Delayed release pharmaceutical formulations

Abstract

Delivery of a drug is controlled to impart a delay before release after administration by formulating the drug with a disruption agent to provide a core, and coating the core with a regulatory membrane comprising a water-soluble gel-forming polymer and a water-insoluble film-forming polymer.

Claims

1. A delayed release pharmaceutical composition which provides a lag in delivery of a drug following, administration, the composition comprising a multi-unit dosage of multiparticles, each unit of the composition comprising (a) a core which includes a drug and a disruption agent and (b) a regulatory membrane coating on the core formed from a mixture of a water-soluble gel-forming polymer and a water-insoluble film-forming polymer; wherein said water-soluble gel-forming polymer is a high viscosity grade hydroxyalkylcellulose or methyl cellulose, said water-insoluble film-forming polymer is an alkyl cellulose, and wherein there is a coating weight gain of said regulatory membrane coating of between 20% and 100%, and wherein said composition releases less than 10% of the drug in the lag period of up to 1 to 6 hours, and after said lag period, releases more than 90% of the drug over a release period of not greater than 6 hours.

2. The composition according to claim 1, wherein the disruption agent is selected from polymers which expand on hydration and compounds which generate an internal osmotic pressure within the membrane.

3. The composition according to claim 2, wherein the disruption agent is one or more of a low substituted hydroxypropylcellulose, sodium starch glycolate, sodium carboxymethylcellulose, croscarmellose sodium or carbomer.

4. The composition according to claim 2, wherein the disruption agent is one or more electrolytes, sugars or polyhydric alcohols.

5. The composition according to claim 4, wherein the core includes one or more excipients.

6. The composition according to claim 5, wherein the core is a spheroid and includes a spheronisation aid.

7. The composition according to claim 6, wherein the spheronisation aid is microcrystalline cellulose.

8. The composition according to claim 6, wherein the spheroid further includes a binder.

9. The composition according to claim 8, wherein the binder is a hydroxypropylmethylcellulose.

10. The composition according to claim 1, wherein the amount of drug is 0.1 to 500 mg.

11. The composition according to claim 1, wherein the water-soluble gel-forming polymer is a high viscosity grade hydroxypropylmethylcellulose.

12. The composition according to claim 1, wherein the alkylcellulose is ethyl cellulose.

13. The composition according to claim 1, wherein the lag period is up to 1 to 2 hours.

14. The composition according to claim 1, wherein the drug is selected from the group consisting of hypnotics, anti-inflammatories, steroids, anthelmintics, antifungals, anti-cancers, proteins and peptides, semicarbazones, H2-blockers, asthmatic drugs, beta-blockers, calcium channel blockers, NSAIDs, and anti-emetic drugs.

15. A method for preparing the composition according to claim 1, which comprises coating the core containing the drug and the disruption agent with the mixture of the water-soluble gel-forming polymer and the water-insoluble film forming polymer.

16. A method for controlling delivery of a drug to impart a delay before release after administration, which comprises formulating a delayed release pharmaceutical composition which provides a lag in the delivery of a drug following administration, the composition comprising a multi-unit dosage form of multiparticles, each unit of the composition comprising (a) a core which comprises the drug and a disruption agent, and (b) a regulatory membrane coating on the core comprising a water-soluble gel-forming polymer and a water-soluble film-forming polymer, wherein said water-soluble gel-forming polymer is a high viscosity grade hydroxyalkylcellulose or methyl cellulose, said water insoluble film-forming polymer is an alkyl cellulose, and wherein there is a coating weight gain of said regulatory membrane coating of between 20% and 100%, and wherein said composition releases less than 10% of the drug in the lag period of up to 1 to 6 hours, and after said lag period, releases more than 90% of the drug over a release period of not greater than 6 hours.

17. The composition according to claim 1, wherein less than 5% of the drug is released in the lag period of up to 1 to 6 hours.

18. The composition according to claim 1, which releases less than 2% of the drug in the lag period of up to 1 to 6 hours.

19. The composition according to claim 1, wherein the ratio of water-insoluble film-forming polymer to water-soluble gel-forming polymer within the regulatory membrane coating is 10:90 to 90:10.

20. The composition according to claim 1, wherein the ratio of water-insoluble film-forming polymer to water-soluble gel-forming polymer within the regulatory membrane coating is 20:80 to 80:20.

21. The composition according to claim 1, wherein the drug release from the composition is pH independent.

22. The composition according to claim 11, wherein the high viscosity grade hydroxypropylmethylcellulose is hydroxypropylmethylcellulose K100M or hydroxypropylmethylcellulose K4M.

