Qualification of In Vitro Dissolution Absorption System 2 (IDAS2) with Caco-2 and MDCK Cell Monolayers: Dose Sensitivity Study Using BCS Class I and III Drugs.

This study aimed to validate the In vitro Dissolution Absorption System 2 (IDAS2) containing a biological barrier of Caco-2 or Madin-Darby canine kidney (MDCK) cell monolayer through dose sensitivity studies. Metoprolol and propranolol were selected as Biopharmaceutics Classification System (BCS) Class I model drugs, and atenolol as a Class III model drug. The IDAS2 is comprised of a dissolution vessel (500 mL) and two permeation chambers (2 × 8.0 mL) mounted with Caco-2 or MDCK cell monolayer. One or two immediate-release tablet(s) of the model drug were added to the dissolution vessel, and the time profiles of dissolution and permeation were observed. Greater than 85% of metoprolol and propranolol (tested at two dosing concentrations) were dissolved by 15 min, and all drugs were fully dissolved by 30 min. All three drugs were more permeable across Caco-2 cells than MDCK cells with a linear increase in permeation across both cells at both dose concentrations. Thus, the dose sensitivity of the IDAS2 was demonstrated using both cell barriers. These results indicate a successful qualification of IDAS2 for the development/optimization of oral formulations and that MDCK cells can be utilized as a surrogate for Caco-2 cells.

Lack of an Effect of Polysorbate 80 on Intestinal Drug Permeability in Humans.

PURPOSE: Despite no broad, direct evidence in humans, there is a potential concern that surfactants alter active or passive drug intestinal permeation to modulate oral drug absorption. The purpose of this study was to investigate the impact of the surfactant polysorbate 80 on active and passive intestinal drug absorption in humans. METHODS: The human (n = 12) pharmacokinetics (PK) of three probe substrates of intestinal absorption, valacyclovir, chenodeoxycholic acid (CDCA), and enalaprilat, were assessed. Endogenous bile acid levels were assessed as a secondary measure of transporter and microbiota impact. RESULTS: Polysorbate 80 did not inhibit peptide transporter 1 (PepT1)- or apical sodium bile acid transporter (ASBT)-mediated PK of valacyclovir and CDCA, respectively. Polysorbate 80 did not increase enalaprilat absorption. Modest increases in unconjugated secondary bile acid Cmax ratios suggest a potential alteration of the in vivo intestinal microbiota by polysorbate 80. CONCLUSIONS: Polysorbate 80 did not alter intestinal membrane fluidity or cause intestinal membrane disruption. This finding supports regulatory relief of excipient restrictions for Biopharmaceutics Classification System-based biowaivers.

Development of a Novel Gastric Process Simulation Model: The Successful Assessment of Bioequivalence and Bioinequivalence of a Biopharmaceutics Classification System Class II Weak Acid Drug.

Bioequivalence has been assessed using in vitro dissolution testing, such as in vivo predictive dissolution methodology. However, the assessment of bioequivalence should be performed carefully, considering the effect of the in vivo environment and according to the properties of the drug. The gastric emptying process is a key factor for the assessment of biopharmaceutics classification system class II (BCS class IIa) drugs with acidic properties since they cannot dissolve in the acidic stomach, but do dissolve in the small intestine (SI). The disintegration of a tablet in the stomach affects the distribution/dissolution in the SI due to the difference in the gastric emptying step, which in turn is a result of the varying formulation of the drugs. In this study, we used the reported dynamic pH change method and a novel gastric process simulation (GPS) model, which can compare the gastric emptying of particular-sized drug particles. The in vitro results were compared to clinical data using bioequivalent and bioinequivalent products of candesartan cilexetil. It was revealed that the dynamic pH change method was inappropriate, whereas the amount of filtered drug in GPS studies with 20 and 50 µm pore size filters could reflect the clinical results of all products. The evaluation of the gastric emptying process of drug particles less than 50 µm enabled us to assess the bioequivalence because they probably caused the difference in the distribution in the SI. This study demonstrated the utility of the GPS model for the assessment of bioequivalence of BCS class IIa drugs.

