Source: http://www.google.com/patents/US6733789?dq=6008737
Timestamp: 2017-11-25 12:19:37
Document Index: 359613214

Matched Legal Cases: ['art 1', 'application No. 10', 'application No. 10', 'art 1', 'art 3', 'art 2']

Patent US6733789 - Multiparticulate bisoprolol formulation - Google Patents
A multiparticulate bisoprolol formulation for once-daily oral administration, each particle of which comprises a core of bisoprolol or a pharmaceutically acceptable salt thereof surrounded by a polymeric coating, the polymeric coating being effective to achieve an initial lag of bisoprolol release in...http://www.google.com/patents/US6733789?utm_source=gb-gplus-sharePatent US6733789 - Multiparticulate bisoprolol formulation
Publication number US6733789 B1
Application number US 09/488,103
Publication number 09488103, 488103, US 6733789 B1, US 6733789B1, US-B1-6733789, US6733789 B1, US6733789B1
Inventors Paul Stark, Catherine Mary Kelly, Niall M. Fanning
Original Assignee Biovail Laboratories, Inc.
Patent Citations (33), Non-Patent Citations (45), Referenced by (32), Classifications (11), Legal Events (9)
US 6733789 B1
1. A multiparticulate bisoprolol formulation for once-daily oral administration, said formulation comprising at least two particles comprising a core of bisoprolol or a pharmaceutically acceptable salt thereof, and a polymeric coating comprising at least one polymer that exhibits a pH-dependent dissolution profile and imparts a pH-dependent delay in bisoprolol release, wherein following administration said formulation exhibits a lag in release, producing a bisoprolol plasma concentration of not more than about 1 ng/ml for at least about three hours, and thereafter provides a sustained release of bisoprolol that produces a therapeutic plasma concentration not later than about 12 hours following administration, and wherein said formulation maintains a therapeutic plasma concentration of bisoprolol for the remainder of a twenty-four hour period measured from administration.
4. The multiparticulate bisoprolol formulation according to claim 1, which, when measured in a U.S. Pharmacopoeia 2 Apparatus (Paddles) in phosphate buffer at pH 6.8 at 37° C. and 50 rpm, exhibits a dissolution profile substantially corresponding to the following:
(a) from 0% to 10% of the total bisoprolol is measured after 2 hours in said apparatus;
(b) from 0% to 50% of the total bisoprolol is measured after 4 hours in said apparatus; and
(c) greater than 50% of the total bisoprolol is measured after 10 hours in said apparatus.
5. The multiparticulate bisoprolol formulation according to claim 1, which, when measured in a U.S. Pharmacopoeia 1 Apparatus (Baskets) at 37° C. and 50 rpm in 0.01 N HCl for the first 2 hours followed by transfer to phosphate buffer at pH 6.8 for the remainder of the measuring period, exhibits a dissolution profile substantially corresponding to the following:
(b) less than 50% of the total bisoprolol is measured after 4 hours in said apparatus; and
(c) greater than 20% of the total bisoprolol is measured after 10 hours in said apparatus.
6. The multiparticulate bisoprolol formulation according to claim 1, wherein at least two particles comprise a sealant or barrier layer between the core and the polymeric coating.
