Source: http://www.google.com/patents/US8133506?dq=6106459
Timestamp: 2016-09-27 15:33:48
Document Index: 185476231

Matched Legal Cases: ['Application No. 60', 'Application No. 60', 'Application No. 570039', 'Application No. 569984', 'Application No. 2008134900', 'Application No. 2008134912', 'Application No. 200780011406', 'Application No. 200780011485', 'Application No. 598']

Patent US8133506 - Drug delivery systems comprising weakly basic drugs and organic acids - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inPatentsThe present invention is directed to pharmaceutical compositions, and methods of making such compositions, wherein the compositions comprise a plurality of TPR and RR particles, wherein: the TPR particles each comprise a core coated with a TPR layer; the core comprises a weakly basic, poorly soluble...http://www.google.com/patents/US8133506?utm_source=gb-gplus-sharePatent US8133506 - Drug delivery systems comprising weakly basic drugs and organic acidsAdvanced Patent SearchTry the new Google Patents, with machine-classified Google Scholar results, and Japanese and South Korean patents.Publication numberUS8133506 B2Publication typeGrantApplication numberUS 12/209,285Publication dateMar 13, 2012Filing dateSep 12, 2008Priority dateMar 12, 2008Fee statusPaidAlso published asCA2718257A1, CA2718257C, CN101977593A, CN101977593B, EP2265261A1, EP2265261A4, EP2265261B1, US20090232885, WO2009114606A1Publication number12209285, 209285, US 8133506 B2, US 8133506B2, US-B2-8133506, US8133506 B2, US8133506B2InventorsGopi Venkatesh, Jin-Wang Lai, Nehal H. Vyas, Vivek PurohitOriginal AssigneeAptalis Pharmatech, Inc.Export CitationBiBTeX, EndNote, RefManPatent Citations (45), Non-Patent Citations (25), Referenced by (3), Classifications (23), Legal Events (9) External Links: USPTO, USPTO Assignment, EspacenetDrug delivery systems comprising weakly basic drugs and organic acids
US 8133506 B2Abstract
The present invention is directed to pharmaceutical compositions, and methods of making such compositions, wherein the compositions comprise a plurality of TPR and RR particles, wherein: the TPR particles each comprise a core coated with a TPR layer; the core comprises a weakly basic, poorly soluble drug and a pharmaceutically acceptable organic acid separated from each other by an SR layer; the RR particles each comprise the weakly basic, poorly soluble drug, and release at least about 80 wt. % of the weakly basic, poorly soluble drug in about 5 minutes when dissolution tested using United States Pharmacopoeia (USP) dissolution methodology (Apparatus 2—paddles@50 RPM and a two-stage dissolution medium at 37� C. (first 2 hours in 0.1N HCl followed by testing in a buffer at pH 6.8).
the rapid release particles each comprise the weakly basic, poorly soluble drug, and release at least about 80 wt. % of the weakly basic, poorly soluble drug in about 15 minutes when dissolution tested using United States Pharmacopoeia (USP) dissolution methodology (Apparatus 2—paddles@50 RPM and a two-stage dissolution medium at 37� C. (first 2 hours in 0.1N HCl followed by testing in a buffer at pH 6.8).
In one embodiment, pharmaceutical compositions of the present invention comprise a plurality of TPR and RR particles, wherein the TPR particles each comprise a core coated with a TPR layer; the core comprises a weakly basic, poorly soluble drug and a pharmaceutically acceptable organic acid separated from each other by an SR layer; the RR particles each comprise the weakly basic, poorly soluble drug, and release at least about 80 wt. % of the weakly basic, poorly soluble drug in about 5 minutes when dissolution tested using United States Pharmacopoeia (USP) dissolution methodology (Apparatus 2—paddles@50 RPM and a two-stage dissolution medium at 37� C. (first 2 hours in 0.1N HCl followed by testing in a buffer at pH 6.8).
U.S. Provisional Application No. 60/762,750 filed Jan. 27, 2006, U.S. Provisional Application No. 60/762,766 filed Jan. 27, 2006, U.S. application Ser. No. 11/668,167, filed Jan. 29, 2007, and U.S. application Ser. No. 11/668,408, filed Jan. 29, 2007, are each incorporated herein by reference in their entirety for all purposes.
