Intestinal Permeation Research Articles

Tri-block co-polymer nanocarriers for enhancement of oral delivery of felodipine: preparation, in vitro characterization and ex vivo permeation

This study aimed to prepare, optimize and characterize novel felodipine-loaded polymeric nanomicelles, using a pluronic mixture of F127 and P123. Thin-film hydration method was adopted for the preparation of different polymeric nanomicelles (T1–T12) according to a 41.31 full factorial design. Factors studied were: Pluronic®:drug ratio (P:D ratio) (10, 20, 30 and 40 w/w) and percent of hydrophilic polymer (F127%) (33.33%, 50% and 66.67% w/w). Optimization criteria were to maximize transmittance percent (T%) and entrapment efficiency percent (EE%) and to minimize particle size (PS) and polydispersity index (PDI). The optimized formulation was further characterized by DSC, FTIR and 1H NMR studies. It was also subjected to stability testing and ex vivo permeation using rabbit intestines. Spherical nanomicelles of particle size ranging from 26.18 to 87.54 nm were successfully obtained. The optimized formulation was found to be the already prepared formulation T12 (P:D ratio of 40 and 66.67% F127) with suitable T% and EE% of 95.12% and 91.75%, respectively. DSC, FTIR and 1H NMR studies revealed felodipine (FLD) incorporation within T12 nanomicelles. T12 enhanced the ex vivo intestinal permeation of FLD when compared to a drug suspension and showed good stability. Therefore, pluronic nanomicelles could be promising for improved oral delivery of FLD.

Oral microemulsion of phytoconstituent found in licorice as chemopreventive against benzo(a)pyrene induced forestomach tumors in experimental mice model

Dibenzoylmethane (DBM), a minor phytoconstituent found in roots of licorice (Glycyrhiza glabra) has been reported to exhibit antioxidant and chemopreventive effects. It suffers from a problem of poor aqueous solubility and permeability leading to low oral bioavailability. Microemulsion, a novel colloidal carrier was proposed to improve its solubility in order to achieve enhanced oral biodistribution and efficacy. The microemulsion was prepared using peppermint oil and Tween 20 as oil phase and surfactant respectively. The spherical globules of microemulsion depicted a mean globule size of 157 nm and polydispersity index (PDI) of 0.715. The results of exvivo intestinal permeation using non everted intestinal sac technique demonstrated 5.7 time enhancement in intestinal permeability from microemulsion. During the invivo chemopreventive evaluations using benzo(a)pyrene [B(a)P] induced forestomach tumors in mice model, the treatment with DBM microemulsion, resulted in almost 100% reduction in tumor incidence after the last dose of B(a)P. The histopathological studies suggested the regression of stomach tumors after treatment with DBM microemulsion. Also, the biochemical estimations for oxidative stress markers depicted its improved efficacy in chemoprevention. The above results suggested that oral microemulsion formulation augmented the permeability and effectiveness of DBM as potential chemopreventive agent.

Development of novel amisulpride-loaded liquid self-nanoemulsifying drug delivery systems via dual tackling of its solubility and intestinal permeability

Objective: The aim of the current investigation was at enhancing the oral biopharmaceutical behavior; solubility and intestinal permeability of amisulpride (AMS) via development of liquid self-nanoemulsifying drug delivery systems (L-SNEDDS) containing bioenhancing excipients.Methods: The components of L-SNEDDS were identified via solubility studies and emulsification efficiency tests, and ternary phase diagrams were constructed to identify the efficient self-emulsification regions. The formulated systems were assessed for their thermodynamic stability, globule size, self-emulsification time, optical clarity and in vitro drug release. Ex vivo evaluation using non-everted gut sac technique was adopted for uncovering the permeability enhancing effect of the formulated systems.Results: The optimum formulations were composed of different ratios of Capryol™ 90 as an oil phase, Cremophor® RH40 as a surfactant, and Transcutol® HP as a co-surfactant. All tested formulations were thermodynamically stable with globule sizes ranging from 13.74 to 29.19 nm and emulsification time not exceeding 1 min, indicating the formation of homogenous stable nanoemulsions. In vitro drug release showed significant enhancement from L-SNEDDS formulations compared to aqueous drug suspension. Optimized L-SNEDDS showed significantly higher intestinal permeation compared to plain drug solution with nearly 1.6–2.9 folds increase in the apparent permeability coefficient as demonstrated by the ex vivo studies.Conclusions: The present study proved that AMS could be successfully incorporated into L-SNEDDS for improved dissolution and intestinal permeation leading to enhanced oral delivery.

