Lipid prodrug of guanidinium-containing drug and drug plastid thereof

A drug substance and prodrug technology, which is applied in the field of amphiphilic lipid prodrug and its drug substance, can solve the problems of difficult to achieve and low bioavailability, optimize the operation process, and slow down the fluctuation of blood drug concentration , reduce the effect of gastrointestinal irritation

Inactive Publication Date: 2016-05-11
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is difficult to control the tablet weight (below 1 gram) while controlling the in vitro release of sustained-release tablets for more than 12 hours by using common sustained-release technology, so the preparation technology of sustained-release preparations still needs to be further improved and perfected.
Metformin enteric-coated tablets are mainly developed for its gastrointestinal side effects. The purpose is to reduce gastrointestinal side effects and facilitate patients to take it, but it does not fundamentally solve the problem of low bioavailability.
[0005] Therefore, for a new type of drug delivery system that can fundamentally solve the problem of low bioavailability of guanidine-containing drugs (such as metformin) and optimize its in vivo operation process to slow down the fluctuation of blood drug concentration and reduce the stimulation of the digestive tract, There is a great clinical need

Method used

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  • Lipid prodrug of guanidinium-containing drug and drug plastid thereof
  • Lipid prodrug of guanidinium-containing drug and drug plastid thereof
  • Lipid prodrug of guanidinium-containing drug and drug plastid thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 2

[0023] The preparation of embodiment 1. dipalmitin

[0024]

[0025] Heat and melt the palmitic acid solid (60°C), add excess SOCl dropwise to it 2 , distilled after stirring for several hours, first distilled SOCl at low temperature 2 , Distilled under reduced pressure to obtain colorless palmitoyl chloride, sealed and waterproof.

[0026] When dilute sulfuric acid is added dropwise to hot water dissolved in calcium glycerate, a large amount of white precipitate is formed immediately. After the dropwise addition was completed, the white precipitate was removed by hot filtration under the condition of maintaining the temperature to obtain an aqueous solution of glyceric acid. The water was distilled off under reduced pressure until the mother liquor was a viscous white liquid, and then the heating was stopped. Add anhydrous acetone, shake well to dissolve, add anhydrous magnesium sulfate to dry overnight. The next day, the desiccant was removed by filtration, and the ...

Embodiment 2 2

[0028] Example 2. Synthesis of Dipalmitoyl Glycerate-Metformin

[0029]

[0030] Put 0.58 g (1 mmol) of dipalmitoyl glyceride into a 50 ml flask, add 5 ml of SOCl 2 . Reflux for 8 hours, and the water pump decompresses to remove the generated HCl and SOCl 2 . 5 ml of anhydrous dichloromethane was added thereto, and 0.1 ml of anhydrous pyridine and 0.13 g of metformin were dissolved in 3 ml of methanol. The methanol solution was added dropwise into the reaction flask, stirred at room temperature for 24 hours, refluxed for 4 hours, and cooled. The obtained solution was directly spin-dried, 30 ml of dichloromethane was added, and the insoluble matter was filtered off. Wash twice with 10 mL of water, dry the organic layer and spin dry. Ethyl acetate was added, and 0.45 g of a white solid was precipitated. 1 H-NMR (CDCl 3 ): 0.85(t, 6H), 1.23(s, 48H), 1.52(m, 4H), 2.27(t, 2H), 2.32(t, 2H), 2.50(s, 6H), 4.34(m, 1H), 4.43 (m, 1H), 5.2 (m, 1H).

Embodiment 3

[0031] Example 3. Synthesis of Palmitoyl-Metformin

[0032]

[0033]Metformin hydrochloride (0.33 g, 2 mmol) was added to 2 ml of water and stirred to dissolve, then sodium hydroxide (0.08 g, 2 mmol) was added, and stirred at room temperature for 1 hour. A solution of palmitoyl chloride (0.7 g, 2.5 mmol) in acetone was added dropwise and stirred at room temperature for 2 hours. Add acetone until the precipitate no longer separates out, filter, and spin the filtrate to dryness. Add 5 ml of dichloromethane to dissolve, and filter to remove insoluble matter. Wash twice with 5 mL of water, dry the organic layer and spin dry. Ethyl acetate was added, and 0.48 g of a white solid was precipitated. 1 H-NMR (CDCl 3 ): 0.96(t, 3H), 1.31(s, 24H), 1.57(m, 2H), 2.18(t, 2H), 2.47(s, 6H).

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Abstract

The invention relates to a lipid prodrug of a drug containing guanidino and pharmacosome thereof. The lipid prodrug is a medicinal compound which is in covalent union with long-chain fatty acid with a single chain or double chains and contains guanidino. The pharmacosome is formed in such a way that the lipid prodrug disperses freely in a proper medium, is orderly arranged into a single-layer or double-layer structure, and is automatically assembled finally. The pharmacosome has biological targeting property, can effectively enhance the bioavailability of the drug and opens up a novel concept for solving the problems of poor transmembrane capability, low bioavailability and the like of a water soluble drug.

Description

technical field [0001] The present invention generally relates to an amphiphilic lipid prodrug of a guanidine group-containing drug and a drug substance thereof, and specifically relates to an amphiphilic lipid prodrug of metformin and a drug substance thereof. Background technique [0002] Pharmacosome (PS) is an emerging drug delivery system, and the research on PS is in the ascendant. The concept of pharmacosomes was first proposed by Vaizoglu et al. It refers to the formation of amphiphilicity after the drug is combined with lipids through covalent bonds, and self-assembles into highly dispersed ordered aggregates in the medium due to the change of solubility properties. A self-assembling drug delivery system. The essential feature of the drug plasmid is that the drug is both an active substance and a carrier substance, so it has many advantages, (1) the amphiphilic lipid prodrug effectively improves the transmembrane ability, and promotes the drug to pass through physi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C279/26C07C277/08A61K9/127A61K47/48A61K31/155A61P3/10A61K47/54
Inventor 梅兴国梅丹宇杨媛
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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