Nikoletta Fotaki

Biorelevant Dissolution Methods and Their Applications in In Vitro- In Vivo Correlations for Oral Formulations

Dissolution tests that can predict the in vivo performance of drug products are usually called biorelevant dissolution tests. Biorelevant dissolution testing can be used to guide formulation development, to identify food effects on the dissolution and bioavailability of orally administered drugs, and to identify solubility limitations and stability issues. To develop a biorelevant dissolution test for oral dosage forms, the physiological conditions in the gastrointestinal (GI) tract that can affect drug dissolution are taken into consideration according to the properties of the drug and dosage form. A variety of biorelevant methods in terms of media and hydrodynamics to simulate the contents and the conditions of the GI tract are presented. The ability of biorelevant dissolution methods to predict in vivo performance and generate successful in vitro-in vivo correlations (IVIVC) for oral formulations are also discussed through several studies.

Paediatric oral biopharmaceutics: key considerations and current challenges.

The complex process of oral drug absorption is influenced by a host of drug and formulation properties as well as their interaction with the gastrointestinal environment in terms of drug solubility, dissolution, permeability and pre-systemic metabolism. For adult dosage forms the use of biopharmaceutical tools to aid in the design and development of medicinal products is well documented. This review considers current literature evidence to guide development of bespoke paediatric biopharmaceutics tools and reviews current understanding surrounding extrapolation of adult methodology into a paediatric population. Clinical testing and the use of in silico models were also reviewed. The results demonstrate that further work is required to adequately characterise the paediatric gastrointestinal tract to ensure that biopharmaceutics tools are appropriate to predict performance within this population. The most vulnerable group was found to be neonates and infants up to 6 months where differences from adults were greatest.

Pharmaceutical characterisation and evaluation of cocrystals: Importance of in vitro dissolution conditions and type of coformer.

The objectives of this study were to demonstrate the importance of experimental set-up and type of coformer for the enhanced dissolution properties of cocrystals. Carbamazepine-saccharin and carbamazepine-nicotinamide cocrystals were prepared by the sonic slurry method and characterised with SEM, DSC, XRPD and particle size analysis. Solubility and dissolution testing (closed and open system) were performed in compendial media and media with a physiologically relevant amount of surfactant. Carbamazepine cocrystals (1:1 molar ratio) did not show a difference in the equilibrium solubility compared to the carbamazepine in compendial media but a substantial difference was observed in modified media. In compendial media, a faster dissolution rate was obtained only from the carbamazepine-saccharin cocrystal, whereas in modified media both cocrystals had a substantial higher dissolution compared to carbamazepine. With the selected method a clear difference in the dissolution profiles of each cocrystal is shown, driven by the characteristics of the coformer used. This study demonstrated that improved dissolution of carbamazepine from the cocrystal forms can be revealed only by appropriate selection of in vitro conditions. The characteristics of the coformer define a critical variable for dissolution of pharmaceutical cocrystals with important implications for their in vivo performance.

Flow-through cell apparatus (USP apparatus 4):Operation and features

INTRODUCTION Dissolution testing plays an important role in several areas during drug development. It can be used as a quality control tool to monitor batch-to-batch consistency of drug release from a dosage form and as an in vitro surrogate for in vivo performance that can guide formulation development and ascertain the need for bioequivalence tests. Several apparatus (compendial and noncompendial) are used for the study of dissolution of compounds and dosage forms. The flow-through cell method for the study of dissolution first appeared in 1957 as a flowing medium dissolution apparatus developed by FDA (1). The method was adapted by USP, the European Pharmacopoeia (Ph. Eur.), and the Japanese Pharmacopoiea (JP), and the flowthrough cell became an official apparatus (Apparatus 4 for the USP and Ph. Eur., Apparatus 3 for JP). Specifications and methodology are described in the relevant chapters of the pharmacopeias—USP Chapter Dissolution (2), Ph. Eur. 2.9.3 (3), and JP XV, 6.10 Dissolution Test (4)—and there is good harmonization among them.