Hexagonal Liquid Crystalline Nanodispersions Proven Superiority for Enhanced Oral Delivery of Rosuvastatin: In Vitro Characterization and In Vivo Pharmacokinetic Study

This study aimed to explore the potential of tailoring the liquid crystalline structure for augmenting the oral absorption and biopharmaceutical performance of rosuvastatin. Rosuvastatin (ROS)-loaded liquid crystalline nanodispersions (LCNDs) were prepared via emulsification technique. The effect of incorporating oleic acid (OA) in various proportions in the lipid domain of the LCNDs was studied. The formulations were characterized for particle size, zeta potential, in vitro release, ex vivo intestinal permeation, in vivo oral bioavailability, and stability. All the prepared LCNDs possessed uniform nanometric size and negative zeta potential. Employing OA in the lipid domain enhanced ROS entrapment efficiency, and resulted in structural transition from cubic to hexagonal phase as proved by transmission electron microscopy. Increasing OA proportion up to a certain ratio prolonged the in vitro drug release rate, after which further increase in OA had no significant effect. The OA bearing hexagonal LCNDs provided a significant enhancement in the intestinal permeation compared to glyceryl monooleate cubical nanodispersion and demonstrated an outstanding in vivo performance by maintaining higher ROS plasma levels up to 8 h and enhancing oral bioavailability compared to commercial tablet. They proved to be promising carriers for improved oral delivery of ROS with substantial bioavailability enhancing effects, and superiority compared to cubosomes and OA emulsion.

ATRP-grown protein-polymer conjugates containing phenylpiperazine selectively enhance transepithelial protein transport

Despite its patient-friendliness, the oral route is not yet a viable strategy for the delivery of biomacromolecular therapeutics. This is, in part, due to the large size of proteins, which greatly limits their absorption across the intestinal epithelium. Although chemical permeation enhancers can improve macromolecular transport, their positive impact is often accompanied by toxicity. One element potentially contributing to this toxicity is the lack of co-localization of the enhancer with the protein drug, which can result in non-specific permeation of the intestine as well as enhancer overdosing in some areas due to non-uniform distribution. To circumvent these issues, this study describes a new way of increasing protein permeability via a polymer conjugation process that co-localizes permeation enhancer with the protein. Based on previous reports demonstrating the utility of 1-phenylpiperazine as an intestinal permeation enhancer, we synthesized protein-polymer conjugates with a phenylpiperazine-containing polymer using polymer-based protein engineering. A novel phenylpiperazine acrylamide monomer was synthesized and chain extended using atom transfer radical polymerization from the model protein bovine serum albumin (BSA). At non-cytotoxic doses, the protein-polymer conjugates induced a dose dependent reduction in the trans-epithelial electrical resistance of Caco-2 monolayers and an impressive ~30-fold increase in BSA permeability. Furthermore, this permeability increase was selective, as the permeability of the small molecule calcein co-incubated with the protein-polymer conjugate increased only 5-fold. Together, these data represent an important first step in the development of protein polymer conjugates that facilitate selective protein transport across membranes that are typically impermeable to macromolecules.

Sleeve Gastrectomy Alters Intestinal Permeability in Diet-Induced Obese Mice.

Increased lipopolysaccharide (LPS) translocation due to altered intestinal permeability has been suggested as a mechanism for obesity-associated insulin resistance. The goal of this study was to assess the effect of sleeve gastrectomy (SG) on intestinal barrier permeability in diet-induced obese mice. Four weeks after surgery, the effects of SG on intestinal permeabilities were assessed ex vivo and in vivo in male C57Bl/6J mice fed a high-fat diet. Gene expression of tight junction proteins and inflammatory cytokines was measured in jejunum, colon, liver, and inguinal adipose tissue. Plasma LPS was quantified by HPLCMS/MS spectrometry. SG significantly reduced body weight and improved glucose homeostasis, as expected. SG decreased paracellular (p=0.01) and transcellular permeability (p=0.03) in the jejunum; and increased mRNA levels of the tight junction proteins Jam A (p=0.02) and occludin (p=0.01). In contrast in the distal colon, paracellular permeability tended to be increased (p=0.07) while transcellular permeability was significantly induced (p=0.03) after SG. In vivo, the paracellular permeability was significantly increased 3weeks after SG (p=0.02). Plasma LPS level were increased after SG (p=0.03), as well as mRNA levels of adipose and hepatic inflammatory markers (p=0.02). SG significantly modifies intestinal permeability in a differential manner between the proximal and distal intestine. These changes promote LPS translocation in plasma, induce a low-grade pro-inflammatory state in adipose tissue and liver, but do not impair the SG-induced glucose homeostasis improvement.

