Intestinal Permeability Studies Research Articles

Application of Box-Behnken Design for Formulation Optimization of Sorafenib loaded Nanoparticles Targeting to Liver Carcinoma: Ex-vivo Intestinal Permeation and Cytotoxicity Study.

The anticancer drug sorafenib (SFB) was formulated as a polymeric nanoparticle using Box-Behnken design. The solvent evaporation method was utilized to develop the sorafenib polymeric nanoparticles. Formulations were then evaluated in terms of their morphological structure, entrapment efficiency (EE%), zeta potential, polydispersity index (PDI), and particle size. Ex-vivo intestinal permeation studies for pure drugs, as well as optimized formulation, were performed in rats. Furthermore, the anticancer activity was evaluated using the HepG2 cancer cell lines. Transmission electron microscopy (TEM) revealed that the improved formulation had a particle size of 175 nm, PDI of 0.134, zeta-potential of -23.8 mV, and the sorafenib-loaded PLGA NP were recognized as spherical particles. Over 90% of the drug was released in less than 24 hours, with an EE% of 85.1%. Sorafenib-loaded PLGA NP efficiently inhibited HepG2 cells.

Enhancing Oral Bioavailability of Domperidone Maleate: Formulation, In vitro Permeability Evaluation In-caco-2 Cell Monolayers and In situ Rat Intestinal Permeability Studies.

The domperidone maleate, a lipophilic agent classified as a Biopharmaceutical Classification System Class II substance with weak water solubility. Self- Emulsifying Drug Delivery System is a novel approach to improve water solubility and, ultimately bioavailability of drugs. This study aimed to develop and characterize new domperidone-loaded self-emulsifying drug delivery systems as an alternative formulation and to evaluate the permeability of domperidone-loaded self-emulsifying drug delivery systems by using Caco-2 cells and via single-pass intestinal perfusion method. Three self-emulsifying drug delivery systems were prepared and characterized in terms of pH, viscosity, droplet size, zeta potential, polydispersity index, conductivity, etc. Each formulation underwent 10, 100, 200, and 500 times dilution in intestinal buffer pH 6.8 and stomach buffer pH 1.2, respectively. Female Sprague Dawley rats were employed for in situ single-pass intestinal perfusion investigations. Results of the study revealed that the ideal self-emulsifying drug delivery systems formulation showed narrow droplet size, ideal zeta potential, and no conductivity. Additionally, as compared to the control groups, the optimum formulation had better apparent permeability (12.74 ± 0.02×10-4) from Caco-2 cell monolayer permeability experiments. The study also revealed greater Peff values (2.122 ± 0.892×10-4 cm/s) for the optimal formulation from in situ intestinal perfusion analyses in comparison to control groups (Domperidone; 0.802 ± 0.418×10-4 cm/s). To conclude, prepared formulations can be a promising way of oral administration of Biopharmaceutical Classification System Class II drugs.

Exploration of Abiraterone acetate loaded Nanostructured lipid carriers for bioavailability improvement and circumvention of fast-fed variability.

Abiraterone acetate (ABA), a biopharmaceutical class IV drug suffers from solubility and permeability pitfalls resulting in limited oral bioavailability and positive food effect, i.e. multi-fold enhancement in drug absorption in the presence of food. This poses difficulties to physicians towards the estimation of dose and dosage regimen required for efficacious therapy of prostate cancer (PCa). Nanostructured lipid carriers (NLC) have demonstrated tremendous outcomes in enhancing the oral bioavailability of various entities along with food effect attenuation. In this study, Quality by design and multivariate analysis was employed for optimization of ABA loaded NLC (ABA NLC). The optimal size, PDI and zeta potential obtained using QbD were 134.6nm, 0.163 and -15.7mV respectively. Ex vivo qualitative and quantitative intestinal permeability studies demonstrated improved traversion of NLC through the intestinal segments. In vitro dissolution profile in biorelevant fast and fed gastric and intestinal media revealed minimal differences for ABA NLC compared to ABA. In vivo pharmacokinetics was performed to decipher the efficacy of ABA NLC in mitigating the food effect of ABA. The studies demonstrated 14.51-fold and 1.94-fold improvement in oral bioavailability during fasted and fed state respectively as compared to free ABA. The absorption mechanism of ABA NLC using chylomicron flow blocking approach conveyed lymphatic uptake as the major mechanism. Cmax fast/fed ratio was 0.9758 whereas, AUC fast/fed ratio was 0.9386, which being nearly equivalent, confirmed the food effect attenuation. Therefore, the results of the study demonstrate optimal pharmacokinetics of ABA NLC and its utility in circumventing the fast fed variability.