The term “weakly basic, poorly soluble drug” refers to a basic drug, pharmaceutically acceptable salts, polymorphs, solvates, esters, stereoisomers and mixtures thereof. “Weakly basic” refers to drugs which are freely to moderately soluble at acidic pHs, but are poorly to practically insoluble at neutral and alkaline pHs, and have pKa values in the range of about 5 to 14. For example ondansetron hydrochloride contains an α-hydroxyl secondary amine with a pKa of 7.4. The pH-dependent solubility data for exemplary weakly basic drugs are presented in Table 1, below. For example, ondansetron hydrochloride is freely soluble at a pH of less than 2, but has a solubility of less than 50 μm/mL at a pH of 6.8 or higher. Iloperidone has a solubility in 0.1N HCl (hydrochloric acid) of about 3 mg/mL, but at pH 6.8 has a solubility of only about 30 μg/mL. Clonazepam is practically insoluble at physiological pHs.
Ondansetron is indicated for the prevention of nausea and vomiting associated with radiotherapy and/or chemotherapy and prevention of postoperative nausea and/or vomiting. Zofran� Tablets (Ondansetron HCl dihydrate, 4, 8, and 24 mg base equivalent) are commercially available. Ondansetron is administered 8 mg “bid” for chemotherapy and 8 mg “tid” for radiotherapy. A once-daily dosing of ondansetron hydrochloride is commercially desirable and would simplify the dosing regimen and enhance patient compliance. Ondansetron exists as a racemate and it contains an α-hydroxyl secondary amine, with a pKa of 7.4. Ondansetron HCl exhibits a pH-dependent solubility profile (solubility decreasing by 2-3 orders of magnitude as the pH increases). Ondansetron is well absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. The elimination half-life averages approximately 3.8�1 hrs. Since the drug dissolution is the rate-limiting factor for absorption in the distal part of the GI tract potentially due to the decrease in solubility, the once-daily dosage form in accordance with one embodiment would comprise at least two bead populations—one IR or RR particle population and another TPR particle population.
As used herein, the term “immediate release” or IR refers to release of greater than or equal to about 50% (especially if taste-masked for incorporation into an orally disintegrating tablet dosage form), in some embodiments greater than about 75%, in other embodiments greater than about 90%, and in accordance with certain embodiments greater than about 95% of the active within about 2 hours, for example within about one hour following administration of the dosage form. The term can also refer to the release of the active from a timed, pulsatile release dosage form characterized by an immediate release pulse after the designed lag time. As used herein, as well as in specific examples thereof, the term “RR (rapid release) drug particles” includes drug layered 45-60 mesh, in other embodiments 60-80 mesh sugar spheres and water-soluble lactose and fumaric acid containing microgranules comprising said drug designed to provide dissolution profiles similar to that of a reference drug product (for example, in the case of ondansetron HCl, RR drug particles and Zofran� having similar dissolution profiles).
In specific embodiments, the drug is layered onto SR coated fumaric acid-containing beads (e.g., a sugar bead coated with a fumaric acid-containing layer). The drug (e.g., ondansetron) and a polymeric binder (e.g., povidone) solution are coated onto the SR coated fumaric acid-containing bead, and subsequently coated with a protective seal-coat comprising a hydrophilic polymer such as Pharmacoat 603 (Hypromellose 2910 3 cps) or Opadry� Clear, to form IR beads. In one embodiment, the drug-containing IR beads may be coated twice—an inner barrier coating membrane with a water-insoluble polymer (e.g., ethylcellulose) alone or in combination with a water-soluble polymer and a lag-time coating of a water-insoluble polymer in combination with an enteric polymer to produce TPR beads with a lag-time (release with a delayed-onset) of approximately 1 to 10 hours upon oral administration. The water-insoluble polymer and enteric polymer may be present at a weight ratio of from about 9:1 to about 1:4, for example at a weight ratio of from about 3:1 to 1:1. The coating typically comprises from about 5% to about 60%, for example from about 10% to about 50% by weight of the coated beads. In accordance with yet another embodiment, the IR beads may simply be coated with a combination of a water-insoluble polymer and an enteric polymer in the aforementioned amounts.
