Comparator product issues for biowaiver implementation: the case of Fluconazole

The aim of this work was to assess if the commercially available Fluconazole drug products (Reference, Generic and Similar) would meet the biowaiver criteria from Food and Drug Administration (FDA) and Brazilian Agency for Health Surveillance (ANVISA) agencies. All formulations were evaluated considering the dissolution profile carried out in Simulated Gastric Fluid (SGF) pH 1.2, Acetate Buffer (AB) pH 4.5 and Simulated Intestinal Fluid (SIF) pH 6.8. The results demonstrated that all formulations fulfilled the 85% of drug dissolved at 30 min criterion in SGF pH 1.2. However, in AB pH 4.5 and SIF pH 6.8, some formulations, including the comparator, did not achieve this dissolution percentage. The discrepant dissolution profiles also failed the ƒ2 similarity factor analysis, since none of the formulations showed values between 50 and 100 in the three dissolution media. Comparative dissolution profiles were not similar, considering that the main issues concerning the dissolution were evidenced for the comparator product. Hence, a revision in the regulatory norms in order to establish criteria to switch the comparator could result in an increased application of drugs based on biowaiver criteria

An update on oral drug delivery

Orally administered drug entities have to survive the harsh gastrointestinal environment, penetrate the enteric epithelia and circumvent hepatic metabolism before reaching the systemic circulation. Whereas the gastrointestinal stability can be well maintained by taking proper measures, hepatic metabolism presents as a formidable barrier to drugs suffering from first-pass metabolism. The pharmaceutical academia and industries are seeking alternative pathways for drug transport to circumvent problems associated with the portal pathway. Intestinal lymphatic transport is emerging as a promising pathway to this end. In this review, we intend to provide an updated overview on the rationale, strategies, factors and applications involved in intestinal lymphatic transport. There are mainly two pathways for peroral lymphatic transport-the chylomicron and the microfold cell pathways. The underlying mechanisms are being unraveled gradually and nowadays witness increasing research input and applications.

A systematic evaluation of biopharmaceutics classification system of main efficacy and toxic ingredients in Polygoni Multiflori Radix Praeparata / 中草药

Objective: Biopharmaceutics classification system (BCS) of five main pharmacological/toxic components (gallic acid, emodin, stilbene glycoside, physcion, and emodin-8-O-β-D-glucoside) of Polygoni Multiflori Radix Praeparata (PMRP) were carried out. Methods: The solubility and permeability of each representative component were studied by equilibrium solubility method and everted intestinal sac method, respectively. Using two softwares (Pipeline Pilot 7.5, ChemDraw 7.0) to predict the solubility and permeability parameters of each component. Classical BCS classification of measured and predicted values of representative components was conducted according to Food and Drug Administration (FDA) standards, and their correlation was evaluated. Results: The emodin, emodin-8-O-β-D-glucoside, and physcion in PMRP was preliminary determined as BCS IV drugs. THSG and gallic acid belong to BCS III drugs, and permeability was the main limiting factor in their absorption process. There was software which predicts false positives of anthraquinone in BCS classification studies. Conclusion: In this study, five main pharmacodynamic/toxic components of PMRP were classified by BCS method, which provided data support and technical reference for in vivo absorption prediction and in vitro safety evaluation of traditional Chinese medicine.

Research and development thought on biopharmaceutics classification system of Chinese materia medica / 中国中药杂志

The biopharmaceutics classification system( BCS) is a scientific framework or method for classifying drugs based on drug solubility and permeability,which can be used to provide drug bioavailability-absorption correlation analysis. Based on the characteristics of multi-component and multi-target of traditional Chinese medicine( TCM) as well as the concept,method and technology of BCS,the research group proposed biopharmaceutics classification system of Chinese materia medica( CMMBCS) and carried out research and data accumulation of classical prescriptions. Based on the previous research results,further development ideas under the CMMBCS concept and framework were further proposed in this study. In the course of research,the influence of the intermediate links of the complex interactions of the multi-component environment was omitted,and the component absorption studies on the main clinical effects of prescription ingredients were directly concerned,or the components and data were reversely extracted from the aspects of metabolism,pharmacodynamic pathways and absorption principles. Studies were conducted from two aspects( single component and compound prescription) to comprehensively evaluate the absorption properties of TCM compound. In the research path,the different ways in which Chinese medicine could exert its efficacy were fully considered,and CMMBCS classification and establishment rules were clarified mainly by focusing on the absorption pathway into the blood. Specifically,the network pharmacology and molecular docking technology were used to screen the compound index components of TCM; the absorption rules were studied by the physiologically based pharmacokinetic models and the absorption parameters of CMMBCS were calculated by reverse reasoning. Then the CMMBCS classification of TCM prescription was corrected by studying the efficacy or absorption pathway. In this paper,the theoretical framework and research methodology of CMMBCS were systematically improved based on the establishment of CMMBCS basic theory,the supplementary of drug-oriented research ideas and the application of modern mature Chinese medicine methodology.