Effects of lipid formulations on clove extract spray dried powders: comparison of physicochemical properties, storage stability and in vitro intestinal permeation

Clove is an aromatic plant spice with potent antioxidant and anti-inflammatory activity. Eugenol is the main compound which contributes to such medicinal and nutritional benefits. To date, the formulation of unstable, volatile and poorly water-soluble compounds remains a challenging task. Lipid formulations can be used to improve physicochemical and biopharmaceutical properties of poorly soluble compounds. The aim of this study is to investigate the effects of lipids, such as Gelucire and Compritol on physicochemical properties; stability and in vitro intestinal permeation of spray dried powdered formulations loaded with clove’s bioactive compounds. Results showed that eugenol retention in spray-dried powders could be correlated with antioxidant activity and with mass recovery after spray drying. Adding Gelucire but not Compritol to clove extract formulations, improved solubility of spray dried powders. Stability test in high humidity environment (63.5% RH) suggested that formulations including both Gelucire and Compritol were significantly more stable compared to the formulation without any lipid at the two tested temperatures (25 °C and 40 °C). This suggests that lipid additions to clove (Syzygium aromaticum) extract formulations provide protective effects for the spray dried powders in high-humidity environments. In addition, results from in vitro intestinal permeation studies suggested that eugenol uptake, was not being hindered by transporters nor was the absorption being affected by lipid formulations.

Structure-Function Analysis of Phenylpiperazine Derivatives as Intestinal Permeation Enhancers.

A major obstacle preventing oral administration of macromolecular therapeutics is poor absorption across the intestinal epithelium into the bloodstream. One strategy to improve transport across this barrier is the use of chemical permeation enhancers. Several molecular families with permeation enhancing potential have been identified previously, including piperazines. In particular, 1-phenylpiperazine has been shown to enhance transepithelial transport with minimal cytotoxicity compared to similarly effective molecules. To better understand how the chemistry of 1-phenylpiperazine affects its utility as an intestinal permeation enhancer, this study examined a small library of 13 derivatives of 1-phenylpiperazine. The efficacy and cytotoxicity of 13 phenylpiperazine compounds were assessed in a Caco-2 model of the intestinal epithelium. Efficacy was measured using the paracellular diffusion marker calcein as well as by immunostaining and confocal imaging of Caco-2 monolayers. Of the 13 derivatives, two enhanced the permeability of the fluorescent marker calcein over 100-fold. It was found that hydroxyl or primary amine substitutions on the phenyl ring significantly increased toxicity, while aliphatic substitutions resulted in efficacy and toxicity profiles comparable to 1-phenylpiperazine. Several potent derivatives, including 1-methyl-4-phenylpiperazine and 1-(4-methylphenyl)piperazine, displayed lower toxicity than 1-phenylpiperazine, suggesting promise in future applications.

Enhanced intestinal absorption of curcumin in Caco-2 cell monolayer using mucoadhesive nanostructured lipid carriers.

