A single-dose, randomized crossover study in healthy Chinese subjects to evaluate pharmacokinetics and bioequivalence of two capsules of calcium dobesilate 0.5 g under fasting and fed conditions.

OBJECTIVES: To compare the rate and extent of absorption of a launched generic calcium dobesilate capsule versus the branded reference formulation under fasting and fed conditions in healthy Chinese subjects, and to assess their bioequivalence and tolerability. METHODS: This single-dose, open-label, randomized-sequence, 2-period crossover bioequivalence study was conducted on healthy Chinese volunteers aged 18 to 45 years. Subjects received a single 0.5 g dose of calcium dobesilate capsule under fasting or fed conditions, with a 3-day washout period between doses of the test (T) and reference (R) formulations. Blood samples were collected before and up to 24 hours after administration. The plasma concentration of calcium dobesilate was determined by a validated Liquid chromatography-tandem mass spectrometry method. Non-compartmental analysis was applied to identify the pharmacokinetic (PK) properties. The primary PK parameters including the maximal plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC0-t), and the AUC extrapolated to infinity (AUC0-inf) were used for bioequivalence evaluation. RESULTS: The mean of PK parameters for T and R capsules under fasting (fed) condition were: Cmax, 13.57 (6.71) and 12.59 (7.25) µg/mL; AUC0-t, 97.32 (79.74) and 96.97 (80.71) h*µg/mL; AUC0-inf, 101.68 (88.01) and 101.64 (87.81) h*µg/mL. The 90% confidence intervals (CIs) of GMRs under fasting (fed) condition were: Cmax, 97.91%-116.62% (88.63%-96.53%); AUC0-t, 97.15%-104.00% (96.58%-101.39%); and AUC0-inf, 97.19%-102.89% (98.67%-103.99%). These 90% CIs were all within the bioequivalence range of 80%-125%. All adverse events were mild. CONCLUSION: In this study, the T calcium dobesilate 0.5 g capsule was bioequivalent to the reference product under both fasting and fed conditions. Taking food would slow down its rate and reduce its amount of absorption. Both formulations were generally well tolerated.

The gut microbiota can be a potential regulator and treatment target of bone metastasis.

The gut microbiota, an often forgotten organ, have a tremendous impact on human health. It has long been known that the gut microbiota are implicated in cancer development, and more recently, the gut microbiota have been shown to influence cancer metastasis to distant organs. Although one of the most common sites of distant metastasis is the bone, and the skeletal system has been shown to be a subject of interactions with the gut microbiota to regulate bone homeostasis, little research has been done regarding how the gut microbiota control the development of bone metastasis. This review will discuss the mechanisms through which the gut microbiota and derived microbial compounds (i) regulate gastrointestinal cancer disease progression and metastasis, (ii) influence skeletal remodeling and potentially modulate bone metastasis, and (iii) affect and potentially enhance immunotherapeutic treatments for bone metastasis.

Review of paediatric gastrointestinal physiology relevant to the absorption of orally administered medicines.

Despite much progress in regulations to improve paediatric drug development, there remains a significant need to develop better medications for children. For the design of oral dosage forms, a detailed understanding of the specific gastrointestinal (GI) conditions in children of different age categories and how they differ from GI conditions in adults is essential. Several review articles have been published addressing the ontogeny of GI characteristics, including luminal conditions in the GI tract of children. However, the data reported in most of these reviews are of limited quality because (1) information was cited from very old publications and sometimes low quality sources, (2) data gaps in the original data were filled with textbook knowledge, (3) data obtained on healthy and sick children were mixed, (4) average data obtained on groups of patients were mixed with data obtained on individual patients, and (5) results obtained using investigative techniques that may have altered the outcome of the respective studies were considered. Consequently, many of these reviews draw conclusions that may be incorrect. The aim of the present review was to provide a comprehensive and updated overview of the available original data on the ontogeny of GI luminal conditions relevant to oral drug absorption in the paediatric population. To this end, the PubMed and Web of Science metadatabases were searched for appropriate studies that examined age-related conditions in the oral cavity, esophagus, stomach, small intestine, and colon. Maturation was observed for several GI parameters, and corresponding data sets were identified for each paediatric age group. However, it also became clear that the ontogeny of several GI traits in the paediatric population is not yet known. The review article provides a robust and valuable data set for the development of paediatric in vitro and in silico biopharmaceutical tools to support the development of age-appropriate dosage forms. In addition, it provides important information on existing data gaps and should provide impetus for further systematic and well-designed in vivo studies on GI physiology in children of specific age groups in order to close existing knowledge gaps and to sustainably improve oral drug therapy in children.