Modeling of In Vitro Dissolution Profiles of Carvedilol Immediate-Release Tablets in Different Dissolution Media.

Quantitative evaluation of drug dissolution characteristics based on mathematical models is essential to understand and predict a particular drug release profile. In this study, model-dependent evaluation of the dissolution kinetics of reference and five test products (25-mg, immediate-release (IR) tablets) of an antihypertensive drug, carvedilol, was carried out using the DDSolver® program. The effects of pH (pH 1.2, 4.5, and 6.8) and various media with/without 0.5% (w/v) anionic, cationic, and nonionic surfactants (sodium lauryl sulfate (SLS), hexadecyltrimethylammonium bromide (CTAB), and polysorbate 80) on the dissolution kinetics of the bioequivalent IR products of carvedilol were investigated. The Weibull-1 model was fitted successfully to the dissolution data of all products at pH 1.2 and pH 4.5, as well as in the pH 6.8 medium with CTAB according to the model goodness of fit (r2 = 0.981-0.999, AIC = 14.5-42.6, MSC = 1.99-5.25). Model fitting produced good fits to Gompertz-1 for all products at pH 6.8 without a surfactant (r2 = 0.975-0.998, AIC = 28.3-55, MSC = 2.53-5.82). For pH 6.8 media containing SLS or polysorbate 80, Logistic-2 was fitted successfully to the dissolution data of all products (r2 = 0.974-0.999, AIC = 20.9-52.1, MSC = 1.90-5.69). Overall, the model-dependent analysis of in vitro dissolution data indicated in vitro equivalence of the reference and test products of carvedilol in each medium in terms of kinetic models, suggesting that it would have an important role in developing generic drug products of the BCS class II drug carvedilol.

Evaluating Solubility of Celecoxib in Age-Appropriate Fasted- and Fed-State Gastric and Intestinal Biorelevant Media Representative of Adult and Pediatric Patients: Implications on Future Pediatric Biopharmaceutical Classification System.

Prediction of performance of traditional, reformulated, and novel oral formulations in adults and pediatrics is of great importance. This study was conducted to assess solubility of celecoxib in age-appropriate fasted- and fed-state gastric and intestinal biorelevant media, classify celecoxib into biopharmaceutical classification system (BCS), and assess the effects of age-related developmental changes in the composition and volume of gastrointestinal fluids on the solubility and performance of oral formulations containing celecoxib. Solubility of celecoxib was assessed at 37°C in the pH range specified by the BCS-based criteria in 13 age-appropriate biorelevant media reflective of the gastric and proximal small intestinal environment in both fasted and fed states in adults and different pediatric subpopulations. A validated HPLC-UV method was used to quantify celecoxib. Experimental and computational molecular descriptors and in vivo pharmacokinetic data were used to assign the permeability class of celecoxib. Celecoxib belonged to BCS class 2. The pediatric to adult solubility ratios were outside the 80-125% boundaries in 3 and borderline in 1 biorelevant media. Significant age-related variability could be predicted for oral formulations containing celecoxib intended for pediatric use. Findings of this study indicated that the criteria used in the adult BCS might not be directly applied to pediatric subpopulations.

Prediction of plasma concentrations using in silico modelling and simulation approach: Case of Acebutolol.