Enhancing lymphatic uptake of Darunavir Ethanolate through TPGS-enriched lipid nanocarriers for oral delivery

Darunavir ethanolate (DRVE) is a promising molecule against wild-type protease inhibitors in human immunodeficiency virus (HIV) infection. It has a 37% oral bioavailability. In this study, the d-alpha-Tocopheryl Polyethylene Glycol 1000 Succinate (TPGS)-decorated DRVE-loaded lipid nanocarriers (DRVE-TPGS-LNCs) were optimized via central composite rotatable design using a modified solvent emulsification method. Various characteristic features of DRVE-TPGS-LNCs, such as globule size, polydispersity index, zeta potential, % entrapment efficiency, and % drug loading, were determined and found to be 116.5 ± 2.52 nm, 0.269 ± 0.0221, −10.8 ± 0.265 mV, 94.31% ± 10.75%, and 8.79% ± 0.937%, respectively. The spherical shape was evaluated by cryo-transmission electron microscopy. In-vitro study demonstrated % cumulative drug release of 81.70% ± 7.35% at pH 1.2 and 73.03% ± 7.17% at pH 6.8 after 12 h of drug release study. Moreover, the intestinal permeation and confocal microscope studies revealed approximately two-fold increased permeation in optimized nanoformulation across the gut sac compared to a drug suspension, and the inhibition of p-glycoprotein efflux was also confirmed by obtaining a minimum efflux ratio (0.253) of the optimized formulation compared to a drug suspension. The pharmacokinetic study demonstrated that the relative bioavailability of TPGS-DRVE-LNCs and drug suspension were found to be 19.85 ± 1.75 and 8.72 ± 0.753 μg.h/mL, respectively, which is approximately 2.25-fold more than the drug suspension which means approximately threefold increase in oral bioavailability compared to the drug suspension. The increased bioavailability in optimized DRVE-TPGS-LNCs was due to improved lymphatic uptake and p-glycoprotein efflux inhibition. Thus, the improved bioavailability of DRVE can meet the need to reduce the high dose of antiretroviral drugs to minimize the peripheral adverse reactions associated with the dose-related burden.

Sono-assembly of ellagic acid into nanostructures significantly enhances aqueous solubility and bioavailability

IntroductionEllagic acid (EA), commonly found in foods, offers significant health benefits in combating chronic diseases. However, its therapeutic potential is hindered by its extremely poor solubility and bioavailability. MethodIn this study, EA nanoparticles (EA NPs) were produced using a sono-assembly method, without additional agents. ResultsEA NPs exhibited stick-like nanoparticle structures with an average size of 147.3 ± 0.73 nm. EA NPs likely adopt a tunnel-type solvate structure, with 4 water participating in disruption of intramolecular hydrogen bonds in EA and establishment of intermolecular hydrogen bonds between EAs. Importantly, EA NPs exhibited remarkable enhancements in water solubility, with 120.7-fold increase in water, and 97.8-fold increase in pH 6.8 buffer. Moreover, ex vivo intestinal permeability studies demonstrated significant improvements (P < 0.5). These findings were further supported by in vivo pharmacokinetic studies, where EA NPs significantly enhanced the relative bioavailability of EA by 4.69 times.

Fabrication of TPGS decorated Etravirine loaded lipidic nanocarriers as a neoteric oral bioavailability enhancer for lymphatic targeting

