| Objective:In order to better inherit the traditional classic dosage form of black plaster,it was proposed to fundamentally improve the preparation process and prescription of black plaster on the basis of mastering the characteristic of black plaster matrix.Modern advanced technology and new materials were adopted to construct a new transdermal delivery matrix with consistent microstructure of black plaster,and its reduction on the basis of drug release unit and drug efficacy were realized.Thus,it provided a new idea for the matrix research of traditional Chinese medicine compound transdermal drug delivery system.Method:1.The electrospinning were used to construct the fiber phase in dual phase microstructure.High spinnability synthetic polymer PCL and pvpk-90 were selected as the fiber phase matrix materials,the electrospinning voltage,electrospinning liquid velocity,receiving distance and concentration of electrospinning liquid were selected by single factor selection and the fiber morphology as the evaluation index.Then,the single axis and coaxial fibers were constructed by the optimal prescription technology.FESEM was used to observe the morphology of the fibers and the shell core structure of the coaxial fibers was observed by TEM.On the basis of the successful construction of the blank fiber phase,Ci and EM were loaded into the fiber phase and characterized by FESEM,TEM,DTA and XRD.Meanwhile,the stability of the volatile component Ci and the in vitro release behavior of Ci in different fiber structures were evaluated.2.Firstly,SIS 1105 with the same microstructure as the continuous phase in black plaster matrix was used to prepare the continuous phase,and the fibers constructed by PCL and PVPK-90 were used as the fiber phase.Different proportions of fibers were sprayed into the continuous phase to construct the two-phase microstructure system.The morphology of the two-phase micro-structure was observed by FESEM,and the viscosity,mechanical strength and air permeability of the two-phase microstructure systems were characterized,and the microstructure was quantita-tively analyzed to select the most similar construction system with the black plaster matrix.3.Ci and EM,two known active components in Goupi Gao,were loaded into different parts of the biphasic reduction system(the ratio of two phases was 1:3)and divided into three groups:the drug was only distributed in the fiber phase(A and B),the drug was only distributed in the continuous phase(C and D),and the drug was distributed in both the fiber phase and the continuous phase(E and F).The microstructural parameters,viscosity,mechanical properties,air permeability,thermal stability,crystalline characteristics of EM,stability of Ci,drug loading and entrapment efficiency of the three groups of preparations were investigated,and the in vitro release behaviors of the three groups of preparations and Goupi Gao were evaluated.4.The percutaneous penetration test was carried out with a precise controlled in vitro percutaneous penetration test system.According to the distribution of Ci and EM in the preparation,the experiment was divided into three groups:Goupi Gao,group C and D;group A and B;Group E and F.Through the comparative analysis between the groups,the in vitro transdermal permeation of the two drugs in different distribution sites was evaluated.In vivo microdialysis method was established to study the pharmacokinetic behavior in vivo,the drug time curves were drawn,and the pharm-acokinetic parameters were statistical analysed;atrioventricular model was determined for correlation analysis in vivo and in vitro.Result:1.The results showed that the surface of the uniaxial and coaxial fibers were smooth,the particle size distribution was uniform,there was no adhesion,no beads;the coaxial fiber had an obvious shell core structure,the core was completely wrapped in the shell,and the drug loading had no obvious effect on the fiber morphology.The fibrosis inhibited the crystallization of EM to some extent,and made it distribute in the fiber in amorphous state.The inhibition of shell inhibited the volatilization of Ci and enhanced its stability.Ci in the fiber could be sustained release in different degrees.However,the release of Ci in fibers with different structures followed different rules.There was a sudden release of Ci in uniaxial fibers,and the sudden release of Ci in coaxial fibers was inhibited by the barrier of the shell.2.The two phases could be clearly observed in the FESEM photos of the system with different fiber phase content.The combination system of electrospinning fiber and SIS 1105 hot-melt pressure-sensitive adhesive showed a three-dimensional network structure with highly entangled fibers.The viscosity of the two-phase reduction system decreased with the increase of the fiber phase,that was,it increased with the increase of the continuous phase.In all the two-phase reduction systems investigated,the viscosity was between the fiber phase and the continuous phase,and it was stronger than 32? Goupi Gao,which was suitable for directly acting on the skin for a long time.The two-phase reduction system was full of toughness under the interaction of fiber phase and continuous phase.It had suitable water vapor permeability,increasing the comfort of application to a certain extent,and could make the sweat discharge in time,so as to avoid the phenomenon of falling off and skin whitening in the process of application.The void area,long diameter and short diameter were highly positively correlated with the phase content of uniaxial fibers,while the void area,long diameter and short diameter were moderately correlated with the phase content of coaxial fibers.The results showed that the two-phase reducing system with the ratio of fiber phase to continuous phase of 1:3 had the most similar adhesion properties,mechanical