of about 0.5 wt % to about 3 wt %, based on the total weight of the coatable core.
7: The method as claimed in claim 1, wherein the one or more additional pharmacologically acceptable excipient is present and comprises a lubricant.
8: The method as claimed in claim 7, wherein the lubricant is present in an amount of about 0.5 wt % or less, based on the total weight of the coatable core.
9: The method as claimed in claim 1, wherein the drug is present in the core in an amount selected from the group consisting of from about 350 mg to about 1650 mg, from about 450 mg to about 1650 mg, from about 750 mg to about 1650 mg, from about 1150 mg to about 1650 mg, from about 1450 mg to about 1650 mg, and from about 1550 mg to about 1650 mg.
10: The method as claimed in claim 9, wherein the drug is present in the core in an amount selected from the group consisting of about 400 mg, about 800 mg, about 1200 mg, about 1500 mg, and about 1600 mg.
11: The method as claimed in claim 1, wherein the granules have a bulk density of at least about 540 g/l.
12: The method as claimed in claim 1, wherein the compression blend has a bulk density of at least about 600 g/l.
13: A coatable core for a modified release drug formulation for oral administration, the coatable core having a high drug load of at least 70 wt %, based on a total weight of the coatable core, the coatable core comprising: a drug in an amount of more than about 1200 mg; a pharmacologically acceptable lubricant in an amount of less than about 0.5 wt %, based on the total weight of the coatable core; a pharmacologically acceptable disintegrant in an amount of from about 0.5 wt % to about 5 wt %, based on the total weight of the coatable core; and optionally, one or more additional pharmacologically acceptable excipients.
14: The coatable core as claimed in claim 13, wherein the coatable core has a friability of more than 0% to about 0.5%.
15: The coatable core as claimed in claim 13, wherein the coatable core has a disintegration time of less than about 10 minutes.
16: The coatable core as claimed in claim 13, wherein the coatable core has a drug load of from about 85 wt % to about 95 wt %, based on the total weight of the coatable core.
17: The coatable core as claimed in claim 13, wherein the disintegrant is present in an amount of about 0.5 wt % to about 3 wt %, based on the total weight of the coatable core.
18: The coatable core as claimed in claim 13, wherein the lubricant is present in an amount of about 0.25 wt % or less, based on the total weight of the coatable core.
19: The coatable core as claimed in claim 13, wherein the drug is present in the core in an amount selected from the group consisting of from about 1250 mg to about 1650 mg, from about 1450 mg to about 1650 mg, from about 1550 mg to about 1650 mg, and about 1600 mg.
20: A delayed release drug formulation for oral administration to deliver a drug to the intestine of a subject, said formulation comprising: a coatable core having a high drug load of at least 70 wt %, based on a total weight of the coatable core, the coatable core comprising: a drug in an amount of more than about 1200 mg; a pharmacologically acceptable lubricant in an amount of less than about 0.5 wt %, based on the total weight of the coatable core; a pharmacologically acceptable disintegrant in an amount of from about 0.5 wt % to about 5 wt %, based on the total weight of the coatable core; and optionally, one or more additional pharmacologically acceptable excipients; a coating for the coatable core, the coating comprising an outer layer, and optionally, at least one layer between the coatable core and the outer layer selected from the group consisting of an isolation layer and an inner layer; wherein said outer layer comprises a film-forming enteric polymer having a pH threshold at about pH 5 or above, and optionally, an enzymatically degradable polymer that is degraded by colonic enzymes; wherein said inner layer comprises a polymeric material which is soluble in intestinal fluid or gastrointestinal fluid, said polymeric material being selected from the group consisting of a polycarboxylic acid polymer that is at least partially neutralised, and a first non-ionic polymer, provided that, where said polymeric material is the first non-ionic polymer, said inner layer comprises at least one additive selected from a buffer agent and a base; and wherein said isolation layer comprises a second non-ionic polymer which is soluble in intestinal fluid or gastrointestinal fluid.