PURPOSE: The aim of this study was to predict the plasma concentrations of acebutolol tablets with different dissolution profiles using computer modelling and evaluating whether they are bioequivalent using simulated population studies. METHODS: The dissolution behaviour of acebutolol was studied in the USP Apparatus-II using different dissolution media for pH 1.2, 4.5, and 6.8 at 37±0.5°C. The obtained dissolution data, as well as plasma concentration-time data of the reference product from the literature were used as inputs to build pharmacokinetic model of acebutolol within GastroPlus™ software (version 9.7, Simulations Plus Inc., Lancaster, CA, USA) to simulate the in vivo profiles of the drug. RESULTS: The dissolution profiles of the reference product Sectral® 400mg tablets and a locally produced generic product were>85% in 15min in three dissolution media. Simulation results demonstrated that the brand and generic products would show the same in vivo performance. Population simulation results of the ln-transformed 90% confidence interval for the ratio of Cmax, AUC0-t and AUC0-inf values for the two products were within the 80-125% interval, showing to be bioequivalent. CONCLUSION: Based on the in vitro results combined with in silico simulations using GastroPlus™, a biowaiver for immediate release acebutolol tablets is justified. Furthermore, computer modelling has shown to be a very intersting tool to prove the bioequivalence for these products.

ICH M9 Guideline in Development on Biopharmaceutics Classification System-Based Biowaivers: An Industrial Perspective from the IQ Consortium.

In October 2016, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) ICH began efforts to provide recommendations to harmonize guidances for biopharmaceutics classification system (BCS)-based biowaivers. Topics to be addressed included consideration of the dose used to classify solubility, tests, and criteria for establishing highly permeable, dissolution conditions, the influence of excipients, and aspects of product strength. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) is a technically focused organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators, and the broader R&D community. Its members have substantial expertise in all scientific domains associated with BCS-based waivers and drug product quality, as well as considerable experience in the application of BCS-based biowaivers. The ICH process recognizes that harmonization is achieved through the development of guidelines via a process of scientific consensus with regulatory and industry experts working side-by-side. Thus, to facilitate these efforts and to encourage open and transparent discussion of other perspectives that may exist, IQ offers their perspective on these and related topics.

Preparation of stabilized submicron fenofibrate crystals on niacin as a hydrophilic hydrotropic carrier.

Fenofibrate is antihyperlipidemic which has low and variable oral bioavailability due to erratic dissolution characteristics. Niacin showed a potential atheroprotective effects suggesting possible co-administration with fenofibrate with a potential for development of fixed dose combination. The chemical structure of both drugs highlights the opportunity for interaction upon co-processing due to the existence of complementary hydrogen bonding sites. Accordingly, fenofibrate and niacin were co-processed by wet co-grinding and the resulting product was assessed using scanning electron microscopy, FTIR, thermal analysis and X-ray diffraction in addition to dissolution studies. The instrumental analysis indicated the development of submicron fenofibrate crystals stabilized over the surface of niacin crystals. The developed submicron crystals showed fast dissolution of fenofibrate depending on the relative proportions of fenofibrate to niacin. Co-processing of both drugs at dose ratio which contained higher proportion of niacin resulted in further enhancement in the dissolution rate. This further enhancement was attributed to the hydrotropic effect of niacin which was proved by solubility study in addition to size reduction. This supposition was confirmed from the inferior dissolution of fenofibrate from the physical mixture. The study introduces fenofibrate/niacin as potential fixed dose combination for augmented dissolution rate and pharmacological effects.

[Effect of physicochemical properties on the pharmacokinetic parameters of the new representative of benzothiazinones antituberculosis drug macozinonе].