As described herein IR particles release greater than about 50% of the drug within about two hours of dosing. RR particles are a particular type of immediate release particle having a significantly higher rate of release of the drug compared to IR particles, for example, releasing at least about 80% of the drug within about fifteen minutes when dissolution tested using United States Pharmacopoeia (USP) dissolution methodology (Apparatus 2—paddles@50 RPM and a two-stage dissolution medium at 37� C. (first 2 hours in 0.1N HCl followed by testing in a buffer at pH 6.8). In one embodiment, the RR particles comprise the weakly basic, poorly soluble drug layered onto small particle size inert cores, such as 60-80 mesh sugar spheres. In other embodiments, the RR particles comprise the drug granulated with at least one water soluble excipient such as lactose and at least one organic acid such as fumaric acid. Both of the types of ondansetron-containing RR particles described above show rapid dissolution similar to that of reference drug product, Zofran� IR Tablets, 8 mg under a discriminating in vitro dissolution method using USP Apparatus 2 in 500 mL buffer at pH 6.8.
1.A Fumaric Acid-Containing Cores: Hydroxypropyl cellulose (Klucel LF, 23.9 g) was slowly added to denatured SD 3C 190 proof alcohol while stirring rigorously to dissolve and then fumaric acid (215.4 g) was slowly added to dissolve. A Glatt GPCG 5 equipped with a 9″ bottom spray Wurster insert, 10″ partition column and 16 mm tubing was charged with 3750 g of 25-30 mesh sugar spheres. The sugar spheres were layered with the fumaric acid solution while maintaining the product temperature at about 33-34� C. and inlet air velocity at flap opening of 38%. The acid cores were dried in the unit for 10 min to drive off residual solvent/moisture and sieved through 20-30 mesh screens.
1.B SR-coated Fumaric acid Cores: The fumaric acid cores (3750 g) from above were coated with a solution of EC-10 and PEG 400 dissolved in 98/2 acetone/water (6% solids) for a weight gain of 10% by weight at two ratios, viz., (B.1) 60/40 and (B.2) 75/25 to examine its effect on the drug release from SR and TPR beads. The processing conditions were as follows: atomization air pressure: 2.0 bar; nozzle diameter: 1.0 mm; bottom air distribution plate: ‘B’ with 15 gauge 100 mesh screen; spray/shake interval: 30 s/3 s; product temperature maintained at 35�1� C.; inlet air volume: 155-175 cfm (cubic meters per second), and spray rate increased from 8 to 30 g/minute;
2.E Ondansetron Hydrochloride TPR Beads: Ondansetron hydrochloride SR beads from D.1 and D.2 above were further coated with a lag-time coating membrane of EC-10/HP-55/TEC at three ratios of 45.5/40/14.5 (E.1—Lot#1084-066), 50.5/35/14.5 (E.2—Lot#1117-025) and 60.5/25/14.5 (E.3—Lot#1117-044) dissolved in 90/10 acetone/water (7.5% solids) for a gain of up to 50% by weight. The TPR beads were dried in the Glatt to drive off residual solvent and sieved through an 18 mesh sieve. FIG. 3 shows the release profiles for ondansetron hydrochloride from TPR beads coated with EC-10/HP-55/TEC at three different ratios (E.1, E.2 and E.3). More specifically, FIG. 3 shows the release profiles for the following formulations:
(3) TPR beads Lot#1117-044—The coating of EC-10/HP-55/TEC at a ratio of 60.5/25/14.5 at 50% by weight applied on IR heads coated with 90/10 EC-10/TEC at 10% while IR beads (6% drug layered from 90/10 ondansetron/Klucel LF) comprise fumaric acid cores (layered on sugar spheres from acid/PVP) coated with 90/10 EC-10/TEC at 10%.