21: The delayed release drug formulation as claimed in claim 20, wherein said outer layer comprises an enzymatically degradable polymer that is degraded by colonic enzymes.
22: The delayed release drug formulation as claimed in claim 21, wherein said outer layer comprises an enzymatically degradable polymer that is degraded by colonic enzymes; and wherein said outer layer is applied to the core using a coating preparation formed by combining said enzymatically degradable polymer in an aqueous medium with said film-forming enteric polymer in an organic medium.
23: The delayed release drug formulation as claimed in claim 20, wherein the coatable core has a friability of more than 0% to about 0.5%.
24: The delayed release drug formulation as claimed in claim 20, wherein the coatable core has a disintegration time of less than about 10 minutes.
25: The delayed release drug formulation as claimed in claim 20, wherein the coatable core has a drug load of from about 85 wt % to about 95 wt %, based on the total weight of the coatable core.
26: The delayed release drug formulation as claimed in claim 20, wherein the disintegrant is present in an amount of from about 0.5 wt % to about 3 wt %, based on the total weight of the coatable core.
27: The delayed release drug formulation as claimed in claim 20, wherein the lubricant is present in an amount of about 0.25 wt % or less.
28: The delayed release drug formulation as claimed in claim 20, wherein the drug is present in the core in an amount selected from the group consisting of from about 1250 mg to about 1650 mg, from about 1450 mg to about 1650 mg, from about 1550 mg to about 1650 mg, and about 1600 mg.
Description
EXAMPLES
[0167] A number of preferred embodiments of the present invention will now be described with reference to the drawings, in which:—
[0168]
[0169]
[0170]
[0171]
[0172]
MATERIALS
[0173] Eudragit® S 100 was purchased from Evonik GmbH, Darmstadt, Germany. Maize starch (Eurylon® 6 and Amylo N-400) was purchased from Roquette, Lestrem, France. Polysorbate 80 (Tween 80), butan-1-ol, triethylcitrate (TEC), ethanol 96%, 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. Hydroxypropyl methylcellulose (HPMC, Pharmacoat® 603) was purchased from Shin-Etsu. Glyceryl monostearate (GMS) was purchased from Cognis. Iron oxide red and iron oxide yellow (Sicovit) were purchased from BASF. Microcrystalline cellulose (Avicel® pH 102) was purchased from FMS Biopolymer. Sodium starch glycolate (Explotab®) was purchased from JRS Pharma. Colloidal silicon dioxide (Aerosil® 200) was purchased from Degussa.
[0174] Preparation of Tablet Cores
Example 1—Preparation of 1200 mg 5-ASA Tablet Cores Using External Lubrication (Laboratory Scale)
[0175] Oblong shaped 1200 mg cores were prepared according to the following method. The amount of each component per tablet core is summarised in Table 1.
[0176] Mesalazine was added to a high shear mixer granulator and an aqueous composition of hydroxypropyl methylcellulose (Pharmacoat® 603) was slowly added over a period of 2 minutes at a mixing speed of 650 rpm. After mixing for an additional minute at 650 rpm, the deposit was removed from the mixing vessel wall and top and the remaining mixture mixed for an additional 3 minutes at 650 rpm with a chopper blade velocity of 600 rpm. The wet granules were passed through an oscillating granulator (2 mm sieve) before drying in a fluid bed dryer at an inlet air temperature of about 50° C. and a product temperature of 38° C. The dry granules were sieved through an oscillating granulator (1 mm sieve).
[0177] The dry granules were blended with for 10 minutes at 20 rpm with microcrystalline cellulose (Avicel® pH 102) and sodium starch glycolate (Explotab®) in a cube blender. Tableting was performed using a single punch excenter tablet press. Magnesium stearate was applied to the punches and dies of the tablet press with a brush.
Comparative Examples 1A to 1C—Preparation of 1200 mg 5-ASA Tablet Cores Using Internal Lubrication (Laboratory Scale)
[0178] Oblong shaped 1200 mg cores were prepared according to the following method. The amount of each component per tablet core is summarised in Table 1.
