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1.  In Silico Prediction of Drug Dissolution and Absorption with variation in Intestinal pH for BCS Class II Weak Acid Drugs: Ibuprofen and Ketoprofen§ 
The FDA Biopharmaceutical Classification System guidance allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms only for BCS class I. Extensions of the in vivo biowaiver for a number of drugs in BCS Class III and BCS class II have been proposed, particularly, BCS class II weak acids. However, a discrepancy between the in vivo- BE results and in vitro- dissolution results for a BCS class II acids was recently observed. The objectives of this study were to determine the oral absorption of BCS class II weak acids via simulation software and to determine if the in vitro dissolution test with various dissolution media could be sufficient for in vitro bioequivalence studies of ibuprofen and ketoprofen as models of carboxylic acid drugs.
The oral absorption of these BCS class II acids from the gastrointestinal tract was predicted by GastroPlus™. Ibuprofen did not satisfy the bioequivalence criteria at lower settings of intestinal pH=6.0. Further the experimental dissolution of ibuprofen tablets in the low concentration phosphate buffer at pH 6.0 (the average buffer capacity 2.2 mmol L-1/pH) was dramatically reduced compared to the dissolution in SIF (the average buffer capacity 12.6 mmol L -1/pH). Thus these predictions for oral absorption of BCS class II acids indicate that the absorption patterns largely depend on the intestinal pH and buffer strength and must be carefully considered for a bioequivalence test. Simulation software may be very useful tool to aid the selection of dissolution media that may be useful in setting an in vitro bioequivalence dissolution standard.
doi:10.1002/bdd.1800
PMCID: PMC3466597  PMID: 22815122
weak acid; ibuprofen; ketoprofen; pH; simulation; GastroPlus; in vitro dissolution; dissolution media
2.  An Investigation into the Importance of “Very Rapid Dissolution” Criteria for Drug Bioequivalence Demonstration using Gastrointestinal Simulation Technology 
The AAPS Journal  2009;11(2):381-384.
The Biopharmaceutics Classification System (BCS) is based on the mechanistic assumptions that the rate and extent of oral drug absorption are governed by drug solubility, intestinal permeability, and dissolution rate from the dosage form administered. One of the goals of BCS is to identify classes of drugs for which bioequivalence may be established based solely on the in vitro dissolution data, i.e., which would be eligible for biowaiver. On the basis of BCS, currently, the biowaiver concept is adopted and recommended for immediate release of drug products containing highly soluble and highly permeable compounds (BCS class 1 drugs). Dissolution testing properties are proposed to be more stringent: very rapid dissolution is demanded when generic drug application is submitted with the exemption of in vivo bioequivalence study. In the present paper, Gastrointestinal Simulation Technology has been applied in order to evaluate the potential for different in vitro drug dissolution kinetics to influence dosage forms in vivo behavior and the relevance of “very rapid dissolution” criteria to be met (i.e., more than 85% of dose dissolved in 15 min).
doi:10.1208/s12248-009-9114-3
PMCID: PMC2691474  PMID: 19455428
BCS; bioequivalence; dissolution; gastrointestinal simulation
3.  Use of the Biopharmaceutical Classification System in Early Drug Development 
The AAPS Journal  2008;10(1):208-212.
The Biopharmaceutics Classification System (BCS) is not only a useful tool for obtaining waivers for in-vivo bioequivalence studies but also for decision making in the discovery and early development of new drugs. Measurement of solubility and permeability in the discovery/development settings is described. These data can be utilized for the preliminary BCS classification of pipeline compounds. A decision tree is described in the prioritization of salt and polymorph screening studies prior to in vivo studies in animals. For BCS class 1 and 3 compounds, polymorphism is less likely to impact on bioavailability. The polymorph screening study may be postponed after animal studies. The BCS classification can also be used in the design of animal and human formulations. A BCS-based animal formulation development decision tree is presented. A compound is triaged based on a series of decision points into one of the five formulation strategies. Human formulation has different requirements than animal formulation. A comparison between animal and human formulation strategies is presented. In conclusion, for non-BCS 1 compounds, the right-first-time polymorph and formulation selection ensures consistent pharmacokinetic performance and avoids bridging BA/BE studies. It is in line with FDA’s initiative to reduce R&D cycle time through quality by design for pharmaceutical products.
doi:10.1208/s12248-008-9020-0
PMCID: PMC2751465  PMID: 18446521
biopharmaceutics classification; decision tree; formulation; polymorphism; salt
4.  An Investigation into the Influence of Experimental Conditions on In Vitro Drug Release from Immediate-Release Tablets of Levothyroxine Sodium and Its Relation to Oral Bioavailability 
AAPS PharmSciTech  2011;12(3):938-948.
