Relative Oral Bioavailability Research Articles

Enhancement of Intestinal Permeability Utilizing Solid Lipid Nanoparticles Increases γ‐Tocotrienol Oral Bioavailability

γ-Tocotrienol (γ-T3), a member of the vitamin E family, has been reported to possess an anticancer activity. γ-T3 is a lipophilic compound with low oral bioavailability. Previous studies showed that γ-T3 has low intestinal permeability. Thus, we have hypothesized that enhancing γ-T3 intestinal permeability will increase its oral bioavailability. Solid lipid nanoparticles (SLN) were tested as a model formulation to enhance γ-T3 permeability and bioavailability. γ-T3 intestinal permeability was compared using in situ rat intestinal perfusion, followed by in vivo relative oral bioavailability studies. In addition, in vitro cellular uptake of γ-T3 from SLN was compared to mixed micelles (MM) in a time and concentration-dependent studies. To elucidate the uptake mechanism(s) of γ-T3 from SLN and MM the contribution of NPC1L1 carrier-mediated uptake, endocytosis and passive permeability were investigated. In situ studies demonstrated SLN has tenfold higher permeability than MM. Subsequent in vivo studies showed γ-T3 relative oral bioavailability from SLN is threefold higher. Consistent with in situ results, in vitro concentration dependent studies revealed γ-T3 uptake from SLN was twofold higher than MM. In vitro mechanistic characterization showed that while endocytosis contributes to γ-T3 uptake from both formulations, the reduced contribution of NPC1L1 to the transport of γ-T3, and passive diffusion enhancement of γ-T3 are primary explanations for its enhanced uptake from SLN. In conclusion, SLN successfully enhanced γ-T3 oral bioavailability subsequent to enhanced passive permeability.

Protease inhibition and absorption enhancement by functional nanoparticles for effective oral insulin delivery

Complexing agents such as diethylene triamine pentaacetic acid (DTPA) are known to disrupt intestinal tight junctions and inhibit intestinal proteases by chelating divalent metal ions. This study attempts to incorporate these benefits of DTPA in functional nanoparticles (NPs) for oral insulin delivery. To maintain the complexing agent concentrated on the intestinal mucosal surface, where the paracellular permeation enhancement and enzyme inhibition are required, DTPA was covalently conjugated on poly(γ-glutamic acid) (γPGA). The functional NPs were prepared by mixing cationic chitosan (CS) with anionic γPGA-DTPA conjugate. The γPGA-DTPA conjugate inhibited the intestinal proteases substantially, and produced a transient and reversible enhancement of paracellular permeability. The prepared NPs were pH-responsive; with an increasing pH, CS/γPGA-DTPA NPs swelled gradually and disintegrated at a pH value above 7.0. Additionally, the biodistribution of insulin orally delivered by CS/γPGA-DTPA NPs in rats was examined by confocal microscopy and scintigraphy. Experimental results indicate that CS/γPGA-DTPA NPs can promote the insulin absorption throughout the entire small intestine; the absorbed insulin was clearly identified in the kidney and bladder. In addition to producing a prolonged reduction in blood glucose levels, the oral intake of the enteric-coated capsule containing CS/γPGA-DTPA NPs showed a maximum insulin concentration at 4 h after treatment. The relative oral bioavailability of insulin was approximately 20%. Results of this study demonstrate the potential role for the proposed formulation in delivering therapeutic proteins by oral route.

Enhanced oral bioavailability of a sterol-loaded microemulsion formulation of Flammulina velutipes, a potential antitumor drug.

