Controlled release of optimized electroporation enhances the transdermal efficiency of sinomenine hydrochloride for treating arthritis in vitro and in clinic

Abstract

Sinomenine hydrochloride (SH) is an ideal drug for the treatment of rheumatoid arthritis and osteoarthritis. However, high plasma concentration of systemically administered SH can release histamine, which can cause rash and gastrointestinal side effects. Topical delivery can increase SH concentration in the synovial fluid without high plasma level, thus minimizing systemic side effects. However, passive diffusion of SH was found to be inefficient because of the presence of the stratum corneum layer. Therefore, an effective method is required to compensate for the low efficiency of SH passive diffusion. In this study, transdermal experiments in vitro and clinical tests were utilized to explore the optimized parameters for electroporation of topical delivery for SH. Fluorescence experiment and hematoxylin and eosin staining analysis were performed to reveal the mechanism by which electroporation promoted permeation. In vitro, optimized electroporation parameters were 3 KHz, exponential waveform, and intensity 10. Using these parameters, transdermal permeation of SH was increased by 1.9–10.1 fold in mice skin and by 1.6–47.1 fold in miniature pig skin compared with passive diffusion. After the electroporation stimulation, the intercellular intervals and epidermal cracks in the skin increased. In clinical tests, SH concentration in synovial fluid was 20.84 ng/mL after treatment with electroporation. Therefore, electroporation with optimized parameters could significantly enhance transdermal permeation of SH. The mechanism by which electroporation promoted permeation was that the electronic pulses made the skin structure looser. To summarize, electroporation may be an effective complementary method for transdermal permeation of SH. The controlled release of electroporation may be a promising clinical method for transdermal drug administration.

Electroporation-enhanced transdermal diclofenac sodium delivery into the knee joint in a rat model of acute arthritis

“…Effective concentrations in target tissues can be augmented with EP. 32 In accordance with literature data, our results revealed that EP causes higher concentration values in the serum as compared with the topical administration. The diclofenac concentration in the synovia was equal to the serum concentrations; however, conventional topical treatment did not result in a detectable amount of diclofenac sodium in the synovial fluid.…”

“…30 , 31 However, electrotransfer of painkiller drugs into the knee joint is less widespread. 32 According to a recent review, plasma levels of diclofenac after topical administration decrease from 0.2% to 8% of those after oral administration. 33 Unfortunately, the resultant synovial concentration is also decreased, as compared to an equivalent oral dose.…”

Sinomenine attenuates cancer-induced bone pain via suppressing microglial JAK2/STAT3 and neuronal CAMKII/CREB cascades in rat models

“… 10 – 13 A large number of preclinical and clinical studies have confirmed that sinomenine is effectively against rheumatoid arthritis, arrhythmia, and glomerular diseases. 14 – 16 Recently, there was evidence suggesting that sinomenine alleviated mechanical allodynia and heat hyperalgesia in the models of neuropathic and inflammatory pain. 17 – 19 In addition, sinomenine was demonstrated to attenuate brain injury by inhibiting microglial activation in intracerebral hemorrhages.…”

The Effect of Acupoint Application of Sinomenine for Rheumatoid Arthritis Measured by Microdialysis and UPLC-MS/MS

“…Traditional administration routes of sinomenine have several limitations, such as side effects and low absorption rates. Previous studies have proposed several methods to resolve the problem, such as optimizing control release with electroporation, adding bacterial cellulose to the formulation, and drug delivery using elastic liposomes [10, 21, 22]. However, such methods have limitations regarding high costs and complex operations.…”