| Bulleyaconitine A ( BLA ), a diester alkaloid extracted from Aconitum longtounense T.L.Ming, is an excellent analgetic and anti-inflammatory agent and can be used for the treatment of rheumatoid arthritis, osteoarthritis, periarthritis humeroscapularis, lumbar muscle strain, sprain, etc. Due to the potential toxicity, the adverse drug reactions of the marketed products of BLA such as injections, tablets and capsules, are severe. Therefore, it is necessary to enrich the dosage forms of BLA, and transdermal delivery system is strongly recommended for its extraordinary safety. In this paper, the transdermal characteristic of BLA was studied in detail. On the results of the preformulation studies, the transdermal patch and transdermal liposomes of BLA were developed.A HPLC-MS-MS method was established to determine the plasma concentration of BLA in healthy volunteers after muscle injection of 20mg BLA. The results showed that the pharmacokinetic model of BLA in healthy volunteers after injection conformed to single compartment model, and values of Tmax, Cmax, AUC0-∞, k and t1/2 were 0.9h, 1.134ng/ml, 6.014ng.h/ml, 0.147h-1 and 4.877h, respectively. Based on the above pharmacokinetic parameters, the appropriate penetration rate of BLA transdermal patch was calculated. It suggested that the penetration rate of BLA should be 0.67μg/cm2.h～2.66μg/cm2.h for the patch of 10cm2 or be 0.33μg/cm2.h～1.33μg/cm2.h for the patch of 20cm2.The transdermal characteristic of BLA was investigated with a HPLC method to determine the concentration of BLA in the skin extraction. It was found that the back skin of SD rat was a suitable model of human skin and the stratum corneum was the main barrier to the penetration of BLA. The fluxes of BLA were affected by temperature, pH value of solvent and the components of buffer solution. Studies of penetration enhancers of BLArevealed that the effect of ethanol and propylene glycol, used alone, was neglectable, and both of them showed negative influence in high concentration. Azone, oleic acid, lauryl alcohol and eucalyptus oil could increase the fluxes of BLA, and the effect of these enhancers could still be heightened by ethanol. The mixture of ethanol and eucalyptus oil was the optimum enhancer combination.The results of the studies of the transdermal patch of BLA showed that the penetration rate of BLA was influenced greatly by the pressure sensitive adhesive ( PSA ) and the backing materials of the patch. Azone and oleic oil, in silicone PSA, could increase the fluxes of BLA, and Azone seemed to be the relative better choice. The increment of the content of BLA in PSA could result in the increment of the fluxes, but had little influence on the maintaining time of the zero-order penetration. The optimal transdermal patch was a single-layer-type patch, with BLA dispersed uniformly in adhesive matrix, which was composed mainly by silicone PSA. Nonwoven fabric was chose for the backing of the patch, and Scotchpak 1022(r) for the release liner. The permeation profile of BLA from the optimal patch through human skin conformed to zero-order kinetics, and could maintain the steady flux for at least 3 days. The adhesive quality of that patch was also satisfying. The results of pharmacodynamics and skin irritation tests showed that the anti-inflammatory analgesic activities of that patch were excellent, while the skin irritation was slight.Transdermal liposomes of BLA was also developed for the topical usage. Orthogonal test was employed to study the influence of liposomes components on entrapment efficiency and the skin permeability. The permeability of BLA in liposomes and in saturated aqueous solution through rat skin was compared. The effect of BLA liposomes on the edema of mouse ear induced by dimethylbenzene and the writhing induced by acetic acid was also investigated. It was founded that fairly satisfying entrapment efficiency could be obtained by adopting oleic acid as solvent for BLA. The results of orthogonal test showed that t...
|
PDF Full Text Request