载盐酸罗哌卡因聚乳酸-羟基乙酸共聚物微球的制备与评价及其低突释。

Development and Evaluation of Ropivacaine Loaded Poly(Lactic-Co-Glycolic Acid) Microspheres with Low Burst Release.

机构信息

Institute of Pharmacology and Toxicology, Academy of Military Medicine Sciences, Beijing 100850, China.

Department of Pharmacy, The Sixth People's Hospital of Zhengzhou, Zhengzhou, 450015, China.

出版信息

Curr Drug Deliv. 2019;16(6):490-499. doi: 10.2174/1567201816666190528122137.

DOI:10.2174/1567201816666190528122137

PMID:31132975

Abstract

BACKGROUND

The local anesthetic drugs, especially ropivacaine, were considered favorable analgesia for postoperative management because of their effective local pain relief and low adverse effects. However, the short half-life and the resulting in bolus doses lead to the indistinctive improvement of these drugs in postoperative pain relief. Therefore, the ropivacaine microspheres with sustained release and low initial burst release were anticipated.

METHODS

Three methods including oil in water (O/W), water in oil in water (W/O/W), and solid in oil in water (S/O/W) emulsion solvent evaporation method were used to optimize the ropivacaine loaded PLGA microspheres. The microspheres were evaluated both in vitro and in rats. The in vitro-in vivo correlation (IVIVC) was also investigated.

RESULTS

The microspheres prepared by O/W method showed more satisfactory properties and the microspheres used for evaluation were prepared by O/W method. The particle size, drug loading, encapsulation efficiency and burst release were 11.19±1.24 µm, 28.37±1.15%, 98.15±3.98%, and 10.96±5.37% for microspheres with PLGA of 12 kDa, and 6.64±0.61 μm, 19.62±0.89%, 92.74±4.21%, and 18.42±5.12% for microspheres with PLGA of 8 kDa, respectively. These microspheres were also injected into rats by subcutaneous, intramuscular and intraperitoneal route, respectively. It was indicated that the detectable concentration of ropivacaine could last for at least 20 days for both kinds of microspheres in spite of injection routes. The low burst releases at 1 d were also manifested in rats and they were 6.62%, 6.99%, 6.48% for the microspheres with PLGA of 12 kDa, and 4.72%, 4.33%, 4.48% for the microspheres with PLGA of 8 kDa by intraperitoneal, intramuscular and subcutaneous route, respectively. A linear relationship between the in vitro release and the in vivo adsorption of ropivacaine from microspheres was also established.

CONCLUSION

The ropivacaine microspheres with sustained release and low burst release were acquired, which indicated that the postoperative pain relief might last longer and the side effects might get lower. Therefore, the ropivacaine microspheres prepared in this paper have great potential for clinical use.

摘要

背景

局部麻醉药物，尤其是罗哌卡因，因其具有有效缓解局部疼痛和不良反应低的特点，被认为是术后管理的理想镇痛药物。然而，由于其半衰期短，导致推注剂量增加，这些药物在术后疼痛缓解方面的改善并不明显。因此，人们期望开发出具有持续释放和低初始突释的罗哌卡因微球。

方法

采用油包水（O/W）、水包油包水（W/O/W）和固包油包水（S/O/W）乳液溶剂蒸发法三种方法对载罗哌卡因 PLGA 微球进行优化。对微球进行了体外和体内评价，并研究了体外-体内相关性（IVIVC）。

结果

O/W 法制备的微球显示出更满意的性能，用于评价的微球采用 O/W 法制备。对于 12 kDa 的 PLGA 微球，微球的粒径、载药量、包封率和突释分别为 11.19±1.24 µm、28.37±1.15%、98.15±3.98%和 10.96±5.37%，对于 8 kDa 的 PLGA 微球，微球的粒径、载药量、包封率和突释分别为 6.64±0.61 µm、19.62±0.89%、92.74±4.21%和 18.42±5.12%。这些微球分别通过皮下、肌肉和腹腔途径注入大鼠体内。结果表明，两种微球在体内的检测浓度至少可维持 20 天，尽管注射途径不同。在大鼠体内也表现出较低的 1 天突释率，分别为 6.62%、6.99%、6.48%，对于 12 kDa 的 PLGA 微球，4.72%、4.33%、4.48%，对于 8 kDa 的 PLGA 微球。还建立了微球体外释放与体内吸附罗哌卡因之间的线性关系。