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Carrier for transmembrane delivery of molecules and preparation method of carrier

A carrier and molecular technology, applied in non-active ingredient medical preparations, active ingredient-containing medical preparations, pharmaceutical formulations, etc., can solve the limited loading capacity of hydrophilic drugs, easy adhesion, and efficient cholesterol transmembrane characteristics Issues such as not being able to achieve better

Pending Publication Date: 2021-04-13
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The carrier material constructed in this way has the following problems: in this type of material, cholesterol is mostly wrapped in the core part of the carrier, and the amount exposed on the surface of the carrier is very small, and the high-efficiency transmembrane properties of cholesterol cannot be well realized; The ability to entrap hydrophilic drugs is limited, and other drug entrapment methods must be added, such as electrostatic adsorption and other methods
The main reasons are as follows: First, some studies have shown that excessive intake of cholesterol will affect the health of the body. Therefore, research on the high-efficiency transmembrane properties of cholesterol, especially the high-efficiency absorption of cholesterol in the intestine, mainly focuses on inhibiting cholesterol absorption. There are very few studies on promoting the transmembrane absorption of drugs, especially biomacromolecules, with the help of cholesterol's high intestinal absorption capacity; secondly, cholesterol is extremely hydrophobic, and when it is distributed on the surface of the carrier to promote transmembrane or barrier absorption, The main performance of the carrier is hydrophobic, which makes the carrier poorly dispersed in water and easy to stick; at the same time, there is no suitable way to distribute cholesterol on the surface of the carrier

Method used

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  • Carrier for transmembrane delivery of molecules and preparation method of carrier
  • Carrier for transmembrane delivery of molecules and preparation method of carrier
  • Carrier for transmembrane delivery of molecules and preparation method of carrier

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] diethylene glycol As a linking group, couple cholesterol and phosphate groups to form a new carrier material with the structure:

[0094]

[0095] The specific synthesis process is as follows: Take 10 g of cholesterol, 8 g of p-toluenesulfonyl chloride, and 50 ml of pyridine to dissolve, stir and react at room temperature for 24 hours, track the reaction by thin-layer chromatography, separate and purify to obtain product A. Take 5g of product A, 20g of diethylene glycol, dissolve in 90mL of epoxyhexacycline, heat and reflux at 120°C for 10h, follow the reaction by thin layer chromatography, separate and purify to obtain product B. Take 1.6g of product B, add 6g of tetrabutyl disodium hydrogen phosphate, dissolve it with 16mL of chloroform, add 2mL of trichloroacetonitrile under the condition of stirring in an ice bath, react for 30min, separate and purify to obtain the final product, the product is white solid.

[0096] The linking group of embodiment 1 is changed...

Embodiment 2

[0098] 1,6-hexanediol As a linking group, couple cholesterol and phosphate groups to form a new carrier material with the structure:

[0099]

[0100] The specific synthesis steps are as follows: after dissolving 5 g of cholesterol, 4 g of p-toluenesulfonyl chloride, and 30 ml of pyridine, the mixture was stirred and reacted at room temperature for 24 hours. Take 5g of product A, 20g of hexanediol, dissolve it in 90mL of epoxyhexacycline, heat and reflux at 120°C for 10h, follow the reaction by thin layer chromatography, separate and purify to obtain product B. Take 0.9g of product B, add 6g of tetrabutyl disodium hydrogen phosphate, dissolve it with 8mL of chloroform, add 1.1mL of trichloroacetonitrile under ice-bath stirring conditions, react for 30min, separate and purify to obtain the final product, the product is white solid.

[0101] The linking group of embodiment 2 is changed into: The carrier material can still be synthesized according to the synthesis steps...

Embodiment 3

[0103] Weigh 100 mg of the final product of Example 2 and dissolve it in 16 mL of chloroform to form an oil phase; weigh 20 mg of triptorelin acetate and dissolve it in 1200 μL of purified water to form an inner aqueous phase 1; 600 μL of 200 mM calcium nitrate solution, pH 5.0, forming the inner water phase 2; adding the inner water phase 1 and the inner water phase 2 to the oil phase at the same time, ultrasonically forming a water-in-oil emulsion, removing chloroform under reduced pressure, drying to remove residual water, and forming a carrier.

[0104] It was analyzed by high performance liquid chromatography, and the drug loading and encapsulation efficiency of the preparation were monitored respectively according to the following formulas. The drug loading and encapsulation efficiency of the carrier prepared in Example 3 are shown in Table 1.

[0105]

[0106]

[0107] Drug loading and encapsulation efficiency of Table 1 Example 3

[0108]

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Abstract

The invention discloses a carrier for transmembrane delivery of molecules and a preparation method of the carrier, and particularly provides an amphiphilic small molecular carrier material, namely a cholesterol phosphate conjugate. The carrier is characterized in that cholesterol is taken as a shell, a phosphate group is taken as an inner core, additional soluble calcium salt takes the phosphate group in the inner core as a calcification binding site, adjacent phosphate groups are combined through calcium, a calcification layer is formed on the surface of the phosphate group in the inner core, and the structure of the carrier is more stable due to the formation of the calcification layer. The carrier is high in encapsulation efficiency, high in drug loading capacity and good in stability in a delivery process, has high transmembrane efficiency, and can achieve efficient delivery of molecules.

Description

Technical field: [0001] The invention belongs to the field of pharmaceutical preparations, and relates to a carrier for transmembrane delivery of molecules and a preparation method thereof, in particular to an amphiphilic small molecule compound cholesterol phosphate conjugate used for preparing the carrier. Background technique: [0002] Biomacromolecular drugs mainly represented by proteins, peptides, antibodies, vaccines, and nucleic acids. Compared with small molecule chemical drugs, biomacromolecular drugs have the advantages of high selectivity, high targeting and high efficacy. It plays an extremely important role in the prevention and control of major epidemic diseases and is one of the most promising fields of drug research and development in the 21st century. However, biomacromolecules have large molecular weight, complex structure, poor stability in vivo and in vitro, and it is difficult to effectively cross biological barriers in vivo (cell membrane, gastrointest...

Claims

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Application Information

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IPC IPC(8): A61K9/51A61K9/50A61K45/00A61K47/28
CPCA61K9/5123A61K45/00A61K9/5015Y02A50/30
Inventor 周卫丁宇王翘楚
Owner CHINA PHARM UNIV
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