A representative in vitro dissolution profile for pH independent multiparticulates is an in vitro dissolution which when measured in a U.S. Pharmacopoeia 2 Apparatus (Paddles) in phosphate buffer at pH 6.8 at 37° C. and 50 rpm substantially corresponds to the following:
A representative in vitro dissolution profile for pH dependent multiparticulates is an in vitro dissolution which when measured in a U.S. Pharmacopoeia 1 Apparatus (Baskets) at 37° C. and 50 rpm in 0.01 N HCl for the first 2 hours followed by transfer to phosphate buffer at pH 6.8 for the remainder of the measuring period substantially corresponds to the following:
A wide range of polymers can be used in the polymer coating. These polymers include enteric polymer coating materials, such as cellulose acetate phthalate, cellulose acetate trimaletate, hydroxy propyl methylcellulose phthalate, polyvinyl acetate phthalate, Eudragit® poly acrylic acid and poly acrylate and methacrylate coatings such as Eudragit® S or Eudragit® L, polyvinyl acetaldiethylamino acetate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, shellac; hydrogels and gel-forming materials, such as carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin, starch and cellulose based cross-linked polymers in general—the degree of cross-linking should be low so as to facilitate adsorption of water and expansion of the polymer matrix, hydoxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, cross-linked starch, microcrystalline cellulose, chitin, cellulose acetate cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose triacetate, aminoacryl-methacrylate copolymer (Eudragit® RS-PM, Rohm & Haas), pullulan, collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose, carboxymethyl ethyl cellulose, (swellable hydrophilic polymers) poly (hydroxyalkyl methacrylate) (m. wt. ˜5 k-5,000 k), polyvinylpyrrolidone (m. wt. ˜10 k-360 k), anionic and cationic hydrogels, polyvinyl alcohol having a low acetate residual, a swellable mixture of agar and carboxymethyl cellulose, copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, pectin (m. wt. ˜30 k-300 k), polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar, polyacrylamides, Polyox® polyethylene oxides (m. wt. ˜100 k-5,000 k), AquaKeep® acrylate polymers, diesters of polyglucan, cross-linked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, sodium starch glucolate (e.g. Explotab®; Edward Mandell C. Ltd.); hydrophilic polymers such as polysaccharides, methyl cellulose, calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitrocellulose, carboxymethyl cellulose, cellulose ethers, poly(ethylene terphthalate), poly(vinyl isobutyl ether), polyurethane, polyethylene oxides (e.g. Polyox®, Union Carbide), methyl ethyl cellulose, ethylhydroxy ethylcellulose, cellulose acetate, ethylcellulose, cellulose butyrate, cellulose propionate, gelatin, collagen, starch, maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, ammonio methacrylate copolymers such as Eudragit® RL or Eudragit® RS (e.g. Eudragit®, Rohm and Haas), other acrylic acid derivatives, sorbitan esters, polydimethyl siloxane, natural gums, lecithins, pectin, alginates, ammonia alginate, sodium, calcium, potassium alginates, propylene glycol alginate, agar, gums: arabic, karaya, locust bean, tragacanth, carrageenans, guar, xanthan, scleroglucan and mixtures and blends thereof.
The suspension was sprayed onto 0.85-1.00 mm non-pareil seeds (NP Pharma SA, France) in a fluid bed apparatus (GPCG-3, Glatt) using Wurster coating. The drug was layered onto the non-pareil seeds to give a 5% drug weight gain. The spray rate for drug layering was 1.5-3.6 g/min/kg, the inlet temperature was 50° C. and the non-pareils were maintained at 37-42° C. The drug loaded instant release multiparticulates were cooled in the Glatt GPCG-3 for 10 minutes. The multiparticulates were screened to remove oversized beads and fine material.
The resulting combined dispersion was sprayed onto instant release multiparticulates prepared according to Example 1, using a fluid bed apparatus as used in Example 1. Spray rate was 3-10 g/min/kg, and the inlet temperature was 45-50° C. The instant release multiparticulates were maintained at 30-40° C. and the air volume was 150-190 m3/h. A polymer coating of 40.08% polymer weight gain was coated onto the instant release multiparticulates. The coated multiparticulates were cooled in the Glatt GPCG-3 for 30 minutes post coating, then dried/cured in the following manner:
Phase 1 50° C. phase: 50° C. for 11 h. 25 min., temperature dropped (steamer down) to a low of 40° C. over 1 h. 35 min. Temperature fluctuated between 40-56° C. for 30 min. Temperature remained at 50° C. for a further 34 h. 30 min;
Phase 2: 35° C. phase: Temperature dropped to 35° C. over 2 h. 25 min. Temperature remained at 35° C. for a further 29 h. 9 min. (Total time at 50° C.—45 h. 55 min. Total time at 35° C.—29 h. 9 min.)
50° C. for 8 h. 45 min., temperature dropped (steamer down) to a low of 30° C. over 5 h. 55 min. Oven reset and remained at 50° C. for a further 24 h. 25 min. Oven reset again (to account for loss of hours when steamer down). Temperature fluctuated between 38 and 53° C. for 1 h. 45 min. Temperature remained at 50° C. for 15 h. 38 min. Temperature ramped down to 29° C. over the next 5 hr 30 mins.
(Total time at 50° C.—48 h. 48 min).
The resulting polymer solution was sprayed onto bisoprolol multiparticulates coated to 29.93% polymer weight gain with Eudragit RS:Eudragit RL (90:10) polymer coat described above in this Example. The Eudragit L solution was coated with a fluid bed apparatus (Glatt GPCG-3) using Wurster coating. Spray rate was 6-16 g/min /kg, and the inlet temperature was 35-40° C. The multiparticulates were maintained at 30-32° C. during coating and the air volume was 120-140 m3/h. A polymer coating of 20.05% Eudragit L weight gain was coated onto the Eudragit RS:Eudragit RL (90:10) coated multiparticulates. The Eudragit L coated multiparticulates were cured in the Glatt GPCG-3 for 60 minutes post coating. The multiparticulates were screened to remove oversized multiparticulates and fine material.
