Ginkgolide B amorphous solid dispersion prepared through hot-melt extrusion method

Abstract

The invention discloses a ginkgolide B amorphous solid dispersion and a preparation method, and belongs to the field of a pharmaceutical preparation. Specifically, the solid dispersion is prepared by the following steps: micronizing ginkgolide B and medicinal adjuvant materials by virtue of dry grinding, so that an eutectic mixture with grain size less than 10 [mu]M (M refers to mol / L) is formed by medicines and a carrier, lowering a melting point to 300 DEG C and then conducting hot-melt extrusion at a certain rate within an extrusion temperature range from 60 DEG C to 180 DEG C, so that the solid dispersion is prepared. An in vitro dissolving experiment shows that the dissolving-out amount of the solid dispersion preparation is more than 80% within 30min, and an in vivo bioavailability experiment on a Beagle dog shows that the relative bioavailability of the ginkgolide B amorphous solid dispersion, compared to a normal tablet, is 322.8%.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and particularly designs a ginkgolide B amorphous solid dispersion and a preparation method thereof. Background technique [0002] Ginkgo biloba is the dry leaf of Ginkgobilogba L., a plant of the Ginkgo family. Studies have found that Ginkgo biloba is rich in total flavonoids and ginkgolides (including ginkgolide A, ginkgolide B, bilobalide, etc.). At present, the research on Ginkgo biloba in the field of domestic pharmacy only stays in the modification of the dosage forms of the total flavonoids of Ginkgo biloba or ginkgolide extracts, and there is not much research on its single active ingredient. [0003] Ginkgolide B (GinkgolideB, GB) is an effective monomer with the strongest anti-platelet activating factor (PAF), anti-platelet aggregation and anti-thrombotic activity in total ginkgolides. Studies have shown that ginkgolide B in ginkgo has a special molecular structure and signif...

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Problems solved by technology

The injection powder has the following defects: 1) the open-ring form is used as the medicinal form, and the clinical curative effect is relatively poor; 2) the powder injection becomes alkaline after reconstitution, and Lin Chunying et al. have shown that ginkgolides B has poor stability under alkaline conditions (Lin Chunying, Liang Lijun, Zeng Cuimei, Chinese New Drugs and Clinical Pharmacology, November 2013, Volume 24, Issue 6); 3) Its freeze-dried powder injection also has the disadvantage of poor reconstitution ( Bai Lin, Mei Shichang, Tao Zhonghua, China Pharmaceutical Industry, Volume 16, Issue 3, 2007)

The main defect that this invention exists has: 1) in the invention, the ginkgolide after micronization still exists in the excipient in the state of fine crystal particles, and aggregation will occur in the tableting and placement process, resulting in a decrease in solubility (A Jiye, Liu Yun , Feng Lin, the influence of solid preparation technology on drug crystal form, Chinese Journal of Pharmaceutical Industry, 2000, No. 11); 2) According to the relationship between drug solubility, dissolution rate and particle size proposed by Ostwald-Freundlich, only the drug crystal particle The solubility and dissolution rate of the drug can be significantly improved only after the spherical particle diameter is reduced to 100nm, while the microcrystals in this invention can only reach 5-10μm, which cannot significantly improve the dissolution rate, and the ability to improve bioavailability is limited

The defects of this invention are as follows: 1) organic solvents such as ethyl acetate and methanol are used in the preparation process, and the safety is poor; 2) the patent does not characterize the crystal form of ginkgolide B in the solid dispersion; 3) The patent only studied the improvement of in vitro dissolution, and did not conduct in vivo bioavailability studies

[0009] Chinese patent literature (publication number CN102204879A) adopts solvent method to prepare GB-povidone solid dispersion, this patent utilizes solid dispersion technology to improve drug solubility, improves drug absorption effect, but still has the following defects: 1. use toxicity relatively in the preparation process Large organic solvents, there are safety problems such as solvent residues; ② To obtain a molecularly dispersed solid dispersion requires the use of a large amount of carrier materials, resulting in low drug loading

However, ginkgolide B is a high-melting compound with a melting point of 346.6°C. It is difficult to prepare solid dispersions by hot-melt extrusion in the range of 50-250°C. Higher extrusion temperatures are required, which are higher than most carrier materials. maximum temperature

[0013] After patent and literature search, there is no relevant report on the combination of grinding micronization and hot-melt extrusion technology for the preparation of high melting point drug solid dispersions

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