TABLE-US-00001 TABLE 1 Comparative Comparative Comparative Example 1 Example 1A Example 1B Example 1C Component Amount per tablet core (mg) Mesalazine 1200 1200 1200 1200 Hypromellose 24 24 24 24 Microcrystalline 136 129 127 125 cellulose Sodium starch 40 40 40 40 glycolate Magnesium 0* 7 (0.5 9 (0.64 11 (0.79 Stearate wt %) wt %) wt %) *Tableting performed using external lubrication
[0179] Mesalazine was added to a high shear mixer granulator and an aqueous composition of hydroxypropyl methylcellulose (Pharmacoat® 603) was slowly added over a period of 2 minutes at a mixing speed of 650 rpm. After mixing for an additional minute at 650 rpm, the deposit was removed from the mixing vessel wall and top and the remaining mixture mixed for an additional 3 minutes at 650 rpm with a chopper blade velocity of 600 rpm. The wet granules were passed through an oscillating granulator (2 mm sieve) before drying in a fluid bed dryer at an inlet air temperature of about 50° C. and a product temperature of 38° C. The dry granules were sieved through an oscillating granulator (1 mm sieve).
[0180] The dry granules were blended with for 10 minutes at 20 rpm with microcrystalline cellulose (Avicel® pH 102) and sodium starch glycolate (Explotab®) in a cube blender. Magnesium stearate was added and the resulting mixture was mixed for 3 minutes. Tableting was performed using a single punch excenter tablet press.
Examples 2A to 2G—Preparation of 1600 mg 5-ASA Tablet Cores Using External Lubrication (Pilot Scale)
[0181] Oblong shaped 1600 mg cores were prepared according to the following method. The amount of each component per tablet core and per batch of 20,000 tablet cores is summarised in Table 2.
TABLE-US-00002 TABLE 2 Amount per Amount per batch of tablet 20,000 tablet Component core (mg) cores (g) Mesalazine 1600 32000 Hypromellose P 32 640 Microcrystalline cellulose 178 3560 Sodium starch glycolate 54 1080 Magnesium stearate 1 20 Colloidal silicon dioxide 2 40 TOTAL MASS 1867 37340
[0182] Mesalazine (8 kg) and an aqueous solution containing hydroxypropyl methylcellulose (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. The granulation was repeated for three further 8 kg batches of mesalazine.
[0183] The combined batches of 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 compression blend and passed through a 1 mm sieve before adding to the remaining compression blend. The mixture was blended for about 5 minutes at 28 rpm to form a final compression blend.
[0184] 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. The tableting machine was operated at a range of compression forces.
Comparative Examples 3A to 3H—Preparation of 1600 mg 5-ASA Tablet Cores Using Internal Lubrication (Pilot Scale)
[0185] Oblong shaped 1600 mg cores were prepared according to the following method. The amount of each component per tablet core and per batch of 20,000 tablet cores is summarised in Table 3.
TABLE-US-00003 TABLE 3 Amount per Amount per batch of tablet 20,000 tablet Component core (mg) cores (g) Mesalazine 1600 32000 Hypromellose 32 640 Microcrystalline cellulose 167 3340 Sodium starch glycolate 54 1080 Magnesium stearate 12 240 Colloidal silicon dioxide 2 40 TOTAL MASS 1867 37340
[0186] Mesalazine (8 kg) and an aqueous solution of hydroxypropyl methylcellulose (160 g, Pharmacoat® 603) were granulated in a high shear 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. The granulation was repeated for three further 8 kg batches of mesalazine.
[0187] The combined batches of 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 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.
[0188] Compression of the final compression blend was performed using a Fette P1200 tableting machine at a compression speed of 20,000 tablets/hour. The tableting machine was operated at a range of compression forces between 27 and 40 kN.
Examples 3 and 4—Scale Up of Method for Producing 1600 mg 5-ASA Tablet Cores Using External Lubrication
[0189] Oblong shaped 1600 mg cores were prepared according to the following method. The amount of each component per tablet core is summarised in Table 4.