INTRODUCTION: Tuberculosis (TB) is one of the top ten causes of death worldwide. Improvement of the treatment options via development of new drugs and treatment regimens that would be more convenient for patients is one of key options of improving the effecacy of the TB prevention and careis. Since the creation of new treatment regimens by minimizing the number of the drugs used and reducing the duration of treatment is the most promising and correct direction, macozinone, a new candidate of the benzothiazinone series, can become the basis for development of new chemotherapy regimens for drug-resistant forms of TB including the combination of macozinone with the most effective modern anti-TB drugs. AIM: Comparative evaluation of the pharmacokinetic properties of macozinone capsules 80 mg and the new dosage form a dispersible tablet for preparation of oral solution. MATERIALS AND METHODS: Solubility of the substance macozinone in biorelevant media in vitro, permeability of macozinone in the test Caco-2 in vitro, as well as pharmacokinetics of macozinone in dogs in vivo were evaluated. RESULTS: The solubility assessment in biorelevant media showed that the average limit of macozinone substance dissolution in the pH 5.0 acetate buffer solution was from 6 to 9 mg/l, in FaSSIF medium (fasted) from 2.5 to 4 mg/l, and in FeSSIF medium (after meals) from 16.8 to 29 mg/l. It is established that the cell permeability of the pharmaceutical substance macozinone in the CACO-2 test system is on average 2.510-6cm/s in the forward direction from the apical to basolateral cell membrane, and 1.510-6cm/s in the reverse direction, which corresponds to low permeability. The main pharmacokinetic parameters of macozinone dispersable tablets 160 mg, after dosing with food and on an empty stomach, as well as capsules 80 mg, when administered on an empty stomach in vivo studies in dogs are presented. DISCUSSION: The specific physicochemical properties of macozinone, the problems of developing the new dosage form, as well as ways of solving some of them are presented. CONCLUSION: In the process of new dosage forms development, the existing chemical properties of the macozinone substance should be considered. One of the promising ways of increasing bioavailability and, consiquently, efficacy is development a fundamentally new drug form with modified release within the absorption window.

Application of data mining approach to identify drug subclasses based on solubility and permeability.

Solubility and permeability are recognized as key parameters governing drug intestinal absorption and represent the basis for biopharmaceutics drug classification. The Biopharmaceutics Classification System (BCS) is widely accepted and adopted by regulatory agencies. However, currently established low/high permeability and solubility boundaries are the subject of the ongoing scientific discussion. The aim of the present study was to apply data mining analysis on the selected drugs data set in order to develop a human permeability predictive model based on selected molecular descriptors, and to perform data clustering and classification to identify drug subclasses with respect to dose/solubility ratio (D/S) and effective permeability (Peff ). The Peff values predicted for 30 model drugs for which experimental human permeability data are not available were in good agreement with the reported fraction of drug absorbed. The results of clustering and classification analysis indicate the predominant influence of Peff over D/S. Two Peff cut-off values (1 × 10-4 and 2.7 × 10-4  cm/s) have been identified indicating the existence of an intermediate group of drugs with moderate permeability. Advanced computational analysis employed in the present study enabled the recognition of complex relationships and patterns within physicochemical and biopharmaceutical properties associated with drug bioperformance.

Designing of Stable Co-crystals of Zoledronic Acid Using Suitable Coformers.

In this present study a new co-crystals of zoledronic acid with DL-tartaric acid and nicotinamide has been developed with improved solubility. Zoledronic acid is a class III drug with poor oral bioavailability due to its poor permeability and low aqueous solubility; hence an attempt has been made to improve its solubility by co-crystallization technology. Pharmaceutical cocrystals are multi-component crystals with a stoichiometric ratio of active pharmaceutical ingredients (APIs) and cocrystal coformers (CCFs) that are assembled by noncovalent interactions such as hydrogen bonds, π-π packing, and Vander Waals forces. In this study the coformers selected were DL-tartaric acid and nicotinamide based on ease of hydrogen bond formation. The co-crystal of zoledronic acid with DL-tartaric acid were prepared in three ratios (1 : 1, 1 : 2 and 2 : 1) by slow solvent evaporation method and with nicotinamide in 1 : 1 ratio by dry grinding method. The formation of co-crystal was confirmed by powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC) and Fourier transform (FT)IR. The dynamic solubility of co-crystals with DL-tartaric acid in the ratios 1 : 1, 1 : 2 and 2 : 1 increased by fold as compared to pure drug.

Comparative Oral Drug Classification Systems: Acetazolamide, Azithromycin, Clopidogrel, and Efavirenz Case Studies.

