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Preparation method of hyaluronic acid-alendronate sodium- methotrexate nanometer granules

A technology of sodium alendronate and hyaluronic acid, which is applied to medical preparations with no active ingredients, medical preparations containing active ingredients, and pharmaceutical formulas, etc., which can solve adverse effects on human body treatment, high solvent toxicity, and complicated processes etc. to achieve the effects of low toxicity and side effects, good dispersion, and high targeting efficiency

Pending Publication Date: 2019-09-17
YANGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Chinese patent application CN105055322A discloses a method for preparing a methotrexate phospholipid complex. The preparation process involves many raw materials, high solvent toxicity, and complicated process, and the obtained nanoparticles have a wide distribution of diameters, ranging from 100-500nm. There is distribution, which is not conducive to the application in the human body for treatment

Method used

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  • Preparation method of hyaluronic acid-alendronate sodium- methotrexate nanometer granules
  • Preparation method of hyaluronic acid-alendronate sodium- methotrexate nanometer granules
  • Preparation method of hyaluronic acid-alendronate sodium- methotrexate nanometer granules

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] The first step is to weigh 800mg of high-efficiency catalyst EDC and 400mg of NHS, add 60mL of deionized water to dissolve, then add 200mg of hyaluronic acid, react for 1 hour under stirring conditions to activate the carboxylic acid part, then add 360mg of alendronate sodium and continue stirring for 24 hours . The obtained product was dialyzed with purified water, the molecular weight of the dialysis bag was 300-1000, stopped after 2 days, and then freeze-dried to collect HA-ALN samples.

[0031] In the second step, the prepared HA-ALN (84mg) was dissolved in 30mL DMF, stirred continuously, then diluted with 25mL DMSO, and stirred.

[0032] In the third step, MTX (84 mg, 0.184 mM) was dissolved in 5 mL DMSO, 152 mg EDC and 90 mg DMAP were weighed, mixed with MTX, and stirred slowly for 30 min under magnetic stirring conditions.

[0033] The fourth step is to mix the solutions of step 2 and step 3, react at room temperature for 24h, and dialyze it for 48h. The molecul...

Embodiment 2

[0037]In the first step, weigh 800mg of high-efficiency catalyst EDC and 400mg of NHS, add 60mL of deionized water to dissolve, then add 200mg of hyaluronic acid, react for 1 hour under stirring to activate the carboxylic acid part, then add 400mg of alendronate sodium and continue stirring for 24 hours . The obtained product was dialyzed with purified water, the molecular weight of the dialysis bag was 300-1000, stopped after 2 days, and then freeze-dried to collect HA-ALN samples.

[0038] In the second step, the prepared HA-ALN (100mg) was dissolved in 30mL DMF, stirred continuously, then diluted with 25mL DMSO, and stirred.

[0039] In the third step, MTX (84 mg) was dissolved in 5 mL DMSO, 152 mg EDC and 90 mg DMAP were weighed, mixed with MTX, and stirred slowly for 30 min under magnetic stirring conditions.

[0040] The fourth step is to mix the solutions of step 2 and step 3, react at room temperature for 24h, and dialyze it for 48h. The molecular weight of the dialys...

Embodiment 3

[0049] In the first step, weigh 800mg of high-efficiency catalyst EDC and 400mg of NHS, add 60mL of deionized water to dissolve, then add 200mg of hyaluronic acid, react for 1 hour under stirring to activate the carboxylic acid part, then add 440mg of alendronate sodium and continue stirring for 24 hours . The obtained product was dialyzed with purified water, the molecular weight of the dialysis bag was 300-1000, stopped after 2 days, and then freeze-dried to collect HA-ALN samples.

[0050] In the second step, the prepared HA-ALN (126mg) was dissolved in 30mL DMF, stirred continuously, then diluted with 25mL DMSO, and stirred.

[0051] In the third step, MTX (84 mg) was dissolved in 5 mL DMSO, 152 mg EDC and 90 mg DMAP were weighed, mixed with MTX, and stirred slowly for 30 min under magnetic stirring conditions.

[0052] The fourth step is to mix the solutions of step 2 and step 3, react at room temperature for 24h, and dialyze it for 48h. The molecular weight of the dialy...

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Abstract

The invention discloses a preparation method of hyaluronic acid-alendronate sodium-methotrexate nanometer granules. The method comprises the steps of adding hyaluronic acid to an aqueous solution of EDC and NHS, after carboxyl activation, adding alendronate sodium, continuing a stirring reaction, and performing dialysis to obtain an HA-ALN coupling substance; then enabling the HA-ALN coupling substance to dissolve in DMF, adding DMSO, performing diluting to prepare an HA-ALN coupling substance solution, enabling methotrexate to dissolve in dimethylsulfoxide, and adding EDC and DMAP, to prepare a methotrexate solution; and finally, mixing the HA-ALN coupling substance solution with the methotrexate solution, and performing a normal-temperature reaction to prepare the hyaluronic acid-alendronate sodium-methotrexate nanometer granules. The prepared HA-ALN-MTX coupling substance is high in stability and favorable in dispersibility, can be targeted to cancer cells to effectively kill cancer cells, and besides, is low in toxic and side effect, and has application prospect in tumor targeted therapy.

Description

technical field [0001] The invention belongs to the technical field of preparation of anticancer drugs, and relates to a method for preparing hyaluronic acid-sodium alendronate-methotrexate nanoparticles. Background technique [0002] Alendronate sodium (ALN) is an amino bisphosphonate, which is an effective inhibitor of bone resorption, and its inhibition of bone resorption is about 1000 times that of similar drug hydroxyethyl phosphate sodium. ALN has a high affinity with the mineral hydroxyapatite in bone, and can spontaneously accumulate on the bone surface after ingestion by the human body. Therefore, it is often used as a bone-targeting ligand to treat bone-related diseases. On the one hand, ALN can inhibit osteoclasts and induce the apoptosis of osteoclasts; on the other hand, ALN can protect osteoblasts and osteocytes, and inhibit the apoptosis of osteoblasts. However, ALN has the problem of low bioavailability during use. [0003] Hyaluronic acid (HA) is a high-mo...

Claims

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Application Information

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IPC IPC(8): A61K47/69A61K47/61A61K31/663A61K31/519A61P35/00
CPCA61K47/6939A61K31/663A61K31/519A61P35/00A61K2300/00
Inventor 朱沛志吴亚萍王蒙蒙
Owner YANGZHOU UNIV
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