Echinomycin formulation, method of making and method of use thereof

A technology of echinomycin and preparation, applied in the field of composition of liposomal echinomycin preparation, can solve the problems of limited clinical application, serious problems and the like

Pending Publication Date: 2018-09-04
CHILDRENS RES INST CHILDRENS NAT MEDICAL CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Clinical trials of echinomycin also revealed significant reported side effects, such as severe nausea and vomiting, further limiting its clinical utility

Method used

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  • Echinomycin formulation, method of making and method of use thereof
  • Echinomycin formulation, method of making and method of use thereof
  • Echinomycin formulation, method of making and method of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0171] Example 1. Preparation of liposomal echinomycin formulations. The lipid fraction and echinomycin are weighed out on an analytical balance and dissolved in a suitable solvent such as chloroform / methanol (2:1, v / v) in a glass scintillation vial and vortexed Mix in a vortex mixer. A slow stream of nitrogen was used to evaporate the organic solvent and create a uniform lipid film on the walls of the glass vial. To prevent gelation, the drying process was carried out at 65°C. By adding double distilled water (ddH 2 10% sucrose (w / v) in O) hydrated the lipid membrane so that the final concentration of total lipid was 7.1 mg / mL. The hydrated mixture was kept above 65°C and vortexed vigorously until all membranes were dissolved. A hydrated solution of large multilamellar vesicles (LMVs) was rapidly extruded in 1 mL increments through 200 nm, 100 nm, and 50 nm stacked polycarbonate (PC) filters using an AvantiMini-Extruder until lipids in the combined post-extrusion mixture ...

Embodiment 2

[0176] Example 2. Size distribution and physical characterization of liposomal echinomycins. Liposomal echinomycin formulations were characterized using Malvern Zetasizer software to determine mean size and zeta potential. like figure 1 As shown in the representative dynamic light scattering (DLS) curve in Figure A, the size distribution was found to be consistently within a very narrow range with a polydispersity index of less than 0.1. Enhanced penetration and retention rate (EPR) and maximal immunoinvasiveness of pegylated sphingoliposomes due to rapid uptake by the reticuloendothelial system (RES) have been reported for liposomes with liposome size figure 1 , Figure B).

[0177] Measuring the zeta potential of liposome formulations can provide a reliable method for predicting particle stability and aggregation tendency. The average zeta potential of liposomal echinomycin was found to be about -30 mV, which indicates that the product is stable and less likely to aggregate...

Embodiment 3

[0180]Example 3. In vitro release of echinomycin from echinomycin liposomes. Evaluation of liposomal echinomycin in vitro drug release was performed by dialysis by measuring the release rate of echinomycin by HPLC at each time point in water at room temperature over a period of 240 hours. Echinomycin concentrations were calculated at each time point according to the echinomycin standard curve. Percent release was extrapolated as a function of the initial echinomycin concentration detected in the liposomal echinomycin sample prior to initiation of dialysis. The in vitro release characteristics of liposomes are summarized in e.g. figure 2 The cumulative release percentages shown in Panel A. exist figure 2 Representative HPLC chromatograms showing echinomycin peaks at corresponding time points are depicted in panel B.

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Abstract

A liposomal drug formulation for treating a disease in a patient characterized by overexpression of HIF-1[alpha] and / or HIF-2[alpha] includes a plurality of liposomes in a pharmaceutically acceptablecarrier. The liposomes encapsulate echinomycin and are made from a peglyated phospholipid, a neutral phosphoglyceride, and a sterol. The PEGylated liposomes may be used to treat proliferative diseases, leukemia, cancer, autoimmune diseases and graft-versus-host disease.

Description

[0001] This application claims priority to US Provisional Patent Application Serial No. 62 / 253,257, filed on November 10, 2015. The entire contents of all aforementioned applications are incorporated herein by reference in their entirety. technical field [0002] The present application generally relates to compositions and methods for the preparation and delivery of liposomal echinomycin formulations for the treatment of proliferative disorders, autoimmune diseases and allogeneic immune responses. Background technique [0003] Hypoxia-inducible factor (HIF) is a transcription factor and mediates the cellular response to hypoxia. HIF is known to be upregulated in many cancers, autoimmune diseases and allogeneic immune responses. In particular, HIF is involved in tumor metabolism, angiogenesis and metastasis (Semenza, G.L. et al., Nature Rev. Cancer. 2003; 3(10):721-32). [0004] Echinomycin (NSC526417) is a member of the quinoxaline family originally isolated in 1957 from ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K31/395A61K35/74A61K38/08A61K38/12
CPCA61K35/74A61K38/164A61K47/6911A61K9/1271A61P37/02A61P35/02A61P35/00A61K9/19A61K38/08A61K9/1277
Inventor 刘阳王茵刘岩克里斯多佛·贝利郑盼
Owner CHILDRENS RES INST CHILDRENS NAT MEDICAL CENT
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