This study aimed to compare the intestinal permeation of curcumin-loaded polymer coated nanostructured lipid carriers (NLCs) and uncoated NLCs using the Caco-2 cell model. The uncoated NLCs were prepared using a warm microemulsion technique, while polymer-coated NLCs were prepared with the same method but were followed by coating particle surface with polyethylene glycol (PEG) 400 or polyvinyl alcohol (PVA). After lyophilization, all formulations possessed a mean size of <400nm with a zeta potential of ∼-30mV and a high entrapment efficacy up to 90%. All NLCs formulation showed significantly improvement in curcumin water solubility, more than 60-folds as compared to curcumin dispersion. In addition, they could protect curcumin from degradation in basic pH, 90% curcumin remaining after 6h incubation in culture medium. In vitro permeation studies revealed that PEG-NLCs and PVA-NLCs provided significantly higher apparent permeation coefficient (Papp ) value than uncoated NLCs. Moreover, after 6months storage at 4 °C in the absence of sunlight, the physical, and chemical stabilities of the lyophilized curcumin-loaded polymer coated NLCs and uncoated NLCs could be maintained, i.e., the mean particle size and the amount of curcumin showed no significant changes (p>0.05) compared to those freshly prepared formulations. Considered overall, polymer coated NLCs are an important strategy to improve the oral bioavailability of curcumin. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 734-741, 2018.

Insights into Caco-2 cell culture structure using coherent anti-Stokes Raman scattering (CARS) microscopy

We have used coherent anti-Stokes Raman scattering (CARS) microscopy as a novel and rapid, label-free and non-destructive imaging method to gain structural insights into live intestinal epithelial cell cultures used for drug permeability testing. Specifically we have imaged live Caco-2 cells in (bio)pharmaceutically relevant conditions grown on membrane inserts. Imaging conditions were optimized, including evaluation of suitable membrane materials and media solutions, as well as tolerable laser powers for non-destructive imaging of the live cells. Lipid structures, in particular lipid droplets, were imaged within the cells on the insert membranes. The size of the individual lipid droplets increased substantially over the 21-day culturing period up to approximately 10% of the volume of the cross section of individual cells. Variation in lipid content has important implications for intestinal drug permeation testing during drug development but has received limited attention to date due to a lack of suitable analytical techniques. CARS microscopy was shown to be well suited for such analysis with the potential for in situ imaging of the same individual cell-cultures that are used for permeation studies. Overall, the method may be used to provide important information about cell monolayer structure to better understand drug permeation results.

Aceclofenac polymorphs: Preparation, characterization and intestinal permeation studies

PurposeAceclofenac (ACE) is one of the most popular anti-inflammatory drugs, frequently used for the pain relief in conditions like osteoarthritis, muscular pain, rheumatoid arthritis, periarthritis, spondylitis, sprain and alkylosing arthritis. However, being important non-steroidal anti-inflammatory agent (NSAID), still the polymorphic attributes of ACE are relatively less explored. Therefore, we aimed to study the polymorphic transitions of ACE employing various solvents and also to correlate with the biological transport of ACE. MethodsThe various polymorphic forms were prepared using rotatory evaporation and solvent drying techniques. The developed polymorphic forms were characterized by melting point, Fourier-transform infrared (FTIR) spectroscopy, Raman spectroscopy, differential scanning calorimetry (DSC), X-ray powder diffraction and were biologically evaluated in rats vis-à-vis the plain ACE. ResultsThe developed forms were found to enhance the drug permeability across GIT in comparison to that of the granular plain drug, indicating the significant dependence of bioavailability of ACE on the packing arrangement of the drug molecules. ConclusionThese findings are encouraging and provide an insight of the relationship between the polymorphic forms of drugs and the respective biological outcomes.

Development and validation of a reversed-phase high-performance liquid chromatographic method with solid-phase extraction for the quantification of hydrochlorothiazide in ex vivo permeation studies.

Hydrochlorothiazide (HCT) is a diuretic used to treat hypertension. In order to study its intestinal permeation behavior applying an ex vivo methodology, a rapid, sensitive and selective reversed-phase liquid chromatography (RP-HPLC) method coupled with UV detection (RP-HPLC UV) was developed for the analysis of HCT in TC199 culture medium used as mucosal and serosal solutions in the everted rat intestinal sac model. Also, analytical procedures for the quantification of HCT by RP-HPLC with UV detection required a sample preparation step by solid-phase extraction. The method was validated in the concentration range of 8.05 × 10-7 to 3.22 × 10-5 m for HCT. Chromatographic parameters, namely carry-over, lower limit of quantification (1.4491 × 10-7 m), limit of detection (3.8325 × 10-8 m), selectivity, inter- and intraday precision and extraction recovery, were determined and found to be adequate for the intended purposes. The validated method was successfully used for permeability assays across rat intestinal epithelium applying the ex vivo everted rat gut sac methodology to study the permeation behavior of HCT.

