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Peptide compositions and methods of use

A composition and compound technology, applied in the direction of botany equipment and methods, chemical instruments and methods, drug combination, etc., can solve the problems of large material loss, suboptimal, potency loss, etc.

Pending Publication Date: 2021-11-16
ONL医疗股份有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Suspension or gel administration of Met-12 results in great loss of potency
For example, even an apparently clear solution of 10 mg / mL of Met-12 in 20 mM citrate buffer (pH 2.8) showed considerable material loss upon filtration, and when used in the in vitro and in vivo assays described below , resulting in at least a five-fold loss of activity
Despite extensive development work, the only solution formulations of Met-12 that have been found involve some very low pH solution injections (< pH 2.8) or pure DMSO injections, all of which are suboptimal for intravitreal injection

Method used

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  • Peptide compositions and methods of use
  • Peptide compositions and methods of use
  • Peptide compositions and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] Example 1: Compound 1 preparation and testing

[0110] Compound 1 peptide (peptide His-His-Ile-Tyr-Leu-Gly-Ala-Val-Asn-Tyr-Ile-Tyr- NH 2 ; SEQ ID NO: 1). Fmoc protected amino acids were purchased from GL Biochem. Reagents for coupling and cleavage were purchased from Aldrich. Solvents were purchased from Fisher Scientific.

[0111] The peptide chains are assembled on the resin by repeated removal of the Fmoc protecting group and coupling of the protected amino acids. DIC and HOBt were used as coupling reagents with NMM as the base; 20% piperidine in DMF was used as the de-Fmoc-reagent. A ninhydrin test was performed after each coupling to check coupling efficiency.

[0112] After the last coupling, the resin was washed and dried by cleavage mixture (TFA / Tis / H 2 O / DOTA: 95 / 3 / 2 / 2) to cleave the peptide from the resin. The peptide was precipitated from cold ether and collected by filtration to obtain 13 g of crude product with a purity of 46% (yield: 127%).

[011...

Embodiment 2

[0116] Example 2: pH-Solubility Curve of Compound 1

[0117] Compound 1 was obtained as the trihydrochloride salt as described in Example 1 and screened for water solubility at different pH by pH titration according to the following protocol. In some cases, Met-12 was run through the same experimental procedure to determine its pH solubility curve under the same conditions. Previous experiments have not identified any conditions where Met-12 can be satisfactorily formulated in substantially aqueous media at any pH above 2.7.

[0118] Compound 1 (10 mg) was dissolved in water (270-900 μL) in a 2 mL clear plastic centrifuge tube with vortexing, resulting in a solution with a pH of approximately 2.4. In all cases, the peptides formed clear solutions, demonstrating a solubility of at least 40 mg / mL at low pH. The solution was then diluted with an appropriate amount of co-solvent or other excipients (sugar\surfactant, etc.) to yield a clear acidic solution of 10 mg of Compound 1 ...

Embodiment 3

[0120] Example 3: pH-Dependent Solubility of Compound 1 in Cosolvent Mixtures

[0121] The pH-dependent solubility of compound 1 was examined using co-solvents and additives and compared with the solubility of Met-12 under the same conditions.

[0122] The 70% DMSO experiments were similar to the Met-12 titrations that formed gels around pH 5.5, but in this case, probably because the C-terminus could not be ionized, the gels were no longer soluble at higher pH values.

[0123] 70% propylene glycol (PG) improved the solubility of compound 1 compared to Met-12's pH 3.2, gelling did not occur until around pH 4.7, and then remained as a gel until pH 10. The titration was repeated with lower amounts of PG (35%, 10%), but no improvement in solubility over pure water seemed to be found.

[0124] The 70% PEG400 and 70% glycerol solutions did not seem to work, nor did the two sugar additives, 10% mannitol or 10% trehalose.

[0125] From these experiments it can be concluded that prop...

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Abstract

Provided herein are compositions including peptides, pharmaceutical preparations thereof, and methods of preventing photoreceptor death therewith and protecting of retinal cells, including, but not limited to, photoreceptors and retinal pigment epithelium, from Fas- or TRAIL-mediated apoptosis.

Description

[0001] This application is a divisional application of a patent application with an application date of April 29, 2016, an application number of 201680038258.8, and an invention title of "peptide composition and method of use". [0002] The entire contents of all patents, patent applications, and publications, as well as other literature references, cited herein are hereby incorporated by reference. The disclosures of these publications in their entirety are incorporated by reference into this application in order to more fully describe the prior art known to those skilled in the art as of the date of the invention described and claimed herein. [0003] Federally Sponsored Research or Development [0004] This invention was made with government support under Grant Number R44EY022512 awarded by the National Institutes of Health (NIH). The government has certain rights in this invention. [0005] field of invention [0006] Cells that protect cells, particularly retinal cells (...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08A61K38/10A61P27/02A61P9/10
CPCC07K7/08A61P27/02A61P9/10A61K38/00C07K14/71Y02A50/30A01N25/00
Inventor C.G.贝西尔利A.J.布里奇斯J.K.弗雷施利W.A.亨克L.L.约翰逊F.X.史密斯E.西尔万D.N.扎克斯
Owner ONL医疗股份有限公司
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