23. The composition according to claim 12, wherein the water-soluble gel-forming polymer is hydroxypropylmethylcellulose K100M or hydroxypropylmethylcellulose K4M.

Description

DESCRIPTION OF THE DRAWINGS

(1) The examples refer to the accompanying drawings, in which

(2) FIG. 1:i and 1:ii comprise a set of photomicrographs following the hydration of a coated product referred to in Example 4;

(3) FIG. 2 shows dissolution data for products prepared in Example 1;

(4) FIGS. 3 and 4 show dissolution data for products prepared in Example 2

(5) FIG. 5 shows dissolution data for products prepared in Example 3;

(6) FIG. 6 shows dissolution data for products prepared in Example 4;

(7) FIG. 7 shows dissolution data for products prepared in Example 1.

(8) FIGS. 8 to 11 show dissolution data for products prepared in Example 7.

EXAMPLE 1

(9) TABLE-US-00001 a. Expansion Spheroid cores, batch code F667/101: (table 1) Cores were made by dry blending and wet granulation of the following ingredients. Item Role Percentage low substituted expanding agent 35.0 hydroxypropylcellulose LH-20 diltiazem hydrochloride drug 10.0 HPMC high viscosity binder 0.5 grade Avicel PH101 spheronization aid 54.5

(10) Purified water was used as granulating fluid (1.69 kg/kg solids)

(11) The dry blending and wet granulation was carried out in Collette Gral 10 high shear mixer for 5 and 9 minutes respectively. The amount of granulating fluid used was 1.69 kg per kg solid and was added gradually over 3 minutes.

(12) The wet mass was extruded using an Alexanderwerk extruder provided with 1.3 mm diameter perforated cylinder. The extrudates were then spheronised into 1.3 mm mean diameter size spheroids using a Caleva Model 15G spheroniser run at a loading of 0.4 kg and at 800 rpm for 6 minutes.

(13) Drying was carried out in Aeromatic Strea 1 at an inlet temperature of 40 C. for the first 30 minutes of drying to minimize crust formation and to ensure full contraction of the,cores and continued at 60 C. for 105 minutes to a constant weight.

(14) TABLE-US-00002 b. Delay release coating of the Spheroid cores: (table 2). Ingredient Role Percentage diltiazem cores core F667/101 ethyl cellulose N10 film forming water 4.0 insoluble polymer HPMC K100M gel forming water soluble 3.3 polymer triethyl citrate plasticiser 0.2 methylene chloride solvent 37.1 methanol B.P. 1973 solvent 55.4

(15) In the coating solution, a 55:45 ratio of film forming (water insoluble polymer) ethyl cellulose (EC): gel forming (water soluble polymer) hydroxypropylmethylcellulose (HPMC) was used. Triethyl citrate (plasticizer) and methanol/methylene chloride (solvents) were used according to the formulation in table 2

(16) Coating was carried out using an Aeromatic Strea 1 fluid bed spray coater. The air inlet temperature was 52-56 C. and the outlet temperature was 30-34 C. The atomizing air pressure was 1.5-1.6 bar and the spray rate was 6-11 g/min. The product load was 0.350 kg.

(17) Four different levels of coating were added to the expansion core batch F667/101. F669/06, F671/17, F671/47A and F671/47B had coatings of 3.0, 4.6, 5.5, and 6.6 kg coating solution/1.0 kg spheroid beads, respectively.

(18) The dissolution rate and profile are shown in FIG. 2.

(19) The procedure to prepare batch F671/47A was repeated to give a batch F671/98C. The procedure to prepare batch F671/47B was repeated to give batch F671/98D. The dissolution rate and profile for these comparative batches is shown in FIG. 7.

EXAMPLE 2

(20) TABLE-US-00003 a. Expansion Spheroid cores, batch code F666/57 (table 3) Item Role Percentage Explotab expanding agent 20.0 diltiazem hydrochloride Model drug 20.0 Avicel PH101 Spheronization aid 60.0

(21) Purified water used as granulating fluid 0.75 kg per kg solid

(22) An 800 g batch size was made according to table 3 above. All manufacturing processes were as that of example 1.

