RESUMO
The development of second-entry topical products is hampered by several factors. The excipient composition should be similar to the reference product because excipients may also contribute to efficacy. Conventional pharmacokinetic bioequivalence studies were not considered acceptable because drug concentrations are measured downstream after the site of action. There was no agreed methodology to characterize the microstructure of semisolids, and waivers of therapeutic equivalence studies with clinical endpoints were not possible. Only the vasoconstrictor assay for corticosteroids was accepted as a surrogate. This paper describes the implementation of the European Union's stepwise approach for locally acting products to cutaneous products, discusses the equivalence requirements of the EMA Draft Guideline on the Quality and Equivalence of Topical Products, and compares them with the US Food and Drug Administration recommendations. Step 1 includes the possibility of waivers for simple formulations based on in vitro data only (Q1 + Q2 + Q3 + IVRT). Step 2 includes step 1 requirements plus a kinetic study (TS/IVPT/PKBE) to compare the local availability of complex formulations. Step 3 refers to clinical studies with pharmacodynamic/clinical endpoints. As excipients may affect the local tolerability and efficacy of the products, the similarity of excipient composition is required in all steps, except where clinical endpoints are compared.
RESUMO
To firstly accurately overall determine the all components of Compound Danshen Dropping Pills (CDDP) and assess how about the authentic quality is for each bath of samples through a quantified fingerprint that only can qualitatively identified which kind of a herbal or Traditional Chinese Medicine may be. The systematically quantified fingerprint method (SQFM) was employed to identify that the qualities of S4 and S6 were belong to best (grade 1), those of S3, S5, S7, S8 and S9 belong to better (grade 2), those of S2 and S10 belong to good (grade 3), and only S1 falling to fine (grade 4) where those were all with 19 fingerprint peaks. On the basis, the important HPLC dissolution fingerprints (DFPs) of CDDPs were meticulously established to investigate the dynamic process in water, 0.1 mol/L hydrogen chloride (HCl) and 0.5% sodium dodecyl sulphate (SDS), respectively, in which SQFM executed the excellently quantified analyses for the DFPs. During the evaluation, the eighth time points of DFPs were selected as the standards for all dissolving to calculate how high are the macro quantitative similarity ( P m ) of DFPs for the other different time points. Finally in terms of Weibull function, lnln [1/(1- P m )]=-0.5951 x (2)+3.8146 x -4.5195 ( r =0.9974), lnln [1/(1- P m )]=-0.5555 x (2)+3.5814 x -4.6126 ( r =0.9972) were acquired in water and in 0.1 mol/L HCl solution respectively, but without in the SDS solution. In order to specially monitor the dissolution dynamic changes of the important fingerprints to guide the preparation technology and improve their bioavailability, We investigated the four strong peaks of CDDP-DFP and calculated out the fitting equations as follows, lnln [1/(1- A i / A max )]= y , the first one (No.6, Protocatechualdehyde), y =-0.5603 x (2)+3.4516 x -3.8974 ( r =0.9988); the second one (No.19, Salvianolic acid B), y =-1.7127 x (2) +9.6655x-11.947 ( r =0.9897); the third one (No.4, Danshensu), y =-0.4239 x (2)+3.0436 x -3.6276 ( r =0.9985); the forth one (No.17, unkown), y =-0.5019 x (2)+3.3706 x -4.1053 ( r =0.9979), which indicated Salvianolic acid B with a prominent discrepancy from others. The quantified HPLC fingerprint can perfectly both quantitatively reflected the authentic quality of CDDPs and accurately overall quantitatively measure the dissolution dynamic varieties in vitro to provide the important information for bioavailability, in which water is proven to be the best dissolution medium for CDDP whose T 50 =4.1 min (released 50%) and T 90 =8.0 min (released 90%).