Etravirine (ERVN) is a potential NNRTI (non-nucleoside reverse transcriptase inhibitor) in treating HIV infection. It possesses extremely low oral bioavailability. The present research aims to optimize the formulation and characterization of TPGS-enriched ERVN-loaded lipid-based nanocarriers (NLCs) for HIV-infected patients. The formulation, ERVN–TPGS–NLCs, was optimized by central composite rotational design using a modified-solvent emulsification process. Various characterization parameters of NLCs were evaluated, including globule size of 121.56 ± 2.174 nm, PDI of 0.172 ± 0.042, the zeta potential of − 7.32 ± 0.021 mV, %EE of 94.42 ± 8.65% of ERVN and %DL was 8.94 ± 0.759% of ERVN and spherical shape was revealed by TEM. PXRD was also performed to identify the crystallinity of the sample. In-vitro drug release showed % a cumulative drug release of 83.72 ± 8.35% at pH 1.2 and 90.61 ± 9.11% at pH 6.8, respectively, whereas the % cumulative drug release from drug suspension (ERVN-S) was found to be 21.13 ± 2.01% at pH 1.2 and 24.84 ± 2.51 at pH 6.8 at the end of 48 h. Further, the intestinal permeation study and confocal microscope showed approximately three-fold and two-fold increased permeation in ERVN–TPGS–NLCs and ERVN-NLCs across the gut sac compared to ERVN-S. Hemolysis compatibility and lipolysis studies were performed to predict the in-vivo fate of the formulation. The pharmacokinetic study revealed a 3.13-fold increment in the relative bioavailability, which agrees with the ex-vivo studies, and lymphatic uptake was validated by using cycloheximide along with designed formulation, which showed the impact of lymphatic uptake in AUC. This study ensures that ERVN–TPGS–NLCs take lymphatic uptake to minimize the first-pass metabolism followed by improved oral bioavailability of ERVN. Thus, the enhanced bioavailability of ERVN can reduce the high dose of ERVN to minimize the adverse effects related to dose-related burden.Graphical abstract

A cross-sectional study of correlations among blood-based biomarkers for intestinal permeability: A pilot study of United States veterans with posttraumatic stress disorder symptoms

While many studies of intestinal permeability (IP) are focused on those with gastrointestinal (GI) disorders, there is a rising trend to analyze IP among individuals with mental health conditions including posttraumatic stress disorder (PTSD) with and without diagnosed GI conditions. This interest stems from the association between gut dysbiosis and chronic inflammation, which are mechanisms linked to stress-related somatic and mental health conditions. Efforts to date have resulted in the exploration of non-invasive and feasible measures to identify an IP biomarker that could also serve as a treatment target. Additionally, those conducting studies regarding IP often recruit individuals without health problems and compare levels of biomarkers of IP to those obtained from participants with conditions of interest. This study aimed to assess correlations between blood-based biomarkers of IP, as well as examine the association between blood-based biomarkers of IP and PTSD symptoms. Blood was sampled from seventeen United States military Veterans with variable severity of PTSD symptoms per the posttraumatic checklist for DSM-5 (PCL-5) (n = 6 with scores over 31 indicating clinically meaningful symptoms of PTSD; overall range 0–49, mean 20.8, standard deviation 15.7) and analyzed blood biomarkers of IP including citrulline, diamine oxidase, glucagon-like peptide-2, intestinal fatty-acid binding protein, lipopolysaccharide binding protein, lipopolysaccharide, and zonulin. Correlations between the IP blood-based biomarkers ranged from ρ of −0.31 to 0.35. None of the measured biomarkers were significantly correlated to PTSD symptom severity scores (ρ of −0.34 to 0.05). Although based on limited sample size, our results call into question the specificity of blood-based biomarkers of IP when: (1) studying persons with and without PTSD symptoms in whom clinical GI disorders are not necessarily the focus of the study; and (2) comparing IP results among individuals with well-defined disease states to those without the disease (e.g., controls). Further studies are needed to explore the role of external factors (e.g., nutrition, obesity, alcohol use) on IP and to determine if the biomarkers studied are appropriate for measuring IP in people with a range of symptoms related to PTSD.

Comparison of Ussing Chamber and Caco-2 Model in Evaluation of Intestinal Absorption Mechanism of Compounds from Different BCS Classifications.