TABLE-US-00004 TABLE 4 Example 3 Example 4 Amount per Amount per Amount per 10,000 Amount per 80,000 tablet tablet tablet tablet Component core (mg) cores (g) core (mg) cores (g) Mesalazine 1600 16000 1600 128000 Hypromellose 32 320 32 2560 Micro- 178 1780 178 14240 crystalline cellulose Sodium starch 54 540 54 4320 glycolate Magnesium 1 10 1 80 stearate Colloidal 2 20 2 160 silicon dioxide TOTAL MASS 1867 18670 1867 149360
[0190] A mixture of mesalazine (8 kg) and an aqueous solution of hydroxypropyl methylcellulose (160 g, Pharmacoat® 603) was granulated in a high shear 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 80° C. and product temperature of about 42° C. for about 45 minutes. The dry granules were sieved using a 1.6 mm grater (Comil). Depending on the total batch size, multiple granulation batches were performed and combined before final blending.
[0191] The combined batches of dry granules were blended with microcrystalline cellulose (Avicel® pH 102) and sodium starch glycolate (Explotab®) in an 80 L bin blender at 28 rpm. Magnesium stearate and colloidal silicon dioxide (Aerosil® 200) were both individually pre-blended with about 500 g 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
[0192] Various properties were determined for the granules and the compression blend as summarised in Table 5 below.
TABLE-US-00005 TABLE 5 Example 3 Example 4 Granule LOD (%) 0.33 0.26 Flow (s) 4.2 8 Bulk density (g/l) 610 550 Tapped density (g/l) 775 660 Angle of repose (°) 36.0 28.9 Compression blend LOD (%) 1.20 0.97 Flow (s) 4.0 4.0 Bulk density (g/l) 650 625 Tapped density (g/l) 787 750 Angle of repose (°) 32 26
[0193] Compression of the final compression blend was performed using a Fette P1200 tableting machine combined with an external lubrication system (PKB) at a compression speed of 20,000 tablets/hour. Magnesium stearate was sprayed onto the punches and dies of the tableting machine at a dose of 400 g/h.
[0194] Drug Release Test #1—Dissolution in 0.05 M Phosphate Buffer at pH 7.2
[0195] In vitro dissolution studies were performed on a USP type II apparatus using a 0.05 M phosphate buffer at pH 7.2. A paddle rotation speed of 50 rpm was used for the dissolution period (30 minutes) following by a rotation speed 100 rpm for further 30 minutes to confirm recovery of drug content in the dosage form.
[0196] Results
[0197] The physical properties of the 1200 mg tablet cores produced in Example 1 and Comparative Examples 1A to 1C are summarised in Table 6 below. The tablet cores according to Example 1 demonstrate superior hardness and friability when compared with Comparative Examples 1A to 1C. This data demonstrates that the use of external lubrication produces tablet cores having superior physical properties to those produced using only an internal lubricant when produced on a laboratory scale.
TABLE-US-00006 TABLE 6 Comparative Comparative Comparative Example 1 Example 1A Example 1B Example 1C Average tablet 6.92 6.84 6.92 6.88 core thickness, (mm) Average tablet 307.9 258.6 260.6 244.4 core hardness, (N) Hardness 293-325 248-282 252-270 210-256 range (N) Tablet 0.042 0.10 0.064 0.178 friability (%) Disintegration 3.35-4.42 7.09-7.49 6.39-7.51 7.26-7.54 time, range (min) Drug release in phosphate buffer @ pH 7.2 (%) 5 minutes 43 20 29 23 10 minutes 57 33 48 37 15 minutes 67 42 61 50 20 minutes 73 51 71 59 25 minutes 78 55 75 64 30 minutes 79 59 79 69
[0198] The drug release profiles for the tablets cores of Example 1 and Comparative Examples 1A to 1C after exposure to phosphate buffer at 0.05 M (drug release test #1) are also summarised in Table 6. The data clearly demonstrate that tablet cores according to the present invention produced using external lubrication (Example 1) have a significantly shorter disintegration time and a faster dissolution rate when compared to those prepared using internal lubrication (Comparative Examples 1A to 1C).