properties,permeability and micro-structure parameters as the matrix of black plaster matrix.3.The results showed that the loading of the drug had no significant effect on the microstructure of the reduced system and the microstructure of the drug loaded reduced system was very similar to that of the black plaster matrix when the two-phase ratio was 1:3.There was no significant difference between the viscosity of the drug loaded biphasic reduction system and the blank matrix.The addition of drugs had no significant effect on the viscosity of the system.The viscosity of each preparation was as follows:Goupi Gao<A and B<C and D<E and F.The results showed that the mechanical properties of the preparation decreased compared with the blank matrix.At the test temperature,the mechanical properties of each preparation were A and B>C and D>E and F>Goupi Gao.Compared with the blank biphasic reducing matrix,the water vapor permeability of the matrix after drug loading was weakened,and the water vapor permeability of Goupi Gao was the weakest.XRD results show that when EM only existed in fiber phase(A),most of the diffraction peaks disappeared,and the crystal form was destroyed,and it would disperse in the fiber phase without shape;while when it was loaded into continuous phase(C and E),some diffraction peaks were retained,and some crystal forms still existed.Compared with the bare drug Ci,the stability of the loaded fiber phase was higher than that of the continuous phase,the stability of the loaded fiber phase was the strongest when it was loaded into the core of coaxial fiber(there was no significant difference between B and F),and the stability was the worst when it was only distributed in the continuous phase(C and D).In vitro release behavior showed that the p values in Goupi Gao,C and D were greater than 0.05,indicating that there was no significant difference in drug release among Goupi Gao,C and D.The f2 values in vitro release curves of Ci were 71.15,74.41,66.25,53.87,more than 50 in C,D,E and F,indicating that the in vitro release behaviors of Ci in C,D,E and F samples were similar with Goupi Gao,The f2 values in vitro release curves of Ci were 38.72,34.48,less than 50 in A and B,indicating that the in vitro release behaviors of Ci in A and B samples were not similar with Goupi Gao.The f2 values in vitro release curves of EM were 82.61,81.04,51.87,more than 50 in C,D and E,indicating that the in vitro release behaviors of EM in C,D and E samples were similar with Goupi Gao,The f2 values in vitro release curves of EM were 40.61,35.09,47.36,less than 50 in A,B and F,indicating that the in vitro release behaviors of EM in A,B and F samples were not similar with Goupi Gao.The results of model fitting showed that the drug loaded in different parts followed different release models,and the Ci and EM in Goupi Gao,C and D followed Weibull release model.4.Ci and EM could penetrate into the receiving medium from different preparations at different permeation rates through the skin in vitro.Compared with the two-phase reduction system,the drug loading matrix of Goupi Gao was thicker,and the amount of drug on the surface was less,so the permeation rate of Ci and EM was the slowest.The topical pharmacokinetic behavior indicated the Tmax of Ci in rat skin was 9h,9h,7h,8h,7.6h,7hand 7h,respectively(According to the order of preparations in table 5-2-6),There was no significant difference from Goupi Gao,C,D,E and F,but significant difference from GoupiGao,A and B.The Cmax of Ci was 16.774 mg/L,12.446 mg/L,22.843 mg/L,22.76 mg/L,0.198 mg/L,24.899 mg/L and 27.421 mg/L,respectively.There was no significant difference from C,D and Goupi Gao,but significant difference from A,B,E,F and Goupi Gao.The difference between AUC(0-t)and AUC(0-?)is consistent with Cmax.For the t1/2 of Ci,there was no significant difference from Goupi Gao,C,D,E and F,and significant difference with A and B;MRT(0-?)discrepancy was consistent with t1/2.The Tmax of EM was 9.4 h,8.8 h,6 h,7 h,6.8 h,7 h,and 9 h,respectively,and the Tmax of Goupi Gao was not significantly different from that of C,D,and E,and was significantly different from that of A,B,and F.The Cmax was 3.178 mg/L,3.250mg/L,3.435 mg/L,3.545 mg/L,0.035 mg/L,3.392 mg/L and 3.256 mg/L,respectively,and there was no significant difference between Goupi Gao,C and D,and there were significant differences with A,B,E and F.The differences in AUC(0-?)and MRT(0-t)between formulations were consistent with Cmax.There were significant differences in MRT(0-?)between Goupi Gao and A,B,C,E and F,but not with D.The transdermal administration of the seven preparations conformed to the one compartment atrioventricular model with good correlation in vivo and in vitro.Conclusion:On the basis of mastering the important role of black plaster matrix in the process of playing the pharmacological role of black plaster,we abandoned the previous idea of simply reforming the preparation process and prescription of black plaster,started from the microstructure of black plaster matrix,and stands in the angle of transformation and better inheritance,and adopted modern advanced technology and new materials to realize the reduction of the microstructure of black plaster matrix.It was also verified that the drug loaded biphasic reduced system exhibited a high degree of consistency in drug release behavior with Goupi Gao,exhibited the unique function of matrix microstructure in transdermal drug delivery system,demonstrated the viewpoint that "matrix microstruc-ture is a embodiment of the uniqueness of this classical dosage form",Furthermore,it revealed the importance of matrix in transdermal drug delivery forms,established a new model for the research and inheritance of traditional Chinese medicine transdermal drug deli-very forms,and excavated new connotation. |
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