Biorelevant dissolution: Methodology and application in drug development

INTRODUCTION Dissolution testing can play an important role in several areas for drug products as a quality control tool to monitor batch-to-batch consistency of drug release from a dosage form and as an in vitro surrogate for in vivo performance that can guide formulation development and ascertain the need for bioequivalence tests. The possibility of substituting dissolution tests for clinical studies has been revealed by the development of the Biopharmaceutics Classification System, and dissolution tests that can predict the in vivo performance of drug products (usually called “biorelevant” dissolution tests) could serve this purpose (1, 2). In terms of media and hydrodynamics, biorelevant dissolution testing should provide a baseline for drug and dosage-form performance and should be used to guide formulation development, to identify food effects on the dissolution and bioavailability of orally administered drugs, and to identify solubility limitations and stability issues. The importance of the development of predictive dissolution testing is increased by the fact that the majority of drugs currently in development are poorly soluble drugs and by the challenges for new dosage-form approaches.

The flow through cell methodology in the evaluation of intralumenal drug release characteristics

In this paper the usefulness of the flow through cell apparatus in the evaluation of intralumenal drug release characteristics is reviewed. Initially,the basic characteristics of this setup are presented. Then,the relative advantages and disadvantages of the flow through cell apparatus over other in vitro release setups are summarized. Finally,potential applications of this setup are discussed according to the solubility characteristics of the tested compound and the release characteristics of the dosage form.

Enhanced paracellular transport of insulin can be achieved via transient induction of myosin light chain phosphorylation

The intestinal epithelium functions to effectively restrict the causal uptake of luminal contents but has been demonstrated to transiently increase paracellular permeability properties to provide an additional entry route for dietary macromolecules. We have examined a method to emulate this endogenous mechanism as a means of enhancing the oral uptake of insulin. Two sets of stable Permeant Inhibitor of Phosphatase (PIP) peptides were rationally designed to stimulate phosphorylation of intracellular epithelial myosin light chain (MLC) and screened using Caco-2 monolayers in vitro. Apical application of PIP peptide 640, designed to disrupt protein–protein interactions between protein phosphatase 1 (PP1) and its regulator CPI-17, resulted in a reversible and non-toxic transient reduction in Caco-2 monolayer trans-epithelial electric resistance (TEER) and opening of the paracellular route to 4 kDa fluorescent dextran but not 70 kDa dextran in vitro. Apical application of PIP peptide 250, designed to impede MYPT1-mediated regulation of PP1, also decreased TEER in a reversible and non-toxic manner but transiently opened the paracellular route to both 4 and 70 kDa fluorescent dextrans. Direct injection of PIP peptides 640 or 250 with human insulin into the lumen of rat jejunum caused a decrease in blood glucose levels that was PIP peptide and insulin dose-dependent and correlated with increased pMLC levels. Systemic levels of insulin suggested approximately 3–4% of the dose injected into the intestinal lumen was absorbed, relative to a subcutaneous injection. Measurement of insulin levels in the portal vein showed a time window of absorption that was consistent with systemic concentration-time profiles and approximately 50% first-pass clearance by the liver. Monitoring the uptake of a fluorescent form of insulin suggested its uptake occurred via the paracellular route. Together, these studies add validation to the presence of an endogenous mechanism used by the intestinal epithelium to dynamically regulate its paracellular permeability properties and better define the potential to enhance the oral delivery of biopharmaceuticals via a transient regulation of an endogenous mechanism controlling the intestinal paracellular barrier.

Assessment of Age-Related Changes in Pediatric Gastrointestinal Solubility.

