Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence(BE)testing for approval of immediate release(IR)solid dosage forms containing moxifloxacin hydrochloride as the API...Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence(BE)testing for approval of immediate release(IR)solid dosage forms containing moxifloxacin hydrochloride as the API manufactured by the Government Pharmaceutical Organization(GPO)are evaluated.The solubility of moxifloxacin hydrochloride determined by the shake flask method in six different pH mediums(1.2,4.5,5.4,6.4,6.8 and 7.5)was 4.988±0.1962,27.012±0.4138,21.668±0.5165,47.200±0.8095,73.438±1.7310 and 196.475±4.4624 mg/mL,respectively.The Dose/Solubility(D/S)Ratio of the highest strength(400 mg)available in the market of moxifloxacin tablets was 80.192,14.808,18.460,8.475,5.447 and 2.036 mL,respectively.展开更多
Objective: To determine the in vitro and in vivo absorption properties of active ingredients of the Chinese medicine, baicalein, to enrich mechanistic understanding of oral drug absorption.Methods: The Biopharmaceutic...Objective: To determine the in vitro and in vivo absorption properties of active ingredients of the Chinese medicine, baicalein, to enrich mechanistic understanding of oral drug absorption.Methods: The Biopharmaceutic Classification System(BCS) category was determined using equilibrium solubility, intrinsic dissolution rate, and intestinal permeability to evaluate intestinal absorption mechanisms of baicalein in rats in vitro. Physiologically based pharmacokinetic(PBPK) model commercial software GastroPlus~(TM) was used to predict oral absorption of baicalein in vivo.Results: Based on equilibrium solubility, intrinsic dissolution rate, and permeability values of main absorptive segments in the duodenum, jejunum, and ileum, baicalein was classified as a drug with low solubility and high permeability. Intestinal perfusion with venous sampling(IPVS) revealed that baicalein was extensively metabolized in the body, which corresponded to the low bioavailability predicted by the PBPK model. Further, the PBPK model predicted the key indicators of BCS, leading to reclassification as BCS-II. Predicted values of peak plasma concentration of the drug(C_(max)) and area under the curve(AUC)fell within two times of the error of the measured results, highlighting the superior prediction of absorption of baicalein in rats, beagles, and humans. The PBPK model supported in vitro and in vivo evidence and provided excellent prediction for this BCS class II drug.Conclusion: BCS and PBPK are complementary methods that enable comprehensive research of BCS parameters, intestinal absorption rate, metabolism, prediction of human absorption fraction and bioavailability, simulation of PK, and drug absorption in various intestinal segments across species. This combined approach may facilitate a more comprehensive and accurate analysis of the absorption characteristics of active ingredients of Chinese medicine from in vitro and in vivo perspectives.展开更多
Natural products(NPs) are compounds that are derived from natural sources such as plants, animals, and microisms. Therapeutics has benefited from numerous drug classes derived from natural product sources. The Biophar...Natural products(NPs) are compounds that are derived from natural sources such as plants, animals, and microisms. Therapeutics has benefited from numerous drug classes derived from natural product sources. The Biopharmaceutics Drug position Classification System(BDDCS) was proposed to serve as a basis for predicting the importance of transporters and enzymes in determining drug bioavailability and disposition. It categorizes drugs into one of four biopharmaceutical classes according to their water solubility and extent of metabolism. The present paper reviews 109 drugs from natural product sources: 29% belong to class 1(high solubility, extensive metabolism), 22% to class 2(low solubility, extensive metabolism), 40% to class 3(high solubility, poor metabolism), and 9% to class 4(low solubility, poor metabolism). Herein we evaluated the characteristics of NPs in terms of BDDCS class for all 109 drugs as wells as for subsets of NPs drugs derived from plant sources as antibiotics. In the 109 NPs drugs, we piled 32 drugs from plants, 50%(16) of total in class 1, 22%(7) in class 2 and 28%(9) in class 3, none found in class 4; Meantime, the antibiotics were found 5(16%) in class 2, 22(71%) in class 3, and 4(13%) in class 4; no drug was found in class 1. Based on this classification, we anticipate BDDCS to serve as a useful adjunct in evaluating the potential characteristics of new natural products.展开更多
To study the biopharmaceutics characteristics of paris saponin Ⅶ(PSⅦ). The solubility of PSⅦ was evaluated by measurement of the equilibrium solubility in different solvents and media. The permeability of PSⅦ was ...To study the biopharmaceutics characteristics of paris saponin Ⅶ(PSⅦ). The solubility of PSⅦ was evaluated by measurement of the equilibrium solubility in different solvents and media. The permeability of PSⅦ was evaluated by measuring the oil/water partition coefficient(lgP_(app)) and determining the apparent permeability coefficient(PC_(app)) on a mono-layer Caco-2 cell model. The effects of p-glycoprotein and multidrug resistance related protein 2 on PSⅦ transport in mono-layer Caco-2 cell model were further investigated. Finally, the small intestinal absorption of PSⅦ was investigated in rat. In solvents of different pH, the equilibrium solubility of PSⅦ was quite low, and the dose number of PSⅦ was larger than 1. The lgP_(app) of PSⅦ was less than 0. The apparent permeability coefficient [PC_(app)(AP-BL)] of PSⅦ in mono-layer Caco-2 cell model was less than 14.96 × 10^(-6) cm·s^(-1), and the efflux ratio of PSⅦ in mono-layer Caco-2 cell model was less than 1. The transport rate of PSⅦ in mono-layer Caco-2 cell model was not affected by the inhibitors of p-glycoprotein and multidrug resistance related protein 2. After oral administration, PSⅦ could be detected in rat intestinal contents, but could not be detected in the small intestinal mucosa. PSⅦ showed low solubility and permeability,which would result in low oral bioavailability in clinic. PSⅦ belonged to Class IV compound in biopharmaceutics classification system.展开更多
文摘Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence(BE)testing for approval of immediate release(IR)solid dosage forms containing moxifloxacin hydrochloride as the API manufactured by the Government Pharmaceutical Organization(GPO)are evaluated.The solubility of moxifloxacin hydrochloride determined by the shake flask method in six different pH mediums(1.2,4.5,5.4,6.4,6.8 and 7.5)was 4.988±0.1962,27.012±0.4138,21.668±0.5165,47.200±0.8095,73.438±1.7310 and 196.475±4.4624 mg/mL,respectively.The Dose/Solubility(D/S)Ratio of the highest strength(400 mg)available in the market of moxifloxacin tablets was 80.192,14.808,18.460,8.475,5.447 and 2.036 mL,respectively.