The aim of this study was to investigate the influence of experimental conditions on levothyroxine sodium release from two immediate-release tablet formulations which narrowly passed the standard requirements for bioequivalence studies. The in vivo study was conducted as randomised, single-dose, two-way cross-over pharmacokinetic study in 24 healthy subjects. The in vitro study was performed using various dissolution media, and obtained dissolution profiles were compared using the similarity factor value. Drug solubility in different media was also determined. The in vivo results showed narrowly passing bioequivalence. Considering that levothyroxine sodium is classified as Class III drug according to the Biopharmaceutics Classification System, drug bioavailability will be less sensitive to the variation in its dissolution characteristics and it can be assumed that the differences observed in vitro in some of investigated media probably do not have significant influence on the absorption process, as long as rapid and complete dissolution exists. The study results indicate that the current regulatory criteria for the value of similarity factor in comparative dissolution testing, as well as request for very rapid dissolution (more than 85% of drug dissolved in 15 min), are very restricted for immediate-release dosage forms containing highly soluble drug substance and need further investigation. The obtained results also add to the existing debate on the appropriateness of the current bioequivalence standards for levothyroxine sodium products.
doi:10.1208/s12249-011-9660-8
PMCID: PMC3167270  PMID: 21748540
bioequivalence; dissolution; immediate release; levothyroxine sodium; solubility
5.  Prediction of Solubility and Permeability Class Membership: Provisional BCS Classification of the World’s Top Oral Drugs 
The AAPS Journal  2009;11(4):740-746.
The Biopharmaceutics Classification System (BCS) categorizes drugs into one of four biopharmaceutical classes according to their water solubility and membrane permeability characteristics and broadly allows the prediction of the rate-limiting step in the intestinal absorption process following oral administration. Since its introduction in 1995, the BCS has generated remarkable impact on the global pharmaceutical sciences arena, in drug discovery, development, and regulation, and extensive validation/discussion/extension of the BCS is continuously published in the literature. The BCS has been effectively implanted by drug regulatory agencies around the world in setting bioavailability/bioequivalence standards for immediate-release (IR) oral drug product approval. In this review, we describe the BCS scientific framework and impact on regulatory practice of oral drug products and review the provisional BCS classification of the top drugs on the global market. The Biopharmaceutical Drug Disposition Classification System and its association with the BCS are discussed as well. One notable finding of the provisional BCS classification is that the clinical performance of the majority of approved IR oral drug products essential for human health can be assured with an in vitro dissolution test, rather than empirical in vivo human studies.
doi:10.1208/s12248-009-9144-x
PMCID: PMC2782078  PMID: 19876745
BA/BE; biopharmaceutics classification system; biowaiver; intestinal absorption; molecular biopharmaceutics; oral drug product
6.  Summary Workshop Report: Bioequivalence, Biopharmaceutics Classification System, and Beyond 
The AAPS Journal  2008;10(2):373-379.
The workshop “Bioequivalence, Biopharmaceutics Classification System, and Beyond” was held May 21–23, 2007 in North Bethesda, MD, USA. This workshop provided an opportunity for pharmaceutical scientists to discuss the FDA guidance on the Biopharmaceutics Classification System (BCS), bioequivalence of oral products, and related FDA initiatives such as the FDA Critical Path Initiative. The objective of this Summary Workshop Report is to document the main points from this workshop. Key highlights of the workshop were (a) the described granting of over a dozen BCS-based biowaivers by the FDA for Class I drugs whose formulations exhibit rapid dissolution, (b) continued scientific support for biowaivers for Class III compounds whose formulations exhibit very rapid dissolution, (c) scientific support for a number of permeability methodologies to assess BCS permeability class, (d) utilization of BCS in pharmaceutical research and development, and (e) scientific progress in in vitro dissolution methods to predict dosage form performance.
doi:10.1208/s12248-008-9040-9
PMCID: PMC2751390  PMID: 18679807
bioavailability; bioequivalence; biopharmaceutics classification system (BCS); oral absorption; permeability; regulatory science; solubility
7.  Summary Workshop Report: Facilitating Oral Product Development and Reducing Regulatory Burden Through Novel Approaches to Assess Bioavailability/Bioequivalence 
The AAPS Journal  2012;14(3):627-638.
This summary workshop report highlights presentations and over-arching themes from an October 2011 workshop. Discussions focused on best practices in the application of biopharmaceutics in oral drug product development and evolving bioequivalence approaches. Best practices leverage biopharmaceutic data and other drug, formulation, and patient/disease data to identify drug development challenges in yielding a successfully performing product. Quality by design and product developability paradigms were discussed. Development tools include early development strategies to identify critical absorption factors and oral absorption modeling. An ongoing theme was the desire to comprehensively and systematically assess risk of product failure via the quality target product profile and root cause and risk analysis. However, a parallel need is reduced timelines and fewer resources. Several presentations discussed applying Biopharmaceutics Classification System (BCS) and in vitro–in vivo correlations in development and in post-development and discussed both resource savings and best scientific practices. The workshop also focused on evolving bioequivalence approaches, with emphasis on highly variable products (HVDP), as well as specialized modified-release products. In USA, two bioequivalence approaches for HVDP are the reference-scaled average bioequivalence approach and the two-stage group-sequential design. An adaptive sequential design approach is also acceptable in Canada. In European Union, two approaches for HVDP are a two-stage design and an approach to widen Cmax acceptance limits. For some specialized modified-release products, FDA now requests partial area under the curve. Rationale and limitations of such metrics were discussed (e.g., zolpidem and methylphenidate). A common theme was the benefit of the scientific and regulatory community developing, validating, and harmonizing newer bioequivalence methodologies (e.g., BCS-based waivers and HVDP trial designs).
doi:10.1208/s12248-012-9376-z
PMCID: PMC3385831  PMID: 22684402
8.  Bioequivalence Requirements in the European Union: Critical Discussion 
The AAPS Journal  2012;14(4):738-748.
The aim of the present paper is to summarize the revised European Union (EU) Guideline on the Investigation of Bioequivalence and to discuss critically with respect to previous European requirements and present US Food and Drug Administration guidelines its more relevant novelties such as the following: in order to facilitate the development of generic medicinal products, the EU guideline includes the eligibility for Biopharmaceutics Classification System (BCS)-based biowaivers not only for BCS class I drugs but also for class III drugs with tighter requirements for dissolution and excipient composition. The permeability criterion of BCS classification has been substituted with human absorbability, as per the Biopharmaceutical Drug Disposition Classification System. The widening of the acceptance range for Cmax is possible only for highly variable reference products with an additional clinical justification. This scaled widening is carried out with a proportionality constant of 0.760 which is more conservative than the FDA approach and maintains the consumer risk at a 5% level when the intra-subject CV is close to 30%, due to the smooth transition between the scaled and the constant criteria. The guideline allows for the possibility of two-stage designs to obtain the necessary information on formulation differences and variability from interim analyses as a part of the pivotal bioequivalence study, instead of undertaking pilot studies. The guideline also specifies that the statistical analyses should be performed considering all factors as fixed, which has implications in the case of replicate designs.
doi:10.1208/s12248-012-9382-1
PMCID: PMC3475855  PMID: 22826032
bioequivalence; generic medicinal products; regulatory requirements
9.  The Biopharmaceutics Classification System: Subclasses for in vivo predictive dissolution (IPD) methodology and IVIVC 
The Biopharmaceutics Classification System (BCS) has found widespread utility in drug discovery, product development and drug product regulatory sciences. The classification scheme captures the two most significant factors influencing oral drug absorption; solubility and intestinal permeability and it has proven to be a very useful and a widely accepted starting point for drug product development and drug product regulation. The mechanistic base of the BCS approach has, no doubt, contributed to its wide spread acceptance and utility. Nevertheless, underneath the simplicity of BCS are many detailed complexities, both in vitro and in vivo which must be evaluated and investigated for any given drug and drug product. In this manuscript we propose a simple extension of the BCS classes to include subspecification of acid (a), base (b) and neutral (c) for classes II and IV. Sub-classification for Classes I and III (high solubility drugs as currently defined) is generally not needed except perhaps in border line solubility cases. It is well known that the , pKa physical property of a drug (API) has a significant impact on the aqueous solubility dissolution of drug from the drug product both in vitro and in vivo for BCS Class II and IV acids and bases, and is the basis, we propose for a sub-classification extension of the original BCS classification.
This BCS sub-classification is particularly important for in vivo predictive dissolution methodology development due to the complex and variable in vivo environment in the gastrointestinal tract, with its changing pH, buffer capacity, luminal volume, surfactant luminal conditions, permeability profile along the gastrointestinal tract and variable transit and fasted and fed states. We believe this sub-classification is a step toward developing a more science-based mechanistic in vivo predictive dissolution (IPD) methodology. Such a dissolution methodology can be used by development scientists to assess the likelihood of a formulation and dosage form functioning as desired in humans, can be optimized along with parallel human pharmacokinetic studies to set a dissolution methodology for Quality by Design (QbD) and in vitro–in vivo correlations (IVIVC) and ultimately can be used as a basis for a dissolution standard that will ensure continued in vivo product performance.
doi:10.1016/j.ejps.2014.01.009
PMCID: PMC4112588  PMID: 24486482
BCS Class II; Sub-classification; In vivo predictive dissolution; Simulation; GastroPlus™
10.  Toward Global Standards for Comparator Pharmaceutical Products: Case Studies of Amoxicillin, Metronidazole, and Zidovudine in the Americas 
The AAPS Journal  2012;14(3):462-472.
This study compared in vitro dissolution characteristics and other quality measures of different amoxicillin, metronidazole, and zidovudine products purchased in the Americas to a comparator pharmaceutical product (CPP). These three drugs are classified as Biopharmaceutics Classification System Class I drugs with the possibility that dissolution findings might be used to document bioequivalence. All investigated zidovudine products were found to be in vitro equivalent to the CPP. Only 3 of 12 tested amoxicillin products were found to be in vitro equivalent to the CPP. None of the tested metronidazole products were in vitro equivalent to the CPP. These findings suggest but do not confirm bioinequivalence where in vitro comparisons failed, given that an in vivo blood level study might have confirmed bioequivalence. At times, identifying a CPP in one of the selected markets proved difficult. The study demonstrates that products sold across national markets may not be bioequivalent. When coupled with the challenge of identifying a CPP in different countries, the results of this study suggest the value of an international CPP as well as increased use of BCS approaches as means of either documenting bioequivalence or signaling the need for further in vivo studies. Because of increased movement of medicines across national borders, practitioners and patients would benefit from these approaches.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-012-9350-9) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-012-9350-9
PMCID: PMC3385829  PMID: 22528504
bioequivalence; Biopharmaceutics Classification System; comparator pharmaceutical products; equivalence; standards
11.  The FDA Should Eliminate the Ambiguities in the Current BCS Biowaiver Guidance and Make Public the Drugs for which BCS Biowaivers Have Been Granted 
Although FDA approved BCS Class 1 drugs are designated as high permeability, in fact, the criterion utilized is high extent of absorption. This ambiguity should be eliminated and the FDA criterion should explicitly be stated as ≥ 90% absorption based on absolute bioavailability or mass balance. Maintaining confidentiality of the drugs for which the FDA has approved BCS waivers of in vivo bioequivalence studies is not good public policy and should be reversed.
doi:10.1038/clpt.2010.149
PMCID: PMC4169211  PMID: 20668447
Biopharmaceutics Classification System; BCS; FDA; intestinal permeability; extent of absorption
12.  Comparative in vitro and in vivo evaluation of three tablet formulations of amiodarone in healthy subjects 
Background and the purpose of the study
The relative in vivo bioavailability and in vitro dissolution studies of three chemically equivalent amiodarone generic products in healthy volunteers was evaluated in three separate occasions. The possibility of a correlation between in vitro and in vivo performances of these tablet formulations was also evaluated.
Methods
The bioequivalence studies were conducted based on a single dose, two-sequence, cross over randomized design. The bioavailability was compared using AUC0–72, AUC0–8, Cmax and Tmax. Similarity factor, dissolution efficiency (DE), and mean dissolution time (MDT) was used to compare the dissolution profiles. Polynomial linear correlation models were tested using either MDT vs mean residence time (MRT) or fraction of the drug dissolved (FRD) vs fraction of the drug absorbed (FRA).
Results
Significant differences were found in the dissolution performances of the tested formulations and therefore they were included in the development of the correlation. The 90% confidence intervals of the log-transformed AUC0-72, AUC0–8, and Cmax of each two formulations in each bioequivalence studies were within the acceptable range of 80–125%. Differences were not observed between the untransformed Tmax values. Poor correlation was found between MRT and MDT of the products. A point-to-point correlation which is essential for a reliable correlation was not obtained between pooled FRD and FRA. The dissolution condition which was used for amiodarone tablets failed for formulations which were bioequivalent in vivo and significant difference between the dissolution characteristics of products (f2<50) did not reflect their in vivo properties.
Major conclusions
Bioequivalence studies should be considered as the only acceptable way to ensure the interchangeability and in vivo equivalence of amiodarone generic drug products. The dissolution conditions used of the present study could be used for routine and in-process quality control of amiodarone tablet formulations.
PMCID: PMC3304356  PMID: 22615617
Bioequivalence; Bioavalability; Dissolution; Correlation
13.  In Vitro Dissolution of Generic Immediate-Release Solid Oral Dosage Forms Containing BCS Class I Drugs: Comparative Assessment of Metronidazole, Zidovudine, and Amoxicillin Versus Relevant Comparator Pharmaceutical Products in South Africa and India 
AAPS PharmSciTech  2014;15(5):1076-1086.
Biowaivers are recommended for immediate-release solid oral dosage forms using dissolution testing as a surrogate for in vivo bioequivalence studies. Several guidance are currently available (the World Health Organization (WHO), the US FDA, and the EMEA) where the conditions are described. In this study, definitions, criteria, and methodologies according to the WHO have been applied. The dissolution performances of immediate-release metronidazole, zidovudine, and amoxicillin products purchased in South African and Indian markets were compared to the relevant comparator pharmaceutical product (CPP)/reference product. The dissolution performances were studied using US Pharmacopeia (USP) apparatus 2 (paddle) set at 75 rpm in each of three dissolution media (pH1.2, 4.5, and 6.8). Concentrations of metronidazole, zidovudine, and amoxicillin in each dissolution media were determined by HPLC. Of the 11 metronidazole products tested, only 8 could be considered as very rapidly dissolving products as defined by the WHO, whereas 2 of those products could be considered as rapidly dissolving products but did not comply with the f2 acceptance criteria in pH 6.8. All 11 zidovudine products were very rapidly dissolving, whereas in the case of the 14 amoxicillin products tested, none of those products met any of the WHO criteria. This study indicates that not all generic products containing the same biopharmaceutics classification system (BCS) I drug and in similar strength and dosage form are necessarily in vitro equivalent. Hence, there is a need for ongoing market surveillance to determine whether marketed generic products containing BCS I drugs meet the release requirements to confirm their in vitro bioequivalence to the respective reference product.
doi:10.1208/s12249-014-0135-6
PMCID: PMC4179660  PMID: 24848760
BCS; dissolution testing; generic drug; immediate-release solid oral dosage forms; WHO criteria
14.  In Vitro Studies are Sometimes Better than Conventional Human Pharmacokinetic In Vivo Studies in Assessing Bioequivalence of Immediate-Release Solid Oral Dosage Forms 
The AAPS Journal  2008;10(2):289-299.
Human pharmacokinetic in vivo studies are often presumed to serve as the “gold standard” to assess product bioequivalence (BE) of immediate-release (IR) solid oral dosage forms. However, when this general assumption is re-visited, it appears that in vitro studies are sometimes better than in vivo studies in assessing BE of IR solid oral dosage forms. Reasons for in vitro studies to sometimes serve as the better method are that in vitro studies: (a) reduce costs, (b) more directly assess product performance, and (c) offer benefits in terms of ethical considerations. Reduced costs are achieved through avoiding in vivo studies where BE is self-evident, where biopharmaceutic data anticipates BE, and where in vivo BE study type II error is high. In vitro studies more directly assess product performance than do conventional human pharmacokinetic BE studies, since in vitro studies focus on comparative drug absorption from the two products, while in vivo BE testing can suffer from complications due to its indirect approach. Regarding ethical considerations, in vitro studies better embrace the principle “No unnecessary human testing should be performed” and can result in faster development. Situations when in vitro test should be viewed as preferred include Class I drugs with rapid dissolution, Class III drugs with very rapid dissolution, and highly variable drugs with rapid dissolution and that are not bio(equivalence)problem drugs. Sponsors of potential in vivo human pharmacokinetic BE testing should be required to justify why in vitro data is insufficient, similar to proposed animal testing requires justification to not employ an in vitro approach.
doi:10.1208/s12248-008-9027-6
PMCID: PMC2751377  PMID: 18500564
bioavailability; bioequivalence; biopharmaceutics; Biopharmaceutics Classification System; dissolution; in vitro; therapeutic equivalency
15.  Clinical Relevance of Dissolution Testing in Quality by Design 
The AAPS Journal  2008;10(2):380-390.
Quality by design (QbD) has recently been introduced in pharmaceutical product development in a regulatory context and the process of implementing such concepts in the drug approval process is presently on-going. This has the potential to allow for a more flexible regulatory approach based on understanding and optimisation of how design of a product and its manufacturing process may affect product quality. Thus, adding restrictions to manufacturing beyond what can be motivated by clinical quality brings no benefits but only additional costs. This leads to a challenge for biopharmaceutical scientists to link clinical product performance to critical manufacturing attributes. In vitro dissolution testing is clearly a key tool for this purpose and the present bioequivalence guidelines and biopharmaceutical classification system (BCS) provides a platform for regulatory applications of in vitro dissolution as a marker for consistency in clinical outcomes. However, the application of these concepts might need to be further developed in the context of QbD to take advantage of the higher level of understanding that is implied and displayed in regulatory documentation utilising QbD concepts. Aspects that should be considered include identification of rate limiting steps in the absorption process that can be linked to pharmacokinetic variables and used for prediction of bioavailability variables, in vivo relevance of in vitro dissolution test conditions and performance/interpretation of specific bioavailability studies on critical formulation/process variables. This article will give some examples and suggestions how clinical relevance of dissolution testing can be achieved in the context of QbD derived from a specific case study for a BCS II compound.
doi:10.1208/s12248-008-9034-7
PMCID: PMC2751384  PMID: 18686045
bioequivalence; biopharmaceutics classification system (BCS); biowaiver; in vitro dissolution; in vitro in vivo correlation (IVIVC); quality by design (QbD)
16.  Application of the Biopharmaceutical Classification System in Clinical Drug Development—An Industrial View 
The AAPS Journal  2008;10(2):306-310.
The biopharmaceutical classification system (BCS) classifies compounds based on their solubility and permeability. Regulatory agencies and health organizations have utilized this classification system to allow dissolution to be used to establish bioequivalence for highly soluble and highly permeable compounds. The pharmaceutical industry has taken advantage of this and BCS-based waivers are becoming more routine and result in significant savings. Further, there is strong scientific rationale to allow BCS-based waivers for even more compounds to realize even more savings. Yet just as clear as the benefits are the barriers that limit application: lack of international regulatory harmonization, uncertainty in regulatory approval, and organizational barriers within the pharmaceutical industry. Once these barriers are overcome and additional applications are fully allowed, the full benefits of BCS applications will be realized.
doi:10.1208/s12248-008-9036-5
PMCID: PMC2751386  PMID: 18500563
biopharmaceutical classification system; dissolution; formulations development; permeability; solubility
17.  FDA Critical Path Initiatives: Opportunities for Generic Drug Development 
The AAPS Journal  2008;10(1):103-109.
FDA’s critical path initiative documents have focused on the challenges involved in the development of new drugs. Some of the focus areas identified apply equally to the production of generic drugs. However, there are scientific challenges unique to the development of generic drugs as well. In May 2007, FDA released a document “Critical Path Opportunities for Generic Drugs” that identified some of the specific challenges in the development of generic drugs. The key steps in generic product development are usually characterization of the reference product, design of a pharmaceutically equivalent and bioequivalent product, design of a consistent manufacturing process and conduct of the pivotal bioequivalence study. There are several areas of opportunity where scientific progress could accelerate the development and approval of generic products and expand the range of products for which generic versions are available, while maintaining high standards for quality, safety, and efficacy. These areas include the use of quality by design to develop bioequivalent products, more efficient bioequivalence methods for systemically acting drugs (expansion of BCS waivers, highly variable drugs), and development of new bioequivalence methods for locally acting drugs.
doi:10.1208/s12248-008-9010-2
PMCID: PMC2751455  PMID: 18446510
bioequivalence; critical path initiative; generic drugs
18.  Study on Biopharmaceutics Classification and Oral Bioavailability of a Novel Multikinase Inhibitor NCE for Cancer Therapy 
Specific biopharmaceutics classification investigation and study on phamacokinetic profile of a novel drug candidate (2-methylcarbamoyl-4-{4-[3- (trifluoromethyl) benzamido] phenoxy} pyridinium 4-methylbenzenesulfonate monohydrate, NCE) were carried out. Equilibrium solubility and intrinsic dissolution rate (IDR) of NCE were estimated in different phosphate buffers. Effective intestinal permeability (Peff) of NCE was determined using single-pass intestinal perfusion technique in rat duodenum, jejunum and ileum at three concentrations. Theophylline (high permeability) and ranitidine (low permeability) were also applied to access the permeability of NCE as reference compounds. The bioavailability after intragastrical and intravenous administration was measured in beagle dogs. The solubility of NCE in tested phosphate buffers was quite low with the maximum solubility of 81.73 μg/mL at pH 1.0. The intrinsic dissolution ratio of NCE was 1 × 10−4 mg·min−1·cm−2. The Peff value of NCE in all intestinal segments was more proximate to the high-permeability reference theophylline. Therefore, NCE was classified as class II drug according to Biopharmaceutics Classification System due to its low solubility and high intestinal permeability. In addition, concentration-dependent permeability was not observed in all the segments, indicating that there might be passive transportation for NCE. The absolute oral bioavailability of NCE in beagle dogs was 26.75%. Therefore, dissolution promotion will be crucial for oral formulation development and intravenous administration route will also be suggested for further NCE formulation development. All the data would provide a reference for biopharmaceutics classification research of other novel drug candidates.
doi:10.3390/ijms15057199
PMCID: PMC4057667  PMID: 24776763
biopharmaceutics classification system; intrinsic dissolution rate; permeability; bioavailability; multikinase inhibitor
19.  Medicines informal market in Congo, Burundi and Angola: counterfeit and sub-standard antimalarials 
Malaria Journal  2007;6:22.
Background
The presence of counterfeits and sub-standards in African medicines market is a dramatic problem that causes many deaths each year. The increase of the phenomenon of pharmaceutical counterfeiting is due to the rise of the illegal market and to the impossibility to purchase branded high cost medicines.
Methods
In this paper the results of a quality control on antimalarial tablet samples purchased in the informal market in Congo, Burundi and Angola are reported. The quality control consisted in the assay of active substance by means of validated liquid chromatographic methods, uniformity of mass determination, disintegration and dissolution tests. Moreover, a general evaluation on label and packaging characteristics was performed.
Results
The results obtained on thirty antimalarial tablet samples containing chloroquine, quinine, mefloquine, sulphadoxine and pyrimethamine showed the presence of different kinds of problems: a general problem concerning the packaging (loose tablets, packaging without Producer name, Producer Country and sometimes without expiry date); low content of active substance (in one sample); different, non-declared, active substance (in one sample); sub-standard technological properties and very low dissolution profiles (in about 50% of samples). This last property could affect the bioavailability and bioequivalence in comparison with branded products and could be related to the use of different excipients in formulation or bad storage conditions.
Conclusion
This paper evidences that the most common quality problem in the analysed samples appears to be the low dissolution profile. Here it is remarked that the presence of the right active substance in the right quantity is not a sufficient condition for a good quality drug. Dissolution test is not less important in a quality control and often evidences in vitro possible differences in therapeutic efficacy among drugs with the same active content. Dissolution profile can be dramatically affected by the choice of excipients in the oral solid formulation and, in many cases, is out of specifications due to the absence of formulation studies by producers of developing countries.
doi:10.1186/1475-2875-6-22
PMCID: PMC1810297  PMID: 17316432
20.  Statistics on BCS Classification of Generic Drug Products Approved Between 2000 and 2011 in the USA 
The AAPS Journal  2012;14(4):664-666.
The Biopharmaceutics Classification system (BCS) classifies drug substances based on aqueous solubility and intestinal permeability. The objective of this study was to use the World Health Organization Model List of Essential Medicines to determine the distribution of BCS Class 1, 2, 3, and 4 drugs in Abbreviated New drug Applications (ANDA) submissions. To categorize solubility and intestinal permeability properties of generic drugs under development, we used a list of 61 drugs which were classified as BCS 1, 2, 3, and 4 drugs with certainty in the World Health Organization Model List of Essential Medicines. Applying this list to evaluation of 263 ANDA approvals of BCS drugs during the period of 2000 to 2011 indicated 110 approvals (41.8%) for Class 1 drugs (based on both biowaiver and in vivo bioequivalence studies), 55 (20.9%) approvals for Class 2 drugs, 98 (37.3%) approvals for Class 3 drugs, and no (0%) approvals for Class 4 drugs. The present data indicated a trend of more ANDA approvals of BCS Class 1 drugs than Class 3 or Class 2 drugs. Antiallergic drugs in Class 1, drugs for pain relief in Class 2 and antidiabetic drugs in Class 3 have received the largest number of approvals during this period.
doi:10.1208/s12248-012-9384-z
PMCID: PMC3475853  PMID: 22718306
ANDA; BCS biowaiver; bioequivalence; Biopharmaceutics Classification System; generic drug product
21.  Statistical Comparison of Dissolution Profiles to Predict the Bioequivalence of Extended Release Formulations 
The AAPS Journal  2014;16(4):791-801.
Appropriate setting of dissolution specification of extended release (ER) formulations should include precise definition of a multidimensional space of complex definition and interpretation, including limits in dissolution parameters, lag time (t-lag), variability, and goodness of fit. This study aimed to set dissolution specifications of ER by developing drug-specific dissolution profile comparison tests (DPC tests) that are able to detect differences in release profiles between ER formulations that represent a lack of bioequivalence (BE). Dissolution profiles of test formulations were simulated using the Weibull and Hill models. Differential equations based in vivo–in vitro correlation (IVIVC) models were used to simulate plasma concentrations. BE trial simulations were employed to find the formulations likely to be declared bioequivalent and nonbioequivalent (BE space). Customization of DPC tests was made by adjusting the delta of a recently described tolerated difference test (TDT) or the limits of rejection of f2. Drug ka (especially if ka is small), formulation lag time (t-lag), the number of subjects included in the BE studies, and the number of sampled time points in the DPC test were the factors that affected the most these setups of dissolution specifications. Another recently described DPC test, permutation test (PT), showed excellent statistical power. All the formulations declared as similar with PT were also bioequivalent. Similar case-specific studies may support the biowaiving of ER drug formulations based on customized DPC tests.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-014-9615-6) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-014-9615-6
PMCID: PMC4070268  PMID: 24854895
bioequivalence; dissolution profile comparisons; f2 similarity factor; in vitro similarity; IVIVC
22.  Bioavailability and Bioequivalence in Drug Development 
Bioavailability is referred to as the extent and rate to which the active drug ingredient or active moiety from the drug product is absorbed and becomes available at the site of drug action. The relative bioavailability in terms of the rate and extent of drug absorption is considered predictive of clinical outcomes. In 1984, the United States Food and Drug Administration (FDA) was authorized to approve generic drug products under the Drug Price Competition and Patent Term Restoration Act based on evidence of average bioequivalence in drug absorption through the conduct of bioavailability and bioequivalence studies. This article provides an overview (from an American point of view) of definition of bioavailability and bioequivalence, Fundamental Bioequivalence Assumption, regulatory requirements, and process for bioequivalence assessment of generic drug products. Basic considerations including criteria, study design, power analysis for sample size determination, and the conduct of bioequivalence trial, and statistical methods are provided. Practical issues such as one size-fits-all criterion, drug interchangeability and scaled average criteria for assessment of highly variable drug products are also discussed.
doi:10.1002/wics.1310
PMCID: PMC4157693  PMID: 25215170
Fundamental Bioequivalence Assumption; Drug interchangeability; Highly variable drugs; Scaled average bioequivalence (SABE) criterion
23.  Effect of Excipients on the Particle Size of Precipitated Pioglitazone in the Gastrointestinal Tract: Impact on Bioequivalence 
The AAPS Journal  2014;16(5):1119-1127.
This study sought to understand the reasons for the bioinequivalence of a newly developed generic product of pioglitazone hydrochloride and to improve its formulation so that it is equivalent to that of the reference listed drug (RLD). In this clinical study, despite a similar in vitro dissolution profile, the new oral product exhibited a lower plasma concentration of pioglitazone compared to the RLD. The strong pH-dependency of pioglitazone solubility as a weak base indicates that pioglitazone would precipitate in the small intestine after being dissolved in the stomach. Thus, in vitro experiments were performed to investigate the effect of excipients on the particle size distribution of precipitated pioglitazone. Then, the impact of particle size on in vivo absorption was discussed. The precipitated pioglitazone from the RLD showed a peak for small particles (less than 1 μm), which was not observed in the precipitate from the new product. As an excipient, hydroxypropyl cellulose (HPC) influenced the particle size of precipitated pioglitazone, and the amount of HPC in the formulation was increased to the same level as that in the RLD. The precipitate from this improved product showed approximately the same particle size distribution as that of the RLD and successfully demonstrated bioequivalence in the clinical study. In conclusion, for drugs with low solubility, this type of analysis of the particle size distribution of precipitated drugs, in addition to the dissolution test, may help to obtain a better in vitro-in vivo correlation for oral absorption and to develop a bioequivalent product.
doi:10.1208/s12248-014-9646-z
PMCID: PMC4147060  PMID: 25070482
bioequivalence study; hydroxypropylcellulose; particle size distribution; pioglitazone; precipitation
24.  Developing In Vitro–In Vivo Correlation of Risperidone Immediate Release Tablet 
AAPS PharmSciTech  2012;13(3):890-895.
The present study was aimed to predict the absorption profile of a risperidone immediate release tablet (IR) and to develop the level A in vitro–in vivo correlation (IVIVC) of the drug using the gastrointestinal simulation based on the advanced compartmental absorption and transit model implemented in GastroPlus™. Plasma concentration data, physicochemical, and pharmacokinetic properties of the drug were used in building its absorption profile in the gastrointestinal tract. Since the fraction absorbed of risperidone in simulation was more than 90% with low water solubility, the drug met the criteria of class II of the Biopharmaceutics Classification System. The IVIVC was developed based on the model built using the plasma data and the in vitro dissolution data in several dissolution media based on the Japanese Guideline for Bioequivalence Studies of Generic Products. The gastrointestinal absorption profile of risperidone was successfully predicted. A level A IVIVC was also successfully developed in all dissolution media with percent prediction error for Cmax and the area under the curve less than 10% for both reference and test drug.
doi:10.1208/s12249-012-9814-3
PMCID: PMC3429671  PMID: 22696224
GastroPlus™; immediate release tablet; in vitro–in vivo correlation; risperidone
25.  Solid Dispersion as an Approach for Bioavailability Enhancement of Poorly Water-Soluble Drug Ritonavir 
AAPS PharmSciTech  2010;11(2):518-527.
Ritonavir is an antiretroviral drug characterized by low solubility and high permeability which corresponds to BCS class II drug. The purpose of the study was to develop solid dispersion by different methods and investigate them for in vitro and in vivo performance for enhancing dissolution and bioavailability, respectively. Since the drug possesses food-related absorption, the effect of biorelevant media (FaSSIF and FeSSIF state) on dissolution behavior was also studied. The solid dispersion was prepared using Gelucire as carrier in 1:4 ratio by different methods and were characterized for differential scanning calorimetry (DSC), X-ray diffractometry, scanning electron microscopy, and FT-IR. Oral bioavailability of 10 mg of ritonavir in solid dispersion prepared by solvent evaporation (SE1) and melt method (MM1) was compared with pure drug after oral administration of solid dispersion and pure drug to Albino Wistar rats of either sex. The results suggested formation of eutectic solid dispersion. In vitro dissolution studies was performed in 0.1 N HCl and biorelevant media showed enhanced dissolution rate as compared to pure drug in both FeSSIF media and 0.1 N HCl. The apparent rate of absorption of ritonavir from SE1 (Cmax 20221.37 ng/ml, tmax 0.5 h) was higher than that of MM1 (Cmax 2,462.2, tmax 1 h) and pure drug (Cmax 1,354.8 ng/ml, tmax 0.5 h). On the basis of the result obtained, it was concluded that solid dispersion is a good approach to enhance solubility and bioavailability of poorly water-soluble ritonavir.
doi:10.1208/s12249-010-9404-1
PMCID: PMC2902348  PMID: 20238187
bioavailability; gelucire; poorly soluble drug; ritonavir; solid dispersion

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