Oral bioavailability (F), which is evaluated by permeability and solubility, is one of the key parameters in drug discovery. Currently, Caco-2 and Ussing chamber are both used in the study of intestinal permeability of drugs at different stages of drug development. However, comparative research between the Ussing chamber and Caco-2 for predicting the intestinal availability data (Fa×Fg) in humans has not been reported. In the present study, we evaluated the permeability of 22 drugs in rat intestines by Ussing chamber and compared them with the reported permeability data from Caco-2. In addition, the active transport of gabapentin was evaluated by Ussing Chamber. Intestine segments were selected by corresponding absorption site for Ussing chamber analysis. BCS Class I and II compounds were more absorbed in the duodenum and jejunum, and Class III and IV compounds were more absorbed in the ileum. Papp values in the Caco-2 model were moderately correlated with human Fa×Fg (R2=0.722), and the Papp of the rat in the Ussing chamber revealed a better correlation with human Fa×Fg (R2=0.952). In addition, we also used the Ussing chamber to identify the transporter of gabapentin, and the results showed that the active absorption of gabapentin was related to LAT1. Ussing chamber combined with rat intestinal tissue would be a significant tool for predicting the intestinal absorption and metabolism of compounds with diverse physiochemical characteristics.

Fecal and Circulating Biomarkers for the Non-Invasive Assessment of Intestinal Permeability.

The study of intestinal permeability is gaining growing interest due to its relevance in the onset and progression of several gastrointestinal and non-gastrointestinal diseases. Though the involvement of impaired intestinal permeability in the pathophysiology of such diseases is recognized, there is currently a need to identify non-invasive biomarkers or tools that are able to accurately detect alterations in intestinal barrier integrity. On the one hand, promising results have been reported for novel in vivo methods based on paracellular probes, i.e., methods that can directly assess paracellular permeability and, on the other hand, on fecal and circulating biomarkers able to indirectly assess epithelial barrier integrity and functionality. In this review, we aimed to summarize the current knowledge on the intestinal barrier and epithelial transport pathways and to provide an overview of the methods already available or currently under investigation for the measurement of intestinal permeability.

Oral Ionic Liquid for Transdermal Delivery and Obesity Treatment.

Obesity is currently a prerequisite for more than 70% of adults, including chronic obesity and long-term obesity. With the increase of diabetes patients in the world, it is urgent to develop effective oral drugs to replace insulin. However, the gastrointestinal tract is a main obstacle to oral drug preparations. Here, a highly effective oral drug was developed, mainly formulated as an ionic liquid (IL) prepared by l-(-)-carnitine and geranic acid. Density functional theory (DFT) calculations showed that l-(-)-carnitine and geranic acid can exist stably through hydrogen bonding. IL can significantly enhance the transdermal transport of drugs. In vitro study of intestinal permeability showed that particles formed by IL can prevent the absorption of intestinal fat. Compared with the control group, oral administration of IL (10 mL kg-1) significantly reduced blood glucose, white adipose tissue in the liver and epididymis, and the expression of SREBP-1c and ACC in IL. Therefore, these results and high-throughput sequencing analysis showed that IL can effectively reduce the intestinal absorption of adipose tissue to reduce blood glucose. IL has good biocompatibility and stability. Therefore, IL has a certain application value in the field of oral drug-delivery carriers, which provides an effective means for the treatment of diabetes and is a potential tool to solve the epidemic of obesity.

Assessment of the bioaccessibility and bioavailability prediction of omega 3 and conjugated fatty acids by in vitro standardized digestion model (INFOGEST) and cell model

Omega 3 EPA and DHA are polyunsaturated fatty acids with relevant health benefits. Conjugated linoleic and linolenic acids are known for their anti-carcinogenic effect, anti-inflammatory properties and body weight reduction. To achieve therapeutical doses, high amounts of these fatty acids’ food sources must be consumed. Thus, the intake of enriched oils with a high concentration of these fatty acids is often used. But several factors influence their bioavailability. Here, by using the INFOGEST static in vitro protocol of gastrointestinal tract digestion it was studied the bioaccessibility of these fatty acids in different matrixes: Pomegranate and Fish oil and omega 3, CLA and CLNA soft-gel enriched capsules. After digestion, the Recovery Index for the major bioactive PUFAs are very low: Pomegranate oil is 2%, Fish oil 11–13%, CLNA 17%, CLA 6% and Omega 3 capsules 3%. Higher initial concentrations of these PUFAs seem to be related to higher degrees of oxidation. In Pomegranate oil, CLNA and Omega 3 capsules, the digestion process negatively influenced the antioxidant potential. The opposite was verified for the Fish oil and CLA capsules. Importantly, bioaccessibility studies of similar matrixes are very scarce and intestinal permeability is absent in most of the studies. Intestinal permeability studies were performed using a Caco-2/HT29-MTX co-culture: there is significative incorporation of the bioactive fatty acids into the intestinal cells, which may affect their permeability performance. Interestingly, most fatty acids remain in the non-bioaccessible fraction which may be relevant when designing oral routes of administration and in gut microbiota modulation.