3.A Fumaric Acid-Containing Cores: Hydroxypropyl cellulose (Klucel LF, 53.6 g) was slowly added to 90/10 190 proof alcohol/water at 4% solids while stirring rigorously until dissolved and then fumaric acid (482.1 g) was slowly added until dissolved. A Glatt GPCG 5 equipped with a 9″ bottom spray Wurster insert, 10″ partition column was charged with 3750 g of 25-30 mesh sugar spheres. The sugar spheres were layered with the fumaric acid solution while maintaining the product temperature at about 33-35� C. and a spray rate of 8-60 mL/min. The acid cores were dried in the unit for 10 min to drive off residual solvent/moisture and sieved through 40-80 mesh.
3.F Ondansetron Hydrochloride MR Capsules: Ondansetron hydrochloride IR beads (PE364EA0001) and TPR beads (Lot# PE366EA0001 with a lag-time coating of 30%, Lot# PE367EA0001 with a lag-time coating of 45%, and Lot# PE368EA0001 with a lag-time coating of 50%) were encapsulated at a ratio of 35%/65% into hard gelatin capsules to produce MR (modified-release) Capsules, 16 mg (lots# PF380EA0001, lots# PF381EA0001, and lots# PF382EA0001) QD (dosed once-daily) for a pilot bioavailability study in humans in comparison to marketed Zofran� 8 mg (as ondansetron) dosed bid (two times a day). FIG. 4 shows the drug-release profiles from the three MR Capsules comprising IR and TPR beads. Using the in vitro drug release profiles presented in FIG. 4, the calculated ondansetron plasma concentration—time profiles are presented in FIG. 5.
A 4-arm crossover pilot POC (proof of concept) study was conducted which included 12 Caucasian male, healthy volunteers aged 18 to 55 years with a wash-out period of 7 days. Each volunteer was dosed with 250 mL of mineral water a single dose of 16 mg Test Formulation (either A (PF380EA0001), B (PF381EA0001), or C (PF382EA0001) of Example 3) at 8 am or two 8 mg Zofran� (i.e., one at 8 am and the other at 4:30 pm after an overnight fasting (at least 12 hrs), and lunch was served at 11 am. Blood samples were drawn at 0 (pre-dose), 20 min, 40 min, 1 hr, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8.5 hrs (before second dose), 9 hrs 10 min, 9.5 hrs, 10 hrs, 10.5 hrs, 11.5 hrs, 12.5 hrs, 14.5 hrs, 17 hrs, 20 hrs, 22 hrs, 24 hrs and 36 hrs. The PK (pharmacokinetics) profiles are presented in FIG. 6. The pilot PK study demonstrate that the plasma profiles of Test Formulations A (PE380EA0001), B (PE381EA0001), and C (PE382EA0001) are those characteristic of sustained release formulations, i.e., apparent half-life is significantly longer than that with Zofran�. AUC or Cmax of Test Formulations does not deviate substantially from that of Zofran� (i.e., AUC within �25% and Cmax approximately 70% of Zofran�). The actual Cmax for Zofran� 8 mg was 30 ng/mL in comparison to the predicted 24 ng/mL while the actual Cmax for the IR component was about 24 ng/mL when normalized. Approximately 70% of Zofran� 8 mg bid (twice-dosed) was absorbed in 24 hrs. Test Formulations A to C exhibited the expected trend post-dosing up to the crossover point at about 15-16 hrs; thereafter, Formula C continued to exhibit a lower plasma concentration-time profile contrary to the predicted behavior.
5.A Ondansetron Hydrochloride RR Beads at a drug load of 5%: Hydroxypropylcellulose (Klucel LF from Aqualon, 16.5 g) was slowly added to 50/50 water/Denatured Alcohol 3C, 190 Proof (1500 g each) while mixing to dissolve. Ondansetron hydrochloride dihydrate (150 g) was slowly added to the binder solution to dissolve the drug. 60-80 mesh sugar spheres (2773.5 g) were coated in the Glatt GPCG 5 with the drug solution (5% solids) to achieve a drug load of 5% by weight under the following conditions (air distribution plate: B with 100 mesh screen; nozzle diameter: 1 mm; partition height: 10″; 9″ bottom spray Wurster insert; product temperature at 36-37� C.; inlet air volume at 60-65 cfm and spray rate being increased from about 20-25 g/min). The drug-layered beads were provided with a protective seal-coat of Pharmacoat 603 (hypromellose 2910; 3 cps) (2% weight gain) to form RR beads. The RR beads were dried in the unit for 10 min to drive off residual solvent/moisture and sieved through 40-80 mesh screens. More than 90% of the IR beads were in the particle size range of <50-100> mesh.