Applicability analysis and evaluation of aglycones in single-pass intestinal perfusion technique based on PBPK model / 中国中药杂志

Single-pass intestinal perfusion( SPIP) is the common carrier of biopharmaceutics classification system( BCS) to study compound permeability. With the application and deepening study of BCS in the field of traditional Chinese medicine( TCM),SPIP model is becoming more and more common to study the intestinal absorption of TCM ingredients. Based on the limitations of the SPIP model in some researches on TCM permeability,it was speculated in this study that aglycone may be more suitable than the glycoside to study the intestinal absorption problem by using SPIP model. Furthermore,applicability of aglycone components was analyzed and evaluated. In this study,with quercetin,daidzein,formononetin,genistein and glycyrrhetinic acid used as research objects,the quantitative study of SPIP was used to evaluate the intestinal permeability of these aglycones and to predict the effective permeability coefficient( Peff) and absorption fraction( Fa) in human body. By combining studies comparison and analysis on multiple permeability research methods and prediction of human body absorption of aglycones in physiological-based pharmacokinetic models,this paper can further illustrate that the SPIP model is a good tool for studying the permeability of aglycones and predicting human absorption,which can provide data foundation and theoretical reference for researches on SPIP technique and BCS in intestinal absorption of TCM ingredients.

Study on biopharmaceutics classification system of Chinese materia medica for Gegen Qinlians Tablets based on anti-inflammatory activity / 中国中药杂志

The research on biopharmaceutics classification system of Chinese materia medica( CMMBCS) should be finally implemented to the holistic research level of traditional Chinese medicine compounds,while the overall biopharmaceutical properties of traditional Chinese medicine compounds are not only the sum of solubility and permeability of each component. In this study,Gegen Qinlian Tablets was used as the research object,and the contents of 12 representative components,i.e. puerarin,daidzin,baicalin,daidzein,wogonoside,baicalein,wogonin,glycyrrhizic acid,coptisine hydrochloride,epiberberine,berberine hydrochloride and palmatine hydrochloride,were simultaneously determined by HPLC to obtain the mass weight of each component. The in vitro lipopolysaccharide( LPS)-induced RAW264. 7 cells inflammation model was established to investigate the anti-inflammatory effects of 12 representative components and obtain the efficacy weight of each component. In order to obtain the number of doses and effective permeability coefficient which can represent the overall biopharmaceutical properties of Gegen Qinlian Tablets,mass weight was combined with efficacy weight to integrate the solubility and permeability data of each component determined by typical shake flask method and in situ single pass intestinal perfusion model respectively. The results indicated that Gegen Qinlian Tablets should be categorized Ⅳ drug of the CMMBCS with low solubility and low permeability.

Impacts of multicomponent environment on intrinsic dissolution rate of berberine in biopharmaceutics classification system of Chinese materia medica / 中国中药杂志

To illustrate the intrinsic dissolution rate(IDR) involved in biopharmaceutics classification system of Chinese materia medica(CMMBCS), investigate the effect of artificial multicomponent environment on IDR of berberine, by using a non-disintegrating disk, and summarize related rules by using the obtained data. Progressive levels design was used to investigate the effects of single component environment (puerarin, baicalin, and glycyrrhizic acid); double-component environment(puerarin+baicalin, puerarin+ glycyrrhizic acid, baicalin+glycyrrhizic acid); and triple-component environment(puerarin+baicalin+glycyrrhizic acid) on IDR of berberine, laying a foundation for further researches on the absorption mechanism of multiple components.