Impact of Composition and Morphology of Ketoconazole-Loaded Solid Lipid Nanoparticles on Intestinal Permeation and Gastroplus-Based Prediction Studies.

Ketoconazole (KTZ) is a potential oral antifungal agent to control systemic and local infections. This study addresses the impact of composition (tween 80 and compritol as CATO) and morphology on permeation (stomach, jejunum, and ileum) profiles of KTZ-loaded solid lipid nanoparticles (SLNs) in rats followed by in vivo pharmacokinetic prediction and simulation using GastroPlus. The selected formulations were characterized for size, size distribution, zeta potential, entrapment efficiency, total drug content, morphology, in vitro drug release, ex vivo permeation and drug deposition, penetration potential, and GastroPlus-based in vivo prediction in rats. The results showed that there was considerable impact of pH, composition (CATO and tween 80), size, total drug content, and entrapment efficiency on in vitro drug release and permeation across the stomach, jejunum, and ileum. Ex vivo findings suggested pH, composition, size, and permeability coefficient-dependent permeation of SLNs across the stomach, jejunum, and ileum. Confocal laser scanning microscopy (CLSM) confirmed a relatively high degree of penetration of the optimized formulation “K-SLN4” (66.1% across the stomach, 51.5% across the jejunum, and 47.9% across the ileum) as compared to KSUS (corresponding values of 21.7%, 18.2%, and 17.4%). Finally, GastroPlus predicted in vivo dissolution/absorption as 0.012 μg/mL of K-SLN4 as compared to KSUS (the drug suspension with 0.0058 μg/mL) and a total regional absorption of 80.0% by K-SLN4 as compared to 60.1% of KSUS. There was only an impact of dose on Cmax (maximum plasma concentration) and area under the curve (AUC) in rats. Thus, the present strategy could be a promising alternative to parenteral and topical delivery systems for long-term therapy against systemic and local mycoses with high patient compliance.

A different approach to immunochemotherapy for colon Cancer: Development of nanoplexes of cyclodextrins and Interleukin-2 loaded with 5-FU

Immune system deficiencies are crucial in the progression of cancer, predominantly because immune cells are not stimulated by cytokines to eradicate cancer cells. Immunochemotherapy is currently considered an innovative approach that creates pathways in cancer treatment, sometimes also aiding in the efficacy of chemotherapeutics. The aim of this study was to prepare a cyclodextrin (CD) nanoplex based on charge interaction to deliver the anticancer drug 5-fluorouracil (5-FU) and Interleukin-2 (IL-2), thereby forming a nanoscale drug delivery system aimed at chemo-immunotherapy for colorectal cancers. The CD:IL-2 nanoplexes were obtained with a particle size below 100 nm and a cationic surface charge based on the extent of charge interaction of the cationic CD polymer with negatively charged IL-2. The loading capacity of CD nanoplexes was 40% for 5-FU and 99.8% for IL-2. Nanoplexes maintained physical stability in terms of particle size and zeta potential in aqueous solution for 1 week at + 4 °C. Moreover, the structural integrity of IL-2 loaded into CD nanoplexes was confirmed by SDS-PAGE analysis. The cumulative release rates of both 5-FU and IL-2 were found to be more than 80% in simulated biological fluids in 12 h. Cell culture studies demonstrate that CD polymers are safe on healthy L929 mouse fibroblast cells. Drug-loaded CD nanoplexes were determined to have a higher anticancer effect than free drug solution against CT26 mouse colon carcinoma cells. In addition, intestinal permeability studies supported the conclusion that CD nanoplexes could be promising candidates for oral chemotherapy as well. In conclusion, effective cancer therapy utilizing the absorptive/cellular uptake effect of CDs, the synergic effect and co-transport of chemotherapeutic drugs and immunotherapeutic molecules is a promising approach. Furthermore, the transport of IL-2 with this nano-sized system can reduce or avoid its toxicity problem in the clinic.

