Oral Drug Product Development Research Articles

Challenges in Permeability Assessment for Oral Drug Product Development.

Drug permeation across the intestinal epithelium is a prerequisite for successful oral drug delivery. The increased interest in oral administration of peptides, as well as poorly soluble and poorly permeable compounds such as drugs for targeted protein degradation, have made permeability a key parameter in oral drug product development. This review describes the various in vitro, in silico and in vivo methodologies that are applied to determine drug permeability in the human gastrointestinal tract and identifies how they are applied in the different stages of drug development. The various methods used to predict, estimate or measure permeability values, ranging from in silico and in vitro methods all the way to studies in animals and humans, are discussed with regard to their advantages, limitations and applications. A special focus is put on novel techniques such as computational approaches, gut-on-chip models and human tissue-based models, where significant progress has been made in the last few years. In addition, the impact of permeability estimations on PK predictions in PBPK modeling, the degree to which excipients can affect drug permeability in clinical studies and the requirements for colonic drug absorption are addressed.

Challenges and Strategies for Solubility Measurements and Dissolution Method Development for Amorphous Solid Dispersion Formulations

This manuscript represents the view of the Dissolution Working Group of the IQ Consortium on the challenges of and recommendations on solubility measurements and development of dissolution methods for immediate release (IR) solid oral dosage forms formulated with amorphous solid dispersions. Nowadays, numerous compounds populate the industrial pipeline as promising drug candidates yet suffer from low aqueous solubility. In the oral drug product development process, solubility along with permeability is a key determinant to assure sufficient drug absorption along the intestinal tract. Formulating the drug candidate as an amorphous solid dispersion (ASD) is one potential option to address this issue. These formulations demonstrate the rapid onset of drug dissolution and can achieve supersaturated concentrations, which poses significant challenges to appropriately characterize solubility and develop quality control dissolution methods. This review strives to categorize the different dissolution and solubility challenges for ASD associated with 3 different topics: (i) definition of solubility and sink conditions for ASD dissolution, (ii) applications and development of non-sink dissolution (according to conventional definition) for ASD formulation screening and QC method development, and (iii) the advantages and disadvantages of using dissolution in detecting crystallinity in ASD formulations. Related to these challenges, successful examples of dissolution experiments in the context of control strategies are shared and may lead as an example for scientific consensus concerning dissolution testing of ASD.

Current State and Challenges of Physiologically Based Biopharmaceutics Modeling (PBBM) in Oral Drug Product Development.

Physiologically based biopharmaceutics modeling (PBBM) emphasizes the integration of physicochemical properties of drug substance and formulation characteristics with system physiological parameters to predict the absorption and pharmacokinetics (PK) of a drug product. PBBM has been successfully utilized in drug development from discovery to postapproval stages and covers a variety of applications. The use of PBBM facilitates drug development and can reduce the number of preclinical and clinical studies. In this review, we summarized the major applications of PBBM, which are classified into six categories: formulation selection and development, biopredictive dissolution method development, biopharmaceutics risk assessment, clinically relevant specification settings, food effect evaluation and pH-dependent drug-drug-interaction risk assessment. The current state of PBBM applications is illustrated with examples from published studies for each category of application. Despite the variety of PBBM applications, there are still many hurdles limiting the use of PBBM in drug development, that are associated with the complexity of gastrointestinal and human physiology, the knowledge gap between the in vitro and the in vivo behavior of drug products, the limitations of model interfaces, and the lack of agreed model validation criteria, among other issues. The challenges and essential considerations related to the use of PBBM are discussed in a question-based format along with the scientific thinking on future research directions. We hope this review can foster open discussions between the pharmaceutical industry and regulatory agencies and encourage collaborative research to fill the gaps, with the ultimate goal to maximize the applications of PBBM in oral drug product development.

Superiority of Mesoporous Silica-Based Amorphous Formulations over Spray-Dried Solid Dispersions.

The aim of this study was to compare the performance of two amorphous formulation strategies: mesoporous silica via solvent impregnation, and solid dispersions by spray drying. Poorly soluble fenofibrate was chosen as the model drug compound. A total of 30% Fenofibrate-loaded mesoporous silica and spray-dried solid dispersions (SDD) were prepared for head-to-head comparisons, including accelerated stability, manufacturability, and in vitro biorelevant dissolution. In the accelerated stability study under 40 °C/75% RH in open dish, mesoporous silica was able to maintain amorphous fenofibrate for up to 3 months based on solid-state characterizations by PXRD and DSC. This result was superior compared to SDD, as recrystallization was observed within 2 weeks. Under the same drug load, fenofibrate-loaded mesoporous silica showed much better flowability than fenofibrate-loaded SDD, which is beneficial for powder handling of the intermediate product during the downstream process. The in vitro 2-stage dissolution results indicated a well-controlled release of fenofibrate from mesoporous silica in the biorelevant media, rather than a burst release followed by fast precipitation due to the recrystallization in the early simulated gastric phase for SDD. The present study demonstrates that mesoporous silica is a promising formulation platform alternative to prevailing spray-dried solid dispersions for oral drug product development.

A Toolbox for Mimicking Gastrointestinal Conditions in Children: Simulated Paediatric Breakfast Media (SPBM) for Addressing the Variability of Gastric Contents After Typical Paediatric Breakfasts

Since co-administration of dosage forms with food can impact drug exposure, food effect studies became an integral part of oral drug product development. Studies are usually performed in healthy adults and the dosage form is co-administered with a high-fat high-calorie standard breakfast meal to mimic worst-case dosing conditions. A corresponding study design for children is lacking but would be essential for a proper risk-assessment in this vulnerable patient group. To protect healthy children from unnecessary in vivo studies, it would be even more desirable to predict food effects based on other than in vivo studies in the target age group. In the present study, typical children's breakfasts in different parts of the world were identified, prepared and physicochemical properties were assessed. Subsequently, Simulated Paediatric Breakfast Media (SPBM) resembling breakfast composition and properties were designed and applied in in vitro dissolution experiments mimicking the initial composition of the postprandial stomach after breakfast ingestion. Study results indicate the impact of different simulated gastric conditions on drug release. SPBM enabled to better estimate the variability of in vivo drug release in fed dosing conditions and their use will aid in better assessing food effects in children in different parts of the world.

Development and evaluation of a biorelevant medium simulating porcine gastrointestinal fluids

Simulated human intestinal media, have proved to be a useful biopharmaceutics tool as a dissolution media for predicting in vivo dissolution and pharmacokinetic profile in humans. During drug product development preclinical animal models are also required to assess drug product performance, and there is a need to develop species specific intestinal media to similarly predict in vivo pharmacokinetic profiles in each preclinical model. Pigs, are increasingly being used in preclinical drug development, however to date there is a lack of quantitative information about the composition of porcine gastrointestinal (GI) fluids. As a result, a porcine biorelevant medium has not yet been developed, which is essential to improve interpretation and forecast of preclinical results using biorelevant in vitro dissolution studies. GI fluid samples, were collected from landrace pigs, and characterized. Fasted State Simulated Intestinal Fluid of pigs (FaSSIFp) was developed based on the physiological composition of the GI fluids in terms of pH, buffer capacity, osmolality, surface tension, as well as the bile salt, phospholipid and free fatty acid content. This study demonstrated that FaSSIFp was superior at predicting the solubility of the six model drugs in porcine intestinal fluids (PIF). A markedly high correlation (r2 0.98) was observed between the solubility obtained in PIF and FaSSIFp, whereas poor correlation (r2 0.12) was found for the solubility of the model drugs between human FaSSIF and PIF. This confirms that species specific biorelevant intestinal media are crucial to provide more accurate predictions of pharmacokinetic studies in preclinical models. Additionally, the availability of a species specific intestinal medium offers the potential to improve in vitro-in silico approaches to predict in vivo absorption and to reduce the overall number of animals needed in oral drug product development testing.

In vitro models for the prediction of in vivo performance of oral dosage forms: Recent progress from partnership through the IMI OrBiTo collaboration

The availability of in vitro tools that are constructed on the basis of a detailed knowledge of key aspects of gastrointestinal (GI) physiology and their impact on formulation performance and subsequent drug release behaviour is fundamental to the success and efficiency of oral drug product development. Over the last six years, the development and optimization of improved, biorelevant in vitro tools has been a cornerstone of the IMI OrBiTo (Oral Biopharmaceutics Tools) project. By bringing together key industry and academic partners, and by linking tool development and optimization to human studies to understand behaviour at the formulation/GI tract interface, the collaboration has enabled innovation, optimization and implementation of the requisite biorelevant in vitro tools. In this paper, we present an overview of the in vitro tools investigated during the collaboration and offer a perspective on their future use in enhancing the development of new oral drug products.

Application of a Dynamic Fluid and pH Model to Simulate Intraluminal and Systemic Concentrations of a Weak Base in GastroPlus™

The application of preclinical in vitro and in silico models can help formulation scientists to predict the in vivo performance of a drug in an early stage of oral drug product development. An important aspect is that these models should include equations that represent mechanisms that are biorelevant and are sensitive to changes in parameter values. Human gastrointestinal physiology involves many processes that change as a function of time. In this work, a dynamic fluid and pH model was applied in GastroPlus™ to simulate intraluminal and systemic concentrations of the weak base posaconazole in a biorelevant manner. Simulated results were compared with observed data, extracted from a previously reported human in vivo gastrointestinal aspiration study. Three different formulations were explored (i.e., 1 solution [20 mg dose strength] and 2 suspensions [both 40 mg dose strength]). Simulated results were compared and in line with the observed results for different intraluminal (e.g., precipitated fraction) and systemic parameters (e.g., plasma Cmax). The optimization of the advanced compartmental and absorption transit model related to fluid dynamics and dynamic pH in this work creates perspectives to validate this model with other reference data derived from aspiration/magnetic resonance imaging studies.

Dissolution and Translational Modeling Strategies Enabling Patient-Centric Drug Product Development: the M-CERSI Workshop Summary Report.

On May 15th-17th, 2017, the US FDA and the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) held a workshop at the University of Maryland's Center of Excellence in Regulatory Science and Innovation (M-CERSI), to discuss the role of dissolution testing and translational modeling and simulation in enabling patient-centric solid oral drug product development. This 3-day event was attended by scientists from regulatory agencies, pharmaceutical companies, and academia. The workshop included podium presentations followed by breakout session discussions. The first day of the meeting focused on the challenges in dissolution method development and the role of dissolution testing throughout drug product development. On the second day, approaches to establish a link between in vitro testing and in vivo drug product performance (e.g., systemic exposure) were presented. Overall success rates and challenges in establishing IVIVCs via traditional and modern physiologically based pharmacokinetic (PBPK) modeling and simulation approaches were discussed. Day 3 provided an opportunity to discuss the expectations for establishing clinically relevant drug product specifications (CRDPS). It was recognized that understanding the impact of formulation and process variations on dissolution and in vivo performance is critical for most drug products formulated with poorly soluble drugs to ensure consistent product performance. The breakout sessions served as platforms for discussing controversial topics such as the clarification of dissolution terminology, PBPK model development and validation expectations, and approaches to set CRDPS. The meeting concluded with a commitment to continue the dialog between regulators, industry, and academia to advance overall product quality understanding.

Trade-offs in oral drug product development

Drug products are developed to meet multiple targets, thereby increasing their value. Pharmaceutical scientists encounter several trade-offs during the development of novel oral formulations. These trade-offs are generated by their desire to supply the highest possible quality products under the prevailing conditions of limited time and cost, and feasible options. When there are two incompatible factors, it is sometimes difficult to dismiss one element. This is because a quality target product profile (QTPP) is critical for each product being developed, and all elements should basically be satisfied with the criteria. Therefore, technological innovation becomes important to overcome the trade-offs. This article introduces examples of such innovations which have been successful in doing this, as well as some encountered in the oral formulation development and in the selection of proper dosage forms. Based on these examples, points to be considered in order to produce the drug product are thoroughly discussed.

Provisional in-silico biopharmaceutics classification (BCS) to guide oral drug product development.