Comparison of Two Biopharmaceutics Classification Systems and Discussion of Their Applications / 中国药学杂志

OBJECTIVE: To compare the difference between two kinds of biopharmaceutics classification systems and their applications. METHODS: Literatures and guidelines on biopharmaceutics classification system(BCS) and biopharmaceutics drug disposition classification system(BDDCS) were collected, the differences in conception, classification criteria, and application were compared, and problems which should be paid attention to in application were summarized. RESULTS:A lot of issues such as solubility, permeability, extent of metabolism and so on are involved in the application of BCS and BDDCS. Different classification criteria may have different results. The recognition for the two kinds of pharmaceutics classification systems by different administration organizations is not yet completely consistent. CONCLUSION:BCS and BDDCS play important roles in understanding the properties of drugs, especially in drug development and evaluation of generic drug conformance, however, the source of data should be identified when quoting the data. Possible risks should be considered for rational use of the data.

Dissolution and Permeability Behavior of Diclofenac Sodiumenteric-Coated Tablets In-Vitro / 中国药学杂志

OBJECTIVE: To investigate the permeability of diclofenac sodium(DS)through parallel artificial membrane, and compare the differences in the dissolution rates and fluxes of diclofenac sodium enteric-coated tablets from Novartis in Beijing, Turkey and Germany.METHODS :The permeation of diclofenac sodium in different pH media was studied and determined.The effects of excipients on the permeability of diclofenac sodium were investigated by comparing the differences in the permeability of diclofenac sodium enteric-coated tablets.After being placed in acidic media of pH 6.0 and pH 6.8 for 2 h, the difference in the dissolution profiles and membrane fluxes of three sources diclofenac sodium enteric-coated tablets were determined and compared. RESULTS: The permeability of diclofenac sodium in pH 5.0-6.8 medium increased with the decrease of pH value, which was the smallest in pH 6.8 medium (1.08×10-4 cm•s-1). The excipients did not affect the permeability of the main component. The dissolution rate of the sample from Turkey Novartis was slightly faster than those from Beijing and Germany Novartis. CONCLUSION: The permeability of diclofenac sodium depends on the pH of the medium. The biopharmaceutics classification system(BCS) of diclofenac sodium is classified as class Ⅱ, a drug of low solubility and high permeability. The dissolution of diclofenac sodium enteric-coated tablets depends on the dissolving rate of the enteric-coating and the dissolution rate of the tablet core.The dissolution behaviors of diclofenac sodium enteric-coated tablets from different regions of the same company in pH 6.0 and pH 6.8 media are difference but the membrane fluxes are similar. This study may provide data support for the selection of multi-source reference preparations in the evaluation of generic drug conformance, and plays an important guiding role in prescription screening and bioequivalence risk assessment.

Development, measurement, and application of biopharmaceutics classification system for Chinese materia medica / 中草药

Biopharmaceutics classification system (BCS) is a research method that scientifically classifies drugs based on its solubility and permeability, which is generally applicable to oral chemical products of single-component. Compared with most western medicines, Chinese materia medica (CMM) has a complex system of multiple components, so BCS has certain limitations in the study of CMM. Based on the scientific framework of BCS, domestic scholars have successively proposed some BCS for CMM. This article reviews the development, determination, and application of BCS for CMM by consulting relevant domestic and foreign literatures, in order to lay a reference for the in-depth research of BCS for CMM.

Establishment of dissolution test method of isoniazid tablets and evaluation of dissolution profiles / 药物评价研究

Objective To establish a method for determining the dissolution of isoniazid tablet in vitro and evaluate the dissolution profiles.Methods The paddle method was used for the dissolution test and the rotation rate was set at 50 r/min.The hydrochloric acid solution (pH 1.2),acetate buffer solution (pH 4.5),phosphate buffer solution (pH 6.8) and water (900 mL) were used as the dissolution media.HPLC was used for the determination of dissolution quantity.Results There was a good linear relationship between the quality concentration of i soniazid and peak area in the range of 0.1981-0.9904μg (r =0.9993).The average recovery was 100.2％.Precision,reproducibility,and specificity tests were good.Among the determination of 16 manufactures,the dissolution profiles in water of four manufactures were not similar with Sandoz reference preparation.Conclusion The HPLC method is simple.The accuracy and specificity of determination of isoniazid dissolution are improved.There is significant difference in the dissolution profiles between different manufactures.The method can be used for the determination of dissolution curves for isoniazid tablets.