Integration of advanced methods and models to study drug absorption and related processes: An UNGAP perspective.

This collection of contributions from the European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP) community assembly aims to provide information on some of the current and newer methods employed to study the behaviour of medicines. It is the product of interactions in the immediate pre-Covid period when UNGAP members were able to meet and set up workshops and to discuss progress across the disciplines. UNGAP activities are divided into work packages that cover special treatment populations, absorption processes in different regions of the gut, the development of advanced formulations and the integration of food and pharmaceutical scientists in the food-drug interface. This involves both new and established technical approaches in which we have attempted to define best practice and highlight areas where further research is needed. Over the last months we have been able to reflect on some of the key innovative approaches which we were tasked with mapping, including theoretical, in silico, in vitro, in vivo and ex vivo, preclinical and clinical approaches. This is the product of some of us in a snapshot of where UNGAP has travelled and what aspects of innovative technologies are important. It is not a comprehensive review of all methods used in research to study drug dissolution and absorption, but provides an ample panorama of current and advanced methods generally and potentially useful in this area. This collection starts from a consideration of advances in a priori approaches: an understanding of the molecular properties of the compound to predict biological characteristics relevant to absorption. The next four sections discuss a major activity in the UNGAP initiative, the pursuit of more representative conditions to study lumenal dissolution of drug formulations developed independently by academic teams. They are important because they illustrate examples of in vitro simulation systems that have begun to provide a useful understanding of formulation behaviour in the upper GI tract for industry. The Leuven team highlights the importance of the physiology of the digestive tract, as they describe the relevance of gastric and intestinal fluids on the behaviour of drugs along the tract. This provides the introduction to microdosing as an early tool to study drug disposition. Microdosing in oncology is starting to use gamma-emitting tracers, which provides a link through SPECT to the next section on nuclear medicine. The last two papers link the modelling approaches used by the pharmaceutical industry, in silico to Pop-PK linking to Darwich and Aarons, who provide discussion on pharmacometric modelling, completing the loop of molecule to man.

Effect of Dairy Matrix on the Postprandial Blood Metabolome.

This study investigated the postprandial plasma metabolome following consumption of four dairy matrices different in texture and structure: cheddar cheese (Cheese), homogenized cheddar cheese (Hom. Cheese), and micellar casein isolate (MCI) with cream (MCI Drink) or a MCI Gel. An acute, randomized, crossover trial in male participants (n = 25) with four test days was conducted. Blood samples were collected during an 8-h postprandial period after consumption of a meal similar in micro- and macronutrients containing one of the four dairy matrices, and the metabolome was analyzed using nuclear magnetic resonance (NMR) spectroscopy. A liquid dairy matrix (MCI Drink) resulted in a faster absorption of amino acids compared to products, representing either a semi-solid (MCI Gel and Hom. Cheese) or solid (Cheese) dairy matrix. For the MCI Gel, plasma concentration of acetic acid and formic acid increased approximately 2 h following consumption, while 3-hydroxybyturate and acetoacetic acid increased approximately 6 h after consumption. The structure and texture of the dairy matrix affected the postprandial absorption of amino acids, as revealed by the plasma metabolome. Our study furthermore pointed at endogenous effects associated with consumption of dairy products containing glucono-δ-lactone.