ABSTRACTPurposeCompound solubility serves as a surrogate indicator of oral biopharmaceutical performance. Between infancy and adulthood, marked compositional changes in gastrointestinal (GI) fluids occur. This study serves to assess how developmental changes in GI fluid composition affects compound solubility.MethodsSolubility assessments were conducted in vitro using biorelevant media reflective of age-specific pediatric cohorts (i.e., neonates and infants). Previously published adult media (i.e., FaSSGF, FeSSGF, FaSSIF.v2, and FeSSIF.v2) were employed as references for pediatric media development. Investigations assessing age-specific changes in GI fluid parameters (i.e., pepsin, bile acids, pH, osmolality, etc.) were collected from the literature and served to define the composition of neonatal and infant media. Solubility assessments at 37°C were conducted for seven BCS Class II compounds within the developed pediatric and reference adult media.ResultsFor six of the seven compounds investigated, solubility fell outside an 80–125% range from adult values in at least one of the developed pediatric media. This result indicates a potential for age-related alterations in oral drug performance, especially for compounds whose absorption is delimited by solubility (i.e., BCS Class II).ConclusionDevelopmental changes in GI fluid composition can result in relevant discrepancies in luminal compound solubility between children and adults.

Dissolution of amorphous solid dispersions:theory and practice

Dissolution test is an extremely valuable and powerful tool in understanding the parameters that control dissolution of amorphous formulations as well as in revealing supersaturation effect and the solid-state transformations that might occur after oral administration. Supersaturated/non-sink and biorelevant dissolution conditions could guide in designing the solid dispersion in order to select optimal polymer(s), drug loading, and downstream processing for the desired in vivo performance as well as shelf life stability. The focus of this chapter is to review and describe the different models being used to characterize dissolution of solid oral dosage forms containing amorphous drugs in aqueous and biorelevant media. Dissolution case studies of weak base, weak acid, and neutral compounds are presented, illustrating a rational approach for the development and implementation of the desired dissolution characteristics for the amorphous drug product performance. Finally, case studies of successful in vitro–in vivo correlations of amorphous formulations are presented. This chapter can serve as guidance for the development and understanding of dissolution of amorphous solid dispersions.

Mechanistic understanding of the effect of PPIs and acidic carbonated beverages on the oral absorption of itraconazole based on absorption modeling with appropriate in vitro data.

Proton pump inhibitors (PPIs) are potent gastric acid suppressing agents and are among the most widely sold drugs in the world. However, even though these antisecretory agents are regarded as safe, they can alter the pharmacokinetics of coadministered drugs. Due to the suppression of gastric acid secretion, they can significantly alter the intragastric pH conditions and are thus likely to affect the bioavailability of coadministered drugs requiring an acidic gastric environment for dissolution and subsequent absorption. Among these drugs can be found itraconazole, a poorly soluble triazole-type antifungal compound. Based on observations reported in the literature, gastric pH alterations due to the coadministration of PPIs or acidic beverages can significantly decrease (PPI) or increase (e.g., Coca-Cola) the bioavailability of this compound. In the present work we estimated the fraction of itraconazole that can be absorbed (fabs) from Sporanox capsules or an itraconazole-HBenBCD complex formulation after oral administration with and without coadministration of a PPI or an acidic (carbonated) beverage. For this purpose, the sensitivity of the two formulations toward the impact of various gastric variations (pH, volume, and emptying rate) as they can result from such administration conditions was studied using solubility and dissolution experiments and a physiologically based absorption model. Simulating coadministration of the two formulations with a PPI resulted in a significant (∼ 10-fold) decrease in itraconazole fabs, indicating the pH to be essential for in vivo dissolution and subsequent absorption. The fabs of itraconazole after coadministration of an acidic beverage (Coca-Cola) was far lower than the fabs obtained for itraconazole alone and did not support the observations reported in the literature. These results clearly indicate that in contrast to PPIs, which seem to affect itraconazole bioavailability mainly via intragastric pH changes, coadministered Coca-Cola is likely to alter a range of gastrointestinal parameters relevant to in vivo dissolution rather than solely affecting the intragastric pH.