75 research outputs found

    Increasing the biorelevance of simulated intestinal fluids for better predictions of drug equilibrium solubility in the fasted upper small intestine

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    To date the importance of luminal species other than bile salts and phosphatidylcholine on drug equilibrium solubility in the fasted upper small intestine has been evaluated to a very limited extent. In this communication the importance of fatty acids, cholesterol, and proteins on solubility of four model lipophilic compounds was evaluated by including these components into previously proposed simulated intestinal fluids. Data were compared with ex vivo solubility data in aspirates reflecting the mean and the median luminal composition in the upper small intestine. It is concluded that estimation of solubility in aspirates reflecting the median luminal composition is better estimated when the presence of cholesterol and fatty acids is also simulated. In contrast, estimation of solubility in aspirates reflecting the mean luminal composition requires consideration of additional factors (e.g. buffer species identity, non-micellar colloidal structures, and lyso-phosphatidylcholine content)

    Viscosity modulates blood glucose response to nutrient solutions in dogs

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    The relationship between postprandial blood glucose levels and meal viscosity was studied by adding various combinations of hydroxypropylmethylcellulose to glucose solutions and administering them to female mongrel dogs. Glucose was administered as 5% or 20% solutions in water. Hydroxypropylmethylcellulose was dissolved in the glucose solutions to yield low (5000 cP measured at 37[deg]C and 1 s-1), medium (15 000 cP) or high (30 000 cP) viscosities. High viscosity hydroxypropylmethylcellulose significantly reduced the maximum blood glucose concentration, Cmax, by 60% (5% glucose meal) and 40% (20% glucose meal) while reducing the area under the blood level vs. time curve (AUC0-3 h) by 40-50%. Medium viscosity hydroxypropylmethylcellulose reduced the Cmax at both glucose levels, but reduced the AUC only for the 5% glucose meal. Low viscosity HPMC lowered the Cmax only after the 5% glucose meal, and had no significant effect on the AUC at either glucose level. The average time to reach maximum concentration, Tmax, was prolonged two- to three-fold at all viscosity levels for the 5% glucose solutions, but was not affected when 20% glucose solutions were administered. It was concluded that hydroxypropylmethylcellulose can effectively retard the absorption of glucose from the gastrointestinal tract, and that the extent of this effect is related to the viscosity of the solution administered.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29912/1/0000269.pd

    Usefulness of the Beagle Model in the Evaluation of Paracetamol and Ibuprofen Exposure after Oral Administration to Pediatric Populations:An Exploratory Study

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    The present study aimed to explore the usefulness of beagle dogs in combination with physiologically based pharmacokinetic (PBPK) modeling in the evaluation of drug exposure after oral administration to pediatric populations at an early stage of pharmaceutical product development. An exploratory, single-dose, crossover bioavailability study in six beagles was performed. A paracetamol suspension and an ibuprofen suspension were coadministered in the fasted-state conditions, under reference-meal fed-state conditions, and under infant-formula fed-state conditions. PBPK models developed with GastroPlus v9.7 were used to inform the extrapolation of beagle data to human infants and children. Beagle-based simulation outcomes were compared with published human-adult-based simulations. For paracetamol, fasted-state conditions and reference-meal fed-state conditions in beagles appeared to provide adequate information for the applied scaling approach. Fasted-state and/or reference-meal fed-state conditions in beagles appeared suitable to simulate the performance of ibuprofen suspension in pediatric populations. Contrary to human-adult-based translations, extrapolations based on beagle data collected under infant-formula fed-state conditions appeared less useful for informing simulations of plasma levels in pediatric populations. Beagle data collected under fasted and/or reference-meal fed-state conditions appeared to be useful in the investigation of pediatric product performance of the two investigated highly permeable and highly soluble drugs in the upper small intestine. The suitability of the beagle as a preclinical model to understand pediatric drug product performance under different dosing conditions deserves further evaluation with a broader spectrum of drugs and drug products and comparisons with pediatric in vivo data.</p

    A Novel Rheological Method to Assess Drug-Polymer Interactions Regarding Miscibility and Crystallization of Drug in Amorphous Solid Dispersions for Oral Drug Delivery