Biopharmaceutics classification systems based on the properties of solubility and permeability or the extension of metabolism are very important tools in the early stages of the development and regulatory stages of new products. However, until now, there was no clear understanding between the interplay among these classification systems. Therefore, the main objective of this work was to make a comparison of concepts of BCS and BDDCS to understand what are the key factors that allow for the integration of these biopharmaceutics classification systems. Also, the suitability of an in situ single-pass intestinal perfusion assay in rats (SPIP) development was assessed by us to determine the limit between high and low permeability following what the FDA BCS guidance suggests. An excellent correlation was found between the values of permeability obtained by applying SPIP assays and the extensions of the metabolism of the set of compounds studied in this work, with the exception of three compounds that showed disparity between their permeability coefficients ( Peff), obtained herein by SPIP, and their metabolism (acetazolamide, azithromycin, and efavirenz). Discrepancies allowed us to elucidate the interrelationship between BCS and BDDCS.

In Vitro, in Silico, and in Vivo Assessments of Intestinal Precipitation and Its Impact on Bioavailability of a BCS Class 2 Basic Compound.

In this study, a multipronged approach of in vitro experiments, in silico simulations, and in vivo studies was developed to evaluate the dissolution, supersaturation, precipitation, and absorption of three formulations of Compound-A, a BCS class 2 weak base with pH-dependent solubility. In in vitro 2-stage dissolution experiments, the solutions were highly supersaturated with no precipitation at the low dose but increasing precipitation at higher doses. No difference in precipitation was observed between the capsules and tablets. The in vitro precipitate was found to be noncrystalline with higher solubility than the crystalline API, and was readily soluble when the drug concentration was lowered by dilution. A gastric transit and biphasic dissolution (GTBD) model was developed to better mimic gastric transfer and intestinal absorption. Precipitation was also observed in GTBD, but the precipitate redissolved and partitioned into the organic phase. In vivo data from the phase 1 clinical trial showed linear and dose proportional PK for the formulations with no evidence of in vivo precipitation. While the in vitro precipitation observed in the 2-stage dissolution appeared to overestimate in vivo precipitation, the GTBD model provided absorption profiles consistent with in vivo data. In silico simulation of plasma concentrations by GastroPlus using biorelevant in vitro dissolution data from the tablets and capsules and assuming negligible precipitation was in line with the observed in vivo profiles of the two formulations. The totality of data generated with Compound-A indicated that the bioavailability differences among the three formulations were better explained by the differences in gastric dissolution than intestinal precipitation. The lack of intestinal precipitation was consistent with several other BCS class 2 basic compounds in the literature for which highly supersaturated concentrations and rapid absorption were also observed.

Integrating theoretical and experimental permeability estimations for provisional biopharmaceutical classification: Application to the WHO essential medicines.

The accuracy of the provisional estimation of the Biopharmaceutics Classification System (BCS) is heavily influenced by the permeability measurement. In this study, several theoretical and experimental models currently employed for BCS permeability classification have been analysed. The experimental models included the in situ rat intestinal perfusion, the ex vivo rat intestinal tissue in an Ussing chamber, the MDCK and Caco-2 cell monolayers, and the parallel artificial membrane (PAMPA). The theoretical models included the octanol-water partition coefficient and the QSPeR (Quantitative Structure-Permeability Relationship) model recently developed. For model validation, a dataset of 43 compounds has been recompiled and analysed for the suitability for BCS permeability classification in comparison with the use of human intestinal absorption and oral bioavailability values. The application of the final model, based on a majority voting system showed a 95.3% accuracy for predicting human permeability. Finally, the present approach was applied to the 186 orally administered drugs in immediate-release dosage forms of the WHO Model List of Essential Medicines. The percentages of the drugs that were provisionally classified as BCS Class I and Class III was 62.4%, suggesting that in vivo bioequivalence (BE) may potentially be assured with a less expensive and more easily implemented in vitro dissolution test, ensuring the efficiency and quality of pharmaceutical products. The results of the current study improve the accuracy of provisional BCS classification by combining different permeability models.