Oral Iron Absorption Test: A Simple Test with Relevance in the Clinical Setting.

BACKGROUND: Iron deficiency anemia is a widespread problem. Although oral and intravenous therapy are available, iron malabsorption is a distinct possibility. OBJECTIVES: To evaluate the applicability of the oral iron absorption test (OIAT) as a simple and effective means of determining the degree of oral iron absorption. METHODS: The study comprised 81 patients diagnosed with iron deficiency anemia who were referred to a hematology outpatient clinic. Participants were given two ferrous sulphate tablets. Iron levels in the blood were evaluated at intervals from 30 to 180 minutes after iron administration. RESULTS: We divided patients into three distinct groups. The first group consisted of patients with little iron absorption with a maximum iron increment (Cmax) in the blood of 0-49 ug/dl. The second group had a moderate maximum absorption of 50-100 ug/dl, while a third group had considerable absorption of with maximum iron increase of over 100 ug/dl. CONCLUSIONS: The oral iron absorption test, although not clearly standardized, is easy to conduct in any outpatient clinic. This test can readily and clearly determine absorption or nonabsorption of iron. This test can have major implications on the need of oral or intravenous iron therapy and can also determine the need for further gastrointestinal evaluation of the small intestine, where iron absorption takes place and the success of therapy on subsequent iron absorption.

Evaluating pediatric and adult simulated fluids solubility: Abraham solvation parameters and multivariate analysis.

PURPOSE: To understand drug solubilization as a function of age and identify drugs at risk of altered drug solubility in pediatric patients. To assess the discrimination ability of the Abraham solvation parameters and age-related changes in simulated media composition to predict in vitro drug solubility differences between pediatric and adult gastrointestinal conditions by multivariate data analysis. METHODS: Differences between drug solubility in pediatric and adult biorelevant media were expressed as a % pediatric-to-adult ratio [Sp/Sa (%)]. Solubility ratios of fourteen poorly water-soluble drugs (2 amphoteric; 4 weak acids; 4 weak bases; 4 neutral compounds) were used in the analysis. Partial Least Squares Regression was based on Abraham solvation parameters and age-related changes in simulated gastrointestinal fluids, as well as their interactions, to predict the pediatric-to-adult solubility ratio. RESULTS: The use of Abraham solvation parameters was useful as a theory-informed set of molecular predictors of drug solubility changes between pediatric and adult simulated gastrointestinal fluids. Our findings suggest that the molecular solvation environment in the fasted gastric state was similar in the pediatric age-groups studied, which led to fewer differences in the pediatric-to-adult solubility ratio. In the intestinal fasted and fed state, there was a high relative contribution of the physiologically relevant surfactants to the alteration of drug solubility in the pediatric simulated conditions compared to the adult ones, which confirms the importance of an age-appropriate composition in biorelevant media. CONCLUSION: Statistical models based on Abraham solvation parameters were applied mostly to better understand drug solubility differences in adult and pediatric biorelevant media.

Physiological properties, composition and structural profiling of porcine gastrointestinal mucus.

The gastrointestinal mucus is a hydrogel that lines the luminal side of the gastrointestinal epithelium, offering barrier protection from pathogens and lubrication of the intraluminal contents. These barrier properties likewise affect nutrients and drugs that need to penetrate the mucus to reach the epithelium prior to absorption. In order to assess the potential impact of the mucus on drug absorption, we need information about the nature of the gastrointestinal mucus. Today, most of the relevant available literature is mainly derived from rodent studies. In this work, we used a larger animal species, the pig model, to characterize the mucus throughout the length of the gastrointestinal tract. This is the first report of the physiological properties (physical appearance, pH and water content), composition (protein, lipid and metabolite content) and structural profiling (rheology and gel network) of the porcine gastrointestinal mucus. These findings allow for direct comparisons between the characteristics of mucus from various segments and can be further utilized to improve our understanding of the role of the mucus on region dependent drug absorption. Additionally, the present work is expected to contribute to the assessment of the porcine model as a preclinical species in the drug development process.