EXAMPLE 5 Preparation of Eudragit S Coated Multiparticulates Containing Bisoprolol Fumarate 2:1
The resulting solution was sprayed onto instant release multiparticulates prepared according to Example 1, using a fluid bed apparatus as used in Example 1. Spray rate was 3-12 g/min/kg, and the inlet temperature was 38-40° C. The instant release multiparticulates were maintained at 30-35° C. and the air volume was 130-160 m3/hr. A polymer coating of 35.09% polymer weight gain was coated onto the instant release multiparticulates. The coated multiparticulates were cooled in the Glatt GPCG-3 for 10 minutes post coating, then dried/cured in the following manner:
15 h. at 40° C. Cooled to 34° C. over 1 h. 45 min. Remained at 34-35° C. for 7 h. 15 min.
Eudragit Eudragit Eudragit L Eudragit S coated
RS:Eudragit RL Rs:Eudragit RL overcoated multiparticulates
(90:10) coated (90:10) coated multiparticulates
multiparticulates multiparticulates
(hours) released (hours) released (hours) released (hours) released
The resulting combined dispersion was sprayed onto instant release multiparticulates prepared according to Example 1 (but manufactured on the Uni-Glatt), using a fluid bed apparatus (Uni-Glatt) using Wurster coating. Spray rate was 3.2-8.6 g/min/kg, and the inlet temperature was 34-46° C. The outlet air flap setting on the Uni-Glatt was maintained at a setting of 50. A polymer coating of 20.41% polymer weight gain was coated onto the instant release multiparticulates. The coated multiparticulates were cooled in the Uni-Glatt for 30 minutes post coating, then dried/cured in an oven at 50° C. for 86 h. The multiparticulates were screened to remove oversized multiparticulates and fine material.
The resulting combined dispersion was sprayed onto instant release multiparticulates prepared according to Example 1 (but manufactured on the Uni-Glatt), using a fluid bed apparatus (Uni-Glatt) using Wurster coating. Spray rate was 1.4-10.7 g/min/kg, and the inlet temperature was 38-52° C. The outlet air flap setting on the Uni-Glatt was maintained at a setting of 50. A polymer coating of 20.60% polymer weight gain was coated onto the instant release multiparticulates. The coated multiparticulates were cooled in the Uni-Glatt for 30 minutes post coating, then dried/cured in an oven at 50° C. for 48 h. The multiparticulates were screened to remove oversized multiparticulates and fine material.
The resulting combined dispersion was sprayed onto instant release multiparticulates prepared according to Example 1, using a fluid bed apparatus as used in Example 1. Spray rate was 4.2-15.2 g/min/kg, and the inlet temperature was 48-54° C. The instant release multiparticulates were maintained at 37-44° C. and the air volume was 147-231 m3/h. A polymer coating of 20.86% polymer weight gain was coated onto the instant release multiparticulates. The coated multiparticulates were cooled in the Glatt GPCG-3 for 30 minutes post coating, then dried/cured in an oven at 50° C. for 46 h. The multiparticulates were screened to remove oversized multiparticulates and fine material.
The suspension was sprayed onto the instant release bisoprolol multiparticulates (manufactured as described in Step A) in a fluid bed apparatus (GPCG-3, Glatt) using Wurster coating. The Opadry White was layered onto 2.2 Kg of instant release multiparticulates to give 2% solids weight gain. The spray rate for coating with the Opadry White suspension was 1.7-2.5 g/min/kg, the inlet temperature was 44-47° C. and the non-pareils were maintained at 36-39° C. The Opadry coated multiparticulates were cooled in the Glatt GPCG-3 for 10 minutes. The multiparticulates were screened to remove oversized beads and fine material.
The resulting combined dispersion was sprayed onto the 2% Opadry White coated multiparticulates prepared according to Step B, using a fluid bed apparatus as used in Step A. Spray rate was 2.7-10.9 g/min/kg, and the inlet temperature was 45-48° C. The Opadry White coated multiparticulates were maintained at 28-40° C. and the air volume was 149-169 m3/hr. A polymer coating of 29.96% polymer weight gain was coated onto the Opadry White multiparticulates. The coated multiparticulates were cooled in the Glatt GPCG-3 for 30 minutes post coating.
