| Semen Strychni is notable for its therapeutic effects on local muscle and joint pain. The major active constituents of Semen Strychni are the total Strychnos alkaloids, mainly strychnine and brucine which together comprise more than80%of the total Strychnos alkaloids. Because the strychnine content of semen strychni may be significantly altered according to the growth regions or processing procedure. the ingest dose of strychnine ranges from3.6mg to13.2mg after legitimate oral administration of semen strychni. Therefore, the oral administration of Semen Strychni and the Chinese preparation containing Semen Strychni poses a great risk.Objectives:The purpose of the current study was to develop a drug-in-adhesive patch containing total Strychnos alkaloids, and to evaluate its transdermal delivery in vivo to find out how much the drug doses reach the knee joints and musle, what factors can affect the process of effect the drug reaching the knee joints and musle and how the drugs arrive at the target tissue.Methods:Different penetration enhancers were optimized to maximize the fluxes of strychnine and brucine through the skin of porcine ear in vitro. Adhesive matrices, amounts of drugs and permeation enhancers were investigated to maximize the fluxes of strychnine and brucine through the skin of porcine ear in vitro. Samples were collected at0.5,1.0,2.0,4.0,6.0and8.0h after1.0cm2patches of total Strychnos alkaloids applied to the shaved abdomen of the mice. Blood samples were collected in dried heparinized tubes from the ophthalmic venous plexus. After the residual adhesive on the skin surface was carefully wiped off using cotton soaked in ethyl acetate, the abdominal skin and muscle beneath the drug application site were carefully separated and accurately weighed. Microdialysis probes were implanted into rabbit muscle, and the dialysate was then sampled at60min intervals for up to480min after the total Strychnos alkaloid patches were applied at the point where the microdialysis probe was implanted. After the residual adhesive on the skin surface was carefully wiped off using cotton soaked in ethyl acetate, the rabbit skin, fat tissues and muscle beneath the drug application site were carefully separated and accurately weighed. Microdialysis probes were also implanted into rabbit knee joints, and the dialysate was then sampled at60min intervals for up to480min after the total Strychnos alkaloid patches were applied at the point where the microdialysis probe was implanted.Results:The order of enhancing effect on the permeation of strychnine was tween80<cineole<menthol carvone<oleic acid<limonene<terpinolene; the order of enhancing effect on the permeation of strychnine was cineole<menthol carvone<oleic acid<DMF<limonene. The optimal total Strychnos alkaloids patch contained DURO-TAK(?)87-4098,5%oleic acid,2.32%strychnine and1.59% brucine. The strychnine and brucine were not absorbed into blood too much and accumulated in the skin and muscle of the applied sites. The strychnine and brucine concentration of microdiasate from knee joints and musle remained stable. The strychnine AUC0-8h values of knee joints, musle and plasma were22.55ng·h/mL,95.45ng-h/mL and25.72ng-h/mL, respectively. The brucine AUC0-8hvalues of knee joints, musle and plasma were21.90ng-h/mL,105.17ng-h/mL and44.24ng-h/mL, respectly. When the patch administration was terminated, the strychnine concentration of muscle and blood was524.1±112.0ng/g and0.50±0.22ng/mL, respectly. The brucine concentration of muscle and blood was364.4±57.8ng/g and1.07±0.44ng/mL, respectly.Conclusion:The blood concentration did not rise obviously, and drug would accumulate in the applied sites. The concentrations of non-protein bound drug in muscle and knee joints remained stable, and there is equilibrium between the drug absorbed into muscle and the drug eliminated from muscleand knee joints. The lipophicity of drug is the key factor which affects the drug delivery to knee joints and muscle. |
PDF Full Text Request