Lactobacillus johnsonii BS15 combined with abdominal massage on intestinal permeability in rats with nonalcoholic fatty liver and cell biofilm repair.

This study aimed to analyze the effect of lactobacillus johnsonii BS15 (isolation of homemade yogurt from Ahu Hongyuan Grassland) combined with abdominal massage on intestinal permeability in rats with nonalcoholic fatty liver disease (NAFLD) and cell biofilm repair. Forty-five rats were divided randomly into five groups, four of which were fed with high-fat diet to establish NAFLD models. According to the treatment methods, they were grouped into group A (lactic acid bacteria feeding), group B (abdominal massage), group A + B (a combination of the two methods), model group (distilled water feeding), and normal group (distilled water feeding). Then, the pathological indexes of liver and intestinal permeability were observed. FITC-Dextran content of the model group elevated markedly compared with normal group (P < 0.01), indicating that the intestinal permeability of NAFLD rats fed with high-fat diet increased. The intestinal permeability of groups A, B, and A + B was lower sharply than that of model group (P < 0.01), and the effect of group A + B was the most obvious. HE staining of liver tissues showed that combined treatment could improve structural changes in liver cells caused by modeling and restore the normal structure of intestinal cells. Lactobacillus combined with abdominal massage was better than two treatments alone, further promoting the permeability of intestinal mucosa in NAFLD rats and repair biofilm of hepatocytes. The results initially verified the intervention effect of abdominal massage on intestinal mucosal permeability, and further revealed the mechanism of abdominal massage in treatment of NAFLD by improving intestinal mucosal barrier permeability.

What are the digestion and absorption models used to reproduce gastrointestinal protein processes?: A protocol for systematic review.

BACKGROUND: Animal, cell, and in vitro studies have been applied to simulate the human gastrointestinal tract (GIT) and evaluate the behavior of biomolecules. Understanding the peptides and/or proteins stability when exposed to these physiological conditions of the GIT can assist in the application of these molecules in the treatment of diseases such as obesity. This study describes a protocol of systematic reviews to analyze the methodologies that mimic the digestive and absorptive processes of peptides and/or proteins. METHODS: The protocol follows the guidelines described by Preferred Reporting Items for Systematic Reviews and Meta-Analyzes Protocols (PRISMA-P). The search strategies will be applied in the electronic databases PubMed, ScienceDirect, Scopus, Web of Science, Evidence portal, Virtual Health Library, and EMBASE. The intervention group will be formed by in vivo, in cells, and in vitro (gastrointestinal simulating fluids) studies of digestion and absorption of peptides and/or proteins presenting a schedule, duration, frequency, dosages administered, concentration, and temperature, and the control group consisting in studies without peptides and/or proteins. The selection of studies, data extraction, and assessment of the risk of bias will be carried out independently by 2 reviewers. For animal studies, the risk of bias will be assessed by the instrument of the Systematic Review Center for Experimentation with Laboratory Animals (SYRCLE) and the Office of Health Assessment and Translation (OHAT) tool will be used to assess the risk of bias in cell studies. RESULTS: This protocol contemplates the development of 2 systematic reviews and will assist the scientific community in identifying methods related to the digestive and absorptive processes of peptides and/or proteins. CONCLUSION: Both systematic reviews resulting from this protocol will provide subsidies for the construction of research related to the clinical application of bioactive peptides and/or proteins. In this context, they will make it possible to understand the gastrointestinal processes during administering these molecules, as the gastrointestinal environment can affect its functionality. Therefore, validating the effectiveness of these protocols is important, as it mimics in vitro biological conditions, reducing the use of animals, being consistent with the reduction, refine and replace program.

Effect of Elevated pH on the Commercial Enteric-Coated Omeprazole Pellets Resistance: Patent Review and Multisource Generics Comparison.

