Liposomal compositions of epoxyketone-based proteasome inhibitors

Inactive Publication Date: 2015-07-30
ONYX THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0018]In a further aspect, the present invention relates to methods of treating a disease or condition in a subject in need of treatment, comprising administering a therapeutically effective amount of a pharmaceutical liposomal composition comprising liposomes comprising a peptide epoxyketone compound. In some embodiments the methods of treating further comprise simultaneous, sequential, or separate administration of a therapeutically effective amount of another the

Problems solved by technology

However, intravenous administration of the carfilzomib SBE-β-CD composition results in a short half-life due to rapid metabolism.
In

Method used

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  • Liposomal compositions of epoxyketone-based proteasome inhibitors
  • Liposomal compositions of epoxyketone-based proteasome inhibitors
  • Liposomal compositions of epoxyketone-based proteasome inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Molecularly Dispersed Carfilzomib in Thin Lipid Film

[0254]To make liposomal carfilzomib, the following materials in the indicated ratios were added to a suitably sized round bottom flask: drug to total lipid weight ratio of 1:19 to 1:2.33. Total lipids typically comprise the lipids EPC, HSPC, DSPC, DPPC, DSPE, and / or sphingomyelin (SPH) alone, or with cholesterol. If cholesterol is added, the lipid to cholesterol weight ratio (lipid:cholesterol) is from 0.9:0.1 to 0.5:0.5. An appropriate volume of phosphate buffer saline was used to rehydrate the lipid film to give a target carfilzomib concentration of 1 and 2 mg / mL, respectively.

[0255]To make PEGylated liposomal carfilzomib, the following materials in the indicated ratios were added to a suitably sized round bottom flask: drug to total lipid weight ratio of 1:19 to 1:2.33. Total lipids typically comprise the lipids EPC, HSPC, DSPC, DPPC, DSPE, and / or sphingomyelin with PEG-modified lipids (e.g., PEG-modified phosphol...

example 2

Lipid Hydration

[0259]The thin-filmed, round-bottom flask was immersed in a water bath set above the highest gel-liquid crystal phase transition. When EPC was used, rehydration occurred at room temperature. For DSPC, DPPC, and mPEG-DSPE, the water bath temperature should be set greater than 55° C., 41° C., and 50° C., respectively. An appropriate volume of phosphate buffered saline, pH 7.2, or water for injection was added to the lipid film to achieve the desired target carfilzomib concentration or dose. The flask was mildly agitated or shaken with intermittent vortexing, as needed, and sonicated in water bath at the appropriate Tc temperature for 1 to 2 minutes to facilitate complete hydration from flask walls.

[0260]After the film was dispersed, the mixture was transferred to a vial and sonicated for an additional 20 to 40 minutes in a water bath above the Tc to size the liposomes. When EPC was used, the temperature of the water bath in the sonicator was kept near room temperature. ...

example 3

Characterization of Liposomes

[0262]Particle size reduction and / or deagglomeration of the rehydrated liposomal suspension was carried out by sonication (20 to 60 minutes).

[0263]The CFZ content of exemplary liposomal carfilzomib compositions was determined by HPLC as described above. The liposomal compositions were each diluted in methanol to dissolve lipids and carfilzomib. The solution was filtered through a 0.2μm PTFE filter prior to HPLC analysis. The percent difference between the theoretical and experimental liposomal drug concentrations for the prepared lots (FIG. 1) were typically 2% or less (except for one of the first lots which had a 12% difference). The results of the HPLC analysis are presented in FIG. 1.

[0264]Based on polarized light microscope it was qualitatively determined that nearly all of the drug was entrapped in the liposomes as any free drug would precipitate in the aqueous medium due to its extremely low aqueous solubility of <1 μg / mL and any precipitated mater...

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Abstract

Liposomal compositions comprising peptide epoxyketone compounds are described, as well as methods of making and using such liposomal compositions. These liposomal compositions provide prolonged drug exposure (relative to non-liposomal compositions comprising peptide epoxyketone compounds) without significantly affecting biodistribution of the drug. Tolerability of peptide epoxyketone compounds was also enhanced when formulated in the liposomal compositions.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application Ser. No. 61 / 673,017, filed 18 Jul. 2012, now pending, and U.S. Provisional Application Ser. No. 61 / 794,603, filed 15 Mar. 2013, now pending, both of which applications are herein incorporated by reference in their entireties.TECHNICAL FIELD[0002]The present invention relates to compositions for the treatment of cancer, as well as methods of preparing such compositions. Aspects of the present invention include, but are not limited to, methods for formulating stable liposomal compositions comprising peptide epoxyketone compounds, liposomal compositions comprising peptide epoxyketone compounds, and methods of using such liposomal compositions.BACKGROUND OF THE INVENTION[0003]In eukaryotes, protein degradation is predominately mediated through the ubiquitin pathway in which proteins targeted for destruction are ligated to the 76 amino acid polypeptide ubiquitin. Once targeted...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K45/06A61K47/22A61K38/07A61K47/48
CPCA61K9/127A61K38/07A61K47/48969A61K45/06A61K47/22A61K9/1271A61K9/1277A61K47/6951A61P11/00A61P17/14A61P19/08A61P21/00A61P25/00A61P25/14A61P25/16A61P25/28A61P27/02A61P29/00A61P3/00A61P3/12A61P31/04A61P31/10A61P31/12A61P31/18A61P33/14A61P35/00A61P35/02A61P37/06A61P39/02A61P43/00A61P9/10
Inventor CHU, KATHERINE A.CHAN, ELENA T.FANG, YINGJAMAA, MOUHANNADKIRK, CHRISTOPHER JUSTINMUCHAMUEL, TONYWANG, ZHENGPINGJIANG, JINGJONES, JEFFREY JOSEPH
Owner ONYX THERAPEUTICS
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