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Kidney-targeted drug delivery carrier having excellent biodegradability

A drug and carrier technology, applied in drug delivery, radioactive carrier, drug combination, etc., can solve the problems of difficult synthesis, cost, limited usefulness, etc., and achieve excellent release effect

Pending Publication Date: 2022-03-11
KYOTO PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, generally dendrimers have limited usefulness in humans due to their toxicity, difficulty in synthesis, cost, etc. (Non-Patent Document 5)

Method used

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  • Kidney-targeted drug delivery carrier having excellent biodegradability
  • Kidney-targeted drug delivery carrier having excellent biodegradability
  • Kidney-targeted drug delivery carrier having excellent biodegradability

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0150] Example 1: Kidney-targeted drug delivery carrier (serine modified poly-L-lysine (compound of the present invention) (Compound (Ia))) Synthesis

[0151] In DMF / DMSO (1:1), mix 1.1 Equivalent of Boc-Ser(t-Bu)-OH (manufactured by Watanabe Chemical Industry Co., Ltd.), 1.1 equivalent of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3 oxide Hexafluorophosphate (HBTU) (manufactured by Merck Millipore), 1.1 equivalents of anhydrous 1-hydroxy-1H-benzotriazole (HOBt) (manufactured by Watanabe Chemical Industry Co., Ltd.) and 2.2 equivalents of N,N - Diisopropylethylamine (DIPEA). Next, the reaction mixture was stirred at room temperature until the ninhydrin test was negative by TLC analysis, and allowed to react. After the coupling was completed, the solution was purified by precipitating three times with diethyl ether. These precipitates were dissolved in trifluoroacetic acid (TFA) mixture (cocktail) (95% TFA, 2.5% thioanisole (TIS) and 2.5% purified water), so that...

Embodiment 2

[0159] Example 2: 111 In labeled serine modified poly-L-lysine ( 111 Synthesis of In labeled compound (Ia))

[0160] According to the method known per se (Hnatowich, D.J. et al., Int. J. Appl. Radiat. Isot., 1982, 33 (5), 327-332; Nishikawa, M. et al., Biol. Pharm. Bull., 1999,22(2), 214-218), the diethylenetriaminepentaacetic anhydride (DTPA anhydride) as bifunctional chelating agent is combined in compound (Ia), then by using 111 In carries out radioactive labeling to synthesize the medicine of the present invention ( 111 In labeled compound (Ia)). Specifically, compound (Ia) was dissolved in 1 mL of 0.1M HEPES buffer (pH 7), and diethylenetriamine-N,N,N',N",N"-pentaacetic acid (DTPA) dissolved in DMSO was added Anhydride (manufactured by Dojin Chemical Laboratory Co., Ltd.) 10 μL (2 equivalents of compound (Ia)), reacted at room temperature for 30 minutes, and then removed unreacted DTPA anhydride by gel filtration using a PD10 column (manufactured by GE Healthcare) ...

Embodiment 3

[0162] Example 3: Synthesis of FITC-labeled serine modified poly-L-lysine (FITC-labeled compound (Ia))

[0163] Compound (Ia) was dissolved in 1 mL of 0.1M HEPES buffer (pH 7), and 10 μL of fluorescein isothiocyanate isomer (manufactured by Sigma-Aldrich Co. LLC.) dissolved in DMSO was added (compound ( 2 equivalents of Ia)) was reacted at room temperature for 30 minutes, and unreacted fluorescein isothiocyanate isomers were removed by gel filtration using a PD10 column (manufactured by GE Healthcare), followed by purification by ultrafiltration.

[0164] The physicochemical properties (particle size and zeta potential) of FITC-labeled compound (Ia) are the same as those of compound (Ia).

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Abstract

The purpose of the present invention is to provide a drug delivery carrier which is selectively enriched in the kidney in vivo and which has high biodegradability and drug release ability in the kidney. The present invention relates to: a compound in which a carbonyl group of serine is linked to a terminal amino group of a linear polylysine directly or via a linker; a carrier for drug delivery comprising the compound; and a drug for diagnosing, preventing or treating kidney diseases. The drug is obtained by bonding a drug to the drug delivery carrier directly or via a linking body, or by encapsulating the drug with the drug delivery carrier.

Description

technical field [0001] The present invention relates to a kidney-targeted drug delivery carrier, which is selectively enriched in the kidney, especially the proximal renal tubule, and has excellent drug release and biodegradability. Background technique [0002] Drug delivery systems, which are drug delivery systems for the most effective and safe administration of drugs by controlling their pharmacokinetics, have attracted attention in drug development in recent years, but drug delivery carriers that are selectively enriched in the kidney Almost undeveloped. [0003] For example, it is known that drugs modified with succinic acid or aconitic acid are relatively easy to accumulate in the kidney, but also accumulate in the liver at the same time (Non-Patent Document 1). [0004] In addition, polyvinylpyrrolidone-based compounds have attracted attention as targeting elements for selective enrichment in the kidney. However, since they are artificial polymers, they are difficul...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/00A61K47/64A61K47/42A61K45/00A61K51/08A61K103/32A61K103/20
CPCC07K14/00A61K47/645A61K47/42A61K45/00A61K51/08A61P7/02A61P13/12A61P35/00A61K9/19A61K38/00A61K51/088A61K49/0043A61K49/0056A61K47/26A61K47/64A61K31/7088
Inventor 胜见英正山本昌
Owner KYOTO PHARMA UNIVERSITY