Omeprazole is a widely used over-the-counter (20 mg) proton pump inhibitor, usually supplied as oral enteric-coated pellets intended to release at pH 5.5 and higher; however, it is sensitive to acidic pH. The likelihood of elevated gastric pH in practice is very high for patients; thus, the aim of this study was to investigate the effect of elevated pH on the performance of commercial omeprazole pellets. Commercial enteric-coated delayed-release pellets were tested with water uptake-weight loss (WU-WL) test at pH range between 1.2 and 4.5 in addition to "gastric" (pH 1.2 or 4.5) and "intestinal" (pH 7.4) phase dissolution tests. The range of physical characteristics of pellets was determined with a single pellet size and sedimentation time measurement, followed by the application of modified Stokes' Law equation. The coefficient of variation of pellet size and density, and volume-density determination coefficient (R2) as descriptors of coating thickness and microstructure variability, degree of ionisation of enteric polymers, aqueous solubility and molecular weight of plasticisers have been found useful to explain commercial delayed-release pellets behaviour during WU-WL and dissolution test. Investigated commercial delayed-release pellets demonstrated pH-dependent WU-WL results. "Gastric phase" dissolution testing of pellets at pH 4.5 showed the highest omeprazole degradation (48.1%) for Nosch Labs, intermediate values of dose loss (23.4% and 17.1%) for Teva and UQUIFA delayed-release pellets, respectively. Lab Liconsa pellets have been found as the least susceptible (3.2% of dose loss). Additionally, "gastric phase" dissolution test at pH 4.5 significantly influenced omeprazole release during the "intestinal phase". The risk of inadequate therapy associated with intake of investigated enteric-coated delayed-release pellets at elevated gastric pH has been found as minimal for Lab Liconsa and has increased from UQUIFA and Teva to Nosh Labs pellets.

Process Optimization for the Continuous Production of a Gastroretentive Dosage Form Based on Melt Foaming.

Several drugs have poor oral bioavailability due to low or incomplete absorption which is affected by various effects as pH, motility of GI, and enzyme activity. The gastroretentive drug delivery systems are able to deal with these problems by prolonging the gastric residence time, while increasing the therapeutic efficacy of drugs. Previously, we developed a novel technology to foam hot and molten dispersions on atmospheric pressure by a batch-type in-house apparatus. Our aim was to upgrade this technology by a new continuous lab-scale apparatus and confirm that our formulations are gastroretentive. At first, we designed and built the apparatus and continuous production was optimized using a Box-Behnken experimental design. Then, we formulated barium sulfate-loaded samples with the optimal production parameters, which was suitable for in vivo imaging analysis. In vitro study proved the low density, namely 507 mg/cm3, and the microCT record showed high porosity with 40 µm average size of bubbles in the molten suspension. The BaSO4-loaded samples showed hard structure at room temperature and during the wetting test, the complete wetting was detected after 120 min. During the in vivo study, the X-ray taken showed the retention of the formulation in the rat stomach after 2 h. We can conclude that with our device low-density floating formulations were prepared with prolonged gastric residence time. This study provides a promising platform for marketed active ingredients with low bioavailability.

In Vitro Analysis of N-Nitrosodimethylamine (NDMA) Formation From Ranitidine Under Simulated Gastrointestinal Conditions.

