GSH concentration responsive pharmacosome for treating hyperthyroidism and preparation method

A technology of thyroid function and responsiveness, which is applied in the direction of pharmaceutical formulations, liposome delivery, and medical preparations of non-active ingredients. It can solve the problems of short biological half-life, large oral doses of drugs, and frequent taking times to achieve enhanced penetration. Sexuality, prolonged action time, and the effect of optimal drug selection

Active Publication Date: 2020-11-17
WUHAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the short biological half-life of methimazole, the large oral dose of the drug, and frequent administration may lead to serious consequences, there have been reports of death from acute liver failure caused by methimazole

Method used

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  • GSH concentration responsive pharmacosome for treating hyperthyroidism and preparation method
  • GSH concentration responsive pharmacosome for treating hyperthyroidism and preparation method
  • GSH concentration responsive pharmacosome for treating hyperthyroidism and preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] (1) Preparation of 3-[(1-methyl-1H-imidazol-2-yl)thio]-2-acrylic acid (methimazole acrylic acid, MMI-AA)

[0034] Methimazole (10mmol) was dissolved in methanol (1mol), sodium methoxide (10mmol) was added thereto under stirring until the methimazole was completely dissolved, and then propiolic acid (100mmol) was added therein. Reaction temperature: 10°C, under nitrogen protection, and react under reflux for 200 hours. After the reaction, use a rotary evaporator to rotate the reaction solution at 32°C for 10 minutes to obtain a thick white liquid; freeze-dry the thick white liquid for 10 hours, and obtain MMI-AA (white flake solid) after lyophilization .

[0035] (2) Preparation of 3-[(1-methyl-1H-imidazol-2-yl)thio]-2-propenoic acid-ethyl ester (methimazole ethyl acrylate, MMI-AA-OEt)

[0036]The obtained methimazole acrylic acid (1 mmol) and EDC (6 mmol) were dissolved in DMF (129 mmol), activated under stirring for 20 min, and NHS (15 mmol) was added after 20 min to...

Embodiment 2

[0038] (1) Preparation of 3-[(1-methyl-1H-imidazol-2-yl)thio]-2-acrylic acid (methimazole acrylic acid, MMI-AA)

[0039] Methimazole (10 mmol) was dissolved in methanol (0.8 mol), sodium methoxide (10 mmol) was added thereto under stirring until the methimazole was completely dissolved, and then propiolic acid (10 mmol) was added therein. Reaction temperature: 20°C, under nitrogen protection, under reflux for 150 hours. After the reaction, use a rotary evaporator to rotate the reaction solution at 32°C for 20 minutes to obtain a thick white liquid; freeze-dry the thick white liquid for 30 hours, and obtain MMI-AA (white flake solid) after lyophilization .

[0040] (2) Preparation of 3-[(1-methyl-1H-imidazol-2-yl)thio]-2-acrylic acid-n-octyl ester (methimazole n-octyl acrylate, MMI-AA-OCa)

[0041] The obtained methimazole acrylic acid (10mmol) and EDC (10mmol) were dissolved in DMF (129mmol), activated under stirring for 20min, and NHS (10mmol) was added after 20min to stabi...

Embodiment 3

[0043] (1) Preparation of 3-[(1-methyl-1H-imidazol-2-yl)thio]-2-acrylic acid (methimazole acrylic acid, MMI-AA)

[0044] Methimazole (30mmol) was dissolved in methanol (0.5mol), sodium methoxide (10mmol) was added thereto under stirring until the methimazole was completely dissolved, and then propiolic acid (10mmol) was added therein. Reaction temperature: 50°C, under nitrogen protection, and react under reflux for 100 hours. After the reaction, use a rotary evaporator to evaporate the reaction solution at 32°C for 60 minutes to obtain a thick white liquid; freeze-dry the thick white liquid for 50 hours, and obtain MMI-AA (white flake solid) after lyophilization .

[0045] (2) Preparation of 3-[(1-methyl-1H-imidazol-2-yl)thio]-2-acrylic acid-dodecyl (methimazole acrylate dodecyl, MMI-AA-OLa)

[0046] Dissolve methimazole acrylic acid (9mmol) and EDC (27mmol) in DMF (260mmol) and activate for 20min with stirring. After 20min, add NHS (45mmol) and stabilize for 1 hour with sti...

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Abstract

The invention relates to a GSH concentration responsive pharmacosome for treating hyperthyroidism and a preparation method. The pharmacosome provided by the invention has good GSH responsiveness, canrespond to glutathione concentration stimulation in cells, and realizes intelligent release of drugs through a Michael elimination reaction. The pharmacosome is suitable for being made into a transdermal drug delivery system and is used for treating the hyperthyroidism.

Description

technical field [0001] The invention relates to a methimazole drug plastid, in particular to a GSH concentration-responsive methimazole drug plastid and a preparation method thereof. Background technique [0002] Methimazole (MMI) is an imidazole antithyroid drug, its mechanism of action is to inhibit the peroxidase in the thyroid, hinder the oxidation of iodide absorbed into the thyroid and the coupling of tyrosine, and then hinder the thyroxine ( T4) and triiodothyronine (T3) synthesis. MMI does not affect the absorption of iodine and the release of synthesized hormones. Studies have shown that MMI accumulates in the thyroid after oral absorption. Only when it enters the thyroid can it exert its therapeutic effect of inhibiting thyroxine synthesis. The strength of the effect depends on the local drug concentration in the thyroid. Due to the strong hydrophilicity of MMI, it is difficult to pass through the thyroid bubble membrane, resulting in a low concentration of oral a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/00A61K9/06A61K47/44A61K47/69A61K47/54A61K31/4164A61P5/16
CPCA61K9/0004A61K9/06A61K9/0014A61K47/44A61K47/6911A61K47/541A61K31/4164A61P5/16
Inventor 戴红莲代悦
Owner WUHAN UNIV OF TECH
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