Biopharmaceutical evaluation of kavain in Piper methysticum G. Forst dried extract: Equilibrium solubility and intestinal permeability in Caco-2 cell model

Ethnopharmacological relevancePiper methysticum G. Forst, popularly known as kava, is a traditional medicinal plant native from South Pacific islands and widely used to treat anxiety, depression and stress. The psychoactive properties are related to the kavalactones, mainly kavain. Aim of the studyTo evaluate the biopharmaceutical properties of synthetic kavain and when present in kava dried extracts by means of equilibrium solubility and intestinal permeability studies in the Caco-2 cell model. Materials and methodsThe equilibrium solubility of kavain was performed using a shake flask incubator at 37 °C in different media at physiological pH range (1.2–6.8). The intestinal permeability of kavain evaluated in Caco-2 cells in the presence and absence of the P-glycoprotein inhibitor verapamil. Kavain concentrations were determined by reversed phase high performance liquid chromatography (HPLC). ResultsHPLC methods were developed and fully validated for kavain quantitation. Kavain demonstrated low solubility and the pH of the aqueous media did not affect its solubility. Kavain was found to be highly permeable and efflux of kavain mediated by P-glycoprotein was not significant during intestinal permeation. ConclusionThe results of biopharmaceutical studies provided useful information for predicting availability of kavain from the gastrointestinal tract and this compound was ranked as BCS Class II, exhibiting dissolution rate-limited absorption.

The role of the intestinal permeability in the progression of nonalcoholic fatty liver disease in obese children

Many studies in recent years have revealed increased intestinal permeability in the non-alcoholic fatty liver disease (NAFLD) development and progression to nonalcoholic steatohepatitis (NASH) and liver fibrosis. The prevalence, course, and diagnostic criteria of pediatric NAFLD were considered in the article. The role of increased intestinal permeability in the pathogenesis of NAFLD has been demonstrated. Attention was paid to the structure of the intestinal barrier and possible methods for its permeability examination. Current studies of intestinal permeability in NAFLD in adults and children, which confirm its key role in the progression of NAFLD, were reviewed. A literature search was conducted in electronic databases Scopus, MedLine, EMBASE, Pubmed, Google Scholar, etc.

Polysaccharides-based delivery system for efficient encapsulation and controlled release of food-derived active peptides

A polysaccharides-based delivery system was designed to encapsulate and control the release of peanut peptide (PP). The PP-loaded polyelectrolyte complex (TMC-PP-SA) was fabricated based on the electrostatic self-assembly between n-trimethy chitosan (TMC) and sodium alginate (SA). The complex exhibited uniform spherical morphology, satisfactory stability and high encapsulation efficiency. In vitro release behavior indicated that TMC-PP-SA polyelectrolyte complex could inhibit the release of PP at simulated gastric medium and enhance the release of PP at simulated intestinal medium. Moreover, the antioxidant activity of PP after encapsulation was significantly improved compared with that of directly digested PP. Ex vivo intestinal permeation study confirmed that about 41.76 ± 1.43% PP in TMC-PP-SA could be absorbed in the intestinal. The cytotoxicity measurement indicated that the fabricated TMC-PP-SA polyelectrolyte complex was biocompatible and nontoxic. Therefore, these results indicated that the polysaccharides-based delivery system had great potential in protecting active peptides from degradation and facilitating their absorption.

Combining Human Organoids and Organ-on-a-Chip Technology to Model Intestinal Region-Specific Functionality

The intestinal mucosa is a complex physical and biochemical barrier that fulfills a myriad of important functions. It enables the transport, absorption, and metabolism of nutrients and xenobiotics while facilitating a symbiotic relationship with microbiota and restricting the invasion of microorganisms. Functional interaction between various cell types and their physical and biochemical environment is vital to establish and maintain intestinal tissue homeostasis. Modeling these complex interactions and integrated intestinal physiology in vitro is a formidable goal with the potential to transform the way new therapeutic targets and drug candidates are discovered and developed. Organoids and Organ-on-a-Chip technologies have recently been combined to generate human-relevant intestine chips suitable for studying the functional aspects of intestinal physiology and pathophysiology in vitro. Organoids derived from the biopsies of the small (duodenum) and large intestine are seeded into the top compartment of an organ chip and then successfully expandas monolayers while preserving the distinct cellular, molecular, and functional features of each intestinal region. Human intestine tissue-specific microvascular endothelial cells are incorporated in the bottom compartment of the organ chip to recreate the epithelial-endothelial interface. This novel platform facilitates luminal exposure to nutrients, drugs, and microorganisms, enabling studies of intestinal transport, permeability, and host-microbe interactions. Here, a detailed protocol is provided for the establishment of intestine chips representing the human duodenum (duodenum chip) and colon (colon chip), and their subsequent culture under continuous flow and peristalsis-like deformations. We demonstrate methods for assessing drug metabolism and CYP3A4 induction in duodenum chip using prototypical inducers and substrates. Lastly, we provide a step-by-step procedurefor the in vitro modeling of interferon gamma (IFNγ)-mediated barrier disruption (leaky gut syndrome) in a colon chip, including methods for evaluating the alteration of paracellular permeability, changes in cytokine secretion, and transcriptomic profiling of the cells within the chip.

