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Application of midazolam nanocrystal in preparation of drugs for improving blood-brain barrier permeability

A technology of midazolam and blood-brain barrier, applied in the field of medicine

Active Publication Date: 2021-03-02
ACADEMY OF MILITARY MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Nanosuspensions are neutral and less irritating, but because midazolam is a poorly soluble drug, drug dissolution and dissolution become the rate-limiting steps for its in vivo absorption

Method used

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  • Application of midazolam nanocrystal in preparation of drugs for improving blood-brain barrier permeability
  • Application of midazolam nanocrystal in preparation of drugs for improving blood-brain barrier permeability
  • Application of midazolam nanocrystal in preparation of drugs for improving blood-brain barrier permeability

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0227] Example 1 Preparation of midazolam nanocrystal suspension

[0228] Add 2.5g of HPMC E5 into 100ml of water, heat to 50°C, stir until completely dissolved, then add 1g of SDS, 5g of midazolam, and homogenize by ultrasonication for 5min to fully wet the midazolam and suspend evenly. Pour the primary mixture into a wet mill with an initial rotation speed of 1500rpm, and increase the rotation speed by 500rpm every 5min until the rotation speed reaches 3000rpm, and continue grinding for 1h. The ground nano-suspension was diluted 200 times, and the particle size of the prepared nano-crystals was detected to be 286.6 nm, the polydispersity index (PDI) was 0.124, and the Zeta potential was -23.4 mV.

Embodiment 2

[0263] Example 2 Preparation of midazolam nanocrystal suspension

[0264] Add 2.5g of HPMC E5 to 100ml of water, heat to 55°C, stir until completely dissolved, then add 0.5g of SDS and 5g of midazolam, and homogenize by ultrasonication for 5min to fully wet the midazolam and suspend evenly. Pour the initial mixture into a wet mill, the initial speed is 1500rpm, and the speed is increased by 500rpm every 5 minutes until it reaches 3000rpm, and the grinding is continued for 1h to obtain the product. The ground nanosuspension was diluted 200 times, and the particle size of the prepared midazolam nanocrystals was detected to be 267.3 nm, the polydispersity index (PDI) was 0.132, and the Zeta potential was -28.1 mV.

Embodiment 3

[0341] Example 3 Preparation of midazolam nanocrystal suspension

[0342] Add 2.5g of HPMC E5 into 100ml of water, heat to 60°C, stir to dissolve, then add 0.5g of SDS and 10g of midazolam, and homogenize by ultrasonication for 5min to fully wet the midazolam and suspend evenly. Pour the initial mixture into a wet mill, the initial speed is 1500rpm, and the speed is increased by 500rpm every 5 minutes until it reaches 3500rpm, and the grinding is continued for 2h to obtain the product. The ground nanosuspension was diluted 200 times, the detected particle size was 223.6nm, the polydispersity index (PDI) was 0.124, and the Zeta potential was -25.8mV.

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Abstract

The invention provides an application of a midazolam nanocrystal and a composition thereof in medicines for improving blood-brain barrier permeability. According to the midazolam nanocrystal, the solubility problem is solved, the bioavailability is improved, the problem that the treatment effect is poor when tablets and injection are used as anticonvulsant and antiepileptic drugs is solved, and the midazolam nanocrystal can effectively penetrate through a blood brain barrier and is used for treating epilepsy. In addition, the invention provides a technical platform, and the blood-brain barrierpermeability of the brain medicine is improved by the nanocrystalline preparation in the presence of a space protective agent and a charge stabilizer.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to the application of midazolam nanocrystals in the preparation of medicines for improving blood-brain barrier permeability. Background technique [0002] Midazolam [8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-α][1,4]benzodiazepine, the structure is as follows Shown in Ⅰ] It acts through the γ-aminobutyric acid (GABA) receptor binding site, inhibits the reverse transport of glutamate carrier in human glial cells, and reduces the release of excitatory transmitter glutamate, thereby effectively controlling Convulsions. The indications for midazolam maleate tablets are "sleep disorders, insomnia, especially suitable for those who have trouble falling asleep, and premedication for surgery or diagnostic procedures". The indications for midazolam injection are "premedication before induction of anesthesia, induction and maintenance of anesthesia, conscious sedation ...

Claims

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Application Information

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IPC IPC(8): A61K31/5517A61K45/06A61K9/10A61K47/10A61K47/44A61K47/38A61P25/08
CPCA61K31/5517A61K45/06A61K9/10A61K47/10A61K47/44A61K47/38A61P25/08A61K2300/00
Inventor 郑爱萍张洵李蒙张慧高静刘楠王增明高翔
Owner ACADEMY OF MILITARY MEDICAL SCI
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