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Cyclic vinylogous amides as bromodomain inhibitors

A sustained release and formulation technology, applied in the direction of peptide/protein components, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., can solve the problems of unsuccessful deployment of therapeutic proteins, etc.

Inactive Publication Date: 2016-08-17
KINETA ONE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite all these approaches and attempts, therapeutic proteins have largely been unsuccessfully formulated into sustained release systems

Method used

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  • Cyclic vinylogous amides as bromodomain inhibitors
  • Cyclic vinylogous amides as bromodomain inhibitors
  • Cyclic vinylogous amides as bromodomain inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0185] Example 1. Preparation of a reservoir formulation of a therapeutic protein. The weight / volume and ratios of polymer, solvent, aqueous phase, buffer, excipients, and co-solvents are as follows: 1.0 g of polymer was dissolved in 5.0 mL of dichloro in methane. Next, 0.5 mL of 20 mM phosphate-buffered saline (PBS; pH 6.0) containing 100 mg / mL ShK-186 (or ShK-192) was added. The primary emulsion was homogenized for 2 minutes at 20,000 rpm using a 10 x 195 mm probe. The primary emulsion was then added to an aqueous solution of 20 mM phosphate buffer (pH 6.0), 0.5% dioctyl sulfosuccinate (DDS) and 0.05% PVA; Qualify for 2 minutes. A stir bar was added to the secondary emulsion and the suspension was stirred overnight in a fume hood to evaporate volatile solvents. The next day, filter the suspension through a 325 mesh sieve. The filtered material was centrifuged (20,000 g, 5 minutes) and the supernatant layer was drawn off, and passed through an assay involving high perform...

example 2

[0187] Example 2. Measuring encapsulation, mass balance, and in vitro release of a therapeutic protein from a sustained release depot formulation. Typically immediately following a depot formulation, by following a separation method such as centrifugation and using the equation ( 1) Analyze the free protein content of the supernatant layer to measure the encapsulation percentage:

[0188] Encapsulation %=(total ShK-serum layer ShK) / total ShK

[0189] Typical packaging efficiencies are in the range of 60 to 90%.

[0190]Pressurize the system to release the ShK protein almost completely by heating above the glass transition temperature of the polymer, adding a surfactant substance (such as concentrated SDDS), mechanical agitation, sonication, alkaline or acid hydrolysis, or a combination of these accelerated release methods combination to achieve mass balance. A typical in vitro release profile can be obtained by sampling the serum layer at multiple times and under different c...

example 3

[0194] Example 3. Characterization of Physical Properties of Depot Formulations. Standard analytical characterization methods were employed to analyze the physical and chemical properties of depot formulations of ShK-186 disclosed herein and formed according to the method of Example 1 using PLG2A polymer. . Size and electrophoretic mobility were measured by light scattering using a Malvern nanosizer. Morphology / homogeneity was measured by light microscopy. The results are shown in Figures 2-4.

[0195] Figure 2A and 2B Dispersion sizes are shown for three independent batches of tank formulations as measured by dynamic light scattering. Figure 2A and 2B Shown by the intensity of the formulation suspension as measured by dynamic light scattering ( Figure 2A ) and by volume ( Figure 2B ) plotted the size distribution of the reservoir formulation.

[0196] image 3 is a measure of the zeta potential (particle surface charge as measured by electrophoretic mobility) of ...

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Abstract

Depot formulations including therapeutic proteins are provided. The therapeutic proteins can be toxin-based therapeutic proteins. The depot formulations release the therapeutic protein within sustained effective levels for at least one month following a single administration. The toxin-based therapeutic proteins can include ShK-based proteins.

Description

[0001] Cross References to Related Applications [0002] This application claims priority and benefit to US Provisional Patent Application Serial No. 61 / 920,383, filed December 23, 2013, the entire contents of which are incorporated herein by reference. technical field [0003] The present invention relates to formulations for sustained release of therapeutic proteins comprising toxin-based therapeutic proteins having at least one disulfide bridge. Methods of making and using the formulations are also disclosed. The formulation achieves a sustained effective level of the therapeutic protein in the subject for at least one month following a single administration. Background technique [0004] Generally speaking, a therapeutic drug has an acceptable effective content range between the minimum effective dose and the maximum allowable dose, which is called the therapeutic window of the drug. Maintaining a drug within the therapeutic window requires a sustained effective level...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/16A61K9/52
CPCA61K39/08A61K9/0019A61K47/32A61K9/10A61K9/19A61K9/5153A61K38/1767A61P17/06A61P37/06A61P43/00A61K9/5031A61K47/26
Inventor S·P·艾度纳托E·J·穆诺茨J·切斯科E·J·塔查
Owner KINETA ONE
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