A further 10.65% polymer weight gain was achieved by continuing the coating of the Eudragit RS:Eudragit RL (90:10) aqueous dispersion onto 1.00 Kg the 29.96% polymer coated multiparticulates in the Glatt GPCG-3. Spray rate was 7.7-11.3 g/min 1 kg, and the inlet temperature was 46-49° C. The 29.96% polymer coated multiparticulates were maintained at 32.9-40.4° C. and the air volume was 126-136 m3/hr. The total polymer coating applied to the Opadry White coated multiparticulates at the end of this process was 40.61% polymer weight gain. The coated multiparticulates were cooled in the Glatt GPCG-3 for 30 minutes post coating. The coated multiparticulates were dried/cured in an oven at the following temperatures and times:
Phase 1: 50° C. for 33 hr 25 minutes, temperature dropped to a low of 32° C. for 2 hours, temperature returned to 50° C. for a further 12 h. 35 min. Temperature dropped to 35° C. over 2 hours (problem with oven—temperature fell below 35° C. to low of 24° C.—below 35° C. for 17.45 hours). Returned to 35° C. for further 28 hours 45 minutes.
The suspension was sprayed onto the instant release bisoprolol multiparticulates (manufactured as described in Step A) in a fluid bed apparatus (GPCG-3, Glatt) using Wurster coating. The Opadry Aqueous Moisture Barrier was layered onto 1.5 Kg of instant release multiparticulates to give 3% solids weight gain. The spray rate for coating with the Opadry Aqueous Moisture Barrier suspension was 2.7-4.6 g/min/kg, the inlet temperature was 49-55° C. and the non-pareils were maintained at 39.9-44.9° C. during the coating process. The Opadry coated multiparticulates were dried in the Glatt GPCG-3 for 5 minutes, then cooled for 16 minutes in the Glatt. The multiparticulates were screened to remove oversized beads and fine material.
The resulting combined dispersion was sprayed onto the 3% Opadry Aqueous Moisture Barrier coated multiparticulates prepared according to Step B, using a fluid bed apparatus as used in Step A. Spray rate was 5.0-11.7 g/min/kg, and the inlet temperature was 45-48° C. The Opadry Aqueous Moisture Barrier coated multiparticulates were maintained at 32.8-40.9° C. and the air volume was 119-158 m3/hr. A polymer coating of 29.84% polymer weight gain was coated onto the Opadry White multiparticulates. The coated multiparticulates were dried post coating in the Glatt GPCG-3 for 1 hour at inlet temperature of 45-55° C. then cooled for 5 minutes. The multiparticulates were then dried in an oven for 48 hours at 50° C. The temperature dropped to 35° C. over the next 1.5 hours, then the temperature was maintained at 35° C. for the next 13.75 hours. The multiparticulates were screened to remove oversized multiparticulates and fine material.
An open label, single dose, five treatment, five period, balanced, randomised crossover study was designed to compare the bioavailability of the formulations described in Examples 2-5 and as encapsulated according to Example 13 (5 mg bisoprolol fumarate 2:1) relative to a reference Concor® 5 mg tablet (E. Merck). Fifteen healthy male volunteers were dosed as one group with each volunteer being dosed on five occasions with at least a seven-day washout period between each dose. The volunteers fasted from food and beverages other than water for at least four hours prior to dosing in each treatment period and water was proscribed one hour before and one hour after dosing. The Volunteers were fed an evening meal (approximately 17:00 hours) and dosing occurred at night (approximately 22.00 hours) followed by at least a 10-hour fast. Venous blood specimens were obtained from the volunteers at regular time intervals following each dosing.
Cmax 12.697 ± 10.742 ± 13.704 ± 10.070 ± 19.479 ±
(ng/ml) 2.752 2.076 3.539 2.961 3.593
AUC(0-∞) 305.931 ± 272.013 ± 317.212 ± 281.492 ± 317.796 ±
(ng/ml.h) 80.795 58.673 87.166 81.862 91.951
Tmax (h) 14.909 ± 20.727 ± 13.818 ± 22.182 ± 2.591 ±
2.071 4.221 1.662 5.259 1.530
*Tquant reported as a range is the time prior to the first quantifiable bisoprolol plasma concentration.
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U.S. Classification 424/490, 424/464, 424/489, 424/451
International Classification A61K9/50, A61K31/138
Cooperative Classification A61K9/5078, A61K9/5026, A61K31/138
European Classification A61K9/50K2, A61K31/138
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