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Solid dispersions containing an apoptosis-promoting agent

A technology of solid dispersion and solid matrix, which can be used in medical preparations containing active ingredients, organic active ingredients, oil/fat/wax non-active ingredients, etc., and can solve problems such as impracticality

Inactive Publication Date: 2012-11-28
ABBVIE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, daily parenteral administration is often not practical in a clinical setting, especially for outpatients

Method used

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  • Solid dispersions containing an apoptosis-promoting agent
  • Solid dispersions containing an apoptosis-promoting agent
  • Solid dispersions containing an apoptosis-promoting agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0217] Embodiment 1: Preparation of the solid dispersion of ABT-263 diHCl

[0218] ABT-263 diHCl crystalline salt was mixed with surfactant and water-soluble polymer in the following weight ratio:

[0219] 10.8% ABT-263 salt (10% free base equivalent); 10% surfactant; 79.2% polymer

[0220] 21.5% ABT-263 salt (20% free base equivalent); 10% surfactant; 68.5% polymer

[0221] 32.3% ABT-263 salt (30% free base equivalent); 10% surfactant; 57.7% polymer

[0222] 43% ABT-263 salt (40% free base equivalent); 10% surfactant; 47% polymer

[0223] Surfactants in different series are TPGS, Span™ 20 or Tween™ 20. The polymers in different series are copovidone (Kollidon® VA 64), povidone K-30 or HPMC-AS.

[0224] The ingredient mixture was dissolved in methanol in each case. Methanol was removed in vacuo at 65°C using a Genevac® system, and the resulting solid dispersion was allowed to cool to ambient temperature.

[0225] The solid dispersion in each case was sieved through a 4...

Embodiment 2

[0228] Embodiment 2: Preparation of solid dispersion of ABT-263 free base

[0229] ABT-263 diHCl crystalline salt was dissolved in acetone, and NaOH was added to convert ABT-263 diHCl to free base. The NaCl by-product was precipitated and removed by filtration.

[0230] In the acetone solution of obtained ABT-263 free base, add surfactant and water-soluble polymer of following weight ratio:

[0231] 10% ABT-263 free base; 10% surfactant; 80% polymer

[0232] 20% ABT-263 free base; 10% surfactant; 70% polymer

[0233] 30% ABT-263 free base; 10% surfactant; 60% polymer

[0234] 40% ABT-263 free base; 10% surfactant; 50% polymer

[0235] Surfactants in different series are TPGS, Span™ 20 or Tween™ 20. Polymers in different series are copovidone (Kollidon® VA 64) or HPMC-AS.

[0236] Acetone was removed in vacuo at 65°C using a Genevac® system, and the resulting solid dispersion was allowed to cool to ambient temperature.

[0237] The solid dispersion in each case was sie...

Embodiment 3

[0240] Example 3: Dissolution Profile of Solid Dispersions

[0241]Representative dissolution (drug release) profiles in pH 6.5 buffered media containing 7.6 mM Tween® 80 are shown in figure 1 (ABT-263 diHCl) and figure 2 (ABT-263 free base).

[0242] like figure 1 As shown in , at 20% drug loading level, ABT-263 diHCl solid dispersion with 68.5% copovidone and 10% TPGS showed a moderate rate of drug release, which reached a plateau at about 80% release. The release from similar dispersions with Span™ 20 or especially Tween™ 20 as surfactant was much slower.

[0243] In contrast, if figure 2 ABT-263 free base solid dispersion with 70% copovidone and 10% Tween® 20 or TPGS showed fast drug release at the same 20% drug loading level as shown in . In the case of the free base dispersion, only Span™ 20 surfactant resulted in a much slower release.

[0244] The release rate was drug load dependent for both ABT-263 diHCl and free base dispersion formulations, with the 20%...

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Abstract

A pro-apoptotic solid dispersion comprises, in essentially non-crystalline form, a Bcl-2 family protein inhibitory compound, e.g., ABT-263, dispersed in a solid matrix that comprises (a) a pharmaceutically acceptable water-soluble polymeric carrier and (b) a pharmaceutically acceptable surfactant. A process for preparing such a solid dispersion comprises dissolving the compound, the polymeric carrier and the surfactant in a suitable solvent, and removing the solvent to provide a solid matrix comprising the polymeric carrier and the surfactant and having the compound dispersed in essentially non-crystalline form therein. The solid dispersion is suitable for oral administration to a subject in need thereof for treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl-2 family proteins, for example cancer.

Description

[0001] This application claims the benefit of priority to US Provisional Application Serial No. 61 / 185,105, filed June 8, 2009. [0002] Cross-references were made to the following co-filed U.S. application containing subject matter related to the present application: Serial No. 12 / 796,000 filed June 8, 2010, entitled "Inhibitors for Oral Administration of Bcl-2 Family Inhibitors" Pharmaceutical dosage form for oral administration of a Bcl-2 family inhibitor," which claims the benefit of priority of U.S. Provisional Application Serial No. 61 / 185,130, filed June 8, 2009. [0003] The entire disclosures of each of the above applications are incorporated herein by reference. field of invention [0004] The present invention relates to solid dispersions containing apoptosis-promoting agents, pharmaceutical dosage forms comprising such dispersions, methods for the preparation of such dispersions and dosage forms and their use for the treatment of hyperlipidemia characterized by ant...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/00A61K31/5377A61K9/14
CPCA61K9/145A61K9/1652A61K31/495A61K47/38A61K9/4866A61K9/146A61K9/4858A61K9/19A61K47/26A61K9/2027A61K47/32A61K9/1635A61K9/2054A61K47/44A61K47/10A61K47/22A61P1/02A61P1/04A61P1/16A61P1/18A61P11/00A61P13/02A61P13/08A61P13/10A61P13/12A61P15/00A61P17/00A61P19/00A61P21/00A61P25/00A61P27/02A61P35/00A61P35/02A61P43/00A61P5/00
Inventor E.A.施米特童平K.希姆斯特拉C.M.费希尔吴淮亮J.M.米勒Y.李J.S.拉丰泰恩
Owner ABBVIE INC
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