| LDP is an anti-cough drug with a peripheral mode of action. In several pharmacological and clinical studies, LDP exhibits an anti-tussive activity comparable to dropropizine, with a reduced sedative effect on the central nervous system. A sustained-release formulation would further improve its safety profile and allow for a more convenient dosing regimen compared with the immediate-release formulations. The objective of this study was to develop LDP sustained release tablets (SRT) with stable, good sustained release properties and acceptable bioavailability in vivo.Drug-excipient interactions were one of the most important factors which would influence the stability of LDP formulations. A systematic drug-excipient compatibility testing was performed before the excipients selection for LDP SRT. Drug-excipient blends at certain ratio with 200μl water in closed glass vials at 60℃ were analysed for the contents of impurity and degraded substance after 10 and 20 days, and the results demonstrated that many kinds of excipients could interact with LDP.The dissolution method of LDP SRT was established. The maximum absorption of LDP was at 237nm and the excipient has no effects on the drug determination. The linear range of LDP was 2.56-20.48/xg/ml. the average recovery was 99.06% (n=9) , RSD was 1.58%. The effects of the apparatus, medium and rotation speed on the dissolution rate of LDP SRT were studied, and the method was fixed on the rotated basket with 100rpm and 900ml water as the medium. The limitation of 1, 4 and 8hr of dissolution for LDP SRT was 15-30%, 40-60% and above the 75%.A HPLC method for determing the content of LDP in sustained-relaese tablets was developed. The chromatographic condition was as following: Diamonsil C18 column(4.6mmx200mm, 5/xm); methanol and 0.05M byethylamine solution (20:80, adjusted pH to 3.0 with H^PO4) as mobile phase; the detective wavelength was at 240nm. The linear range was 5.03 -50.30 ug-mL-1, the average recovery was 99.2% (n=9), RSD was 0.79% (n=6) . The method is simple, rapid, and accurate and can be used for the assay of LDP SRT.A simple HPLC method using UV detection was developed and validated for the determination of LDP in dog plasma for the first time. The sample was prepared for injection using a liquid-liquid extraction method, with 1-phenypiperazine as the internal standard. The mobile phase was methanol - diethylamine solution (0.05M) (20:80, v/v, pH adjusted to 3.0 with H.1PO4) and the detection wavelength was at 240nm. The LOQ of LDP in biological matrix was determined to be 25.25 ng/ml. The calibration curve was linear across the concentration range of 25.25-2020 ng/ml. The intra-day and inter-day precision (CV %) was within 7% and accuracy (R.E. %) was within 6% of the nominal values for medium (252.5 ng/ml) and high (2020 ng/ml) LDP concentration. For LDP concentration at the LOQ, the intra-day and inter-day precision and accuracy were within 20 and 10%, respectively. The average absolute recovery was 70.3% for LDP. This method was successfully applied to analyze plasma samples in a bioequivalence study of a LDP SRT, with immediate-release tablets (IRT) as the reference. The design of bioequivalence study is a multiple-dose, steady-state two-treatment, two-period, two-sequence crossover with a 10-day washout period between the two phases of the study. Six dogs were randomly assigned to one of the two dosing sequences and scheduled to receive either 90 mg SRT twice daily for five days, or 60 mg IRT thrice daily for five days and then crossed over to the alternative regimen following washout. The pharmacokinetic parameters of LDP SRT and reference were as follows: AUCu-t 1514.57±568.89 and 947.61±347.93ng*h/ml; tnm 2.17±0.41 and 0.67±0.I3h: Cma, 349.06± 150.3! and 452.03±270.20ng/ml; MRT0.T 4.49±0.35 and2.58±0.30h; Cmm 51.89±14.83 and 34.81±10.04 ng/ml; DF 219.33% and 326.29%. The relative bioavailability of the LDP SRT was 106.3 ± 12.8% (n=6) of the reference. The Cn,ax of the LDP SRT was significantly lower than that of the IRT (P<0.05) and the tmax was significantly longer than that of the IRT (P<0.05). The results indicated that the new LDP SRT exhibited good sustained release properties and was bioequivalent to the reference.The in vivo and in vitro correlation of the LDP SRT was evaluated by Loo-Rigelman method and deconvolution method. The linear correlation between the fraction of absorption in vivo and the dissolution rate in vitro has been proved.There was no report about the LDP SRT in the world, so this study has some extent innovation. The stability problem of LDP SRT has been solved by selection of excipient which has no interation with LDP and the technology optimization. A HPLC-UV method for measuring LDP in dog plasma has been developed and validated for the first time and the method was successfully applied to a multiple-dose steady state bioequivalence study of LDP SRT in dogs. The studies demonstrated that the nevviydeveloped LDP SRT exhibited good sustained release properties and acceptable bioavailability. The objective of this study has been attained.
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