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Preparation method with lauroyl aminoacyl proline methyl ester serving as novel chemical penetration enhancer and application

A technology of penetration enhancer and amino acid, applied in the field of biomedicine, can solve the problems of low transdermal absorption rate of drugs

Inactive Publication Date: 2014-12-10
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, in response to the low transdermal absorption rate of drugs generally made into transdermal drug delivery system preparations, many physical, chemical and pharmaceutical methods and technologies for promoting drug percutaneous absorption have been developed. These methods and technologies have their own advantages and disadvantages. The effect of promoting penetration is also different

Method used

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  • Preparation method with lauroyl aminoacyl proline methyl ester serving as novel chemical penetration enhancer and application
  • Preparation method with lauroyl aminoacyl proline methyl ester serving as novel chemical penetration enhancer and application
  • Preparation method with lauroyl aminoacyl proline methyl ester serving as novel chemical penetration enhancer and application

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Embodiment 1

[0028] The preparation of embodiment 1Pro-OMe

[0029] In an ice bath, 1.3 mL of SOCl was added dropwise to 7.5 mL of methanol 2 , after reacting for 30 minutes, dissolve proline in methanol until the reaction is complete, drain the reaction solution under reduced pressure, add a small amount of methanol to dissolve, and drain under reduced pressure, repeat three times, then add anhydrous ether, and drain under reduced pressure dry, and repeat the same three times. Dissolve the treated product with a small amount of methanol, add anhydrous ether drop by drop until crystals precipitate, put it in the refrigerator overnight, filter the crystals to obtain proline methyl ester, and store it in the refrigerator for later use. White snowflake crystals (ESI-MS(m / z): 152.2[M+Na] + )

Embodiment 2C1

[0030] Example 2C 12 - Preparation of L-Gly-L-Pro-OMe

[0031] (1) Synthesis of Boc-Gly-OH

[0032] Under the condition of ice bath, put 0.75g (10mmol) glycine into an eggplant bottle, slowly add 10mL of 1N NaOH solution to completely dissolve the amino acid. In a small beaker 2.398g (11mmol) (Boc) 2 O, add 10mL of 1,4-dioxane to dissolve completely, then slowly add to the eggplant bottle, adjust the pH to 8-9 with NaOH solution, and the reaction is complete under ice bath conditions. Add saturated KHSO to the reaction solution 4 Adjust the pH to neutral, pressurize and concentrate to dryness to obtain a white solid, add a small amount of water to dissolve with saturated KHSO 4 Adjust to pH=2, and extract three times with ethyl acetate solution, combine the ethyl acetate layers, and extract three times with saturated NaCl. Ethyl acetate layer with anhydrous Na 2 SO 4 Dry overnight, filter to remove Na 2 SO 4 , the filtrate was concentrated to dryness under reduced pre...

Embodiment 3C1

[0040] Example 3C 12 - Preparation of L-Ala-L-Pro-OMe

[0041] (1) Synthesis of Boc-Ala-OH

[0042] Under the condition of ice bath, take 0.8909g (10mmol) alanine into the eggplant bottle, slowly add 10mL of 1N NaOH solution to completely dissolve the amino acid. In a small beaker 2.398g (11mmol) (Boc) 2 O, add 10mL of 1,4-dioxane to dissolve completely, then slowly add to the eggplant bottle, adjust the pH to 8-9 with NaOH solution, and the reaction is complete under ice bath conditions. Add saturated KHSO to the reaction solution 4 Adjust the pH to neutral, pressurize and concentrate to dryness to obtain a white solid, add a small amount of water to dissolve with saturated KHSO 4 Adjust to pH=2, and extract three times with ethyl acetate solution, combine the ethyl acetate layers, and extract three times with saturated NaCl. Ethyl acetate layer with anhydrous Na 2 SO 4 Dry overnight, filter to remove Na 2 SO 4 , the filtrate was concentrated to dryness under reduced...

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Abstract

The invention relates to a preparation method with lauroyl aminoacyl proline methyl ester serving as novel chemical penetration enhancer and application, belongs to the field of biological medicines, and mainly aims at solving the problem that the medicine is difficult to be absorbed through the skin. The preparation method comprises the following steps of: performing an esterification reaction on glycine, alanine, valine, proline, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, serine, threonine and methionine through dodecanoic acid respectively; performing hydrophobic modification; then conjugating with proline methyl ester, namely, C12-AA-P-OMe=(AA=G, A, V, P, L, I, F, W, Y, S, T, M) synthesis so as to obtain the novel chemical penetration enhancer with the penetration enhancing effect. According to the preparation method, the penetration enhancer is synthesized by using amino acid with body endogenous, so that the toxic and side effect of the medicine prepared to into a transdermal delivery system is greatly reduced, and the therapeutic index of the medicine is improved.

Description

Technical field: [0001] The invention designs and a novel chemical penetration enhancer, and its preparation process, especially the construction and identification method of amino acid. The invention also relates to the application of the penetration enhancer in the transdermal preparation and the evaluation method in vivo and in vitro, belonging to the field of biomedicine. Background technique: [0002] Transdermal absorption is a drug delivery method in which drugs are absorbed through the skin to achieve local or systemic therapeutic effects. After the drug is applied to the skin, it passes through the stratum corneum, diffuses through the skin, and is absorbed into the systemic circulation through the capillary. The process is called percutaneous absorption or transdermal absorption. Transdermal drug delivery system (TDDS) refers to the administration through the skin surface, so that the drug enters the systemic circulation through each layer of the skin and reaches ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/062C07K5/065C07K5/078A61K47/22
CPCY02P20/55
Inventor 崔国辉吕鲜艳
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES