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Impact of the US FDA "biopharmaceutics Classification System" (BCS) Guidance on Global Drug Development
Abstract
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 world-wide interest among biopharmaceutical scientists in regulatory agencies, academia, and industry towards 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 one hundred sixty 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 CNS area! These findings indicate a robust utilization of the BCS approach towards 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.
... In our opinion, this information provides more transparency for regulatory decision-making and the possibility of knowing which drugs, for which acceptable scientific data, justify waiving bioequivalence studies [31]. In this sense, the impact of the BCS guidance on drug development in USA from 2004 to 2017 has recently been published, evidencing the success of this framework in the development of multisource products and new drugs [32]. ...
... Recently, the impact of the broad application of the BCS principle by the FDA on its regulated industry has been published [32]. More than 160 applications, based on the BCS approach, have been approved between 2004 and the first quarter of 2017. ...
Background
The replacement of traditional in vivo bioequivalence studies by in vitro dissolution assays, based on the biopharmaceutical classification system (BCS), has emerged as an important tool for demonstrating the interchangeability of multisource products. This paper summarizes the current implementation of the BCS-based biowaiver for the development of multisource products in Latin America, and identifies several challenges and opportunities for greater convergence and application of BCS regulatory requirements.Methods
Differences and similarities between the current BCS-based biowaivers’ guidelines proposed by two relevant regulatory agencies for the Latin American region (FDA and WHO) and the new ICH harmonization guideline were identified and compared. An update of the BCS-based biowaiver guideline for Latin American countries was also considered, based on the respective regulatory information on bioequivalence studies, which is publicly available.ResultsAbout 50% of the Latin American countries analyzed have no information on the implementation of any bioequivalence standards, while in the countries where bioequivalence studies are considered, the acceptance and application of BCS-based biowaiver requirements is quite heterogeneous. This situation contrasts with the international trend of global harmonization for BCS-based biowaiver guidance, suggesting the need in Latin America to identify opportunities and overcome challenges to improve the development of BCS-based biowaivers to avoid costly and time-consuming in vivo bioequivalence studies.Conclusions
The study shows that the region is in a position to improve access to safe and effective medicines at a reasonable cost by applying BCS-based biowaiver guidance.
... 192,193 Regulatory agencies have also updated approval policies several times over the years as our understanding of antibodybased biotherapeutics improved. [194][195][196] Due to these changes, it is often difficult to make direct comparisons among marketed antibody-based biotherapeutics. [197][198][199] Despite the above limitations, it is feasible to construct a profile of a therapeutic antibody drug candidate most likely to succeed in product and clinical developments and win regulatory approvals. ...
There is considerable interest in the pharmaceutical industry toward development of antibody-based biotherapeutics because they can selectively bind diverse receptors and often possess desirable pharmacology. Here, we studied product characteristics of 89 marketed antibody-based biotherapeutics that were approved from 1986 to mid-2020 by gathering publicly available information. Our analyses revealed major trends in their emergence as the best-selling class of pharmaceuticals. Early on, most therapeutic monoclonal antibodies were developed to treat cancer, with CD20 being the most common target. Thanks to industrialization of antibody manufacturing technologies, their use has now blossomed to include 15 different therapeutic areas and nearly 60 targets, and the field is still growing! Drug manufacturers are solidifying their choices regarding types of antibodies and their molecular formats. IgG1 kappa continues to be the most common molecular format among marketed antibody-based biotherapeutics. Most antibody-based biotherapeutics approved since 2015 are either humanized or fully human, but the data we collected do not show a direct correlation between humanness and reported incidence of anti-drug antibodies. Furthermore, there have also been improvements in terms of drug product stability and high concentration liquid formulations suitable for subcutaneous route of administration, which are being approved more often in recent years. These improvements, however, have not been uniformly adopted across all therapeutic areas, suggesting that multiple options for drug product development are being used to serve diverse therapeutic purposes. Insights gained from this analysis may help us devise better end-to-end antibody-based biotherapeutic drug discovery and development strategies.
... Hed can be classified in BCS IV class since it shows poor solubility and poor permeability. On the other hand, Het could be called a BCS class II compound due to its poor solubility and high permeability [56]. ...
This study aimed at obtaining hesperidin (Hed) and hesperetin (Het) systems with HP-β-CD by means of the solvent evaporation method. The produced systems were identified using infrared spectroscopy (FT-IR), X-ray powder diffraction (XRPD), and differential scanning calorimetry (DSC). Moreover, in silico docking and molecular dynamics studies were performed to assess the most preferable site of interactions between tested compounds and HP-β-CD. The changes of physicochemical properties (solubility, dissolution rate, and permeability) were determined chromatographically. The impact of modification on biological activity was tested in an antioxidant study as well as with regards to inhibition of enzymes important in pathogenesis of neurodegenerative diseases. The results indicated improvement in solubility over 1000 and 2000 times for Hed and Het, respectively. Permeability studies revealed that Hed has difficulties in crossing biological membranes, in contrast with Het, which can be considered to be well absorbed. The improved physicochemical properties influenced the biological activity in a positive manner by the increase in inhibitory activity on the DPPH radical and cholinoesterases. To conclude the use of HP-β-CD as a carrier in the formation of an amorphous inclusion complex seems to be a promising approach to improve the biological activity and bioavailability of Hed and Het.
... Limited oral bioavailability represents its hydrophobic nature. This hydrophobic nature exacerbates its global image and thus drives pharmaceutical scientists to place it in Class-IV of the Biopharmaceutical Classification System (BCS-IV), representing low solubility and low permeability [8,9]. Various approaches, such as Solid Dispersion and Cyclodextrin inclusion complexes, have been used to improve the solubility and bioavailability of Norfloxacin [10,11]. ...
Norfloxacin (NOR), widely employed as an anti-bacterial drug, has poor oral bioavailability. Nano based drug delivery systems are widely used to overcome the existing oral bioavailability challenges. Lipid–Polymer Hybrid Nanoparticles (LPHNs) exhibit the distinctive advantages of both polymeric and liposomes nanoparticles, while excluding some of their disadvantages. In the current study, NOR loaded LPHNs were prepared, and were solid amorphous in nature, followed by in vitro and in vivo evaluation. The optimized process conditions resulted in LPHNs with the acceptable particle size 121.27 nm, Polydispersity Index (PDI) of 0.214 and zeta potential of -32 mv. The addition of a helper lipid, oleic acid, and polymers, ethyl cellulose, substantially increased the encapsulation efficiency (EE%) (65% to 97%). In vitro study showed a sustained drug release profile (75% within 12 h) for NOR LPHNs. The optimized NOR LPHNs showed a significant increase (p < 0.05) in bioavailability compared to the commercial product. From the acute toxicity study, the LD50 value was found to be greater than 1600 mg/kg. The molecular modelling studies substantiated the experimental results with the best combination of polymers and surfactants that produced highly stable LPHNs. Therefore, LPHNs proved to be a promising system for the delivery of NOR, as well as for other antibiotics and hydrophobic drugs.
... Limited oral bioavailability represents its hydrophobic nature. This hydrophobic nature exacerbates its global image and thus drives pharmaceutical scientists to place it in Class-IV of the Biopharmaceutical Classification System (BCS-IV), representing low solubility and low permeability [8,9]. Various approaches, such as Solid Dispersion and Cyclodextrin inclusion complexes, have been used to improve the solubility and bioavailability of Norfloxacin [10,11]. ...
Norfloxacin (NOR), widely employed as an anti-bacterial drug, has poor oral bioavailability. Nano based drug delivery systems are widely used to overcome the existing oral bioavailability challenges. Lipid–Polymer Hybrid Nanoparticles (LPHNs) exhibit the distinctive advantages of both polymeric and liposomes nanoparticles, while excluding some of their disadvantages. In the current study, NOR loaded LPHNs were prepared, and were solid amorphous in nature, followed by in vitro and in vivo evaluation. The optimized process conditions resulted in LPHNs with the acceptable particle size 121.27 nm, Polydispersity Index (PDI) of 0.214 and zeta potential of 32 mv. The addition of a helper lipid, oleic acid, and polymers, ethyl cellulose, substantially increased the encapsulation efficiency (EE%) (65% to 97%). In vitro study showed a sustained drug release profile (75% within 12 h) for NOR LPHNs. The optimized NOR LPHNs showed a significant increase (p < 0.05) in bioavailability compared to the commercial product. From the acute toxicity study, the LD50 value was found to be greater than 1600 mg/kg. The molecular modelling studies substan-tiated the experimental results with the best combination of polymers and surfactants that pro-duced highly stable LPHNs. Therefore, LPHNs proved to be a promising system for the delivery of NOR, as well as for other antibiotics and hydrophobic drugs.
... Nanotechnology has made a significant contribution to overcome (bio)pharmaceutical drawbacks of drugs such as poor aqueous solubility, low physicochemical stability in the biological milieu, short half-life and low bioavailability and efficacy [1][2][3][4]. For instance, >60% of the approved small-molecule drugs and~90% of new drugs under development are classified as poorly water-soluble according to the Biopharmaceutics Classification System [5][6][7][8]. These drawbacks challenge the translation of drug candidates into new products, contribute to the high drug attrition rates in pharmaceutical development, and motivate the pharmaceutical industry to seek for non-traditional dosage forms and delivery routes [9][10][11][12][13][14]. ...
Nanoprecipitation is one of the most versatile methods to produce pure drug nanoparticles (PDNPs) owing to the ability to optimize the properties of the product. Nevertheless, nanoprecipitation may result in broad particle size distribution, low physical stability, and batch-to-batch variability. Microfluidics has emerged as a powerful tool to produce PDNPs in a simple, reproducible, and cost-effective manner with excellent control over the nanoparticle size. In this work, we designed and fabricated T- and Y-shaped Si-made microfluidic devices and used them to produce PDNPs of three kinase inhibitors of different lipophilicity and water-solubility, namely imatinib, dasatinib and tofacitinib, without the use of colloidal stabilizers. PDNPs display hydrodynamic diameter in the 90–350 nm range as measured by dynamic light scattering and a rounded shape as visualized by high-resolution scanning electron microscopy. Powder X-ray diffraction and differential scanning calorimetry confirmed that this method results in highly amorphous nanoparticles. In addition, we show that the flow rate of solvent, the anti-solvent, and the channel geometry of the device play a key role governing the nanoparticle size.
... In this regard, a Biopharmaceutics Classification System (BCS) has been created by the United States Pharmacopeia (USP), according to which there exist four groups of therapeutics categorized based on membrane permeability and aqueous solubility (Cardot et al. 2016). Among the principal targets of BCS exists the anticipation of the in vivo efficiency of a therapeutic compound through the in vitro investigation of aqueous solubility and membrane permeability (Mehta et al. 2017;Mohanta et al. 2020). ...
Bioactive micro- and macro-molecules (postbiotics) derived from gut beneficial microbes are among natural chemical compounds with medical significance. Currently, a unique therapeutic strategy has been developed with an emphasis on the small molecular weight biomolecules that are made by the microbiome, which endow the host with several physiological health benefits. A large number of postbiotics have been characterized, which due to their unique pharmacokinetic properties in terms of controllable aspects of the dosage and various delivery routes, could be employed as promising medical tools since they exert both prevention and treatment strategies in the host. Nevertheless, there are still main challenges for the in vivo delivery of postbiotics. Currently, scientific literature confirms that targeted delivery systems based on nanoparticles, due to their appealing properties in terms of high biocompatibility, biodegradability, low toxicity, and significant capability to carry both hydrophobic and hydrophilic postbiotics, can be used as a novel and safe strategy for targeted delivery or/and release of postbiotics in various (oral, intradermal, and intravenous) in vivo models. The in vivo delivery of postbiotics are in their emerging phase and require massive investigation and randomized double-blind clinical trials if they are to be applied extensively as treatment strategies. This manuscript provides an overview of the various postbiotic metabolites derived from the gut beneficial microbes, their potential therapeutic activities, and recent progressions in the drug delivery field, as well as concisely giving an insight on the main in vivo delivery routes of postbiotics.
... CLZ is an antiplatelet drug that exhibits vasodilatory effects. CLZ is categorized as a Biopharmaceutics Classification System Class II compound [18] and has no dissociating groups in its molecular structure ( Figure 1a). As such, its low water solubility is a detriment to oral absorption. ...
The cocrystal formation of pharmaceuticals can improve the various physical properties of drugs, such as solubility, without the need for chemical modification of the drug substances. In the present study, we prepared cocrystals of cilostazol and additive coformers (derivatives of hydroxybenzoic acid) using a spray drying method. Based on the preparation of the cocrystals of cilostazol and the coformers as reported previously, the characteristics of the cilostazol cocrystals prepared using solvent evaporation, slurry, and spray drying methods were compared. The physical characterization revealed that the spray drying method successfully produced cilostazol–4-hydroxybenzoic acid and cilostazol–2,4-dihydroxybenzoic acid cocrystals, whereas samples of cocrystals of cilostazol and 2,5-dihydroxybenzoic acid produced via the spray drying process appeared to contain coformer polymorphs. The dissolution of cilostazol was improved using the spray-dried cocrystal samples composed of coformers compared to samples prepared using cilostazol alone or a physical mixture. The present results provide useful information regarding the manufacture of cilostazol cocrystals and pharmaceutical cocrystals via spray drying in large-batch production.
... Combination of two or more active components is very common in TCMs and further combinations are an important approach in the development of new therapeutic agents. Therefore, in the present study, 15 flavonoids, often found in herbs that are compatible with Astragali Radix in TCMs were investigated and APS was taken as a model to systematically evaluate the effects of polysaccharides on the 15 flavonoids (Fig. 1), including their effects on aqueous solubility which is well known as one of the fundamental properties of drug substances properties [26,27] and stability, which is essential for retaining biological activity during processing, storage and even during oral absorption [28]. High performance liquid chromatography (HPLC) coupled with principal component analysis (PCA) were used to analyze and compare the differences between the solubilities of the 15 flavonoids in water and in APS solutions. ...
Poor solubility and stability are limitation factors of flavonoids application. Polysaccharides from herbs have been proven to be functional foods and potential promising natural supplements with large molecular weight and complex structures. Astragalus polysaccharides (APS) are the main components of Astragalus membranaceus (Fisch.) and novel synergistic pharmacological effects between Astragalus polysaccharides and flavonoids have been reported. However, the general effects of polysaccharides when co-administered with flavonoids are currently unknown. Herein, the influences of APS on aqueous solubilities and stabilities of fifteen flavonoids were systematically investigated, and the mechanism of effects of polysaccharides on flavonoids was further considered. The results showed that APS could significantly enhance the solubilities and stabilities of the flavonoids, with solubilization effect improved by 68.88-fold for quercetin and negatively correlated with the aqueous solubility of the flavonoid itself. A phase solubility study and Differential scanning calorimetry characterization indicated that APS could form complexes with flavonoids at 1:1 ratio with K values ranging from 1491 to 55,395 L·mol-1, a tendency to improved solubilization at higher association constant values was also observed. Those findings could provide the basis for a new approach to solving the problems of poor solubility and stability of flavonoids through the application of natural macromolecules.
... Once all class I compounds needn't be conducted BE studies, it would be saved 66 to 76 million dollars per year by making use of the BCS-based biowaivers [5]. Most importantly, this approach is beneficial to speeding up high quality pharmaceutical products applications [6]. ...
Metronidazole, a BCS class I drug, could be waived based on the BCS principles, thus enabling in vitro dissolution data as a surrogate of BE study. However, the impact of dissolution profiles of metronidazole tablets on the in vivo performance has never been studied systematically. So the aim of the present study was to conduct a multipronged approach of in vitro dissolution, in silico simulation and in vivo study to evaluate the effect of dissolution performance on oral absorption of metronidazole tablets, as well as the accuracy of PBPK model to predict the oral bioavailability for BCS I drug. The results demonstrated that the PBPK models were successfully established for immediate release metronidazole tablets. Bioequivalence comparison in dogs indicated that the test products were bioequivalent to the Reference (80-125%, 90% CI), even their dissolution profiles in vitro were significantly different. And the prediction of oral pharmacokinetics of the three formulations in human were also highly similar. In addition, the behavior of in vitro dissolution profiles and in vivo absorption was elucidated. These findings will contribute to understanding the potential risks during the formulation development and justifying the biowaiver for metronidazole tablets.
... The pharmaceutical industry is found in a persistent and urgent search for new scalable and cost-effective technological strategies to overcome (bio)pharmaceutical drawbacks of drugs such as poor aqueous solubility, low physicochemical stability in the biological milieu, short half-life and reduced bioavailability [1][2][3][4][5]. For instance, N50% of the approved drugs and N70% of new chemical entities under development are classified into Classes II and IV of the Biopharmaceutics Classification System (BCS) [6,7]. These limitations increase drug attrition rates [8,9] and lead to a decline in the ability to translate them into new pharmaceutical products [10][11][12]. ...
In recent years, nanotechnology has offered attractive opportunities to overcome the (bio)pharmaceutical drawbacks of most drugs such as low aqueous solubility and bioavailability. Among the numerous methodologies that have been applied to improve drug performance, a special emphasis has been made on those that increase the dissolution rate and the saturation solubility by the reduction of the particle size of pure drugs to the nanoscale and the associated increase of the specific surface area. Different top-down and bottom-up methods have been implemented, each one with its own pros and cons. Over the last years, the latter that rely on the dissolution of the drug in a proper solvent and its crystallization or co-crystallization by precipitation in an anti-solvent or, conversely, by solvent evaporation have gained remarkable impulse owing to the ability to features such as size, size distribution, morphology and to control the amorphous/crystalline nature of the product. In this framework, electrohydrodynamic atomization (also called electrospraying) and spray-drying excel due to their simplicity and potential scalability. Moreover, they do not necessarily need suspension stabilizers and dry products are often produced during the formation of the nanoparticles what ensures physicochemical stability for longer times than liquid products. This review overviews the potential of these two technologies for the production of pure drug nanocrystals and co-crystals and discusses the recent technological advances and challenges for their implementation in pharmaceutical research and development.
... Bu da BCS temelli biyomuafiyetin büyük oranda kabul gördüğünü desteklemektedir. 42 Sonuç olarak, sağlık otoriteleri tarafından biyomuafiyeti kabul edilen ilaçların sayısı her geçen gün artmaktadır ve bu ilaçlar FIP tarafından düzenli olarak değerlendirilerek öneri şeklinde yayınlanmaktadır. 43 WHO ise biyomuafiyet baş= vurusu için çeşitli formlar yayınlayarak firmaların başvuru işlemlerinde yol gösterici olmaktadır. ...
Sigma-1 receptor (S1R) has been considered a promising therapeutic target for several neurodegenerative diseases and S1R agonists have shown neuroprotective activity against glutamate excitotoxicity and oxidative stress. Starting from a previously identified low nanomolar S1R agonist, in this work we prepared and tested novel benzylpiperidine/benzylpiperazine-based compounds designed by applying a ring opening strategy. Among them, 4-benzyl-1-(2-phenoxyethyl)piperidine J o u r n a l P r e-p r o o f 6b (S1R Ki = 0.93 nM) and 4-benzyl-1-(3-phenoxypropyl)piperidine 8b (S1R Ki = 1.1 nM) emerged as high affinity S1R ligands and showed selectivity over S2R and N-methyl-D-aspartate receptor (NMDAR). Candidate compounds behaved as potent S1R agonists being able to enhance the neurite outgrowth induced by nerve growth factor (NGF) in PC12 cell lines. In SH-SY5Y neuroblastoma cell lines they exhibited a neuroprotective effect against rotenone-and NMDA-mediated toxic insults. The neuroprotective activity of 6b and 8b was reverted by co-treatment with an S1R antagonist, PB212. Compounds 6b and 8b were tested for cytotoxicity in-vitro against three human cancer cell lines (A549, LoVo and Panc-1) and in-vivo zebrafish model, resulting in a good efficacy/safety profile, comparable or superior to the reference drug memantine. Overall, these results encourage further preclinical investigations of 6b and 8b on in-vivo models of neurodegenerative diseases.
The novel oral sodium-glucose cotransporter-2 (SGLT2) inhibitor Ertugliflozin (SteglatroTM) is introduced as a monotherapy or in conjunction with another antidiabetic drug regimen for the treatment of type 2 diabetes mellitus (T2DM).Additional safe and efficient treatment options for patients and physicians are of utmost importance as the incidence of T2DM rises. As a standalone therapy or an adjunctive treatment, ertugliflozin seems to be a reliable and safe option.This narrative review seeks to report and analyze ertugliflozin's effectiveness, safety, cardiovascular (CV), and renal outcomes in T2DM. Various combinations of drugs and drug classes have been tried to reduce mortality and comorbidities associated with the use of antidiabetic agents, especially cardiogenic events and renal diseases. With the administration of hypoglycemic drugs like ertugliflozin and the regulation of blood sugar levels, the incidence of therapy-induced hypertension, obesity, and dose-related hypoglycemia has been reduced to a significant extent. Additionally, ertugliflozin prevents hypertension caused by prolonged antidiabetic drug intake, which is advantageous for lowering the chances of end-stage cardiac events in type 2 diabetic patients. As far as the renal safety profile of ertugliflozin is concerned, it has been associated with the maintenance of eGFR (estimated glomerular filtration rate) and a decreased UACR (urine albumin-to-creatinine ratio) in patients with T2DM and coronary artery disease, which reduces the incidence of renal adverse effects due to long-term medication. As a result of common pathophysiological mechanisms, SGLT2 inhibitors represent a feasible therapeutic option and are advantageous for patients with type 1 and type 2 DM in terms of cardiovascular and renal outcomes.
Development of an oral dosage form is ultimately dependent upon both the physicochemical properties and biopharmaceutics of the drug substance, the formulation design and technology selection, and the influence of physiological factors on in vivo drug dissolution, solubility and permeability. A background on gastrointestinal (GI) anatomy and physiology, followed by discussion on the importance of physicochemical properties and biopharmaceutics in drug delivery, the tools that can be used to predict, assess or observe oral transit, metabolism, and absorption, and approaches to formulation to achieve desired delivery goals associated with the therapy are provided. The various methods for improving absorption of poorly soluble and low permeability drugs are discussed. Dosage forms for regional delivery to different regions of the GI tract are elaborated. In particular, gastric retentive dosage forms to deliver to the stomach and upper GI tract are presented. This is followed by targeted delivery to the intestine whether small or large with an introduction to enteric coating and specific release profiles designed to deliver to different regions of the intestine or colon or based on obtaining specific chronotherapeutic delivery profiles.
Ionic liquid (IL) forms of drugs are increasingly being explored to address problems presented by poorly water-soluble drugs and solid-state stability. However, before ILs of active pharmaceutical ingredients (APIs) can be routinely incorporated into oral solid dosage forms (OSDs), challenges surrounding their ease of handling and manufacture must be addressed. To this end a framework for transforming API-ILs into solid forms at high loadings based on spray encapsulation using an immiscible polymer has recently been demonstrated. The current work demonstrates that this framework can be applied to a broad range of newly synthesized low glass transition temperature (Tg) API-ILs. Furthermore, the work explores a second novel approach to solidification of API-ILs based on polymer-API-IL miscibility that, to the best of our knowledge, has not been previously demonstrated. Modulated differential scanning calorimetry (mDSC) and attenuated total reflectance Fourier transform infrared spectroscopy showed that it was possible to produce spray dried solid materials, at acceptable loadings and yields for OSD applications in the form of both two-phase phase encapsulated systems and single phase amorphous solid dispersions (ASDs). This was achieved by the appropriate selection of an API-IL insoluble polymer (ethyl cellulose) for phase separated systems, or a miscible polymer with an exceptionally high Tg (the polysaccharide, maltodextrin) for the ASDs. Both approaches successfully overcame the Tg suppression associated with room temperature ILs.
This work represents the first step to understanding the fundamental critical physical attributes of these systems to facilitate a more mechanistic methodology for their design.
Vanadium compounds are promising anti-diabetic agents and graphene quantum dots (GQD) are emerging as potential drug delivery systems to improve drug solubility in water and membrane transport. Using highly dispersible and water soluble GQD, we herein prepared a novel GQD-VO (p-dmada) complex, in which vanadium coordination compounds [VO(p-dmada)] possibly packed closely on one side surface of GQD sheet via the π-π stacking mechanism. The in vitro tests showed that GQD-VO(p-dmada) exhibited the membrane permeability (Papp) as good as GQD with reduced cytotoxicity. In vivo tests on the type 2 diabetic mice demonstrated that GQD-VO(p-dmada) exhibited a delayed glucose lowering profile but more profound effects on insulin enhancement and β-cells protection after three-week treatment, compared to VO(p-dmada) alone. In addition, GQD alone was for the first time observed to effectively lower the blood lipid level of db/db mice. Overall, GQD-VO(p-dmada) showed improved pharmacokinetic performance and hypoglycemic effects, and using GQD as nano platform for drug delivery may provide vast opportunities for further design of metal-based pharmaceutical agents.
Biopharmaceutics Classification System (BCS) has gained broad acceptance in promoting the development of human drugs. To date, the applicability of existing human BCS criteria has not been evaluated in chickens. The objective of this study was to discuss the feasibility of BCS extrapolation between species and establish a preliminary chicken BCS by classifying seven veterinary commonly used drugs including metronidazole, amoxicillin, sulfamethoxazole, sulfadiazine, ciprofloxacin hydrochloride, doxycycline hydrochloride, and trimethoprim. Firstly, we finished the determination of physiological parameters affecting solubility in chickens, including body temperature, gastrointestinal pH, and the fluid volume in the gastrointestinal tract (GI), and the drug is considered highly soluble in chicken BCS when the highest dose strength is soluble in 20.40 ml (fed) or 6.73 ml (fasted) over the pH range of 1–8 at 41°C. Drug solubility classification was based on dose number calculation. Metronidazol and amoxicillin were classed differently under fed and fasted conditions. Secondly, we discussed the effect of ABC transporters (MDCK vs. MDCK‐chAbcb1/Abcg2) and pH (5.5 vs. 7.4) on drug permeability and classification. The drug is classified as highly permeable when its permeability is equal to or greater than metoprolol tartrate. Though ABC transporters and pH significantly affected the permeability values of drugs (p < .05), the permeability classification of the drugs has not been changed except for sulfamethoxazole. This work highlights some of the significant challenges that would be encountered in order to develop a chicken BCS, this valuable information could serve as a helpful tool during chicken drugs development and to minimize the potential risks when developing formulations.
This article summarizes historic developments, recent expert opinions, and (currently) unresolved challenges concerning the Biopharmaceutics Classification System (BCS)-based Biowaiver. An overview of approval statistics and application potential, case examples addressing the discriminatory power of the procedure, as well as an outlook on possible refinements in the future are provided and critically discussed. Over the last decade, regulatory guidance documents have been harmonized, for example, following scientific consent on allowing biowaivers for BCS class III drugs, making over 50% of orally administered drugs on the World Health Organization Essential Medicines List eligible for an abbreviated approval. Biowaiver monographs that present a complete risk-benefit evaluation for individual drugs have been issued by the International Pharmaceutical Federation for more than 25% of those drugs with the long-range aim of covering all essential drugs. Unresolved issues that have emerged from reported examples of false-negative and false-positive outcomes in the literature demand further adjustments to the regulatory requirements. Possible solutions for resolving these issues are the use of modeling and simulation and refined biorelevant in vitro tests that are better able to discriminate between dosage forms with unequal performance in vivo, potentially allowing biowaivers for selected BCS II drugs.
Polymorphism in co-crystals is known to have a dramatic effect on physiochemical properties. The current contribution covers the characterization, thermodynamic analysis, and cooling seeded crystallization investigation of the urea-barbituric acid (UBA) polymorphic co-crystal system including urea (UA), barbituric acid (BA), and two polymorphic UBA (Forms I and III). Supramolecular synthesis of UBA Forms I and III have been conducted by cooling crystallization in methanol and then systematically characterized by powder X-ray diffraction (PXRD), thermal analysis (DSC and TGA), Raman and IR spectroscopy. Compared to the TGA results, the exothermic and endothermic peaks shown in DSC curves represent the decomposition of UBA and the melting of BA, respectively. Using the measured solubility data, the UBA polymorphs were found to be an enantiotropic polymorphic system, and the transition points in the water and methanol were determined at 35 °C and 33 °C, respectively. Subsequently, the modified Apelblat equation and van't Hoff model were used to correlate the experimental data and to calculate the dissolution enthalpy and entropy of the different system. Moreover, cooling seeded crystallization of two polymorphic co-crystals in methanol was carried out to investigate the influence of process variables, such as seed amount, cooling rate, and stirring rate, on the crystal structure and crystal size distribution of final co-crystals.
This study was designed to theoretically investigate the influence of drug release properties, characterized by the disintegration
of a solid dosage form and dissolution of drug particles, on the systemic exposure of highly soluble drugs in immediate release
products. An absorption model was developed by considering disintegration of a solid dosage form, dissolution of drug particles,
gastrointestinal transit flow, and intestinal absorption processes. The absorption model was linked to a conventional pharmacokinetic
model to evaluate the effect of disintegration and dissolution on the peak exposure (Cmax) and total exposure of area under the curve (AUC). Numerical methods were used to solve the model equations. The simulations
show that the effect of disintegration of a dosage form and dissolution of drug particles depend on the permeability of a
drug, with a low-permeability drug having a greater effect. To provide similar exposure to an oral solution formulation, a
solid dosage form containing a low-permeability drug would need to dissolve more rapidly than a solid dosage form containing
a high-permeability drug. It was shown theoretically for poorly permeable drugs that the disintegration rate constant has
to be greater than 9 hour−1 (equivalent to approximately 90% in 30 minutes) to make both AUC and Cmax ratios higher than .9, ensuring the confidence interval of .80 to 1.25. The rapid in vitro release requirement of at least
85% dissolved in 30 minutes is sufficient for highly soluble and highly permeable drugs. However, for highly soluble and poorly
permeable drugs, the appropriate in vitro release requirement seems to be 90% dissolved in 30 minutes.
A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption. This analysis uses a transport model and human permeability results for estimating in vivo drug absorption to illustrate the primary importance of solubility and permeability on drug absorption. The fundamental parameters which define oral drug absorption in humans resulting from this analysis are discussed and used as a basis for this classification scheme. These Biopharmaceutic Drug Classes are defined as: Case 1. High solubility-high permeability drugs, Case 2. Low solubility-high permeability drugs, Case 3. High solubility-low permeability drugs, and Case 4. Low solubility-low permeability drugs. Based on this classification scheme, suggestions are made for setting standards for in vitro drug dissolution testing methodology which will correlate with the in vivo process. This methodology must be based on the physiological and physical chemical properties controlling drug absorption. This analysis points out conditions under which no in vitro-in vivo correlation may be expected e.g. rapidly dissolving low permeability drugs. Furthermore, it is suggested for example that for very rapidly dissolving high solubility drugs, e.g. 85% dissolution in less than 15 minutes, a simple one point dissolution test, is all that may be needed to insure bioavailability. For slowly dissolving drugs a dissolution profile is required with multiple time points in systems which would include low pH, physiological pH, and surfactants and the in vitro conditions should mimic the in vivo processes.(ABSTRACT TRUNCATED AT 250 WORDS)
The current BSC guidance issued by the FDA allows for biowaivers based on conservative criteria. Possible new criteria and class boundaries are proposed for additional biowaivers based on the underlying physiology of the gastrointestinal tract. The proposed changes in new class boundaries for solubility and permeability are as follows: 1. Narrow the required solubility pH range from 1.0-7.5 to 1.0-6.8. 2. Reduce the high permeability requirement from 90% to 85%. The following new criterion and potential biowaiver extension require more research: 1. Define a new intermediate permeability class boundary. 2. Allow biowaivers for highly soluble and intermediately permeable drugs in IR solid oral dosage forms with no less than 85% dissolved in 15 min in all physiologically relevant dissolution media, provided these IR products contain only known excipients that do not affect the oral drug absorption. The following areas require more extensive research: 1. Increase the dose volume for solubility classification to 500 mL. 2. Include bile salt in the solubility measurement. 3. Use the intrinsic dissolution method for solubility classification. 4. Define an intermediate solubility class for BCS Class II drugs. 5. Include surfactants in in vitro dissolution testing.
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 sub-specification 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.
Biopharmaceutics Classification System and Biopharmaceutics Drug Distribution Classification System are complimentary, not competing, classification systems that aim to improve, simplify, and speed drug development. Although both systems are based on classifying drugs and new molecular entities into four categories using the same solubility criteria, they differ in the criterion for permeability and have different purposes. Here, the details and applications of both systems are reviewed with particular emphasis of their role in drug development. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
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.
The Biopharmaceutics Classification System (BCS) is employed to waive in vivo bioequivalence testing (i.e. provide "biowaivers") for new and generic drugs that are BCS class I. Granting biowaivers under systems such as the BCS eliminates unnecessary drug exposures to healthy subjects and provides economic relief, while maintaining the high public health standard for therapeutic equivalence. International scientific consensus suggests class III drugs are also eligible for biowaivers. The objective of this study was to estimate the economic impact of class I BCS-based biowaivers, along with the economic impact of a potential expansion to BCS class III. Methods consider the distribution of drugs across the four BCS classes, numbers of in vivo bioequivalence studies performed from a five year period, and effects of highly variable drugs (HVDs). Results indicate that 26% of all drugs are class I non-HVDs, 7% are class I HVDs, 27% are class III non-HVDs, and 3% are class III HVDs. An estimated 66 to 76 million dollars can be saved each year in clinical study costs if all class I compounds were granted biowaivers. Between 21 and 24 million dollars of this savings is from HVDs. If BCS class III compounds were also granted waivers, an additional direct savings of 62 to 71 million dollars would be realized, with 9 to 10 million dollars coming from HVDs.
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Molecular Pharmaceutics Perspective DOI: 10.1021/acs.molpharmaceut.7b00687
Molecular Pharmaceutics
Perspective
DOI: 10.1021/acs.molpharmaceut.7b00687
Mol. Pharmaceutics 2017, 14, 4334−4338