Impact of the US FDA "Biopharmaceutics Classification System" (BCS) Guidance on Global Drug Development.

The FDA guidance on application of the biopharmaceutics classification system (BCS) for waiver of in vivo bioequivalence (BE) studies was issued in August 2000. Since then, this guidance has created worldwide interest among biopharmaceutical scientists in regulatory agencies, academia, and industry toward its implementation and further expansion. This article describes how the review implementation of this guidance was undertaken at the FDA and results of these efforts over last dozen years or so across the new, and the generic, drug domains are provided. Results show that greater than 160 applications were approved, or tentatively approved, based on the BCS approach across multiple therapeutic areas; an additional significant finding was that at least 50% of these approvals were in the central nervous system (CNS) area. These findings indicate a robust utilization of the BCS approach toward reducing unnecessary in vivo BE studies and speeding up availability of high quality pharmaceutical products. The article concludes with a look at the adoption of this framework by regulatory and health policy organizations across the globe, and FDA's current thinking on areas of improvement of this guidance.

Biorelevant Dissolution Models for a Weak Base To Facilitate Formulation Development and Overcome Reduced Bioavailability Caused by Hypochlordyria or Achlorhydria.

In this study, two dissolution models were developed to achieve in vitro-in vivo relationship for immediate release formulations of Compound-A, a poorly soluble weak base with pH-dependent solubility and low bioavailability in hypochlorhydric and achlorhydric patients. The dissolution models were designed to approximate the hypo-/achlorhydric and normal fasted stomach conditions after a glass of water was ingested with the drug. The dissolution data from the two models were predictive of the relative in vivo bioavailability of various formulations under the same gastric condition, hypo-/achlorhydric or normal. Furthermore, the dissolution data were able to estimate the relative performance under hypo-/achlorhydric and normal fasted conditions for the same formulation. Together, these biorelevant dissolution models facilitated formulation development for Compound-A by identifying the right type and amount of key excipient to enhance bioavailability and mitigate the negative effect of hypo-/achlorhydria due to drug-drug interaction with acid-reducing agents. The dissolution models use readily available USP apparatus 2, and their broader utility can be evaluated on other BCS 2B compounds with reduced bioavailability caused by hypo-/achlorhydria.

Changing paradigms in bioequivalence trials submitted to the EMA for evaluation - A clinical and regulatory perspective.

BACKGROUND: The selection of a robust bioequivalence (BE) study designs for registering a generic product remains still a hard task. This task is still challenging despite the fact that generic products are much needed by health care providers in economical terms. Thus, BE study designs could be a means to allow companies to reduce costs and reach the market earlier. We therefore investigated whether different approaches in various products assessed by the European Medicines Agency during the approval phase resulted in a reduction in resources required to show bioequivalence for different medicinal products. METHODS: European Public Assessment Reports (EPARs) for off-patent medicinal products authorised within the European Union (EU) through the centralised procedure during the period 2007-2015 were retrieved and reviewed to identify the clinical studies that resulted in fewer number of subjects, the number of centres or trial duration versus the two-period crossover design. RESULTS: 7 studies out of 108 were considered as having benefitted from having a different design. Differences noted included having a different dose allocation scheme, having a different number of dosing periods, having a different number of treatment arms, and having one study evaluating different strengths. Benefits noted included a decrease in the number of subjects and centres required, decreases in study duration and a reduced number of studies required to demonstrate bioequivalence. CONCLUSION: Bioequivalence studies can be designed in a specific manner to require fewer resources to carry out. Fewer resources required to register a medicinal product, could impart an advantage to companies (such as to be first on the market) or could even translate to making medicines more accessible (such as cheaper) to patients.

[Biopharmaceutics classification and absorption mechanisms primary study on four kinds of flavonoids].