The main objective of this work was to investigate in-silico predictions of physicochemical properties, in order to guide oral drug development by provisional biopharmaceutics classification system (BCS). Four in-silico methods were used to estimate LogP: group contribution (CLogP) using two different software programs, atom contribution (ALogP), and element contribution (KLogP). The correlations (r2) of CLogP, ALogP and KLogP versus measured LogP data were 0.97, 0.82, and 0.71, respectively. The classification of drugs with reported intestinal permeability in humans was correct for 64.3%–72.4% of the 29 drugs on the dataset, and for 81.82%–90.91% of the 22 drugs that are passively absorbed using the different in-silico algorithms. Similar permeability classification was obtained with the various in-silico methods. The in-silico calculations, along with experimental melting points, were then incorporated into a thermodynamic equation for solubility estimations that largely matched the reference solubility values. It was revealed that the effect of melting point on the solubility is minor compared to the partition coefficient, and an average melting point (162.7°C) could replace the experimental values, with similar results. The in-silico methods classified 20.76% (±3.07%) as Class 1, 41.51% (±3.32%) as Class 2, 30.49% (±4.47%) as Class 3, and 6.27% (±4.39%) as Class 4. In conclusion, in-silico methods can be used for BCS classification of drugs in early development, from merely their molecular formula and without foreknowledge of their chemical structure, which will allow for the improved selection, engineering, and developability of candidates. These in-silico methods could enhance success rates, reduce costs, and accelerate oral drug products development.

Summary Workshop Report: Facilitating Oral Product Development and Reducing Regulatory Burden Through Novel Approaches to Assess Bioavailability/Bioequivalence

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 C (max) 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).

Integrating drug permeability with dissolution profile to develop IVIVC

In this review article, three different approaches to predict in vivo oral absorption based on the in vitro data of drug permeability, solubility and dissolution were introduced. At the drug discovery stage, the absorption potential of each candidate is most important to select better compounds for further development. The concept of maximum absorbable dose is applied widely, not only to evaluate the absorption potential but also to elucidate the rate-limiting process of oral absorption that helps us to understand the cause of poor absorption. To integrate the permeability of the drug with its dissolution profile, two different approaches, in vitro dissolution/permeation system (D/P system) and in silico model and simulation method, are proposed. In the D/P system, by mimicking the in vivo process of drug absorption, the permeated amount of drugs, that is the total output of dissolution and permeation processes, are correlated with the fraction absorbed in human (F(a)). This system is powerful for evaluating the improved absorption by various formulations and the effect of food intake. On the other hand, in the model and simulation approach, an intrinsic dissolution parameter of drug particle, z, was extracted from the small scale in vitro test and the process of intestinal absorption was re-constructed in silico by incorporating the physiological parameters in human. The effective use of these approaches for the development of oral drug products is discussed through various case studies.

Analysis of Risk Factors in Human Bioequivalence Study That Incur Bioinequivalence of Oral Drug Products

In the study of human bioequivalence (BE), newly developed oral products sometimes fail to prove BE with a reference product due to the high variability in pharmacokinetic (PK) parameters after oral absorption. In this study, risk factors that incur bioinequivalence in BE study were analyzed by applying the Biopharmaceutics Classification System (BCS). Forty-four generic products were selected from a database of BE studies in the past 10 years at Towa Pharmaceutical Co., Ltd. (Osaka, Japan), and 90% confidence interval (CI) of AUC and C(max) in human BE study for all products were converted into coefficient of variation (CV(90)). Then, the required number of subjects to confirm BE was estimated from the 90% CI in human BE study of new products. It was found that both the permeability of drugs to human intestinal membrane (P(eff)) and the dose number calculated from their water solubility did not correlate well to CV(90) and the estimated subject number in human BE study, suggesting the contribution of other factors to cause the variability in oral drug absorption. As the PK parameter of drugs, the value of AUC/dose was calculated and plotted against CV(90) and the estimated subject number by classifying drugs into 4 BCS classes. For drugs in classes 1 and 3, AUC/dose gave a clear criterion to distinguish the drugs with a high risk of bioinequivalence, where drugs with low AUC/dose showed high CV(90) and large number of subjects. It was suggested that the high metabolic clearance (for class 1 drug) and low oral absorption (for class 3 drug) could be significant factors to incur bioinequivalence in human BE study, although for drugs in classes 2 and 4, clear factors were not defined. Consequently, for drugs in BCS classes 1 and 3, risks in human BE study to incur bioinequivalence could be predicted by calculating the AUC/dose. In the case of generic drugs, since the parameter of AUC/dose is available before initiating human BE study, this finding is expected to promote an efficient and cost-saving strategy for the development of oral drug products.