Acid-sensitive polymeric micelle pharmaceutical composition and preparation method thereof

A technology of polymers and synthetic methods, applied in the direction of drug combinations, pharmaceutical formulations, anti-tumor drugs, etc., can solve the problems of loss, toxic side effects, short half-life, etc.

Inactive Publication Date: 2010-11-10
JIANGNAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chemotherapy is currently the clinical dominant method in the process of tumor treatment, but there are insurmountable shortcomings in the chemotherapy of direct administration of antitumor drugs: 1) The half-life of the internal circulation in the body is too short to make the curative effect of the drug poor; 2) The lack of selectivity to use Drugs have strong toxic and side effects on healthy tissues and cells; 3) Drugs and the body are prone to internal immune rejection, which reduces the efficacy of the drug or even completely loses it
However, the common feature of these nano-micelle particles with a primary core-shell structure is that the core-shell structure of the micellar carrier completely disintegrates in a short period of time in a slightly acidic environment, and the drug loaded in it is quickly released, resulting in Local drug concentration is too high, resulting in greater toxic side effects, but also reduce drug tumor killing efficiency and bioavailability

Method used

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  • Acid-sensitive polymeric micelle pharmaceutical composition and preparation method thereof
  • Acid-sensitive polymeric micelle pharmaceutical composition and preparation method thereof
  • Acid-sensitive polymeric micelle pharmaceutical composition and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] The synthetic method of 2-ethoxytetrahydrofuran-2-oxyethyl methacrylate monomer is realized through the following steps:

[0045] 1) Preparation of 2-(2'-hydroxyethoxy)-2-ethoxytetrahydrofuran

[0046] Under nitrogen atmosphere, 7.60g (47.44mmol) of 2,2-diethoxytetrahydrofuran, 11.78g (189.79mmol) of ethylene glycol and a small amount of p-toluenesulfonic acid were reacted at 130°C for 18 hours and then cooled to room temperature. The reaction mixture was dissolved in ethyl acetate, washed with saturated aqueous sodium carbonate and saturated brine, dried over magnesium sulfate, evaporated under reduced pressure to remove the solvent, and dried in vacuo to obtain 6.94 g of a colorless oily pure product with a yield of 83%. 1 H NMR (300MHz, CDCl 3 ): δ (ppm) 1.15-1.20 (t, 3H, CH 3 ), 1.89-1.94 (m, 2H, CH 2 ), 2.42-2.47 (t, 2H, CH 2 ), 3.42-3.61 (m, 4H, OCH 2 ), 3.69-3.82 (m, 2H, CH 2 OH), 4.19-4.23(t, 2H, OCH 2 ). 13 C NMR (CDCl 3 , δppm): 15.22, 25.15, 30.97, 3...

Embodiment 2

[0050] 1.50g (0.29mmol) polyethylene glycol macroinitiator, 2.14g (8.76mmol) 2-ethoxytetrahydrofuran-2-oxyethyl methacrylate, 28.86mg (0.29mmol) cuprous chloride, 90.58mg (0.58mmol) of bipyridine was accurately weighed and put into a dry and clean glass polymerization tube, and finally 4ml of toluene was added. After the polymer was frozen three times, thawed, vacuumed, nitrogen-filled and deoxidized, the tube was sealed, and then the polymerization reaction tube was heated and polymerized in an oil bath at 80°C. After 8 hours of reaction, the reaction mixture was dissolved in tetrahydrofuran and passed through a short period of time. A basic alumina column to remove metal compounds from the catalyst. After most of the tetrahydrofuran was removed by rotary evaporation, the polymer was precipitated with a large amount of hexane, filtered, and vacuum-dried to constant weight to obtain the target copolymer P1. The properties of the copolymer are shown in Table 1.

Embodiment 3

[0052] 1.50g (0.29mmol) polyethylene glycol macroinitiator, 3.57g (14.60mmol) 2-ethoxytetrahydrofuran-2-oxyethyl methacrylate, 28.86mg (0.29mmol) cuprous chloride, 90.58mg (0.58mmol) of bipyridine was accurately weighed and put into a dry and clean glass polymerization tube, and finally 5ml of toluene was added. After the polymer was frozen three times, thawed, vacuumed, nitrogen-filled and deoxidized, the tube was sealed, and then the polymerization reaction tube was heated and polymerized in an oil bath at 80°C. After 12 hours of reaction, the reaction mixture was dissolved in tetrahydrofuran and passed through a short period of time. A basic alumina column to remove metal compounds from the catalyst. After most of the tetrahydrofuran was removed by rotary evaporation, the polymer was precipitated with a large amount of hexane, filtered, and vacuum-dried to constant weight to obtain the target copolymer P2. The properties of the copolymer are shown in Table 1.

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PUM

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Abstract

The invention relates to a synthesis method of an amphiphilic block polymer of which the side chain contains acid-sensitive matrixes (ortho-esters), a delivery carrier thereof and a pH-sensitive controlled-release micelle pharmaceutical composition containing an activator. The pharmaceutical composition can be a partial controllable delivery preparation formulation or an injectable preparation formulation for the activator. Hydrophobic medicines can be loaded in the micelle easily by using a simple method, and the polymeric pharmaceutical composition can greatly improve the intracellular transmission efficiency of medicines and the killing efficiency of cancer cells.

Description

technical field [0001] The invention relates to a method for synthesizing an amphiphilic block polymer with an acid-sensitive group (ortho ester) in its side chain, the delivery carrier thereof, and a controlled-release micelle pharmaceutical composition containing an active agent. The pharmaceutical composition may be in a locally controlled delivery or injectable form for the active agent. The invention belongs to the technical field of polymer carriers and sustained-release materials. Background technique [0002] Tumor is one of the main diseases that threaten human health, and tumor treatment is also a worldwide problem. Chemotherapy is currently the clinical dominant method in the process of tumor treatment, but there are insurmountable shortcomings in the chemotherapy of direct administration of anticancer drugs: 1) The half-life of the internal circulation in the body is too short, which makes the curative effect of the drug poor; 2) The lack of selectivity to use ...

Claims

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Application Information

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IPC IPC(8): C07D307/20C08F293/00A61K47/32A61K31/704A61P35/00
Inventor 唐汝培
Owner JIANGNAN UNIV
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