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Drug Delivery Systems Comprising Solid Solutions of Weakly Basic Drugs

a weakly basic, solid solution technology, applied in the direction of drug compositions, biocide, cardiovascular disorders, etc., can solve the problems of difficult to achieve drug release at constant rates, difficult to develop oral pharmaceutical dosage forms which deliver, and inability to meet the needs of patients,

Inactive Publication Date: 2008-03-20
APTALIS PHARMATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007] In one embodiment, the present invention is directed to a pharmaceutical composition comprising TPR beads, wherein said TPR beads comprise a solid dispersion of at least one active pharmaceutical ingredient and at least one solubility-enhancing polymer; and a TPR coating comprising a water insoluble polymer and an enteric polymer; wherein the active pharmaceutical ingredient comprises a weakly basic active pharmaceutical ingredient having a solubility of not more than 100 μg/mL at pH 6.8.
[0008] In another embodiment, the present invention is directed to a method of preparing a pharmaceutical composition, comprising dissolving an active pharmaceutical ingredien

Problems solved by technology

However, it is often difficult to develop oral pharmaceutical dosage forms which deliver the desired plasma concentrations of the therapeutic agent at constant rates due to the complexity of the absorption process, the many inter-related compositional variables which affect the rate of release of the therapeutic agent from the dosage form, and the physicochemical properties of the therapeutic agent itself.
Consequently, it is often difficult to achieve drug release at constant rates.
However, supersaturated solutions can precipitate, and there is evidence that redissolution and absorption of the drug can then occur at a slower rate.
However, such approaches are not entirely satisfactory because the solubility of the drugs varies with the physiochemical properties of the drug itself, as well as the method of preparing the pharmaceutical formulation.
For example, some weakly basic drugs, such as nifedipine or lercanidipine, do not show significant solubility enhancement in saturated organic acid solutions, and solid dispersions tend to provide an undesirable immediate release of the drug upon oral ingestion.

Method used

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  • Drug Delivery Systems Comprising Solid Solutions of Weakly Basic Drugs
  • Drug Delivery Systems Comprising Solid Solutions of Weakly Basic Drugs
  • Drug Delivery Systems Comprising Solid Solutions of Weakly Basic Drugs

Examples

Experimental program
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example 1

[0088] Turbidity Measurements

[0089] A concentrated solution (3 mL) of lercanidipine hydrochloride in acetone (0.5 mg / ml) was added to 200 mL of a buffer solution (pH 6.0) containing Kollidon VA 64, Methocel E5 (hypromellose), polyethylene glycol (PEG 6000), cyclodextrin or Kollidon 14 PF (polyvinyl pyrrolidone) at the ratio of 1:2 by weight with respect to the polymer. It is evident from FIG. 3A that the drug solutions showed improved stability thus strongly reducing the risk of crystallization of the conjugated base of lercanidipine HCl.

[0090] Intrinsic Dissolution Rate Measurements

[0091] Intrinsic dissolution rates were determined for two different polymorphs of lercanidipine hydrochloride as well as amorphous materials (e.g., amorphous drug and 1:2 solid solutions of lercanidipine hydrochloride with Methocel E5 and Kollidon VA 64). The data are shown in FIG. 4. While the crystalline polymorphs exhibit poor dissolution rates as well as extent of dissolution, the solid solutions...

example 2

[0094] Turbidity Measurements

[0095] A concentrated solution (3 mL) of Nifedipine in acetone (0.5 mg / mL) was added to 200 mL of a buffer solution (pH 6.0) containing Kollidon VA 64, Methocel E5 (hypromellose), polyethylene glycol (PEG 6000), cyclodextrin or Kollidon 14 PF (polyvinyl pyrrolidone) at a nifedipine / polymer ratio of 1:2 by weight. The transmittance of the nifedipine / polymer solutions was monitored over time as shown in FIG. 3B. The more stable solutions exhibited a slower decline in transmittance over time, due to slower crystallization of nifedipine from solution. Methocel E5, Kollidon VA 64, and Kollidon 14 PF exhibited greater stabilization.

[0096] Powder X-Ray Diffraction

[0097] Two co-precipitates of nifedipine and Methocel E5 (hypromellose) were prepared at a nifedipine / Methocel ratio of 1:1 and 1:2 by dissolving the nifedipine and Methocel in a mixture of dichloromethane-methanol (1:1, v / v), then drying the solutions to a residual solvent level of less than 1% (w / ...

example 3

[0098] 3A—Nifedipine IR Beads (Nominal Nifedipine Loading: 10%)

[0099] Kollidon VA 64 (800 g) was slowly added to a 72.5 / 22.5 / 5 mixture of 95% ethanol / acetone / water (4930 g / 1530 g / 340 g) while vigorous stirring until dissolved, and then nifedipine (400 g) was slowly until dissolved. A Glatt GPCG 3 equipped with a 7″ bottom spray / 8″ column height Wurster insert, 20 mm partition gap, air-distribution plate B (250 μm screen), 1.0 mm nozzle port, atomization air pressure of 1.5 bar, and 3.2 mm inner diameter tubing, was charged with 2584 g of 25-30 mesh Sugar Spheres. About 40 g of talc was homogenized into the nifedipine / polymer solution to minimize static build-up. The nifedipine solution, at a solids content of 15% by weight, was sprayed onto the sugar spheres at a spray rate of 8-17 g / min and outlet flap at ˜60-80% (air velocity: ˜85-115 m3 / hr) while maintaining the product temperature at about 36-40° C. The resulting nifedipine-layered beads (batch size: 3724 g) were dried in the G...

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Abstract

The present invention is directed to pharmaceutical compositions and dosage forms comprising TPR beads, wherein said TPR beads comprise a solid dispersion of at least one active pharmaceutical ingredient in at least one solubility-enhancing polymer, and a TPR coating comprising a water insoluble polymer and an enteric polymer, wherein the active pharmaceutical ingredient comprises a weakly basic active pharmaceutical ingredient having a solubility of not more than 100 μg / mL at pH 6.8.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. provisional application Nos. 60 / 841,760 and 60 / 841,893, both filed Aug. 31, 2006, each of which is herein incorporated by reference in its entirety for all purposes.TECHNICAL FIELD [0002] The present invention relates to modified-release compositions with improved bioavailability, and methods of making such compositions. The compositions of the present invention comprise solid dispersions of at least one active pharmaceutical ingredient and a timed pulsatile release coating. BACKGROUND OF THE INVENTION [0003] Many therapeutic agents are most effective when made available at constant rates, at or near the absorption sites. The absorption of therapeutic agents made available in this manner generally results in desired plasma concentrations leading to maximum efficacy, and minimum toxic side effects. However, it is often difficult to develop oral pharmaceutical dosage forms which deliver the desi...

Claims

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Application Information

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IPC IPC(8): A61K9/22A61K31/4406A61K31/4422A61K31/454A61K31/5513A61K47/30A61K47/38A61K9/14
CPCA61K9/5026A61K9/5042A61K9/5047A61K9/5078A61K31/5513A61K31/4422A61K31/454A61K9/5089A61K9/5005A61K31/4406A61P25/08A61P25/18A61P9/10A61P9/12A61K9/14A61K47/34A61K47/38A61K9/16
Inventor VENKATESH, GOPIBOLTRI, LUIGICOLOMBO, ITALOLAI, JIN-WANGFLABIANI, FLAVIOMAPELLI, LUIGI
Owner APTALIS PHARMATECH
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