Insights into Drug Precipitation Kinetics during In Vitro Digestion of a Lipid-Based Drug Delivery System Using In-Line Raman Spectroscopy and Mathematical Modeling

ABSTRACT: Purpose: To determine drug precipitation during in vitro lipolysis of a lipid-based drug delivery system (LBDDS) using Raman spectroscopy as a real-time monitoring technique. A second aim was to describe the kinetics of lipolysis-triggered drug precipitation using a theoretical nucleation and growth model. Methods: A model LBDDS containing different concentration of fenofibrate was digested in vitro and drug precipitation was determined after ultracentrifugation and nanofiltration (off-line methods), as well as by Raman spectroscopy (in-line method). Subsequently, a theoretical nucleation and growth model was fitted to the obtained drug crystallization profiles by considering the lipolysis-triggered change in drug solubility. Results: Compared with standard off-line measurements, Raman spectroscopy enabled a more robust and highly time-resolved analysis of lipolysis-triggered drug precipitation. Although the formulation was rapidly digested, fenofibrate remained in a supersaturated state for several minutes before beginning to crystallize. The in vitro digestion results were in excellent agreement with the theoretical model (R 2  > 0.976). Conclusions: The combination of real-time Raman spectroscopy and mathematical modeling provided insights into the kinetics of lipolysis-triggered drug crystallization. This knowledge allows a better biopharmaceutical understanding and will, ultimately, lead to the improved development of lipid-based drug formulation

Biopharmaceutical Modeling of Drug Supersaturation During Lipid-Based Formulation Digestion Considering an Absorption Sink

Purpose: In vitro lipolysis is widely utilized for predicting in vivo performance of oral lipid-based formulations (LBFs). However, evaluation of LBFs in the absence of an absorption sink may have limited in vivo relevance. This study aimed at employing biopharmaceutical modeling to simulate LBF digestion and drug supersaturation in a continuous absorptive environment. Methods: Three fenofibrate-loaded LBFs were characterized in vitro (dispersion and lipolysis) and drug precipitation was monitored using in-line Raman spectroscopy. In vitro data were combined with pharmacokinetic data derived from an in vivo study in pigs to simulate intestinal LBF transit. This biopharmaceutical model allowed calculation of lipolysis-triggered drug supersaturation while drug and lipolysis products are absorbed from the intestine. Results: The biopharmaceutical model predicted that, in a continuous absorption environment, fenofibrate supersaturation was considerably lower compared to in vitro lipolysis (non-sink). Hence, the extensive drug precipitation observed in vitro was predicted to be unlikely in vivo. The absorption of lipolysis products increased drug supersaturation, but drug precipitation was unlikely for highly permeable drugs. Conclusions: Biopharmaceutical modeling is a valuable approach for predicting LBFs performance in vivo. In the absence of in vitro tools simulating absorptive conditions, modeling strategies should be further considered

Insights into the biopharmaceutical behavior of oral lipid-based formulations using advanced analytical techniques and mathematical modeling