Overall intestinal permeability of multiple components in lotus leaf by in situ single pass intestinal perfusion models / 中国中药杂志

To investigate the overall intestinal permeability of multiple components in lotus leaves and make clear the interaction in composition absorption process. Rat single-pass intestinal perfusion technique was used, and the results showed that the Peff values of nuciferine, demethylanuciferine, rutin, quercetin, kaempferol from lotus leaf were greater than 0.5×10⁻⁴ cm•s⁻¹. In the biopharmaceutics classification system (BCS) intestinal permeability property, these ingredients were high permeable components, while the hyperin was low permeable component. However, in the multi-component environment of the lotus leaf extract, component permeation was changed. Semi quantitative analysis of the unclear components showed that under the multi-component environment, four in seven components with relatively high contents had a Peff value less than 0.5×10⁻⁴ cm•s⁻¹, indicating these 4 components were of low permeability, while other 3 components were of high permeability. The results could be valuable to make clear the overall intestinal permeability of multiple components in lotus leaf, and lay a foundation for studying the mechanism of the lipid-lowering effect of lotus leaf.

In vitro and in vivo intestinal absorption of Huanglian decoction in multi-component environment / 中国中药杂志

The effect of drugs in the body is always inseparable with the dynamic processes of absorption, distribution, metabolism and excretion. For oral drug, absorption, as the first link to enter the body, is particularly valued. Traditional Chinese medicine has multiple components and multiple targets, and the nature of its single composition is different from that in the multicomponent environment. Alkaloids in Huanglian extract was used as the main object in this study to establish an analytical method for determining the content of alkaloids in Huanglian. In addition, the compositions of the Huanglian aqueous extract solution which can be absorbed through intestinal wall into blood, were initially determined by the means of everted gut sac and in intestinal perfusion with venous sampling experiment. This paper can provide data reference and support for the further study on the absorption and metabolism of Huanglian.

Study on biopharmaceutics classification system for Chinese materia medica of extract of Huanglian / 中国中药杂志

One of the advantages of biopharmaceutics classification system of Chinese materia medica (CMMBCS) is expanding the classification research level from single ingredient to multi-components of Chinese herb, and from multi-components research to holistic research of the Chinese materia medica. In present paper, the alkaloids of extract of huanglian were chosen as the main research object to explore their change rules in solubility and intestinal permeability of single-component and multi-components, and to determine the biopharmaceutical classification of extract of Huanglian from holistic level. The typical shake-flask method and HPLC were used to detect the solubility of single ingredient of alkaloids from extract of huanglian. The quantitative research of alkaloids in intestinal absorption was measured in single-pass intestinal perfusion experiment while permeability coefficient of extract of huanglian was calculated by self-defined weight coefficient method.

Solubility evaluation of didanosine: a comparison between the equilibrium method and intrinsic dissolution for biopharmaceutics classification purposes

ABSTRACT BCS (Biopharmaceutics Classification System) and BDDCS (Biopharmaceutics Drug Disposition Classification System) were proposed as tools for classifying drugs into four categories. Both systems consider the solubility as an important characteristic for the classification of compounds in drug development and in vivo disposition prediction. Although some results of drug solubility can be found in the literature, the aforementioned characteristic is not entirely clear when considering didanosine (ddI). Based on that, the solubility of ddI was evaluated using equilibrium and intrinsic dissolution methods. For the equilibrium method, excess amount of ddI was added to each media until obtaining a supersaturated solution and the mixture was submitted to agitation at 37 °C. For the intrinsic dissolution method, the drug was compressed into the Wood's apparatus matrix and subjected to dissolution in each media with agitation at 37 °C. The results obtained from the equilibrium method indicated that it was necessary 139.37 mL of pH 1.2 media, 87.72 mL of pH 4.5 media, 12.54 mL of pH 6.8 media, 5.03 mL of pH 7.5 media and 7.65 mL of purified water for drug solubilization. Furthermore, a very fast intrinsic dissolution rate (IDR) was obtained for each media: 0.1 mg/min/cm² (pH 1.2), 0.2 mg/min/cm² (pH 4.5), 0.2 mg/min/cm² (pH 6.8), 0.1 mg/min/cm² (pH 7.5) and 0.1 mg/min/cm² (purified water). Based on these results, ddI can be considered as a highly soluble drug for both equilibrium and intrinsic dissolution methods.

Comparison of different biopharmaceutics classification systems (BCS) and discussion of its application / 中国药学杂志

Biopharmaceutics classification system is a classification theory based on the solubility and permeability of drugs. Besides its application in in vitro-in vivo correlation studies, it also plays an important role in understanding the properties of drugs, especially in the drug development and evaluation. Nowadays, the definition and classification criteria of BCSs are not unified, therefore the classifications of drugs vary in different data sources, which resulting in confusion in understanding of the properties of drugs and use of BCS data. In this review, we compared the BCSs adopted by three authoritative official agencies ie, FDA, WHO and EMA, and two unofficial organization/enterprise ie, FIP and TSRL company. The problems in the use of BCS were also discussed, which will be helpful to use BCS data more correction and effectively.

