| Objective:Preparation of Salvia miltiorrhiza multicomponent composite microemulsion gel plaster, to improve the solubility and stability of total tanshinones in Salvia miltiorrhiza by microemulsion technique, and promote the transdermal absorption ability of total ketones and total salvianolic acid. providing new ideas and new methods to the study of the effective components in Salvia miltiorrhiza transdermal delivery system.Methods:Choosing the suitable oil phase, surfactant and cosurfactant agent and aqueous phases, combined with the pseudo ternary phase diagram and simplex lattice to design the preparation method of Danshen multi-component composite microemulsion prescription, used the design expert software to optimize and verify the optimal composition of Danshen multi-component composite microemulsion, The quality of microemulsion was evaluated by determining particle diameter, drug entrapment efficiency and drug loading of it. Found out optimal response value, determine the optimal prescription and validation of the optimal prescription.Choosing the suitable prescription ratio of preparing Danshen multi-component composite microemulsion gel plaster refer to the ISP company’s gel emplastrum basic prescription. By orthogonal design method, the uniform matrix, matrix surface gloss, matrix ductility, back lining layer leak, membrane residues, skin to follow, the number of bubbles, to tack and peel strength for gel emplastrum evaluation indexes, were used to determine the final gel plaster’s agent proportion of prescription. Using the final method to prepare Danshen multi-component composite microemulsion gel plaster.According to the solubility and stability of total tanshinones and salvianolic acids choose appropriate medium to receive and investigate the stability of salvianolic acids in skin homogenate in nude mice. Under suitable conditions, transdermal absorption experiment of Danshen multi-component composite microemulsion and Danshen multi-component composite microemulsion gel plaster was proceeded using the modified Franz two compartment diffusion pool method. Every group’s transdermal capacity was studied.Results:In this study, we used isopropyl myristate as oil phase,15-hydroxy stearic acid glycol ester (solutrol-HS 15) as surfactant, diethylene glycol monoethyl ether (Transcutol P) as the cosurfactant, pure water as the aqueous phase, the optimized Danshen multi-component composite microemulsion formulation is isopropyl myristate 15-hydroxy stearic acid glycol ester (solutrol-HS 15)-diethylene glycol monoethyl ether (Transcutol P) (4:1):purified water (13.3:31.7:55), the particle size is 12.88 ± 0.57nm, the encapsulation rate of TSN was 98 ± 2.26%, the drug loading of TSN and sal B were 5.30 ± 0.03mg·g-1 and 2.43±0.01m·g-1.The best prescription proportion of Danshen multi-component composite microemulsion gel plaster is Danshen multi-component composite microemulsion 5g, PVP-K 90 0.4g, tartaric acid 0.04g, water 6g, NP-7001.2g, dihydroxyaluminium aminoacetate 0.06g, glycerol 6g. Under this condition, the Danshen multi-component composite microemulsion gel plaster hasn’t insoluble matter and red brown bulk matter; uncover antisticking layer, the matrix hal smooth surface, no any residue and concave hole; matrix is easy to stir, coating; after the completion of the coating, backing layer without any exudation; uncover the antisticking layer and observed the area of stained matrix in antisticking layer, the area accounted for less than 1/5 of the total area. The microemulsion gel plaster affixed to the wrist and forcibly thrown, more than 10 times do not fall off; no bubble in matrix.Choosing 35% ethanol saline solution as the transdermal receiving media of this study, the results confirm its good stability. Skin homogenate stability study found SalB homogenate group has rapid degradation in 12 hours, has slow degradation after 12h, the degradation process does not conform to the first-order kinetic equation.The results in vitro transdermal delivery experiment shows that for SalB, the permeance of Danshen multi-component composite microemulsion is greater than Danshen aqueous extract group in 22h, in 22h to 24h, Danshen aqueous extract group’s penetration amount is more than that of Salvia miltiorrhiza multi-component composite microemulsion group. In 24h, the penetration amount of Danshen multi-component composite microemulsion gel plaster was significantly less than the other two group. Aqueous extract of Salvia miltiorrhiza group accumulative permeation quantity conforms to the zero order equation and the Hixon-crowell equation model, Danshen multi-component composite microemulsion group and Danshen multi-component composite microemulsion gel plaster group were all conforms to the Hixon-crowell equation model. For TSN, Danshen multi-component composite microemulsion group and Danshen multi-component composite microemulsion gel plaster can permeate through rat skin within 24 hours and the penetration amount of Danshen multi-component composite microemulsion group is larger than Danshen multi-component composite microemulsion gel plaster group. Danshen multi-component composite microemulsion group and Danshen multi-component composite microemulsion gel plaster group were all conforms to the Hixon-crowell equation model.Conclusion:Combined with pseudo ternary phase diagram technique and simplex lattice method, the Salvia miltiorrhiza tanshinone lipid soluble substance water solubility and stability can be increased significantly, the transdermal absorption of the Salvia miltiorrhiza tanshinone lipid soluble substance and salvianolic acid water soluble substance can also be promoted significantly. Combination of gel plaster and microemulsion technology provide new ideas and new methods for the development of drug microemulsion transdermal delivery system. |
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