Increased intestinal permeation and modulation of presystemic metabolism of resveratrol formulated into self-emulsifying drug delivery systems

Despite various beneficial biological properties, resveratrol lacks therapeutic applications because of poor bioavailability due to variable absorption and extensive metabolism. The present study aims at evaluating the capability of self-emulsifying drug delivery systems (SEDDS) to enhance resveratrol permeation across rat intestine and to modulate its presystemic metabolism. For that purpose, semi-solid (SS) and liquid (L) SEDDS were prepared and dispersed in an aqueous buffer to produce nanoemulsions (NE). The jejunal absorptive transepithelial fluxes (Jms) of resveratrol elicited by these formulations (SS-NE and L-NE) and presystemic metabolization were determined on Ussing chambers. The absorptive fluxes through the intestinal epithelium from the nanoemulsions (Jms=20.5±3.1μgh−1cm−2 SS-NE; 28.9±2.9μgh−1cm−2 L-NE) were significantly increased compared to an ethanolic control solution (Jms=3.4±0.3μgh−1cm−2, p<0.05). No significant variations of conductance were observed after two hours of contact between the formulations and the mucosa. Simultaneously, the presystemic metabolization pattern was modified in the case of the nanoemulsions compared to the control solution. In conclusion, our data suggests that oil-in-water nanoemulsions prepared from SEDDS dispersions of medium-chain lipids could be promising formulations for enhancing oral delivery of resveratrol.

Nanoemulsion for improving solubility and permeability of Vitex agnus-castus extract: formulation and in vitro evaluation using PAMPA and Caco-2 approaches

The purpose of this study was to develop new formulation for an improved oral delivery of Vitex agnus-castus (VAC) extract. After the optimization and validation of analytical method for quali-quantitative characterization of extract, nanoemulsion (NE) was selected as lipid-based nanocarrier. The composition of extract-loaded NE resulted in triacetin as oil phase, labrasol as surfactant, cremophor EL as co-surfactant and water. NE contains until 60 mg/mL of extract. It was characterized by DLS and TEM analyses and its droplets appear dark with an average diameter of 11.82 ± 0.125 nm and a polydispersity index (PdI) of 0.117 ± 0.019. The aqueous solubility of the extract was improved about 10 times: the extract is completely soluble in the NE at the concentration of 60 mg/mL, while its solubility in water results less than 6 mg. The passive intestinal permeation was tested by using parallel artificial membrane permeation assay (PAMPA) and the permeation across Caco-2 cells after preliminary cytotoxicity studies were also evaluated. NE shows a good solubilizing effect of the constituents of the extract, compared with aqueous solution. The total amount of constituents permeated from NE to acceptor compartment is greater than that permeated from saturated aqueous solution. Caco-2 test confirmed PAMPA results and they revealed that NE was successful in increasing the permeation of VAC extract. This formulation could improve oral bioavailability of extract due to enhanced solubility and permeability of phytocomplex.

Enhancing biopharmaceutical attributes of phospholipid complex-loaded nanostructured lipidic carriers of mangiferin: Systematic development, characterization and evaluation

Mangiferin (Mgf), largely expressed out from the leaves and stem bark of Mango, is a potent antioxidant. However, its in vivo activity gets tremendously reduced owing to poor aqueous solubility and inconsistent gastrointestinal absorption, high hepatic first-pass metabolism and high P-gp efflux. The current research work, therefore, was undertaken to overcome the biopharmaceutical hiccups by developing the Mgf-phospholipid complex (PLCs) loaded in nanostructured lipidic carriers (NLCs). The PLCs and NLCs were prepared using refluxing, solvent evaporation and hot emulsification technique, respectively with three molar ratios of Mgf and Phospholipon 90G, i.e., 1:1; 1:2; and 1:3. The complex was evaluated for various physicochemical parameters like drug content (96.57%), aqueous solubility (25-fold improved) and oil-water partition coefficient (10-fold enhanced). Diverse studies on the prepared complex using FTIR, DSC, PXRD and SEM studies ratified the formation of PLCs at 1:1 ratio. The PLCs were further incorporated onto NLCs, which were systematically optimized employing a face centered cubic design (FCCD), while evaluating for particle size, zeta potential, encapsulation efficiency and in vitro drug release as the CQAs. Caco-2 cell line studies indicated insignificant cytotoxicity, and P-gp efflux, while bi-directional permeability model and in situ perfusion studies specified enhanced intestinal permeation parameters. In vivo pharmacokinetic studies revealed notable increase in the values of Cmax (4.7-fold) and AUC (2.1-fold), respectively, from PLCs-loaded NLCs vis-à-vis Mgf solution. In a nutshell, the promising results observed from the present research work signify enhanced biopharmaceutical attributes of the novel PLCs-loaded NLCs for potentially augmenting the therapeutic efficacy of Mgf.