PurposeTo investigate the growth inhibition activity of Flammulina velutipes sterol (FVS) against certain human cancer cell lines (gastric SGC and colon LoVo) and to evaluate the optimum microemulsion prescription, as well as the pharmacokinetics of encapsulated FVS.MethodsMolecules present in the FVS isolate were identified by gas chromatography/mass spectrometry analysis. The cell viability of FVS was assessed with methyl thiazolyl tetrazolium (MTT) bioassay. Based on the solubility study, phase diagram and stability tests, the optimum prescription of F. velutipes sterol microemulsions (FVSMs) were determined, followed by FVSMs characterization, and its in vivo pharmacokinetic study in rats.ResultsThe chemical composition of FVS was mainly ergosterol (54.8%) and 22,23-dihydroergosterol (27.9%). After 72 hours of treatment, both the FVS (half-maximal inhibitory concentration [IC50] = 11.99 μg · mL−1) and the standard anticancer drug, 5-fluorouracil (IC50 = 0.88 μg · mL−1) exhibited strong in vitro antiproliferative activity against SGC cells, with IC50 > 30.0 μg · mL−1; but the FVS performed poorly against LoVo cells (IC50 > 40.0 μg · mL−1). The optimal FVSMs prescription consisted of 3.0% medium chain triglycerides, 5.0% ethanol, 21.0% Cremophor EL and 71.0% water (w/w) with associated solubility of FVS being 0.680 mg · mL−1 as compared to free FVS (0.67 μg · mL−1). The relative oral bioavailability (area-under-the-curve values of ergosterol and 22,23-dihydroergosterol showed a 2.56-fold and 4.50-fold increase, respectively) of FVSMs (mean diameter ~ 22.9 nm) as against free FVS were greatly enhanced.ConclusionThese results indicate that the FVS could be a potential candidate for the development of an anticancer drug and it is readily bioavailable via microemulsion formulations.

Effects of polymer molecular weight on relative oral bioavailability of curcumin

BackgroundPolylactic-co-glycolic acid (PLGA) nanoparticles have been used to increase the relative oral bioavailability of hydrophobic compounds and polyphenols in recent years, but the effects of the molecular weight of PLGA on bioavailability are still unknown. This study investigated the influence of polymer molecular weight on the relative oral bioavailability of curcumin, and explored the possible mechanism accounting for the outcome.MethodsCurcumin encapsulated in low (5000–15,000) and high (40,000–75,000) molecular weight PLGA (LMw-NPC and HMw-NPC, respectively) were prepared using an emulsification-solvent evaporation method. Curcumin alone and in the nanoformulations was administered orally to freely mobile rats, and blood samples were collected to evaluate the bioavailability of curcumin, LMw-NPC, and HMw-NPC. An ex vivo experimental gut absorption model was used to investigate the effects of different molecular weights of PLGA formulation on absorption of curcumin. High-performance liquid chromatography with diode array detection was used for quantification of curcumin in biosamples.ResultsThere were no significant differences in particle properties between LMw-NPC and HMw-NPC, but the relative bioavailability of HMw-NPC was 1.67-fold and 40-fold higher than that of LMw-NPC and conventional curcumin, respectively. In addition, the mean peak concentration (Cmax) of conventional curcumin, LMw-NPC, and HMw-NPC was 0.028, 0.042, and 0.057 μg/mL, respectively. The gut absorption study further revealed that the HMw-PLGA formulation markedly increased the absorption rate of curcumin in the duodenum and resulted in excellent bioavailability compared with conventional curcumin and LMw-NPC.ConclusionOur findings demonstrate that different molecular weights of PLGA have varying bioavailability, contributing to changes in the absorption rate at the duodenum. The results of this study provide the rationale for design of a nanomedicine delivery system to enhance the bioavailability of water-insoluble pharmaceutical compounds and functional foods.

Effect of cell-penetrating peptide-coated nanostructured lipid carriers on the oral absorption of tripterine.

PurposeTo develop nanostructured-lipid carriers (NLCs) coated with cell-penetrating peptides (CPP) for improving the oral bioavailability of tripterine.MethodsWe prepared CPP-coated tripterine-loaded NLCs (CT-NLCs) by using a solvent evaporation method, and determined their physical properties. In vitro drug release was determined by using a dialysis bag diffusion technique, and intestinal toxicity was evaluated by performing MTT assay using Caco-2 cells. In vivo absorption was studied in an in situ rat intestinal perfusion model, and oral bioavailability was examined in beagles.ResultsThe average particle size, zeta potential, and encapsulation efficiency of the optimized CT-NLCs were 126.7 ± 9.2 nm, 28.7 ± 3.4 mV, and 72.64% ± 1.37%, respectively. The CT-NLCs showed a controlled release profile in vitro and had significantly lower intestinal cytotoxicity than the tripterine solution (P < 0.05). The absorption levels of tripterine from the CT-NLCs in the rat duodenum and jejunum were markedly higher than with tripterine-loaded NLCs without the CPP coating (T-NLCs), and with tripterine solution. Pharmacokinetic study showed that the maximum concentration of the CT-NLCs was greater than that of the T-NLCs and tripterine suspension, and that the time to maximum concentration of the CT-NLCs as well as the T-NLCs, was longer than that of the tripterine suspension. The relative oral bioavailability of the CT-NLCs compared to that of tripterine suspension and T-NLCs were 484.75% and 149.91% respectively.ConclusionThe oral bioavailability of tripterine is dramatically increased by CT-NLCs. Therefore, CT-NLCs seem to be a promising carrier for oral delivery of tripterine.

