Bla Microemulsion And Its Water-based Matrix Transdermal Delivery Systems

Bulleyaconiting A (Bu-A) is a kind of insoluble alkaloid which has significantly analgesic and anti-inflammatory activity. Pharmacological studies indicated that the Bu-A had stronger activity than morphint without any addictive effect, but it had longer lag time. Bu-A has been wildly used in the treatment of many kinds of acute or chronic pains, such as scapulohumeral, periarthritis, rheumatism arthritis, joint sprain and cancer pain, etc. As for the injections and tablets in the market, the oral administration responses slowly, has lower bioavaiability and it also induces side effects such as irritation of gastrointestinal tract and numbness of oral cavity. The effect of injection starts faster, but intense irritation of injected site are intolerable for most patients. Furthermore, because of the narrowness of the therapeutic window, the obvious fluctuation of blood drug level after injection can easily lead to the hidden danger behind of safety.Object: In this project, we investigated the O/W microemulsion as potential transdermal drug delivery vehicles to increase the solubility, transdermal flux and stability of Bu-A. And we estimated the mechanism of microemulsion as a potential penetration enhancing system.Furthermore, we prepared microemulsion based Bu-A cataplasm to administration easier and safety.Method: There is a correlation between drug solubility in oil and microemulsion. The transdermal flux from microemulsion formulations will be increased by its solubility. Pre-formulation experiments was carried out to investigate the equilibrium solubility of Bu-A in different oils. The surfactant and cosurfactant were screened by determining the transdermal flux of different microemulsions. Pseudo-ternary phased diagram of microemulsion (ME) had been constructed by using adding-solution method, which is usually used to zoom out the O/W type of ME area. The optimum formulation was selected by mice skin permeation experiment. Various O/W microemulsions with different constituent ratios and drug-loaded were used to deliver Bu-A through mice skin in vitro. Transdermal flux of Bu-A was determined using Franz-type diffusion cells and samples were analyzed by HPLC. Scanning electron microscope was used to study vehicle-skin interactions to estimate the mechanism of microemulsion as a potential penetration enhancing system.Microemulsion based Bu-A cataplasm was made by Carbopol U10 and Noverite 7s. The formulation of cataplasm was optimized by orthogonal design method. The cataplasm was evaluated cohesion test, content test, and in vitro permeation test. In addition, the irritation, sensitivity of cataplasm on rabbits were studied. Finally, in vivo pharmacokinetic behavior of Bu-A was invested by LC-MS/MS method. Using the Bu-A pressure sensitive adhesive (PSA) patch as the reference, the bioavailability and pharmacokinetic study of Bu-A microemusion based cataplasm in rats was performed. The pharmacokinetic parameters were studied according to the non-compartment model.Result: For the microemulsions, oleic acid was chosen as oil phase, Cremophor RH40 as surfactants (S), diethylene glycol monoethyl ether (Transcutol)as cosurfactant(CoS) and the double-distilled water as water phase. Pseudo-ternary phase diagrams were constructed to obtain the concentration range of oil, surfactant, cosurfactant for microemulsion formulation, and the effect of these additives on skin permeation of Bu-A was evaluated with excised rat skins. The optimum formulation of the microemulsion consisted of 0.6% Bu-A, 4%oleic acid, 20% Cremophor RH40, 20% Trascutol P. The highest skin permeation rate was 97.72±10.89μg/cm²·h. The experiments proved that the microemulsion was stable after storing 6 month at 25℃.After composition optimization, we designed a Bu-A microemulsion based cataplasm including 4%Noverite 7s , 3% Carbopol U10, 25%glycerin, 0.3% A1C1₃, 0.3% citric acid, 10% microemulsion (6.3mg/ml) with drug content 100μg/cm². Transdermal flux was determined to be about 9.0μg/cm²/h^1/2. The quality control test showed suitable adhesiveness, stability and low irritation. Using pressure sensitive adhesive (PSA) as the reference, the Bu-A microemulsion based cataplasm showed that the maximal blood concentration (C_max), MRT and AUC was increased, T_max was decreased. Using intragstric administration as the reference, the Bu-A microemulsion based cataplasm showed that T_max and MRT was increased, C_max was decreased, and the relative bioavailability is 47.49%.Conclusion: We improved the Bu-A solubility, permeation coefficient, drug stability by preparating O/W microemulsions. Pharmacokinetics study of Bu-A in rat plasma showed that drug resides longer in the body compared with PSA patch, and AUC and C_max of increases contrasted PSA patch.In this study, we provided a foundation for further developing transdermal drug delivery system that had high efficiency, fast speed, low toxicity and convenience.