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    Solid dispersions provide a key technology to formulate poorly water-soluble drugs, and a main task of early development is appropriate selection of polymer. This study investigates the use of a novel rheology-based approach to evaluate miscibility and interactions of drugs with polymers regarding amorphous solid drug dispersions for oral administration. Tacrolimus was used as model drug and hydroxypropyl cellulose, ethylcellulose, Soluplus®, polyethyleneglycol 6000, Poloxamer-188 (Koliphor-188), and Eudragit® S100 were used as excipients. Solvent-based evaporation methods were used to prepare binary solid dispersions of drug and polymer. Data of the dilute solution viscosimetry were compared with in silico calculations of the Hansen solubility parameter (HSP), as well as phase separation/crystallization data obtained from X-ray diffraction and differential scanning calorimetry. HSP calculations in some cases led to false positive predictions of tacrolimus miscibility with the tested polymers. The novel rheology-based method provided valuable insights into drug-polymer interactions and likely miscibility with polymer. It is a rather fast, inexpensive, and robust analytical approach, which could be used complementary to in silico-based evaluation of polymers in early formulation development, especially in cases of rather large active pharmaceutical ingredients

    On the Design of Food Effect Studies in Adults for Extrapolating Oral Drug Absorption Data to Infants:an Exploratory Study Highlighting the Importance of Infant Food

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    In the present investigation, it was explored whether food effect on drug absorption in adults is similar with the food effect after administration of an infant meal with the drug product to adults. After confirming lack of pharmaceutical and pharmacokinetic interaction, a paracetamol suspension and an ibuprofen suspension were co-administered to eight healthy adults on a crossover basis in three different occasions, i.e. in the fasted state (as defined by regulatory agencies, fasted conditions), in the fed state (as defined by regulatory agencies, fed conditions) and under conditions simulating the fed state in infants (infant fed conditions). Unlike under fed conditions, under infant fed conditions early exposure was significantly lower than under fasted conditions for both paracetamol and ibuprofen. Also, for ibuprofen, Cmax values under infant fed conditions were significantly higher than under fed conditions. These data suggest that, even for drugs with non-problematic absorption administered in simple dosage forms, food effects in infants may not be adequately evaluated if the protocol suggested by regulatory agencies is applied. The usefulness of the methodology employed in the present investigation for simulating the fed state in infants deserves further evaluation. Until then, food effects in infants should be considered cautiously or be evaluated in infants.</p

    Evaluation of the impact of excipients and an albendazole salt on albendazole concentrations in upper small intestine using an in vitro biorelevant gastrointestinal transfer (BioGIT) system

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    An in vitro biorelevant gastrointestinal transfer (BioGIT) system was assessed for its ability to mimic recently reported albendazole concentrations in human upper small intestine after administration of free base suspensions to fasted adults in absence and in presence of supersaturation promoting excipients (hydroxypropylmethylcellulose and lipid self-emulsifying vehicles). The in vitro method was also used to evaluate the likely impact of using the sulfate salt on albendazole concentrations in upper small intestine. In addition, BioGIT data were compared with equilibrium solubility data of the salt and the free base in human aspirates and biorelevant media. The BioGIT system adequately simulated the average albendazole gastrointestinal transfer process and concentrations in upper small intestine after administration of the free base suspensions to fasted adults. However, the degree of supersaturation observed in the duodenal compartment was greater than in vivo. Albendazole sulfate resulted in minimal increase of albendazole concentrations in the duodenal compartment of the BioGIT, despite improved equilibrium solubility observed in human aspirates and biorelevant media, indicating that the use of a salt is unlikely to lead to any significant oral absorption advantage for albendazole

    Disposition of two highly permeable drugs in the stomach and the upper small intestine of healthy adults after a standard high-calorie, high-fat meal

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    Objectives: To quantify the presence of two model highly permeable drugs, paracetamol and danazol, in the upper gastrointestinal lumen under conditions simulating the situation after disintegration of immediate release dosage forms administered in bioavailability/bioequivalence studies in the fed state. To understand the drug transfer process from the antral contents through the upper small intestine using the luminal drug data. Methods: 8 healthy male adult volunteers participated in a randomized, single dose, two-phase, crossover study. After evaluating the impact of homogenization on meal’s viscosity and particle size, the meal, containing phenol red as non-absorbable marker, was administered to the antrum via the gastric lumen of a naso-gastro-intestinal tube. The drugs were administered in solution form (Phase I) and in suspension form (Phase II) with a glass of tap water to the antrum of the stomach, 30 min after the initiation of meal administration. Samples were aspirated from the antrum and the upper small intestine up to 4 hours post drug administration. Results: Apparent concentrations in the aqueous contents of the antrum were higher than apparent concentrations in micellar contents of the upper small intestine for paracetamol; the opposite was observed for danazol. Based on total drug amount per volume data in contents of the upper gastrointestinal lumen, the transfer of paracetamol (aqueous solution or suspension) and danazol (aqueous suspension) through the upper small intestine could be described as an apparent first-order process. Transfer of a long-chain triglyceride solution of danazol was highly variable. Conclusions: Concentrations in the aqueous/micellar phase of luminal contents and values of parameters controlling the transfer from bulk gastric contents through the upper small intestine after a high-calorie, high-fat meal, were reported for the first time for highly permeable drugs. Data are expected to enhance the development of biorelevant in vitro and physiologically based biopharmaceutics modelling methodologies

