A novel ropivacaine-loaded in situ forming implant prolongs the effect of local analgesia in rats.
BACKGROUND
Prolonged postoperative analgesia cannot be achieved by a single injection of local anesthetic solution. The objective of this study was to optimize the formulation of a ropivacaine hydrochloride (Ropi-HCl) loaded in situ forming implant (ISI) by addition of different co-solvents, and evaluate the in vitro release of Ropi-HCl, and the analgesic effect and toxicity of the optimized formulation in rats.


METHODS
Triacetin (TA), benzyl benzoate (BB) and polyethylene glycol 400 (PEG 400) were used as additives and added to the solvent of N-methyl-2-pyrrolidone (NMP). Drug release to the surface and inner structural properties of the formed implant were evaluated by scanning electron microscopy (SEM). The analgesic effect was determined by injection near the rat sciatic nerve.


RESULTS
The solvent system added with TA or BB significantly decreased the burst release, whereas PEG 400 increased the Ropi-HCl burst release from the formulation. Over 70% of the incorporated Ropi-HCl was released from all formulations in 14 days in the in vitro assay. The SEM showed that the surface of NMP-BB formulation was less porous and more homogeneous, compared with the other formulations. Compared with Ropi-HCl injection, the optimized formulation (NMP-BB) significantly prolonged the analgesic effect in 48 h (p < 0.05), with a mild degree of motor block from 3 h to 12 h. Histological evaluation of the injection site revealed only mild inflammatory infiltration without obvious pathological nerve alterations.


CONCLUSIONS
The biodegradable Ropi-HCl-loaded ISI system with NMP-BB may prove to be an attractive and safe alternative for the delivery of parenteral local anesthetics to prolong pain relief.
Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai, PR China ; Department of Pharmaceutics, PLA No. 323 Hospital, Xi'an, Shaanxi, PR China.
Lei
L
Lu
Wei
W
Zhang
Xin
X
Wu
Xiaoyu
X
Wang
Min
M
Zhang
Quangang
Q
Zhu
Xueying
X
Ding
Zhiyun
Z
Xu
Shen
S
Gao
Jing
J
Gao
in situ forming implant; local anesthesia; ropivacaine