Lipid-based formulations (LBFs) are effective means for the oral delivery of poorly water-soluble compounds. The drug is already solubilized in the formulation and, thus, the critical dissolution step is circumvented. However, the oral bioavailability is also determined by the fate of the LBF in the gastrointestinal (GI) tract. Formulation dispersion and lipid digestion are particularly critical steps in this regard. The ability to maintain the drug in a solubilized state may be reduced leading to an increased risk of drug precipitation and erratic drug absorption. The present thesis consists of five studies, which aim at improving the biopharmaceutical understanding of LBF performance in the GI tract. To this end, in vitro dispersion and digestion assays are employed along with advanced analytical techniques and mathematical modeling. The findings may improve the predictability of LBF performance upon oral administration. In the first study, we analyzed surfactant/co-solvent systems during aqueous dilution. A theoretical model was proposed to analyze the role of excipient interaction for drug solubilization during dilution. This model indicated that, in undiluted formulations, co-solvent/surfactant domains were responsible for drug solubilization. In contrast, in diluted formulations the co-solvent partitioned out of the surfactant microstructure. This loss of excipient interaction caused formulation-specific supersaturation, which was indicative for the risk of drug precipitation. The analysis of excipient interactions and drug supersaturation facilitated the identification of critical drug-loadings in LBFs that are prone to drug precipitation. The second study focused on the in vitro lipolysis test. We evaluated Raman spectroscopy as an analytical technique for real-time monitoring of lipolysis-triggered drug precipitation. Despite the complex and varying medium composition, in-line analytics provided robust and highly time-resolved drug precipitation profiles. This allowed further analysis of the precipitation kinetics using a theoretical nucleation and growth model. The combination of real-time Raman spectroscopy and mathematical modeling provided valuable insights into the time evolution of lipolysis-triggered drug crystallization. The simulation of formulation digestion in an absorption environment was the purpose of the third study. Current in vitro lipolysis tests are performed in a single compartment and, therefore, they include no absorption sink. In this study, we developed a physiologically based model of formulation digestion in the GI tract based on in vitro lipolysis and in vivo pharmacokinetic data. The resulting system of differential equations allowed the calculation of drug supersaturation during the intestinal transit of LBFs. This approach provided clear evidence that an absorption sink significantly lowers the risk for lipolysis-triggered drug precipitation. Hence, in vitro lipolysis provides the worst-case prediction of LBF performance. Moreover, our results suggested that the intestinal digestion of LBFs is less critical than expected with respect to drug precipitation, especially with highly permeable drugs. The fourth study focused on the solid-state of precipitated weakly basic drugs. Drug-loaded LBFs were dispersed in a simulated intestinal medium with and without digestive enzymes and the resulting precipitate was analyzed by X-ray diffraction and re-dissolution. The study revealed that in vitro conditions can influence the solid-state properties of precipitating weak bases. While a crystalline precipitate was observed upon dispersion, the presence of digestive enzymes led to an amorphous precipitate. These findings are of high practical importance for the prediction of LBF performance in vivo. In contrast to the crystalline form, an amorphous precipitate may re-dissolve rapidly and, hence, become again available for absorption. Finally, in the fifth study, Raman spectroscopy and ultrasound resonator technology were evaluated as process analytical tools for drug quantification in LBFs. This study evidenced the excellence of Raman spectroscopy for drug quantification in complex lipidic matrices and was the basis for using Raman spectroscopy with biopharmaceutical tests. This thesis provided novel insights into the biopharmaceutical behavior of LBFs in the GI tract. The establishment of real-time techniques allowed the examination of highly dynamic formulation changes during dispersion and digestion. Moreover, mathematical modeling provided key insights into biopharmaceutical processes that are hardly accessible using in vitro methods. These advancements may improve the ability to predict LBF performance in vivo

Physiologically Based Biopharmaceutics Modeling of Food Effect for Basmisanil: A Retrospective Case Study of the Utility for Formulation Bridging

Basmisanil, is a lipophilic drug substance, exhibiting poor solubility and good permeability (BCS class 2). A validated physiologically based biopharmaceutics model (PBBM) has been previously described for tablets dosed in the fed state. The PBBM captured the less than proportional increases in exposure at higher doses well and indicated that absorption was dissolution rate-limited below 200 mg while solubility was limiting for higher doses. In this study, a model for dosing in the fasted state is described and is verified for simulation of the food effect where exposures were ~1.5 fold higher when a 660 mg tablet was given with food. The model is then applied to simulate the food effect for a granules formulation given at a lower dose (120 mg). The food effect at the lower dose was reasonably simulated with a ratio of simulated/observed food effect of 1.35 for Cmax and 0.83 for AUC. Sensitivity analysis was carried out for uncertain model parameters to confirm that the model could predict the magnitude of the positive food effect with moderate to high confidence. This study suggests that a verified PBBM can provide a useful alternative to a repeat food effect study when formulation changes are minor. However, there is need for further evaluation of the approach and a definition of what formulation changes are minor in this context. In addition, this work highlights some uncertainties in the handling of solubility in PBBM, in particular around temperature dependency of solubility and the parameterization of bile salt solubilization using measurements in biorelevant media

Correction: Van der Veken et al. Gastrointestinal Fluid Volumes in Pediatrics: A Retrospective MRI Study. <i>Pharmaceutics</i> 2022, <i>14</i>, 1935

In the original publication [...

Gastrointestinal Fluid Volumes in Pediatrics: A Retrospective MRI Study

The volume and distribution of fluids available in the gastrointestinal (GI) tract may substantially affect oral drug absorption. Magnetic resonance imaging (MRI) has been used in the past to quantify these fluid volumes in adults and its use is now being extended to the pediatric population. The present research pursued a retrospective, explorative analysis of existing clinical MRI data generated for pediatric patients. Images of 140 children from all pediatric subpopulations were analyzed for their resting GI fluid volumes in fasting conditions. In general, an increase in fluid volume as a function of age was observed for the stomach, duodenum, jejunum, and small intestine (SI) as a whole. No specific pattern was observed for the ileum and colon. Body mass index (BMI), body weight, body height, and SI length were evaluated as easy-to-measure clinical estimators of the gastric and SI fluid volumes. Although weight and height were identified as the best estimators, none performed ideally based on the coefficient of determination (R2). Data generated in this study can be used as physiologically relevant input for biorelevant in vitro tests and in silico models tailored to the pediatric population, thereby contributing to the efficient development of successful oral drug products for children