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.

Intestinal permeability study of minoxidil: assessment of minoxidil as a high permeability reference drug for biopharmaceutics classification.

The purpose of this study was to evaluate minoxidil as a high permeability reference drug for Biopharmaceutics Classification System (BCS). The permeability of minoxidil was determined in in situ intestinal perfusion studies in rodents and permeability studies across Caco-2 cell monolayers. The permeability of minoxidil was compared with that of metoprolol, an FDA reference drug for BCS classification. In rat perfusion studies, the permeability of minoxidil was somewhat higher than that of metoprolol in the jejunum, while minoxidil showed lower permeability than metoprolol in the ileum. The permeability of minoxidil was independent of intestinal segment, while the permeability of metoprolol was region-dependent. Similarly, in mouse perfusion study, the jejunal permeability of minoxidil was 2.5-fold higher than that of metoprolol. Minoxidil and metoprolol showed similar permeability in Caco-2 study at apical pH of 6.5 and basolateral pH of 7.4. The permeability of minoxidil was independent of pH, while metoprolol showed pH-dependent transport in Caco-2 study. Minoxidil exhibited similar permeability in the absorptive direction (AP-BL) in comparison with secretory direction (BL-AP), while metoprolol had higher efflux ratio (ER > 2) at apical pH of 6.5 and basolateral pH of 7.4. No concentration-dependent transport was observed for either minoxidil or metoprolol transport in Caco-2 study. Verapamil did not alter the transport of either compounds across Caco-2 cell monolayers. The permeability of minoxidil was independent of both pH and intestinal segment in intestinal perfusion studies and Caco-2 studies. Caco-2 studies also showed no involvement of carrier mediated transport in the absorption process of minoxidil. These results suggest that minoxidil may be an acceptable reference drug for BCS high permeability classification. However, minoxidil exhibited higher jejunal permeability than metoprolol and thus to use minoxidil as a reference drug would raise the permeability criteria for BCS high permeability classification.

Biopharmaceutic Risk Assessment of Brand and Generic Lamotrigine Tablets.

The therapeutic equivalence of generic and brand name antiepileptic drugs has been questioned by neurologists and the epilepsy community. A potential contributor to such concerns is pharmaceutical quality. The objective was to assess the biopharmaceutic risk of brand name Lamictal 100 mg tablets and generic lamotrigine 100 mg tablets from several manufacturers. Lamotrigine was characterized in terms of the Biopharmaceutics Classification System (BCS), including aqueous solubility and Caco-2 permeability. A panel of pharmaceutical quality tests was also performed on three batches of Lamictal, three batches of Teva generic, and one batch of each of four other generics: appearance, identity, assay, impurity, uniformity of dosage units, disintegration, dissolution, friability, and loss on drying. These market surveillance results indicate that all brand name and generic lamotrigine 100 mg tablets passed all tests and showed acceptable pharmaceutical quality and low biopharmaceutic risk. Lamotrigine was classified as a BCS class IIb drug, exhibiting pH-dependent aqueous solubility and dissolution. At pH 1.2 and 4.5, lamotrigine exhibited high solubility, whereas lamotrigine exhibited low solubility at pH 6.8, including non-sink dissolution. Lamotrigine showed high Caco-2 permeability. The apparent permeability (Papp) of lamotrigine was (73.7 ± 8.7) × 10(-6) cm/s in the apical-to-basolateral (AP-BL) direction and (41.4 ± 1.6) × 10(-6) cm/s in the BL-AP direction, which were higher than metoprolol's AP-BL Papp of (21.2 ± 0.9) × 10(-6) cm/s and BL-AP Papp of (34.6 ± 4.6) × 10(-6) cm/s. Overall, lamotrigine's favorable biopharmaceutics from a drug substance perspective and favorable quality characteristics from a tablet formulation perspective suggest that multisource lamotrigine tablets exhibit a low biopharmaceutic risk.