Sinomenine, a compound that was first isolated from Caulis Sinomenii by Ishiwari in the 1920s. The chemical name is (9α,13α,14α)-7,8-didehydro-4-hydroxy-3,7-dimethoxy-17-methylmorphinan-6-one, which belongs to morphinan alkaloids, It is composed of phenanthrene nucleus and ethylamine bridge. The structure is shown in Figure 1. Sinomenine is a white or light yellow crystalline powder with a molecular formula of C19H23NO4, a relative molecular mass of 329.38, and a melting point of 161°C. It is soluble in ethanol, acetone, chloroform and dilute alkali, and slightly soluble in water, ether and benzene. Sinomenine is also a highly osmotic drug, which is well absorbed in all intestinal segments of rats. Its apparent oil-water partition coefficient is 1.98. Sinomenine can be classified as a class II compound in the biopharmaceutical classification system. Sinomenine is quickly eliminated in the body, and its oral bioavailability is low, about 30%, which limits its clinical use to a certain extent. Therefore, the research of new dosage forms of sinomenine has important scientific significance.
The combination of sinomenine and methotrexate, diclofenac sodium, leflunomide, celecoxib, hydroxychloroquine sulfate, sulfasalazine and other drugs exerts a synergistic effect and has a significant effect on the treatment of RA. After treatment, the patient's joint swelling index, joint tenderness index, joint function index, and morning stiffness time were significantly reduced, and all indicators improved.
The inflammatory response of RA is closely related to inflammatory cytokines. The level of anti-inflammatory cytokines (AIC) in RA decreases, which leads to an increase in the level of pro-inflammatory cytokines (PIC), and the inflammatory response increases, which may be the progression of RA One of the important reasons is that AIC can inhibit inflammation, and PIC can promote the proliferation of synovial cells and the activation of osteoclasts. Studies have shown that sinomenine can significantly inhibit the secondary lesions of adjuvant arthritis (AA) in rats, and reduce the levels of IL-1 and TNF-α pro-inflammatory factors in the serum and joint infusion of AA rats. The levels of IL-4 and IL-10 anti-inflammatory factors increase, so as to achieve the purpose of reducing inflammation.
RA is a chronic autoimmune disease. There are a variety of immune cells, including T, B lymphocytes and dendritic cells, which participate in and mediate the pathogenesis of RA. Both in vivo and in vitro administration of sinomenine can induce the proliferation of mouse spleen lymphocytes, inhibit leukocyte differentiation antigen (CD) 4+ cells, and down-regulate the ratio of CD4+/CD8+, suggesting that sinomenine has an inhibitory effect on T and B cell activation . In addition, other studies have shown that sinomenine can also significantly reduce the molecular expression of cytokines TNF-γ and TNF-α in T cells in a dose-dependent manner. Helper T cells 17 (Th17) and regulatory T cells (regulatory T-cells, Treg) are both T cells, but the functions of the two in the human body are mutually antagonistic. The imbalance between Th17 and Treg is one of the important causes of RA. Therefore, by inhibiting the differentiation of Th17 cells, enhancing the activity of Treg, and achieving a balance of Th17/Treg in the body, the purpose of treating RA can be achieved.
One of the main manifestations of RA is the excessive proliferation of synovial cells, which in turn leads to thickening of the synovial membrane, formation of pannus, damage to bones and joints, and even loss of function. Therefore, inhibiting synovial cell proliferation and inducing synovial cell apoptosis is one of the important methods for the treatment of RA.
Bone destruction occupies an important position in the occurrence and development of RA, and is one of the main causes of joint deformity, stiffness and dysfunction in RA patients. Studies have shown that receptor activator of nuclear factor-κB (RANK)/receptoractivator of nuclear factor-κB (RANKL)/osteoprotegerin (RANKL) OPG), as a group of osteoclast differentiation regulating signal factors, plays a key role in the process of RA bone destruction. Sinomenine can increase the secretion of OPG by stimulating osteoclast (OC), reduce the secretion of RANKL, promote the differentiation and maturation of osteoblasts, and inhibit bone destruction.
Based on the current clinical efficacy of sinomenine preparations in the treatment of RA, but its half-life is short, the bioavailability is low, and the clinical dosage is too large, and the introduction of new technologies and methods is expected to solve the above shortcomings. In recent years, researchers have carried out research on new dosage forms of sinomenine liposomes, transfer bodies, ethosomes, transmission ethosomes, microemulsions, and microspheres to explore the application of new sinomenine formulations in the treatment of RA .