Enhancement of solubility and permeability of cefpodoxime proxetil by self-micro-emulsifying drug delivery system

The goal of this study was to design Cefpodoxime Proxetil SMEDDS (self-microemulsifying drug delivery system), to improve solubility and permeability which could improve therapeutic performance and drug loading capacity. Castor oil, Tween 80, PEG 400 were used as the oil, surfactant, and, co-surfactant respectively. A ternary phase diagram was used to choose the best formulations. Selected formulations were evaluated for various parameters. According to the findings, all SMEDDS formulations had nano-sized globules, good stability, and rapid dispersibility of microemulsions, which were clear and slightly bluish in colour, and no symptoms of phase separation, creaming or, cracking Intestinal permeability studies of SMEDDS formulations show that the drug diffused through a biological membrane is more when given in form of SMEDDS. The present investigation has shown that it is possible to enhance the solubility and permeability of poorly soluble drugs.

Enhanced dissolution and bioavailability of revaprazan using self-nanoemulsifying drug delivery system

A self-nanoemulsifying drug delivery system (SNEDDS) was developed to enhance the dissolution and oral bioavailability (BA) of revaprazan (RVP). Various SNEDDSs containing 200 mg of RVP were formulated using Capmul MCM, Tween 80, and Brij L4, and they were characterized according to their size, polydispersity index, and dissolution behavior. Dissolution rates of all SNEDDS formulations significantly (p < 0.05) improved with the formation of nanoemulsion with monodispersity. Formulation D resulted in RVP dissolution exceeding 70% at 2 h. Compared to raw RVP, SNEDDS exhibited a 4.8- to 7.4-fold improved effective permeability coefficient (Peff) throughout the intestine in the in situ single pass intestinal permeability study and a 5.1-fold increased oral BA in the in vivo oral absorption assessment in rats. To evaluate the degree of lymphatic uptake, cycloheximide (CYC), a chylomicron flowing blocker, was pretreated prior to the experiment. This pretreatment barely affected the absorption of raw RVP; however, it greatly influenced the absorption of SNEDDS, resulting in an approximately 40% reduction in both the Peff value and oral BA representing lymphatic transport. Thus, we suggest that the SNEDDS formulation is a good candidate for improving oral absorption of RVP through enhanced lymphatic uptake.

Formulation and Evaluation of Polymeric Nanoparticles of Felodipine

Objective: The objective of the present study was to formulate and evaluate polymeric nanoparticles of Felodipine by Nano precipitation technique using EudragitL100 and EudragitS100 as a polymers. The nanoparticles were characterized for particle size, poly-dispersity index, entrapment efficiency (EE), zeta potential, solubility, morphological study, invitro study, Ex vivo intestinal permeability studies and stability studies. Infrared studies showed that there was no drug excipients interaction. Negative values of zetapotential indicated the good stabilization of the prepared nanoparticles. Solubility measurement studies revealed that the solubility of nanoparticles was increased to ten times than the pure drug. The entrapment efficiency was found in between 29.72 ± 3.27% – 63.95 ± 3.50%. The in-vitro drug release was extended maximum up to 12 hrs with Eudragit L100. The curve fitting data shows that the drug release followed first order kinetics, Higuchi’s plots stated non-fickian diffusion controlled. The intestinal permeability of formulated nanoparticles were found to be more than pure drug. SEM shows that nanoparticles were found spherical in structure without aggregation and uniform distribution of the drug within the nanoparticles. Accelerated stability studies were also carried out following ICH Guidelines.