| Improving the transdermal permeability of poorly water-soluble oxaprozin (OXA) considered as main focus of this paper, the sodium hyaluronate hydrogel, microemulsion system, microemulsion gel transdermal therapeutic system were prepared respectively, and the transdermal enhancers, physical enhancing method and microdialysis in vivo were combined synthetically in order to study the in vitro/in vivo transderml permeation kinetic behavior of OXA and the relevant mechanism deeply.During the preformulation study, a great deal of transdermal enhancers in different styles was chosen to study the transdermal permeability of OXA in vitro. It was shown that the effect of enhance concerned with concentrations and dosages of OXA, whenβ-CD and HP-β-CD were used as enhancers. If saturated solution was given, transdermal transit dose of OXA in vitro increased along with the concentration of CDs; contrarily. When the solution was unsaturated, transdermal transit dose of OXA in vitro decreased with the increase of concentration of cyclodextrins, which was supposed that solubility of OXA would increase as the concentration of CDs increased. In unsaturation state, the dissolubility of OXA in CDs would hindrance the distribution of OXA in dermo-lipide, thereby, transdermal permeability woule be reduced. Among the transdermal enhancers which were chosen, isopropyl palmitate showed the best effect. For its lower toxicity and irritation, it was applied in cosmetics as humectant extensively. It was showed that transdermal transit dose in vitro of these drugs was increased by isopropyl palmitate, especially for lipophilic drugs.Basing on the result of preformulation, the transdermal transit cumulate dose chosen as index, the effect of transdermal permeability of OXA by HPMC and sodium hyaluronate was investigated. According to the result of experiment, 0.5% sodium hyaluronate was chosen as gel base to select the enhancers. By the result of rheology, the sodium hyaluronate gel possess the property like pseudoplastic fluid, and viscosity was high/low in low-frequency/high-frequency, which was propitious to spreading and glutinousness.A novel microemulsion was prepared to increase the solubility and enhace the in vitro transdermal delivery of OXA. For the microemulsions, types of oil phase, surfactants, cosurfactant were chosen and the double-distilled water was purified as water phase. Pseudo-ternary phase diagrams were constructed to obtain the concentration range of each component for the microemulsion formation. The effects of various oils and different weight ratios of surfactant to cosurfactant (S/CoS) on the solubility and permeation rate of OXA were investigated. By the result of the experiment, it was showed that if the concentration of surfactant and cosurfactant was stated, permeation rate of OXA increased prominently with S/CoS decreasing from 3:1 to 1:1 (P＜0.01). It was supposed that, because of the decrease of S/CoS, the content of cosurfactant would increase correspondingly, and enhance effect would be increased. When S/CoS decreased from 3:1 to 1:1, self-diffusion coefficient of OXA would rise. Thus, transdermal permeability would be increased. After S/CoS was ascentained, the effect of transdermal permeability of water phase was studied. It was indicated that the cumulate proportion permeation rate would be reduced along with the proportion of the water phase. It was supposed that the degree of hydration of skin was reduced as the proportion of the water phase were decreased, and transdermal permeability was also influenced. According to the result of the experiment, 5% ethyl oleate, 45% the double-distilled water and 50% S/CoS (1:1) as the optimization of microemulsions was ascentained. Besides, stability was investigated primitively, and microemulsion preparation was showed good stability.Microemulsion, as good carrier of drugs, could enhance the permeation rate of OXA prominently. But it was also restricted in transdermal therapeutic system when used externally because of its low- viscosity. If microemulsion preparation was used solely, it was difficult to keep the drug on the skin for a long time. Therefore, dosage would be changed, which was negative at in-service use. Microemulsion gel was also studied in this paper. Microemulsion gel was prepared in the method of swinging the sodium hyaluronate, the base of gel, in the microemulsion. It was also studied in the experiment of permeability in vitro. It was showed that the transdermal permeability of microemulsion gel correlated with the proportion of the water phase, and percutem transit dose in vitro increased evidently when the proportion of the water phase in microemulsion climed, according to the result of experiment of microemulsion preparation.Besides the above mentioned methods, the physical enhancing methods, such as phonophoresis, were applied to improve the transdermal permeation of OXA microemulsion gel. The result of experiment revealed that if the time of ultrasound was fixed, percutem transit dose of drug could be increased with intensity of ultrasound. On the other hand, the intensity of ultrasound stated, percutem transit dose of drug could be increased along with the time at the range of 10 min to 30 min. However, if it was given ultrasound over 40min, percutem transit dose of drug would be reduced significantly. Therefore, it was supposed that skin temperature was increased during a long time of ultrasound, and the skin would be damnified. Stability was investigated primitively, and microemulsion gel showed good stability.On the base of investigation in vitro, permeability of microemulsion gel in vivo was investigated by microdialysis. The result of the experiment indicated that there would be some hold-up of drug in the skin of rats. Moreover, local anti-inflammatory action in the experiment of pharmacodynamics, and non-irritation in the experiment of irritation with rabbit were verified. These findings indicated that the transdermal microemulsion containing OXA was promising in practice and the prospective goal of the paper was satisfactorily arrived. |
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