Importance: A publication reported that N-nitrosodimethylamine (NDMA), a probable human carcinogen, was formed when ranitidine and nitrite were added to simulated gastric fluid. However, the nitrite concentrations used were greater than the range detected in acidic gastric fluid in prior clinical studies. Objective: To characterize NDMA formation following the addition of ranitidine to simulated gastric fluid using combinations of fluid volume, pH levels, and nitrite concentrations, including physiologic levels. Design, Setting, and Participants: One 150-mg ranitidine tablet was added to 50 or 250 mL of simulated gastric fluid with a range of nitrite concentrations from the upper range of physiologic (100 µmol/L) to higher concentrations (10 000 µmol/L) with a range of pH levels. NDMA amounts were assessed with a liquid chromatography-mass spectrometry method. Main Outcomes and Measures: NDMA detected in simulated gastric fluid 2 hours after adding ranitidine. Results: At a supraphysiologic nitrite concentration (ie, 10 000 µmol/L), the mean (SD) amount of NDMA detected in 50 mL simulated gastric fluid 2 hours after adding ranitidine increased from 222 (12) ng at pH 5 to 11 822 (434) ng at pH 1.2. Subsequent experiments with 50 mL of simulated gastric fluid at pH 1.2 with no added nitrite detected a mean (SD) of 22 (2) ng of NDMA, which is the background amount present in the ranitidine tablets. Similarly, at the upper range of physiologic nitrite (ie, 100 µmol/L) or at nitrite concentrations as much as 50-fold greater (1000 or 5000 µmol/L) only background mean (SD) amounts of NDMA were observed (21 [3] ng, 24 [2] ng, or 24 [3] ng, respectively). With 250 mL of simulated gastric fluid, no NDMA was detected at the upper physiologic range (100 µmol/L) or 10-fold physiologic (1000 µmol/L) nitrite concentrations, while NDMA was detected (mean [SD] level, 7353 [183] ng) at a 50-fold physiologic nitrite concentration (5000 µmol/L). Conclusions and Relevance: In this in vitro study of ranitidine tablets added to simulated gastric fluid with different nitrite concentrations, ranitidine conversion to NDMA was not detected until nitrite was 5000 µmol/L, which is 50-fold greater than the upper range of physiologic gastric nitrite concentrations at acidic pH. These findings suggest that ranitidine is not converted to NDMA in gastric fluid at physiologic conditions.

Lipophilic Salts and Lipid-Based Formulations: Enhancing the Oral Delivery of Octreotide.

PURPOSE: Successful oral peptide delivery faces two major hurdles: low enzymatic stability in the gastro-intestinal lumen and poor intestinal membrane permeability. While lipid-based formulations (LBF) have the potential to overcome these barriers, effective formulation of peptides remains challenging. Lipophilic salt (LS) technology can increase the apparent lipophilicity of peptides, making them more suitable for LBF. METHODS: As a model therapeutic peptide, octreotide (OCT) was converted to the docusate LS (OCT.DoS2), and compared to the commercial acetate salt (OCT.OAc2) in oral absorption studies and related in vitro studies, including parallel artificial membrane permeability assay (PAMPA), Caco-2, in situ intestine perfusion, and simulated digestion in vitro models. The in vivo oral absorption of OCT.DoS2 and OCT.OAc2 formulated in self-emulsifying drug delivery systems (SEDDS) was studied in rats. RESULTS: LS formulation improved the solubility and loading of OCT in LBF excipients and OCT.DoS2 in combination with SEDDS showed higher OCT absorption than the acetate comparator in the in vivo studies in rats. The Caco-2 and in situ intestine perfusion models indicated no increases in permeability for OCT.DoS2. However, the in vitro digestion studies showed reduced enzymatic degradation of OCT.DoS2 when formulated in the SEDDS formulations. Further in vitro dissociation and release studies suggest that the enhanced bioavailability of OCT from SEDDS-incorporating OCT.DoS2 is likely a result of higher partitioning into and prolonged retention within lipid colloid structures. CONCLUSION: The combination of LS and LBF enhanced the in vivo oral absorption of OCT primarily via the protective effect of LBF sheltering the peptide from gastrointestinal degradation.

Evaluating Solubility of Celecoxib in Age-Appropriate Fasted- and Fed-State Gastric and Intestinal Biorelevant Media Representative of Adult and Pediatric Patients: Implications on Future Pediatric Biopharmaceutical Classification System.