Overall intestinal permeability of multiple components in lotus leaves / 中国中药杂志

In the study of biopharmaceutics classification system of Chinese materia medica (CMMBCS), the interactions of multiple components in the absorption should be taken into consideration in simultaneous multi-component determination. To investigate the absorption of multiple components, the in vitro everted gut sac model was used in this study, wtih lotus leaves as the research object. Aquantitative analysis was also carried out for the known components in this study. Totally 19 components in lotus extracts were absorbed by the intestinal tract, the Papp levels of the known components were nuciferine (1×10⁻⁵-1×10⁻⁶ cm•s⁻¹), rutin (1×10⁻⁶-1×10⁻⁷ cm•s⁻¹), hyperoside (1×10⁻⁶ cm•s⁻¹), isoquercitrin (1×10⁻⁶-1×10⁻⁷ cm•s⁻¹) and astragalin (1×10⁻⁶-1×10⁻⁷ cm•s⁻¹), respectively. These components showed a low permeability under a multi-component environment. This study was carried out to lay a foundation for further relevant target studies for different categories of components.

Evaluation for impacts of gut wall metabolism of multiple components in Chuanxiong Rhizoma during intestinal absorption with S9 incubation / 中国中药杂志

The information of drug deposition in the intestine is required in the study for the drug absorption in biopharmaceutics classification system (BCS). To illustrate the impacts of gut wall metabolism on the absorption, metabolism of multiple components in Chuanxiong Rhizoma in gut wall was tested by rat S9 incubation in vitro. The chemical fingerprint technology was used in this study to simultaneously detect multiple components in Chuanxiong, and peak areas before and after S9 incubation were compared. The results showed that senkyunolide I and several constituents were metabolized by gut wall, and one new metabolite was founded. However, ferulic acid and other compounds remained unchanged after incubation. Therefore, the subsequent intestinal permeability of multiple components in Chuanxiong that were not metabolized in the intestine was suggested to be detected directly by in situ single-pass intestinal perfusion (SPIP).Nonetheless, the intestinal permeability of the constituents that were metabolized in the intestine shall be explored by appropriate approaches.

Study on property of biopharmaceutics classification system of berberine in Huanglian decoction / 中国中药杂志

The study of single component in the multicomponent environment is one of the basic researches for biopharmaceutics classification system of Chinese materia medica (CMMBCS). That is to say, the classification research shall be based on the respective lift of solubility and permeability in the multicomponent environment, besides solubility and intestinal permeability of the single component. We chose berberine as the main research object to investigate the changes of its solubility and intestinal permeability in Huanglian decoction. Shake-flask and HPLC were used to detect the solubility of berberine in different pH buffer solutions and different concentrations of Huanglian decoction. In situ single-pass intestinal perfusion (SPIP) and intestinal perfusion with venous sampling (IPVS) were carried out to study berberine's intestinal absorption and absorption into blood, respectively.

Biopharmaceutics classification and absorption mechanisms primary study on four kinds of flavonoids / 中国中药杂志

The solubility and permeability on four kinds of flavonoids (kaempferol, hesperidin, apigenin, genistein) were test according to the theory of biopharmaceutics classification system (BCS), and their absorption mechanism. The solubility was investigated by the method in determination of solubility of "Chinese Pharmacopoeia 2010". To detect appearance permeability of compounds mentioned above, the appropriate concentrations were selected by the MTT method in cell transfer experiments in Caco-2 cell model, which established by in vitro cell culture method. Therefore, these compounds were classified with BCS according to solubility and permeability. In addition, to explore absorption mechanisms, the experiments in three different concentrations of compounds in high, medium and low in bidirectional transformation methods in Caco-2 cell model contacted. The study indicated that all of kaempferol, hesperidin, apigenin, genistein have the characteristics in low solubility and high permeability, which belong to BCSⅡ, and the absorption mechanism of kaempferol was active transportation. Whereas, hesperidin, apigenin, genistein were passive transportation. In this study, it carried out initial explorations on establishment of determination for solubility and permeability in flavonoids, and provided theoretical reference for further research on BCS in traditional Chinese medicine.