Novel liver targeting drug carrier

A liver-targeting and drug-based technology, applied in the field of new liver-targeting drug carriers, can solve problems such as large limitations, narrow therapeutic index, and insignificant targeting, and achieve stability, high biological stability, and high efficiency. Effect

Pending Publication Date: 2020-08-11
杭州濡湜生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the lack of stability of liposomes, easy degradation in the body, easy leakage of drugs, and narrow therapeutic index, liposomes hav

Method used

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  • Novel liver targeting drug carrier
  • Novel liver targeting drug carrier
  • Novel liver targeting drug carrier

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: Acetylation of D-galactosamine

[0047] 400 milliliters of anhydrous pyridine (Py) was added 90 grams of acetic anhydride (Ac 2 O) (300 ml) suspension, then add 4.2 g of 4-dimethylaminopyridine (DMAP) and 65 ml of triethylamine (Et 3 N), the reaction mixture was stirred overnight, and the reaction process was monitored by TLC until the raw materials were substantially reacted, and the precipitated solid was filtered, washed with toluene and water respectively, and dried in vacuo to obtain 145 grams of fully acetylated D-galactosamine.

Embodiment 2

[0048] Example 2: Activation of peracetyl-D-galactosamine

[0049] 100 g of peracetyl-D-galactosamine was suspended in 1 liter of anhydrous dichloroethane (DCE) under nitrogen protection, and 56 ml of trimethylsilyl trifluoromethanesulfonate (TMSOTf) was The reaction suspension was slowly added dropwise in the atmosphere, and then the reaction mixture was stirred at room temperature of 25°C for 16 hours. The reaction mixture was carefully transferred to 3 liters of vigorously stirred ice-water suspension containing 15 wt% sodium bicarbonate and continued to stir for 1 hour, the organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (DCM). The organic phases were combined and dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to yield 91 g of product.

Embodiment 3

[0050] Example 3: Protection of glycosyl-linked carboxylate

[0051] 50 grams of the above-mentioned product of Example 2 and 50 grams of benzyl 4-hydroxybutyrate were dissolved in 300 milliliters of anhydrous dichloroethane (DCE), added 50 grams of molecular sieves and stirred for 20 minutes, then added 7 milliliters of trifluoroform Trimethylsilylsulfonate (TMSOTf) and stirred at 25°C for 16 hours. The reaction solution was poured into 600 ml of sodium bicarbonate solution mixed with ice water, stirred for 1 hour, the organic phase was separated, the aqueous phase was extracted twice with DCM, the organic phases were combined and dried with anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product, The crude product was purified by column chromatography to obtain 73 g of light yellow oily liquid.

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Abstract

The present invention discloses a novel liver targeting drug carrier which comprises: a targeting antenna and an adaptor; the targeting antenna is a four antennas capable of being specifically recognized by an asialoglycoprotein receptor on the surfaces of liver cells, and the tail ends of the four antennas are sugar units; and the adaptor is used for connecting drugs and the targeting antennas, and is a polypeptide chain which can be degraded by specific proteolytic enzyme in liver cells. According to the invention, the four-antenna sugar unit, especially N-acetyl-D-galactosamine, is used asa liver specific targeting reagent; and polypeptides capable of being degraded by specific proteolytic enzymes enriched in the liver are combined as adapters, so that the novel carrier can specifically target the liver and enter cells, and is selectively degraded in the liver cells to release drugs. The carrier can be combined with various medicines for treating liver diseases and selectively delivering the medicines to the liver, so that bioavailability of the medicines is improved, the side effect on other tissues is reduced, and the carrier is a novel efficient specific liver targeting medicine carrier.

Description

technical field [0001] The invention relates to the technical field of drug carriers, in particular to a novel liver-targeted drug carrier. Background technique [0002] Liver-targeted drug carriers can efficiently transport drugs to the liver, allow the drug concentration to effectively accumulate in the liver, reduce the distribution of drugs in other organs of the human body, thereby reducing drug dosage and administration times, and reducing drug side effects. Effective utilization, drug compliance, drug safety and disease treatment methods have positive and important significance. [0003] At present, many researches on liver-targeting drug carriers have been carried out in the world, and the main direction is to focus on liposomes as carriers. However, due to the lack of stability of liposomes, easy degradation in the body, easy leakage of drugs, and narrow therapeutic index, liposomes have great limitations as liver-targeted drug carriers, and the liver drug concentr...

Claims

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Application Information

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IPC IPC(8): A61K47/54A61K47/64A61K45/00A61K31/7088A61P1/16
CPCA61K47/549A61K47/64A61K45/00A61K31/7088A61P1/16
Inventor 王喆明谭昊
Owner 杭州濡湜生物科技有限公司
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