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Lipid prodrug of drug containing guanidino and pharmacosome thereof

A technology of prodrugs and drugs, which is applied in the field of amphiphilic lipid prodrugs and their drug plastids, can solve problems such as difficult to achieve and low bioavailability, optimize the operation process, slow down blood drug concentration fluctuations, reduce Effects of gastrointestinal irritation

Inactive Publication Date: 2010-06-09
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 drug containing guanidino and pharmacosome thereof
  • Lipid prodrug of drug containing guanidino and pharmacosome thereof
  • Lipid prodrug of drug containing guanidino and pharmacosome thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 2

[0023] Example 1. Preparation of glyceryl dipalmitate

[0024]

[0025] Heat the palmitic acid to melt (60°C), and add excess SOCl to it 2 , After stirring and reacting for several hours, distill, first distill out SOCl at low temperature 2 , Vacuum distillation to obtain colorless palmitoyl chloride, sealed and waterproof.

[0026] The dilute sulfuric acid was added dropwise to the hot water dissolved in calcium glycerate, and a large amount of white precipitate was immediately formed. After the dripping is completed, the white precipitate is filtered off hot while maintaining the temperature to obtain an aqueous solution of glyceric acid. The water was evaporated under reduced pressure, and the heating was stopped when the mother liquor became a viscous white liquid. Add anhydrous acetone, shake to dissolve, add anhydrous magnesium sulfate and dry overnight. The next day, filter to remove the desiccant and steam to remove acetone to obtain glyceric acid.

[0027] Dissolve palmi...

Embodiment 2 2

[0028] Example 2. Synthesis of dipalmitoyl glycerate-metformin

[0029]

[0030] Put 0.58 g (1 mmol) of dipalmitoyl glycerate in a 50 ml flask, and add 5 ml SOCl to it 2 . Reflux for 8 hours, pump down the generated HCl and SOCl 2 . 5 ml of anhydrous methylene chloride was added, 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 to the reaction flask, stirred at room temperature for 24 hours, refluxed for 4 hours, and cooled. The resulting solution was spin-dried directly, 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 to precipitate 0.45 g of white solid. 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 the mixture was stirred at room temperature for 1 hour. An acetone solution of palmitoyl chloride (0.7 g, 2.5 mmol) was added dropwise and stirred at room temperature for 2 hours. Add acetone until the precipitate no longer precipitates, filter, and spin-dry the filtrate. Add 5 ml of dichloromethane to dissolve, filter to remove insolubles. Wash twice with 5 ml of water, dry the organic layer and spin dry. Ethyl acetate was added to precipitate 0.48 g of white solid. 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 amphiphilic lipid prodrugs of drugs containing guanidine groups and their pharmacological bodies, and specifically relates to amphiphilic lipid prodrugs of metformin and their pharmacological bodies. Background technique [0002] Pharmacosome (PS) is an emerging drug delivery system, and research on pharmacosomes is now in the ascendant. The concept of drug plastid was first proposed by Vaizoglu et al. It refers to that the drug forms amphiphilic properties after being combined with lipids through covalent bonds, and self-assembles into highly dispersed ordered aggregates in the medium due to changes in solubility properties. A self-assembled drug delivery system. The essential feature of the drug plastid is that the drug is both an active substance and a carrier substance, so it has many advantages. (1) Amphiphilic lipid prodrugs can effectively improve the transmembrane ability and promote the drug to pass throu...

Claims

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Application Information

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Patent Type & Authority Applications(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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