Paliperidone-Loaded Nanolipomer System for Sustained Delivery and Enhanced Intestinal Permeation: Superiority to Polymeric and Solid Lipid Nanoparticles

Paliperidone (PPD) is the most recent second-generation atypical antipsychotic approved for the treatment of schizophrenia. An immediate release dose causes extrapyramidal side effects. In this work, a novel nanolipomer carrier system for PPD with enhanced intestinal permeability and sustained release properties has been developed and optimized. PPD was successfully encapsulated into a lipomer consisting of a specific combination of biocompatible materials including poly-ε-caprolactone as a polymeric core, Lipoid S75, and Gelucire® 50/13 as a lipid shell and polyvinyl alcohol as a stabilizing agent. The lipomer system was characterized by dynamic light scattering, TEM, DSC, and FTIR. An optimized lipomer formulation possessed a particle size of 168nm, PDI of 0.2, zeta potential of -23mV and an encapsulation efficiency of 87.27% ± 0.098. Stability in simulated gastrointestinal fluids investigated in terms of particle size, zeta potential, and encapsulation efficiency measurements ensured the integrity of the nanoparticles upon oral administration. PPD-loaded nanolipomers demonstrated a superior sustained release behavior up to 24h and better ex vivo intestinal permeation for PPD compared to the corresponding polymeric and solid lipid nanoparticles and drug suspension. The in vitro hemocompatibility test on red blood cells revealed no hemolytic effect of PPD-loaded lipomers which reflects its safety. The elaborated nanohybrid carrier system represents a promising candidate for enhancing the absorption of PPD providing a 2.6-fold increase in the intestinal permeation flux compared to the drug suspension while maintaining a sustained release behavior. It is a convenient alternative to the commercially available dosage form of PPD.

Pharmacokinetic characterization of anhuienoside C and its deglycosylated metabolites in rats

1. Anhuienoside C (AC), a triterpenoid saponin derived from the traditional Chinese medicine (TCM) “Di Wu”, has significant anti-inflammatory and anti-rheumatoid arthritis activities. Here we aimed to characterize the pharmacokinetics of AC and its deglycosylated metabolites in rats.2. AC was administered to rats by intravenous injection or oral gavage. AC and its four deglycosylated metabolites (M1, M2, M3 and M4) in biological samples were quantified using a UPLC-QTOF/MS system. The pharmacokinetic data were analyzed by compartmental modeling. The metabolism of M1, M2, M3 and M4 was determined using rat liver microsomes (RLM) and rat intestine microsomes (RIM). The intestinal permeabilities of AC and its metabolites were evaluated using Parallel artificial membrane permeability assay (PAMPA) and MDR1-transfected Madin–Darby canine kidney cell (MDCK–MDR1) cell model.3. AC pharmacokinetics was well described by the one-compartment model. The oral bioavailability of AC was exceedingly low (F = 0.03%). Consistently, AC was poorly distributed (< 0.08 μM) in major organs including the heart, liver, spleen, lung and kidney after oral uptake. Three of four deglycosylated metabolites (M2, M3, and M4) underwent further metabolism in RLM, generating five, two and five oxidized products, respectively. Both PAMPA and MDCK-MDR1 experiments showed that AC and its metabolites were poorly permeable. Furthermore, the net flux ratios derived from MDCK-MDR1 versus wild-type MDCK cells were, respectively 1.3, 1.5, 0.7, 1.2 and 0.6 for AC, M1, M2, M3 and M4, suggesting that these compounds were non-substrates of P-glycoprotein.4. In conclusion, extensive pre-systemic metabolism and poor permeability were the main causes of low systemic exposures of oral AC and its four metabolites.

Development of a Non-Aqueous Dispersion to Improve Intestinal Epithelial Flux of Poorly Permeable Macromolecules.