Impact of Tablet Size and Shape on the Swallowability in Older Adults

Older adults represent the major target population for oral medications, due to the high prevalence of multimorbidity. To allow for successful pharmacological treatments, patients need to adhere to their medication and, thus, patient-centric drug products with a high level of acceptability by the end users are needed. However, knowledge on the appropriate size and shape of solid oral dosage forms, as the most commonly used dosage forms in older adults, is still scarce. A randomized intervention study was performed including 52 older adults (65 to 94 years) and 52 young adults (19 to 36 years). Each participant swallowed four coated placebo tablets differing in weight (250 to 1000 mg) and shape (oval, round, oblong) in a blinded manner on three study days. The choice of tablet dimensions allowed for a systematic comparison between different tablet sizes of the same shape, as well as between different tablet shapes. Swallowability was assessed using a questionnaire-based method. All tested tablets were swallowed by ≥80% of adults, independent of age. However, only the 250 mg oval tablet was classified as well swallowable by ≥80% of old participants. The same was true for young participants; however, they also considered the 250 mg round and the 500 mg oval tablet as well swallowable. Furthermore, swallowability was seen to influence the willingness to take a tablet on a daily basis, especially for an intake over longer time periods

Investigating Tacrolimus Disposition in Paediatric Patients with a Physiologically Based Pharmacokinetic Model Incorporating CYP3A4 Ontogeny, Mechanistic Absorption and Red Blood Cell Binding

Tacrolimus is a crucial immunosuppressant for organ transplant patients, requiring therapeutic drug monitoring due to its variable exposure after oral intake. Physiologically based pharmacokinetic (PBPK) modelling has provided insights into tacrolimus disposition in adults but has limited application in paediatrics. This study investigated age dependency in tacrolimus exposure at the levels of absorption, metabolism, and distribution. Based on the literature data, a PBPK model was developed to predict tacrolimus exposure in adults after intravenous and oral administration. This model was then extrapolated to the paediatric population, using a unique reference dataset of kidney transplant patients. Selecting adequate ontogeny profiles for hepatic and intestinal CYP3A4 appeared critical to using the model in children. The best model performance was achieved by using the Upreti ontogeny in both the liver and intestines. To mechanistically evaluate the impact of absorption on tacrolimus exposure, biorelevant in vitro solubility and dissolution data were obtained. A relatively fast and complete release of tacrolimus from its amorphous formulation was observed when mimicking adult or paediatric dissolution conditions (dose, fluid volume). In both the adult and paediatric PBPK models, the in vitro dissolution profiles could be adequately substituted by diffusion-layer-based dissolution modelling. At the level of distribution, sensitivity analysis suggested that differences in blood plasma partitioning of tacrolimus may contribute to the variability in exposure in paediatric patients

A Miniaturized Extruder to Prototype Amorphous Solid Dispersions: Selection of Plasticizers for Hot Melt Extrusion

Hot-melt extrusion is an option to fabricate amorphous solid dispersions and to enhance oral bioavailability of poorly soluble compounds. The selection of suitable polymer carriers and processing aids determines the dissolution, homogeneity and stability performance of this solid dosage form. A miniaturized extrusion device (MinEx) was developed and Hypromellose acetate succinate type L (HPMCAS-L) based extrudates containing the model drugs neurokinin-1 (NK1) and cholesterylester transfer protein (CETP) were manufactured, plasticizers were added and their impact on dissolution and solid-state properties were assessed. Similar mixtures were manufactured with a lab-scale extruder, for face to face comparison. The properties of MinEx extrudates widely translated to those manufactured with a lab-scale extruder. Plasticizers, Polyethyleneglycol 4000 (PEG4000) and Poloxamer 188, were homogenously distributed but decreased the storage stability of the extrudates. Stearic acid was found condensed in ultrathin nanoplatelets which did not impact the storage stability of the system. Depending on their distribution and physicochemical properties, plasticizers can modulate storage stability and dissolution performance of extrudates. MinEx is a valuable prototyping-screening method and enables rational selection of plasticizers in a time and material sparing manner. In eight out of eight cases the properties of the extrudates translated to products manufactured in lab-scale extrusion trials