Prediction of performance of traditional, reformulated, and novel oral formulations in adults and pediatrics is of great importance. This study was conducted to assess solubility of celecoxib in age-appropriate fasted- and fed-state gastric and intestinal biorelevant media, classify celecoxib into biopharmaceutical classification system (BCS), and assess the effects of age-related developmental changes in the composition and volume of gastrointestinal fluids on the solubility and performance of oral formulations containing celecoxib. Solubility of celecoxib was assessed at 37°C in the pH range specified by the BCS-based criteria in 13 age-appropriate biorelevant media reflective of the gastric and proximal small intestinal environment in both fasted and fed states in adults and different pediatric subpopulations. A validated HPLC-UV method was used to quantify celecoxib. Experimental and computational molecular descriptors and in vivo pharmacokinetic data were used to assign the permeability class of celecoxib. Celecoxib belonged to BCS class 2. The pediatric to adult solubility ratios were outside the 80-125% boundaries in 3 and borderline in 1 biorelevant media. Significant age-related variability could be predicted for oral formulations containing celecoxib intended for pediatric use. Findings of this study indicated that the criteria used in the adult BCS might not be directly applied to pediatric subpopulations.

In Vitro Sensitivity Analysis of the Gastrointestinal Dissolution Profile of Weakly Basic Drugs in the Stomach-to-Intestine Fluid Changing System: Explanation for Variable Plasma Exposure after Oral Administration.

An in vitro methodology for simulating the change in the pH and composition of gastrointestinal fluid associated with the transition of orally administered drugs from the stomach to the small intestine was developed (the stomach-to-intestine fluid changing system (the SIFC system)). This system was applied to in vitro sensitivity analysis on the dissolution of weakly basic drugs, and the obtained results were discussed in relation to the intrasubject variability in the plasma exposure in human bioequivalence (BE) study. Three types of protocols were employed (steep pH change: pH 1.6 FaSSGF → pH 6.5 FaSSIF, gradual pH change: pH 1.6 FaSSGF → pH 6.5 FaSSIF, and high gastric pH: pH 4.0 FaSSGF → pH 6.5 FaSSIF). Regardless of the protocols and the forms of drug applied in active pharmaceutical ingredient powder or formulation, dissolution profiles of pioglitazone after fluid shift were similar and the final concentrations in FaSSIF were approximately equal to the saturation solubility in FaSSIF, supporting its small intrasubject variance in human BE study. In contrast, dissolved concentration of terbinafine in the SIFC system became less than half in the high gastric pH protocol than that in other protocols, suggesting the fluctuation of gastric pH as one of the factors of high intrasubject variance of terbinafine in human. Plasma exposure of telmisartan was highly variable especially at the high dose. Although the dissolution of telmisartan in the SIFC system was greatly improved by formulation, it considerably fluctuated during fluid shift especially at the high dose, which corresponds well to in vivo results.

Biopharmaceutics Applications of Physiologically Based Pharmacokinetic Absorption Modeling and Simulation in Regulatory Submissions to the U.S. Food and Drug Administration for New Drugs.

Physiologically based pharmacokinetic (PBPK) absorption modeling and simulation is increasingly used as a tool in drug product development, not only in support of clinical pharmacology applications (e.g., drug-drug interaction, dose selection) but also from quality perspective, enhancing drug product understanding. This report provides a summary of the status and the application of PBPK absorption modeling and simulation in new drug application (NDA) submissions to the U.S. Food and Drug Administration to support drug product quality (e.g., clinically relevant dissolution specifications, active pharmaceutical ingredient (API) particle size distribution specifications). During the 10 years from 2008 to 2018, a total of 24 NDA submissions included the use of PBPK absorption modeling and simulations for biopharmaceutics-related assessment. In these submissions, PBPK absorption modeling and simulation served as an impactful tool in establishing the relationship of critical quality attributes (CQAs) including formulation variables, specifically in vitro dissolution, to the in vivo performance. This article also summarizes common practices in PBPK approaches and proposes future directions for the use of PBPK absorption modeling and simulation in drug product quality assessment.Graphical abstract.