(23) The spheroid cores made of the 1.00 mm diameter extrudates were at their maximum expansion stage before drying. On drying contraction took place producing spheroid cores of less than 1.00 mm mean size. The dried spheroid cores were divided according to their particle size distribution into two lots. Larger spheroid cores<1.8.fwdarw.0.9 mm were selected for further coating. Fine spheroid cores<0.9 mm of batch F666/57 were blended with 0.5% magnesium stearate and talc. The blended spheroid cores were then compressed into 5.0 mm normal concave tablets

(24) TABLE-US-00004 b. Delay release coating of the compressed spheroid cores (table 4) Ingredient Role Percentage compressed diltiazem core F666/74 cores ethyl cellulose n10 film forming water 4.8 insoluble polymer HPMC K100M gel forming water soluble 3.2 polymer triethyl citrate plasticiser 0.2 methylene chloride solvent 30.0 methanol B.P. 1973 solvent 61.8

(25) Fine spheroid cores<0.9 mm of batch F666/57 were blended with 0.5% magnesium stearate and talc. The blended spheroid cores were then compressed into 5.0 mm normal concave tablets (F666/74). The coating solution, ethyl cellulose:HPMC (60:40) was used to coat the compressed spheroid cores at three different levels, 1.0, 2.0 and 3.0 kg/1.0 kg tablets, batch codes F666/77A, F666/77/B, and F666/77C respectively.

(26) TABLE-US-00005 c. Delay release coating of spheroid cores (table 5) Ingredient Role Percentage diltiazem cores core F666/57 ethyl cellulose n10 film forming water 4.8 insoluble polymer HPMC K100M gel forming water soluble 3.2 polymer triethyl citrate plasticiser 0.2 methylene chloride solvent 30.0 methanol B.P. 1973 solvent 61.8

(27) The larger spheroid cores of F666/57 were coated with the same coating for instance 60:40 (EC:HPMC). Two levels of coat 4.0 kg and 6.0 kg coating solution/1.0 kg spheroid cores was applied to F666/98 and F666/106 respectively.

(28) The dissolution results (FIGS. 3 and 4) clearly indicate the significant effect of the surface area/volume on the level of coat and hence on the release rate and profile.

EXAMPLE 3

(29) Example 3 comprises immediate release osmotic spheroid cores containing diltiazem chloride as drug and a modified release coat.

(30) TABLE-US-00006 a. Osmotic spheroid cores F666118 (table 6) Ingredient Role Percentage diltiazem HCl model drug 20.0 Avicel PH101 spheronization aid 65.0 NaCl osmotic agent 15.0

(31) Purified water 0.68 kg/kg solid was used for granulating

(32) A batch of spheroid cores 800 g was made with 15% osmotic agent sodium chloride, 20% drug load and 65% spheronization aid microcrystalline cellulose (F666/18). The processing was as for example 1.

(33) The dry blending and wet granulation was carried out in Collette Grall 10 high shear mixer for 5 and 6 minutes respectively. Moulding (extrusion) was performed using the Alexanderwerk extruder provided with 1.0 mm diameter perforated cylinder. The extrudates were then spheronised into 1.0 mm mean size spheroids.

(34) Drying was carried out in Aeromatic Strea 1 at an inlet temperature of 60 C. for 105 minutes to a constant weight.

(35) TABLE-US-00007 b. Delay release coating (table 7) Ingredient Role Percentage diltiazem cores core F666/18 ethyl cellulose n10 film forming water 4.8 insoluble polymer HPMC K100M gel forming water soluble 3.2 polymer triethyl citrate plasticiser 0.2 methylene chloride solvent 30.0 methanol B.P. 1973 solvent 61.8

(36) In the coating solution, 60:40 film-forming water-insoluble polymer ethyl cellulose (EC): the water-soluble gel-forming polymer hydroxypropylmethylcellulose (HPMC) was used. Triethyl citrate (plasticiser) and methanol/methylene chloride were used according to the formulation in table 7 above.

(37) A total of 1.4 and 4.2 kg coating solution/1.0 kg spheroid cores were applied for F666/46 and F666/65 respectively.

(38) While almost all drug released in the first hour of the low coating batch (F666/46), the two hours time delay followed by a rapid release required by the invention was seen at a high coating level batch (F666/65) (FIG. 5).

