Study On Ropivacaine Loaded Microemulsion And Microemulsion-based Gel For Transdermal Delivery

Ropivacaine (Ropivacaine, ROP), is a novel long-acting amide local anesthetic. It blocks nerve excitability and conduction through inhibiting sodium channels in nerve cells, and thus play the role of a narcotic analgesic. Low lipid solubility of ropivacaine leads to delayed nerve arrival time to gross motor nerves, resulting in motor and sensory block separation. This feature makes ropivacaine more conducive to early postoperative recovery of motor function. Currently, patients are usually ropivacaine mesylate or hydrochloride injection, commonly used for surgical or postoperative anesthesia. However, both injection administration cause poor patients compliance.Microemulsion (ME), as a drug carrier for transdermal administration, can significantly increase the solubility of poorly soluble drugs, thereby forming a high concentration gradient and promoting drug diffusion. In addition, ingredients of ME, such as the oil phase, emulsifier and co-emulsifier, can weaken the barrier function of the stratum corneum, and promote drug penetration through the skin. In this study, ropivacaine loaded ME and ME-based gel for transdermal administration were prepared. The physicochemical properties, in vivo percutaneous penetration process and the analgesic effect were studied in order to achieve a sustained and controlled release of drugs, and improve the patients compliance.The object of the present study was to prepare and evaluate a ropiacaine-loaded microemulsion (ME) formulation and microemulsion-based carbopol gel (ME-Gel) for transdermal delivery. Pseudo-ternary phase diagrams and a simplex lattice experiment design were utilized to screen and optimize the ME formulation. In the process, drug solubility and particle size were inspected as dependent variables whilst Capryol(?) 90 (X1), Smix (X2, Labrasol(?):absolute ethanol=1:2 w/w), water (X3) as independent variables. Following the optimization, the optimal ME formulation was comprised of 15% Capryol(?) 90,53% Smix and 32% water, respectively. ME-Gel was prepared by mixing ME with Carbopol solution (1.5%) at the ratio of 2:1 (v/v). Ropivacaine loaded ME appeared to be spherical under transmission electron microscope (TEM), and the average particle size was 58.79 nm.The results of in vitro permeation study showed that ropivacaine had a significant higher cumulative amount from ME than that from ME-Gel. In In vivo permeation study, the concentrations of ropivacaine in plasma, dermis and epidermis were determined respectively. The result showed that compared with ME, plasma MRT and t1/2 of ropivacaine in ME-Gel were significantly prolonged. Both in vitro and in vivo studies confirmed the formation of in-skin drug depot, which guaranteed the sustained release of ropivacaine. Histopathology study demonstrated that the micro structure of skin surface was significantly changed by the treatment of ME formulation. Skin irritation study indicated that neither ME nor ME-Gel caused any irritation responses. Both ME and ME-Gel presented a remarkable analgesic activity on acetic acid-induced writhing in mice. Furthermore, it was verified that prepared ROP-ME-Gel exerted a remarkable treatment effect on rabbit osteoarthritis. In conclusion, ME-Gel could be a promising vehicle for ropivacaine transdermally administration.