Preparation and Evaluation of Progesterone Nanocrystals to Decrease Muscle Irritation and Improve Bioavailability
Preparation and Evaluation of Progesterone Nanocrystals to Decrease Muscle Irritation and Improve Bioavailability
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黄体酮纳米晶体减少肌肉刺激和提高生物利用度的制备和评价
DOI：
10.1208/s12249-017-0938-3
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发表时间：
2018-04-01
影响因子：
3.3
通讯作者：
Zheng, Aiping
中科院分区：
文献类型：
--
作者：
Li, Li;Li, Wanqing;Zheng, Aiping
孕激素（PG）是妊娠早期重要的免疫调节剂，目前PG油基注射液（PG/OI）在全球有着巨大的市场。然而，PG/OI可能在局部肌肉蓄积，并在长期给药后进一步引起刺激。在这项研究中，PG纳米晶体（PG/NCs）注射剂的开发，以减少肌肉毒性。首先使用湿研磨方法制备含有10%（w/v）PG的PG/NC注射液。然后，进行粒度、zeta电位、粉末形态、X射线衍射（PXRD）、差示扫描量热法（DSC）和傅里叶变换红外（FTIR）研究以评价剂型特征。采用家兔肌肉刺激试验、溶血试验和大鼠药代动力学试验评价PG/NC的体内特性。结果表明，纳米颗粒的平均粒径为299.5 ± 9.0 nm，zeta电位为-36.8 ± 1.5 mV。根据PXRD、DSC和FTIR结果，PG/NC的结晶状态在粒度减小期间没有改变。肌肉刺激性显示PG/NC的刺激性低于PG/OI。溶血试验表明PG/NCs注射液无溶血和红细胞凝集作用。药代动力学研究表明，PG/NC注射液的AUC（0-t）和C（max）分别是PG/OI的3.2倍（p < 0.05）和3.1倍，表明PG/NC注射液的生物利用度高于PG/OI。因此，PG/NCs注射液具有较低的肌肉刺激性、溶血率和较高的生物利用度，是比OI更好的剂型。
Progesterone (PG) is a crucial immunomodulatory agent during early pregnancy, and nowadays PG oil-based injection (PG/OI) has a huge market all over the world. However, PG/OI may accumulate the local muscle and further cause irritations after long-term administration. In this study, PG nanocrystals (PG/NCs) injection was developed to decrease muscle toxicity. PG/NCs injection containing 10% (w/v) PG was first prepared using a wet grinding method. Then, particle size, zeta potential, morphology powder, X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and Fourier transform infrared (FTIR) studies were carried out to evaluate the characteristics of dosage form. The rabbit muscle irritation, hemolysis, and rat pharmacokinetics tests were used to estimate the in vivo characteristics of PG/NCs. The results showed that the mean particle size and the zeta potentials of NCs were 299.5 +/- 9.0 nm and - 36.8 +/- 1.5 mV, respectively. The crystalline state of PG/NCs was not altered during particle size reduction according to PXRD, DSC, and FTIR results. Muscle irritation presented that PG/NCs had lower irritation than that of PG/OI. Hemolysis test suggested that PG/NCs injection was functioned without hemolysis and red cell agglutination. The pharmacokinetics study showed that the AUC (0-t) and C (max) of PG/NCs was 3.2-fold (p < 0.05) and 3.1-fold higher than PG/OI, which demonstrated that PG/NCs injection had greater bioavailability than PG/OI. Therefore, it was obvious that PG/NCs injection exhibited a lower muscle irritation, hemolysis rate, and higher bioavailability, which was a better dosage form than OI.