6.C Ondansetron Hydrochloride IR Beads: IR beads of ondansetron hydrochloride dihydrate with a drug load of 10% by weight were produced by spraying a solution (5% solids) of ondansetron hydrochloride dihydrate (402.8 g) and Klucel LF (44.3 g) in a 50/50 ethanol/water mixture (4247.4 g each) onto fumaric acid SR beads (3500 g) in a Glatt GPCG 5 under the following conditions: Air distribution plate: B with 15 gauge 100 mesh screen; Nozzle diameter: 1 mm; Partition height: 10″; 9″ bottom spray Wurster insert; Product temperature at 34�1� C.; Inlet air volume at 150 cfm; Atomization air pressure—1.5 bar; and Spray rate being increased from 8 to 30 mL/min. The drug-layered beads were provided with a protective seal-coat of Pharmacoat 603 (hypromellose 2910; 3 cps) (2% weight gain) to form IR beads. The IR beads were dried in the unit for 10 min to drive off residual solvent/moisture and sieved to discard oversized and undersized particles.
7.A Ondansetron Hydrochloride MR Capsules PF391E0001: Appropriate amounts of Rapid Release Granules (100.0 mg of RR granules of Lot# PE391EA0001) prepared as disclosed in 5.0 and TPR beads (166.2 mg of TPR beads of Lot# PE392EA0001) prepared as disclosed in 6.E were filled into size ‘0’ hard gelatin capsules to produce Test Formulations A: MR Capsules, 20 mg (8 mg RR+12 mg TPR (T80%˜8 hrs)).
7.B Ondansetron Hydrochloride MR Capsules PF392EA0001: Appropriate amounts of Rapid Release Granules (100.0 mg of RR granules of Lot# PE391EA0001) prepared as disclosed in 5.0 and TPR beads (221.6 mg of TPR beads of Lot# PE292EA0001) prepared as disclosed in 6.E were filled into size ‘0’ hard gelatin capsules to produce Test Formulations B: MR Capsules, 24 mg (8 mg RR+16 mg TPR (T80%˜8 hrs)).
7.C Ondansetron Hydrochloride MR Capsules PF379EA0001: Appropriate amounts of Rapid Release Granules (100.0 mg of RR granules of Lot# PE391EA0001) prepared as disclosed in 5.0 and TPR beads (234.6 mg of TPR beads of Lot# PE393EA0001) prepared as disclosed in 6.D were filled into size ‘0’ hard gelatin capsules to produce Test Formulations C: MR Capsules, 24 mg (8 mg RR+16 mg TPR (T80%˜12 hrs)).
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examinerClassifications U.S. Classification424/455, 514/397, 424/497International ClassificationA61K9/48, A61K31/4178, A61K9/16Cooperative ClassificationA61K9/1676, A61K9/48, A61K9/5042, A61K9/2081, A61K9/5084, A61K31/4178, A61K9/5078, A61K9/1635, A61K9/1617, A61K9/1623, A61K9/1652European ClassificationA61K9/50K2, A61K31/4178, A61K9/16H6B, A61K9/16H6F, A61K9/16H4, A61K9/16H4BLegal EventsDateCodeEventDescriptionFeb 25, 2009ASAssignmentOwner name: EURAND, INC., OHIOFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:VENKATESH, GOPI;LAI, JIN-WANG;VYAS, NEHAL H.;AND OTHERS;REEL/FRAME:022311/0688;SIGNING DATES FROM 20090206 TO 20090213Owner name: EURAND, INC., OHIOFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:VENKATESH, GOPI;LAI, JIN-WANG;VYAS, NEHAL H.;AND OTHERS;SIGNING DATES FROM 20090206 TO 20090213;REEL/FRAME:022311/0688Feb 11, 2011ASAssignmentOwner name: BANK OF AMERICA, N.A., AS ADMINISTRATIVE AGENT, NOFree format text: SECURITY AGREEMENT;ASSIGNOR:EURAND, 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