[0199] Pilot plant scale production of 1600 mg tablet cores using external lubrication was also possible across a wide range of compression forces (Table 7). The low variability of the tablet mass with increasing compression force indicates that the compression blend has acceptable flow properties. No capping is observed for any of the tablets tested. A significant reduction in ejection force is observed when both the dies and the punches of the tableting machine are lubricated (Example 2G).
TABLE-US-00007 TABLE 7 Example No. 2A 2B 2C 2D 2E 2F 2G Compression conditions Compression Force (kN) 15 21.2 25.8 30.8 35.7 39.7 29.3 Ejection Force (N) 88** 120** 148** 196** 388** 498** 145*** Testing on the Tablet Core Hardness (N) 155 187 218 254 274 290 258 Friability (%) 0.54 0.26 0.12 0.063 0.055 0.03 0.058 Tablet thickness (mm) 9.16 8.92 8.77 8.67 8.59 8.56 8.65 Tablet mass (mg) 1865 1864 1867 1866 1865 1870 1862 **only punches were lubricated ***dies and punches were lubricated
[0200] A correlation between increasing compression force and tablet hardness is observed (
[0201] By comparison, tablet cores compressed using only internal lubrication have a tendency for capping during friability testing (Table 8, Comparative Examples 3B and 3D-3F). Sticking of the tablets to the punches of the tableting machine is also observed and the high ejection force values indicate that the level of lubricant in the compression blend is insufficient (Table 8). However, as demonstrated in Comparative Examples 1A to 1B, a further increase in the amount of internal lubricant has a negative effect on the tablet quality.
TABLE-US-00008 TABLE 8 Comparative Example No. 3A 3B 3C 3D 3E 3F 3G 3H Compression conditions Compression Force (kN) 26.9 33.4 35.5 35.9 39.3 39.6 33.4 33.6 Ejection Force (N) 487 530 537 566 593 576 n.p.** 520 Testing on the tablet core Hardness (N) 226 258 251 255 236 273 252 257 Friability (%) 0.54 0.127.sup.+ 0.22 0.37.sup.+ 0.06.sup.+ 0.083.sup.+ 0.21 0.174 Disintegration time (min.) 5.3 7.75 10.75 10 9.22 10.83 7.25 7.63 Tablet thickness (mm) 8.77 8.65 8.59 8.63 8.55 8.55 8.63 8.61 Tablet mass (mg) 1872 1869 1868 1874 1870 1869 1868 1864 .sup.+capping occurred during friability test **n.p. = not performed
[0202] Moreover, with the use of only internal lubrication, compression of the compression blends is only possible across a narrow compression force range and no correlation is observed between compression force and hardness or between hardness and friability (see
[0203] Scale up of the external lubrication process for the preparation of 1600 mg tablet cores was successful, and delivered tablet cores having acceptable strength as exemplified by low friability and high hardness (Table 9). The tablet cores according to the present invention also demonstrate rapid disintegration time.
TABLE-US-00009 TABLE 9 Example 3 Example 4 Mass (mg) 1864-1872 1863-1868 Hardness (N) 262-272 263-269 Friability (%) 0.1 0.14-0.23 Disintegration time (min) 4.5-5 4.9-5.3 Thickness (mm) 8.7 8.65-8.66 Yield (kg) 14.374 142.4 Total Number of tablets 7709 76325
[0204] Preparation of Coated Tablet Cores
Examples 5 and 6—Coating of 1200 mg and 1600 mg 5-ASA Tablet Cores
[0205] Tablet cores containing 1200 mg and 1600 mg mesalazine (5-ASA) were provided.
[0206] The tablet cores of Example 5 (1200 mg 5-ASA) were coated with an isolation layer of hypromellose (hydroxypropyl methylcellulose, HPMC) at 3 mg/cm.sup.2 with 20% macrogol 6000 and an outer layer of 70% methacrylic acid-methyl methacrylate copolymer, ratio 1:2 (Eudragit® S 100) and 30% high amylose starch at 5 mg/cm.sup.2.