    On the usefulness of two small-scale in vitro setups in the evaluation of luminal precipitation of lipophilic weak bases in early formulation development

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    A small-scale biphasic dissolution setup and a small-scale dissolution-permeation (D-P) setup were evaluated for their usefulness in simulating the luminal precipitation of three lipophilic weak bases&mdash;dipyridamole, ketoconazole and itraconazole. The transition from the gastric to intestinal environment was incorporated into both experimental procedures. Emulsification during the biphasic dissolution experiments had a minimal impact on the data, when appropriate risk mitigation steps were incorporated. Precipitation parameters estimated from the in vitro data were inputted into the Simcyp&reg; physiologically based pharmacokinetic (PBPK) modelling software and simulated human plasma profiles were compared with previously published pharmacokinetic data. Average Cmax and AUC values estimated using experimentally derived precipitation parameters from the biphasic experiments deviated from corresponding published actual values less than values estimated using the default simulator parameters for precipitation. The slow rate of transport through the biomimetic membrane in the D-P setup limited its usefulness in forecasting the rates of in vivo precipitation used in the modelling of average plasma profiles

    Factors affecting successful extrapolation of ibuprofen exposure from adults to paediatric populations after oral administration of a paediatric aqueous suspension

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    The importance of physiologically based pharmacokinetic (PBPK) model refinement for adults with data acquired in adults using a paediatric formulation under age-relevant dosing conditions in order to extrapolate drug exposure to infants was recently demonstrated for paracetamol. In the present investigation the aim was to expand the use of PBPK modeling informed by bioavailability data collected in healthy adults under different dosing conditions for a low solubility weak acid, ibuprofen, to simulate exposure across paediatric populations, i.e., infants, pre-school children, and schoolchildren. After developing and evaluating an adult disposition and oral absorption model for the aqueous suspension of ibuprofen, ibuprofen performance was extrapolated to paediatrics simulating exposure as a function of different prandial and dosing conditions: fasted conditions, reference-meal-fed conditions (solid-liquid meal), and infant-formula-fed conditions (homogeneous liquid). Successful predictions were achieved when employing the refined model for fasted or by applying appropriate fed conditions for different age groups, i.e., infant formula for infants and reference meal for children. The present study suggested that ibuprofen performance was primarily guided by gastric emptying events and showed sensitivity towards formulation characteristics and pH changes in the small intestine. Better understanding of luminal conditions’ changes in paediatrics and age-dependent ibuprofen post-absorptive processes could improve modeling confidence for ibuprofen, as well as other drugs with similar properties

    THE IMPACT OF FOOD INTAKE ON THE LUMINAL ENVIRONMENT AND PERFORMANCE OF ORAL DRUG PRODUCTS WITH A VIEW TO IN VITRO AND IN SILICO SIMULATIONS: A PEARRL REVIEW

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    Objective: Using the type of meal and dosing conditions suggested by regulatory agencies as a basis, this review has two specific objectives. First, to summarize our understanding on the impact of food intake on luminal environment and drug product performance. Second, to summarize the usefulness and limitations of available in vitro and in silico methodologies for the evaluation of drug products performance after food intake. Key findings: Characterization of the luminal environment and studies evaluating product performance in the lumen, under conditions suggested by regulatory agencies for simulating the fed state, are limited. Various in vitro methodologies have been proposed for evaluating drug product performance in the fed state but systematic validation is lacking. Physiologically based pharmacokinetic (PBPK) modelling approaches require the use of in vitro biorelevant data and, to date, have been used primarily for investigating the mechanisms via which an already observed food effect is mediated. Conclusion: Better understanding of the impact of changes induced by the meal administration conditions suggested by regulatory agencies on the luminal fate of the drug product is needed. Relevant information will be useful for optimizing the in vitro test methods, and increasing the usefulness of PBPK modelling methodologies
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