采用热熔挤出技术将无定形西罗莫司包封在聚合物薄膜中以防止其自动氧化的制备、表征和预防。

Preparation, Characterization and Prevention of Auto-oxidation of Amorphous Sirolimus by Encapsulation in Polymeric Films Using Hot Melt Extrusion.

机构信息

Institute of Chemical and Engineering Sciences, 1, Pesek Road Jurong Island, Singapore-627833, Singapore.

Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore, Singapore.

出版信息

Curr Drug Deliv. 2019;16(7):663-671. doi: 10.2174/1567201816666190416123939.

DOI:10.2174/1567201816666190416123939

PMID:31038065

Abstract

BACKGROUND

Sirolimus (SIR) is a macrocyclic lactone antibiotic and used therapeutically as a potent immunosuppressant for prophylaxis of kidney transplant rejection. The development of an oral dosage form is challenging because of very poor aqueous solubility (2.6µg/ml). The oral bioavailability of SIR is only 15-20 % and is affected by food and other drugs. The main reasons for low bioavailability are intestinal degradation by enzymes especially by cytochrome P4503A4, efflux by P-glycoprotein and hepatic first-pass metabolism.

OBJECTIVE

The main objective was to prepare a mouth dissolving film dosage form of amorphous SIR to improve dissolution.

METHODS

Crystalline SIR was transformed to its form amorphous by milling for 2 h at room temperature. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and powder x-ray diffraction (PXRD) were used for characterisation. The stability of amorphous SIR was studied at 4°C and 40°C/75% RH. Amorphous SIR was formulated as oral films by melt extrusion with polyvinylpyrrolidone- vinyl acetate (PVP-VA), Soluplus® and hydroxypropyl cellulose (HPC) as carriers. The films were characterized for drug content, physical state, dissolution profile and stability at 4°C and 40°C/75% RH.

RESULTS

The PRXD and DSC confirmed the conversion of crystalline SIR to amorphous form by milling. The solubility of amorphous SIR was several folds higher than its crystalline form, but amorphous SIR was highly unstable at all tested temperatures (4° and 40°C). The extruded films exhibited higher dissolution and stability compared to milled SIR powder alone, but the process of extrusion had some detrimental effect on the chemical stability of amorphous SIR.

CONCLUSION

The film formulations showed a significant improvement in the storage stability of the amorphous form of SIR and the solubility advantage of the amorphous form was evident in the dissolution testing. The oral films can potentially improve the bioavailability of SIR by absorption through the buccal mucosa.

摘要

背景

西罗莫司（SIR）是一种大环内酯类抗生素，临床上用作预防肾移植排斥反应的强效免疫抑制剂。由于其水溶性极差（2.6μg/ml），因此开发口服剂型极具挑战性。SIR 的口服生物利用度仅为 15-20%，并受食物和其他药物的影响。生物利用度低的主要原因是肠道中酶（特别是细胞色素 P4503A4）的降解、P-糖蛋白的外排以及肝脏的首过代谢。

目的

本研究旨在制备 SIR 口溶膜剂以提高其溶解性能。

方法

室温下将 SIR 晶体制备成无定形 SIR，研磨 2 小时。采用热重分析（TGA）、差示扫描量热法（DSC）和粉末 X 射线衍射（PXRD）对其进行了表征。在 4°C 和 40°C/75%RH 下研究了无定形 SIR 的稳定性。采用聚维酮-醋酸乙烯酯（PVP-VA）、Soluplus®和羟丙基纤维素（HPC）作为载体，通过熔融挤出法将无定形 SIR 制成口服薄膜。对薄膜的药物含量、物理状态、溶出度和在 4°C 和 40°C/75%RH 下的稳定性进行了表征。

结果

PXRD 和 DSC 证实了 SIR 晶型向无定形的转变。无定形 SIR 的溶解度比其晶型高几个数量级，但在所有测试温度（4°C 和 40°C）下，无定形 SIR 都极不稳定。与单独研磨的 SIR 粉末相比，挤出的薄膜具有更高的溶出度和稳定性，但挤出过程对无定形 SIR 的化学稳定性有一定的不利影响。