[0207] The tablet cores of Example 6 (1600 mg 5-ASA) were coated with the same isolation layer as for Example 5, an inner layer of methacrylic acid-methyl methacrylate copolymer, ratio 1:2 (Eudragit® S 100) and 1% potassium dihydrogen phosphate neutralized to pH 8 at 5 mg/cm.sup.2, and an outer layer of methacrylic acid-methyl methacrylate copolymer, ratio 1:2 (Eudragit® S 100) at 5 mg/cm.sup.2.
[0208] Isolation Layer
[0209] The isolation layer was applied by spray coating in the following amounts:
TABLE-US-00010 TABLE 10 Component mg/cm.sup.2 HPMC 3 Macrogol 6000 0.6
[0210] The isolation layer coating preparation was sprayed on to the tablets cores using a pan coater until the coating amount of HPMC reached 3 mg/cm.sup.2 to produce intermediate (isolation layer) coated cores.
[0211] The spray coating parameters were as follows:
TABLE-US-00011 TABLE 11 Pan rotation speed (rpm) 10 Nozzle diameter (mm) 1.0 Number of spray guns 1 Spray rate (g/min) 3.2 Angle of spray gun on tablet bed (°) 90 Atomisation air pressure (bar) 0.4 Pattern air pressure (bar) 0.5 Air flow (m.sup.3/h) 30 Outlet air temperature (° C.) 41.3-43.5
[0212] Inner Layer (of Example 6)
[0213] The tablet cores coated with an isolation layer were then coated with an inner layer coating of partially neutralised methacrylic acid-methyl methacrylate copolymer, ratio 1:2 (Eudragit® S 100), and 1% KH.sub.2PO.sub.4 buffer agent.
[0214] The inner layer was applied by spray coating in the in the following amounts:
TABLE-US-00012 TABLE 12 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
[0215] The pH was adjusted using 1M NaOH until pH 8 was obtained. KH.sub.2PO.sub.4 was dissolved in distilled water, followed by dispersion of the partially neutralized Eudragit® S 100.
[0216] The inner layer coating preparation was sprayed on to the isolation layer coated cores using a pan coater until the coating amount of Eudragit® S 100 reached 5 mg/cm.sup.2, to produce intermediate (inner layer) coated cores.
[0217] The spray coating parameters were as follows:
TABLE-US-00013 TABLE 13 Pan rotation speed (rpm) 10-12 Nozzle diameter (mm) 1.0 Number of spray guns 1 Spray rate (g/min) 3.25 Angle of spray gun on tablet bed (°) 90 Atomisation air pressure (bar) 0.4 Pattern air pressure (bar) 0.5 Air flow (m.sup.3/h) 40 Outlet air temperature (° C.) 40.3-42.7
[0218] Outer Layer (of Example 5)
[0219] The isolation layer coated tablet cores were coated with an outer layer coating formed of 70% methacrylic acid-methyl methacrylate copolymer, 1:2 (Eudragit® S 100) and 30% high amylose starch.
[0220] 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:
TABLE-US-00014 TABLE 14 Example 5 Component mg/cm.sup.2 mg/tab Starch dispersion Eurylon ® 6 3.18 28.7 Eudragit ® S 100 suspension Eudragit ®S 100 6.5 37.31 Triethyl citrate 1.86 10.66 Glyceryl monostearate 0.46 2.67 Polysorbate 80 0.19 1.07 Iron oxide red 0.86 4.92 Iron oxide yellow 0.15 0.85
[0221] The aqueous starch dispersion was prepared by dispersing high amylose maize starch, (Eurylon® 6) 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.
[0222] The Eudragit® S 100 solution was prepared by dispersing Eudragit® S 100 in 96% ethanol under high speed stirring. The final solution contained approximately 6% polymer solids.