EXAMPLE 4

(39) TABLE-US-00008 a. Expansion spheroid cores: (table 8) F667/43 Ingredient Role Percentage diltiazem HCl model drug 10.0 Avicel PH101 spheronization aid 59.5 LH-20 osmotic agent 30.0 HPMC K100M binder 0.5

(40) One batch of spheroid cores 800 g batch size (F667/49) was made of 30% w/w low substituted hydroxypropylcellulose (LH-20), 10% w/w diltiazem hydrochloride, 0.5% high viscosity grade HPMC and 59.5% Avicel PH101. The manufactured batch was divided into two equal sub-batches for coating with two different coating solutions. Each sub-batch was coated separately under same condition applying two different coating solutions

(41) TABLE-US-00009 b. Delay release coating of the spheroid cores (60:40): (table 9). Ingredient Role Percentage diltiazem cores core F666/43 ethyl cellulose n10 film forming water 4.8 insoluble polymer HPMC K100M gel forming water soluble 3.2 polymer triethyl citrate plasticiser 0.2 methylene chloride solvent 30.0 methanol B.P. 1973 solvent 61.8

(42) The first batch (F667/50) was coated with the coating solution shown above. The coating solution was made of 60:40 film-forming water-insoluble polymer (ethyl cellulose): gel-forming polymer (high viscosity grade HPMC). A total of 4.0 kg coating solution/1.0 kg spheroid cores was added.

(43) TABLE-US-00010 c. Delay release coating of the spheroid cores (50:50): (table 10). Ingredient Role Percentage diltiazem cores core F666/18 ethyl cellulose n10 film forming water 4.0 insoluble polymer HPMC K100M gel forming water soluble 4.0 polymer triethyl citrate plasticiser 0.2 methylene chloride solvent 30.0 methanol B.P. 1973 solvent 61.8

(44) The second batch was coated under identical condition with a lower ratio of the film-forming polymer, 50:50 ratio of film-forming water-insoluble polymer (ethyl cellulose): gel-forming polymer (high viscosity grade). The same coating level was applied, a total of 4.0 kg coating solution/1.0 kg spheroid cores.

(45) The release rate and profile were significantly different for the two batches. The higher the ratio of film forming polymer (ethyl cellulose) the longer the delay time observed for the same amount of coat (FIG. 6). The expansion and mechanical disruption of the product F667/76 which is F667/50 with an extra 1.5 kg of coating solution additional to that for F667/50 is shown in the photomicrographs of FIGS. 1:i and 1:ii. The photomicrographs were taken of the hydrating multiunits at room temperature gently agitated in 50 ml purified water, where: A is the dry sphere; B is dry sphere washed with water; C is 15 minutes in water; D is 45 minutes in water; E is 75 minutes in water; F is 90 minutes in water; G is 180 minutes in water; H is 180 minutes in water/dried; I is 240 minutes in water; J is 330 minutes in water; K is 24 hours in water/dried.

EXAMPLE 5

(46) A coated spheroid formulation for 5-aminosalicylic acid is made for colonic delivery.

(47) The ingredients for the spheroids are as follows:

(48) TABLE-US-00011 % w/w 5-aminosalicylic acid 50.0 microcrystalline cellulose Ph. Eur Avicel PH101 24.75 HPC LH20 24.75 HPMC K100M 0.5 Purified water Ph. Eur qs

(49) Spheroids are made from these ingredients in a manner similar to the preceding examples. The spheroids are given a delayed release coating using the following ingredients.

(50) TABLE-US-00012 % w/w ethylcellulose N10 USNF 4.03 methocel K100M 3.30 triethyl citrate 0.22 methylene chloride 37.07 methanol BP 1973 55.38

(51) The spheroids with the delayed release coating are then given an enteric coating using the following ingredients.

(52) TABLE-US-00013 weight Eudragit L 30D-55 USNF (30% solids) 24.1 triethyl citrate USNF 1.40 talc Ph Eur 2.40 purified water Ph Eur 20.7

(53) The water is placed in a suitable container and the talc and triethyl citrate are slowly added using a suitable high speed mixer/emulsifier to give a lump-free dispersion. The Eudragit suspension is sieved using a 0.25 mm sieve and mixed using a high speed paddle mixer. The mix is then gradually added to the lump-free dispersion and mixing is continued during the coating process.

EXAMPLE 6

(54) A hypnotic-active formulation is prepared in a manner similar to Examples 1 to 4 using 5-10 mg Zolpidem tartrate and 7.5-15 mg Zolpiclone, giving a delay of 2 to 3 hours before the onset of release.

EXAMPLE 7

(55) Further work was carried out on formulations of 5-aminosalicylic acid, (5ASA), for colonic delivery.