Intestinal permeation enhancers (PEs) offer an attractive strategy to enable oral peptide administration. However, optimal presentation of peptide and PE from solid-dosage forms is offset by slow dissolution rates in the small intestine, which reduces the likelihood that the PE can reach the threshold concentration for sufficient permeability enhancement. The purpose of this study was to design a PE-based liquid dispersion that can improve intestinal permeation of macromolecules across Caco-2 monolayers and isolated rat/human intestinal mucosae mounted in Ussing chambers. An enhancer screen in monolayers based on permeability (TEER, Papp [14C]-mannitol) and cytotoxicity (MTT assay) initially identified methyl 10-hydroxydecanoate (10-OHC10CH3) as a candidate. 10-OHC10CH3 (20mM) increased the Papp of fluorescent dextran of 4kDa (FD4) (167-fold), 10kDa (FD10) (429-fold), and 40kDa (FD40) (520-fold) across monolayers. Blends of 10-OHC10CH3 with low molecular weight PEGs (0.2-1kDa) formed liquid dispersions in which enhancement capacity across monolayers of 10-OHC10CH3 was increased over 10-OHC10CH3 alone in the order PEG200 < PEG400 < PEG600 < PEG1000. Finally, a 1:5 ratio of 10-OHC10CH3 (10-20mM)/PEG600 (50-100mM) increased the Papp of [14C]-mannitol across rat and human intestinal mucosae. This study highlights the potential future role for non-aqueous, PE-based liquid dispersions in oral delivery of macromolecules.

Enhanced oral delivery of risperidone through a novel self-nanoemulsifying powder (SNEP) formulations: in-vitro and ex-vivo assessment

Context: The oral delivery of risperidone encounters a number of problems, such as pH dependent solubility and low bioavailability, due to its lipophilicity and aqueous insolubility.Objective: To improve the solubility, dissolution and intestinal permeation thereby bioavailability of risperidone through a novel self-nanoemulsifying powder (SNEP) formulations.Materials and methods: Oleic acid, Tween® 20, PEG 600 and Aerosil® 200 were chosen as oil, surfactant, co-surfactant and carrier, respectively from solubility and emulsification studies. Ternary phase diagram was constructed to determine emulsifying region.Results and discussion: The Z-average and polydispersity Index of developed formulation was 83.1 nm and 0.306, respectively. Ex vivo permeation studies on isolated rat intestine indicated that the amount of risperidone permeated from SNEP formulation was increased around 4- and 1.8-fold than that of pure drug and marketed formulation, respectively.Conclusion: This developed SNEP formulations can be regarded as novel and commercially feasible alternative to the current risperidone formulations.

Self-emulsifying phospholipid pre-concentrates (SEPPs) for improved oral delivery of the anti-cancer genistein: Development, appraisal and ex-vivo intestinal permeation

Genistein (GEN), a potent anticancer agent, suffers from scanty oral bioavailability due to poor solubility and extensive metabolism. This work endeavored to enhance GEN solubility and intestinal permeability via fabrication of self-emulsifying phospholipid pre-concentrates (SEPPs) using some bioactive surfactants. Moreover, the potential of surfactant-free SEPP to address GEN obstacles was investigated. SEPPs were prepared from Phosal® 53MCT, oil/phosphatidylcholine mixture, alone or with only 30% of different surfactant/co-surfactant mixture (S/CO). In-vitro characterization encompassed globule size analysis, zeta potential (ZP), transmission electron microscopy, and in-vitro release. Ex-vivo intestinal permeation study was performed using non-everted rat intestinal sac technique. Upon aqueous dilution, SEPPs were easily dispersed with spherical globules within a nano-range size (from 165±15 to 425±20nm) and adequate negative ZP (>−30mV). SEPPs demonstrated a significant enhancement in GEN release compared to drug suspension without superior effect due to added S/CO. Permeation study revealed that at least 12.13% free GEN was permeated after 120min from SEPPs compared to only 3.7% from drug suspension. Among different SEPPs, SEPP containing 30% Tween 80/Transcutol HP mixture showed the highest GEN permeation (18.54%). Conclusively, SEPP might be a promising nanocarrier that enhances GEN bioavailability via improving dissolution and inhibition of pre-systemic clearance.