[0223] The starch dispersion was added dropwise to the Eudragit® S 100 solution under stirring to obtain a ratio of Eudragit® S 100:starch of 70:30. The mixture was stirred for 1 hour and 40% TEC (based on Eudragit® S 100 polymer weight) and 10% GMS (based on Eudragit® S 100 polymer weight) were added and mixed for further 30 minutes. A suspension of 13.16% iron oxide red (based on Eudragit® S 100 polymer weight) and 2.23% iron oxide yellow (based on Eudragit® S 100 polymer weight) was added and the mixture was stirred for a further 10 minutes.
[0224] The GMS was added in the form of an emulsion 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.
[0225] The pigment suspension was formed by suspending red and yellow iron oxide pigments in 96% ethanol for 10 minutes under homogenization.
[0226] The final outer layer coating preparation was sprayed on to the isolation layer coated tablet cores until the coating amount of Eudragit® S 100 reached 5 mg/cm.sup.2.
[0227] Outer Layer (Example 6)
[0228] The tablet cores coated with an isolation layer and an inner layer were coated with an outer layer coating formed of methacrylic acid-methyl methacrylate copolymer, 1:2 (Eudragit® S 100).
[0229] The outer layer coating was applied from an ethanolic Eudragit® S 100 solution in the following amounts:
TABLE-US-00015 TABLE 15 Example 6 Component mg/cm.sup.2 mg/tab Eudragit ® S 100 5 34.55 Triethyl citrate 1 13.82 Glyceryl monostearate 0.25 3.46 Polysorbate 80 0.10 1.38 Iron oxide red 0.66 4.55 Iron oxide yellow 0.11 0.79
[0230] The outer coating was prepared by dispersing Eudragit® S 100 in 96% ethanol under high speed stirring following by the addition of TEC and a GMS emulsion (prepared as in Example 5). Lastly, a suspension of iron oxide red and iron oxide yellow (prepared as in Example 5) was added to the mixture and the mixture stirred for further 10 minutes.
[0231] The final outer layer coating preparation was sprayed on to the isolation layer and inner layer coated tablet cores until the coating amount of Eudragit® S 100 reached 5 mg/cm.sup.2.
[0232] The spray coating parameters for applying the outer layer coatings were as follows:
TABLE-US-00016 TABLE 16 Example 5 Example 6 Pan rotation speed (rpm) 16 12-14 Nozzle diameter (mm) 1.0 1 Number of spray guns 1 1 Angle of spray gun on tablet bed (°) 90 90 Atomisation air pressure (bar) 0.4 0.4 Pattern air pressure (bar) 0.5 0.5 Air flow (m.sup.3/h) 40 40 Outlet air temperature (° C.) 40-41 33.1-35.8
[0233] Drug Release Test #2—Simulated Fasted State then Dissolution in Hanks Buffer at pH 6.8
[0234] 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 HCl for 2 hours followed 10 hours in Hanks buffer (pH 6.8).
[0235] 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.
[0236] Drug Release Test #3—Simulated Fasted State then Dissolution in Krebs Buffer at pH 7.4
[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.
[0238] To simulate the “fasted” state, tablets were first tested in 0.1 M HCl for 2 hours followed by 10 hours in Krebs buffer (pH 7.4).
[0239] Results
[0240] It was possible to coat the 1200 mg and 1600 mg tablet cores of the present invention with known delayed release coatings. The results demonstrate that the coated tablets prepared according to the present invention were resistant to simulated gastric fluid and show rapid drug release upon exposure to simulated conditions of the ileo-colonic region.
[0241] The 1200 mg coated tablets of Examples 5 and the 1600 mg coated tablets of Example 6 were tested in vitro for drug release in pH 6.8 Hanks buffer after exposure to simulated gastric conditions. In both cases the coated tablets were gastric resistant and drug release was below 5% when exposed to simulated conditions of the proximal small intestine (Hanks buffer at pH 6.8). This demonstrates robustness of the coated tablets during transit through the small intestine.
[0242] However, it should be noted that, upon exposure to pH 7.4 (drug release test #3) to simulate the conditions in the ileo-colonic region, rapid drug release was observed for both the 1200 mg and 1600 mg coated tablets of the present invention (
[0243] 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.