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联合共晶和纳米晶体技术提高难溶性药物的溶解度和溶出速率。

Combination of co-crystal and nanocrystal techniques to improve the solubility and dissolution rate of poorly soluble drugs.

机构信息

College of Pharmacy, Freie Universität Berlin, Kelchstr. 31, 12169, Berlin, Germany.

出版信息

Pharm Res. 2022 May;39(5):949-961. doi: 10.1007/s11095-022-03243-9. Epub 2022 May 12.

DOI:10.1007/s11095-022-03243-9
PMID:35552985
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9160134/
Abstract

PURPOSE

Solubility and dissolution rate are essential for the oral absorption and bioavailability of poorly soluble drugs. The aim of this study was to prepare nano-co-crystals by combination of nanocrystal and co-crystal technologies, and investigate its effect, in situ, on increased kinetic solubility and dissolution rate.

METHODS

Co-crystals of itraconazole-fumaric acid, itraconazole-succinic acid, indomethacin-saccharin and indomethacin-nicotinamide were prepared and nano-sized by wet milling. The particle size and solid state of the co-crystals were characterized by optical microscope, LD, PCS, DSC and XRPD before and after milling.

RESULTS

300-450 nm sized nano-co-crystals with a stable physical solid state were successfully prepared. Nano-co-crystals exhibited a lower crystallinity reduction than nanocrystals after wet milling. The particle size effect on the kinetic solubility of co-crystals was analysed for macro-, micro- and nano-co-crystals with in situ kinetic solubility studies. The maximum kinetic solubility of nano-co-crystals increased with excess conditions until a plateau. The highest increase was obtained with itraconazole-succinic acid nano-co-crystals with a kinetic solubility of 263.5 ± 3.9 μg/mL which was 51.5 and 6.6 times higher than the solubility of raw itraconazole and itraconazole-succinic acid co-crystal.

CONCLUSIONS

The synergistic effect of nanocrystals and co-crystals with regard to increased kinetic solubility and dissolution rate was proven. The combination of the advantages of nanocrystals and co-crystals is a promising formulation strategy to increase both the solubility and dissolution rate of poorly soluble drugs.

摘要

目的

溶解度和溶出速率对于难溶性药物的口服吸收和生物利用度至关重要。本研究旨在通过纳米晶体和共晶体技术的结合制备纳米共晶体，并考察其对提高动力学溶解度和溶出速率的影响。

方法

制备伊曲康唑-富马酸、伊曲康唑-琥珀酸、吲哚美辛-糖精和吲哚美辛-烟酰胺共晶，并通过湿磨将其纳米化。在研磨前后，通过光学显微镜、LD、PCS、DSC 和 XRPD 对共晶的粒径和固体状态进行了表征。

结果

成功制备了粒径为 300-450nm、具有稳定物理固体状态的纳米共晶体。与纳米晶体相比，湿磨后纳米共晶体的结晶度降低较小。通过原位动力学溶解度研究，对宏观、微观和纳米共晶体的粒径对共晶动力学溶解度的影响进行了分析。纳米共晶体的最大动力学溶解度随过饱和度的增加而增加，直至达到平台。伊曲康唑-琥珀酸纳米共晶体的动力学溶解度最高增加了 51.5 倍和 6.6 倍，达到 263.5±3.9μg/mL，分别高于原料药伊曲康唑和伊曲康唑-琥珀酸共晶的溶解度。

结论

证明了纳米晶体和共晶体协同作用提高动力学溶解度和溶出速率的效果。纳米晶体和共晶体的优势结合是提高难溶性药物溶解度和溶出速率的一种有前途的制剂策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/e51a004275d1/11095_2022_3243_Fig11_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/f3932690a3e2/11095_2022_3243_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/441204128977/11095_2022_3243_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/79e5376ea114/11095_2022_3243_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/92c1de726b90/11095_2022_3243_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/82377e42cadf/11095_2022_3243_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/378ce0985f5f/11095_2022_3243_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/095311b6f204/11095_2022_3243_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/d96480f17fa2/11095_2022_3243_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/331cfafe51b5/11095_2022_3243_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/4236c6952724/11095_2022_3243_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/e51a004275d1/11095_2022_3243_Fig11_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/f3932690a3e2/11095_2022_3243_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/441204128977/11095_2022_3243_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/79e5376ea114/11095_2022_3243_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/92c1de726b90/11095_2022_3243_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/82377e42cadf/11095_2022_3243_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/378ce0985f5f/11095_2022_3243_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/095311b6f204/11095_2022_3243_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/d96480f17fa2/11095_2022_3243_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/331cfafe51b5/11095_2022_3243_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/4236c6952724/11095_2022_3243_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51f4/9160134/e51a004275d1/11095_2022_3243_Fig11_HTML.jpg

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