(56) 50-60% 5ASA was loaded on the cores with the spheronisation aid, microcrystalline cellulose (Avicel PH 102); the disruption aid, low substituted hydroxypropyl cellulose (LH20); and the binder, high viscosity grade hydroxypropylmethylcellulose, (HPMC). Low level binder (less than 1.0%) is required to improve the quality of the spheroids. Several batches of cores were manufactured and individually coated with different coating solutions. Both HPMC K100M and HPMC K4M and the combination of the two were investigated. Coating solutions of 40:60, 50:50 and 60:40 ratios of ethyl cellulose (EC): HPMC were tested. In addition one core batch was divided into three sub batches based on their particle size distribution. The three batches selected were: >1.4-<1.6 mm <2.0 mm and >2.0 mm.

(57) Several examples of the core formulation and coating solution formulation together with drug release from the final spheroids products are presented below.

(58) ASpheroid cores, 50% drug load, different coat levels.

(59) TABLE-US-00014 Core formulation (F676/30) Material weight 5 ASA 50.0 Avicel PH101 25.75 HPC LH20 24.75 HPMC K100M 0.5

(60) TABLE-US-00015 Coat formulation* (F676/49A, B, C, F676/59) Material % w/w Ethyl Cellulose 4.03 HPMC K100M 3.30 Triethyl Citrate 0.22 Methylene Chloride 37.07 *Theoretical weight gains are 5.7, 11.3, 13.7, 17.6% w/w for F676/49 A, B, C and F676/59 respectively.

(61) BSpheroids cores, 60% drug load, different HPMC grades

(62) TABLE-US-00016 Core formulation (F676/66) Material % w/w 5 ASA 60.0 Avicel PH101 19.75 HPC LH20 19.75 HPMC K100M 0.5 Methanol 62.34

(63) TABLE-US-00017 Coat formulations (F676/72B, F676/95B, F676/105B) Material % w/w Ethyl Cellulose 4.0 4.0 4.0 HPMC K100M 4.0 2.0 HPMC K4M 2.0 4.0 Triethyl Citrate 0.24 0.24 0.24 Methylene Chloride 30.0 30.0 30.0 Methanol 61.8 61.8 61.8

(64) Coated to same theoretical weight gain of 27% w/w.

(65) CDifferent particle size distribution

(66) TABLE-US-00018 Core formulation (F676/58) Material % w/w 5 ASA 60.0 Avicel PH101 9.75 HPC LH20 29.5 HPMC K100M 0.75

(67) TABLE-US-00019 Coat formulation (F687/59 (>1.6-<2.0 mm), F687/66 (>2.0 mm), F687/73 (>1.4-<1.6 mm)) Material % w/w Ethyl Cellulose 3.51 HPMC K100M 3.51 Triethyl Citrate 0.21 Methylene Chloride 30.26 Methanol 55.38

(68) DSpheroid cores, 60% drug load, coated with delayed release (DR) and enteric coat(EC).

(69) TABLE-US-00020 Core formulation (F687/58A) Material % w/w 5 ASA 60.0 Avicel PH101 9.75 HPC LH20 29.5 HPMC K100M 0.75

(70) TABLE-US-00021 DR formulation (F687/83) Material % w/w Ethyl Cellulose 3.51 HPMC K100M 3.51 Triethyl Citrate 0.21 Methylene Chloride 30.26 Methanol 62.34

(71) TABLE-US-00022 EC formulation (F676/81A) Eudragit L3OD-55 49.6 Triethyl citrate 2.3 Talc 4.9 Water 43.1

(72) The percent release w/w of the 5ASA over time was measured for the various products, and plotted to give FIGS. 8 to 10. For FIG. 11, the dissolution profile in pH 1.2 and pH 6.8 is shown.

EXAMPLE 8

(73) For steroids such as budesonide, fluticasone and prednisolone sodium metasulphobenzoate, typical formulations are as follows:

(74) Spheroid Cores:

(75) TABLE-US-00023 % w/w Steroid (Active) 1-50 Avicel PH101 (Spheronisation aid) 30-70 HPC LH-20 (Disruption agent) 30-70 HPMC high viscosity grade (Binder) 0-1

(76) Coating Solution:

(77) TABLE-US-00024 % w/w Film forming water- insoluble polymer:Gel forming water-soluble polymer 40:60 50:50 60:40 Ethyl Cellulose 3.2 4.0 4.8 HPMC high viscosity grade 4.8 4.0 3.2 K100M/K4m Triethyl citrate 0.24 0.24 0.24 Methylene chloride 30.0 30.0 30.0 Methanol 61.8 61.8 61.8