基金supported by the National Natural Science Foundation of China (81473362)。
文摘Objective: To determine the in vitro and in vivo absorption properties of active ingredients of the Chinese medicine, baicalein, to enrich mechanistic understanding of oral drug absorption.Methods: The Biopharmaceutic Classification System(BCS) category was determined using equilibrium solubility, intrinsic dissolution rate, and intestinal permeability to evaluate intestinal absorption mechanisms of baicalein in rats in vitro. Physiologically based pharmacokinetic(PBPK) model commercial software GastroPlus~(TM) was used to predict oral absorption of baicalein in vivo.Results: Based on equilibrium solubility, intrinsic dissolution rate, and permeability values of main absorptive segments in the duodenum, jejunum, and ileum, baicalein was classified as a drug with low solubility and high permeability. Intestinal perfusion with venous sampling(IPVS) revealed that baicalein was extensively metabolized in the body, which corresponded to the low bioavailability predicted by the PBPK model. Further, the PBPK model predicted the key indicators of BCS, leading to reclassification as BCS-II. Predicted values of peak plasma concentration of the drug(C_(max)) and area under the curve(AUC)fell within two times of the error of the measured results, highlighting the superior prediction of absorption of baicalein in rats, beagles, and humans. The PBPK model supported in vitro and in vivo evidence and provided excellent prediction for this BCS class II drug.Conclusion: BCS and PBPK are complementary methods that enable comprehensive research of BCS parameters, intestinal absorption rate, metabolism, prediction of human absorption fraction and bioavailability, simulation of PK, and drug absorption in various intestinal segments across species. This combined approach may facilitate a more comprehensive and accurate analysis of the absorption characteristics of active ingredients of Chinese medicine from in vitro and in vivo perspectives.
基金supported by China Scholarship Council(No.201208320187CSC)
文摘Natural products(NPs) are compounds that are derived from natural sources such as plants, animals, and microisms. Therapeutics has benefited from numerous drug classes derived from natural product sources. The Biopharmaceutics Drug position Classification System(BDDCS) was proposed to serve as a basis for predicting the importance of transporters and enzymes in determining drug bioavailability and disposition. It categorizes drugs into one of four biopharmaceutical classes according to their water solubility and extent of metabolism. The present paper reviews 109 drugs from natural product sources: 29% belong to class 1(high solubility, extensive metabolism), 22% to class 2(low solubility, extensive metabolism), 40% to class 3(high solubility, poor metabolism), and 9% to class 4(low solubility, poor metabolism). Herein we evaluated the characteristics of NPs in terms of BDDCS class for all 109 drugs as wells as for subsets of NPs drugs derived from plant sources as antibiotics. In the 109 NPs drugs, we piled 32 drugs from plants, 50%(16) of total in class 1, 22%(7) in class 2 and 28%(9) in class 3, none found in class 4; Meantime, the antibiotics were found 5(16%) in class 2, 22(71%) in class 3, and 4(13%) in class 4; no drug was found in class 1. Based on this classification, we anticipate BDDCS to serve as a useful adjunct in evaluating the potential characteristics of new natural products.
文摘To study the biopharmaceutics characteristics of paris saponin Ⅶ(PSⅦ). The solubility of PSⅦ was evaluated by measurement of the equilibrium solubility in different solvents and media. The permeability of PSⅦ was evaluated by measuring the oil/water partition coefficient(lgP_(app)) and determining the apparent permeability coefficient(PC_(app)) on a mono-layer Caco-2 cell model. The effects of p-glycoprotein and multidrug resistance related protein 2 on PSⅦ transport in mono-layer Caco-2 cell model were further investigated. Finally, the small intestinal absorption of PSⅦ was investigated in rat. In solvents of different pH, the equilibrium solubility of PSⅦ was quite low, and the dose number of PSⅦ was larger than 1. The lgP_(app) of PSⅦ was less than 0. The apparent permeability coefficient [PC_(app)(AP-BL)] of PSⅦ in mono-layer Caco-2 cell model was less than 14.96 × 10^(-6) cm·s^(-1), and the efflux ratio of PSⅦ in mono-layer Caco-2 cell model was less than 1. The transport rate of PSⅦ in mono-layer Caco-2 cell model was not affected by the inhibitors of p-glycoprotein and multidrug resistance related protein 2. After oral administration, PSⅦ could be detected in rat intestinal contents, but could not be detected in the small intestinal mucosa. PSⅦ showed low solubility and permeability,which would result in low oral bioavailability in clinic. PSⅦ belonged to Class IV compound in biopharmaceutics classification system.