Lipid Composition, Digestion, and Absorption Differences among Neonatal Feeding Strategies: Potential Implications for Intestinal Inflammation in Preterm Infants.

Necrotizing enterocolitis (NEC) is a significant cause of morbidity and mortality in the neonatal population. Formula feeding is among the many risk factors for developing the condition, a practice often required in the cohort most often afflicted with NEC, preterm infants. While the virtues of many bioactive components of breast milk have been extolled, the ability to digest and assimilate the nutritional components of breast milk is often overlooked. The structure of formula differs from that of breast milk, both in lipid composition and chemical configuration. In addition, formula lacks a critical digestive enzyme produced by the mammary gland, bile salt-stimulated lipase (BSSL). The gastrointestinal system of premature infants is often incapable of secreting sufficient pancreatic enzymes for fat digestion, and pasteurization of donor milk (DM) has been shown to inactivate BSSL, among other important compounds. Incompletely digested lipids may oxidize and accumulate in the distal gut. These lipid fragments are thought to induce intestinal inflammation in the neonate, potentially hastening the development of diseases such as NEC. In this review, differences in breast milk, pasteurized DM, and formula lipids are highlighted, with a focus on the ability of those lipids to be digested and subsequently absorbed by neonates, especially those born prematurely and at risk for NEC.

The Edible Brown Seaweed Sargassum horneri (Turner) C. Agardh Ameliorates High-Fat Diet-Induced Obesity, Diabetes, and Hepatic Steatosis in Mice.

Sargassum horneri (Turner) C. Agardh (S. horneri) is edible brown seaweed that grows along the coast of East Asia and has been traditionally used as a folk medicine and a local food. In this study, we evaluated the effects of S. horneri on the development of obesity and related metabolic disorders in C57BL/6J mice fed a high-fat diet. S. horneri was freeze-dried, fine-powdered, and mixed with a high-fat diet at a weight ratio of 2% or 6%. Feeding a high-fat diet to mice for 13 weeks induced obesity, diabetes, hepatic steatosis, and hypercholesterolemia. Supplementation of mice with S. horneri suppressed high-fat diet-induced body weight gain and the accumulation of fat in adipose tissue and liver, and the elevation of the serum glucose level. In addition, S. horneri improved insulin resistance. An analysis of the feces showed that S. horneri stimulated the fecal excretion of triglyceride, as well as increased the fecal polysaccharide content. Furthermore, extracts of S. horneri inhibited the activity of pancreatic lipase in vitro. These results showed that S. horneri can ameliorate diet-induced metabolic diseases, and the effect may be partly associated with the suppression of intestinal fat absorption.

Lipidome is lipids regulator in gastrointestinal tract and it is a life collar in COVID-19: A review.

The term lipidome is mentioned to the total amount of the lipids inside the biological cells. The lipid enters the human gastrointestinal tract through external source and internal source. The absorption pathway of lipids in the gastrointestinal tract has many ways; the 1st way, the lipid molecules are digested in the lumen before go through the enterocytes, digested products are re-esterified into complex lipid molecules. The 2nd way, the intracellular lipids are accumulated into lipoproteins (chylomicrons) which transport lipids throughout the whole body. The lipids are re-synthesis again inside the human body where the gastrointestinal lipids are: (1) Transferred into the endoplasmic reticulum; (2) Collected as lipoproteins such as chylomicrons; or (3) Stored as lipid droplets in the cytosol. The lipids play an important role in many stages of the viral replication cycle. The specific lipid change occurs during viral infection in advanced viral replication cycle. There are 47 lipids within 11 lipid classes were significantly disturbed after viral infection. The virus connects with blood-borne lipoproteins and apolipoprotein E to change viral infectivity. The viral interest is cholesterol- and lipid raft-dependent molecules. In conclusion, lipidome is important in gastrointestinal fat absorption and coronavirus disease 2019 (COVID-19) infection so lipidome is basic in gut metabolism and in COVID-19 infection success.