Preparation of a nanoscale baohuoside I-phospholipid complex and determination of its absorption: in vivo and in vitro evaluations

BackgroundBaohuoside I is a potential anticancer drug for a variety of malignancies and has been approved for in vitro use. However, baohuoside I has very poor oral absorption.MethodsIn the present study, we prepared baohuoside I-phospholipid complexes of different diameters and determined their physicochemical properties using transmission electron microscopy, ultraviolet spectroscopy, and differential scanning calorimetry. The in vitro absorption of baohuoside I and baohuoside I-phospholipid complexes of different sizes were compared using the Caco-2 cell culture model, and subsequently, the bioavailability of baohuosidel and its complexes were estimated in vivo.ResultsCompared with the large-sized phospholipid complexes, a nanoscale phospholipid complex improved the oral bioavailability of baohuoside I. In addition, our results suggest that the smaller the particle size, the faster the complexes crossed the Caco-2 monolayer and the faster they were resorbed after oral administration in rats. The relative oral bioavailability of a nanoscale size 81 ± 10 nm baohuoside I-phospholipid complex (area under the concentration-time curve [AUC]0–∞) was 342%, while that of baohuoside I and a 227.3 ± 65.2 μm baohuoside I-phospholipid complex was 165%.ConclusionWe enhanced the oral bioavailability of baohuoside I by reducing the particle size of the phospholipid complex to the nanometer range, thereby improving its potential for clinical application.

Preliminary evaluation of a novel oral delivery system for rhPTH1-34: In vitro and in vivo

rhPTH1-34 is clinically used for osteoporosis treatment. However, this peptide drug has no oral bioavailability because of proteolysis and low membrane permeability in gastrointestinal gut. This study explored the possibility of absorption enhancement for rhPTH1-34 through the oral delivery of the microemulsion. The microemulsion (85:15, oil/water) consisting of Labrasol, Crodamol GTCC, Solutol ® HS 15, d-α-tocopheryl acetate (6:2:1:1, w/w) and saline water was developed and characterized, including particle size, morphology, drug loading efficiency and permeability, stability and pharmacokinetics. The microemulsion showed high drug loading efficiency (83%) and permeability, and significantly higher resistance to proteolysis in vitro study. The relative oral bioavailability was 5.4% and 12.0% when delivered to gastric and ileum. Besides, osteoporosis rats were induced and treated with oral rhPTH1-34 microemulsion (0.05 mg/kg), injection (0.01 mg/kg) and vehicle, respectively, for 8 weeks. The proximal tibia bone mineral content and density in oral rats (0.188 ± 0.008 g, 0.283 ± 0.014 g/cm 2) was significantly increased compared to the control rats (0.169 ± 0.006 g, 0.266 ± 0.011 g/cm 2), reaching to the sham rats. And the proximal tibia microstructure of oral rats was improved greatly, approaching sham level too. These findings revealed that oral microemulsion may represent an effective oral delivery system for rhPTH1-34.

An Integrated Pharmacokinetic Model for the Influence of CYP3A4 Expression on the In Vivo Disposition of Lopinavir and Its Modulation by Ritonavir

Lopinavir, a human immunodeficiency virus protease inhibitor, has a very low oral bioavailability, which can be enhanced with a low dose of the CYPA4 inhibitor ritonavir. Our aim was to separately quantify the role of intestinal and hepatic cytochrome P450 3A (CYP3A4) expression on lopinavir disposition in a novel mouse model. Lopinavir and ritonavir were administered to mice selectively expressing human CYP3A4 in the intestine and/or liver. Using nonlinear mixed-effects modeling, we could separately quantify the effects of intestinal CYP3A4 expression, hepatic CYP3A4 expression, and the presence of ritonavir on both the absorption and elimination of lopinavir, which was previously not possible using noncompartmental methods. Intestinal, but not hepatic, CYP3A4-related first-pass metabolism was the major barrier for systemic entry of lopinavir. Relative oral bioavailability of lopinavir in mice expressing both hepatic and intestinal CYP3A4 was only 1.3% when compared with mice that were CYP3A deficient. In presence of ritonavir, relative bioavailability increased to 9.5% due to inhibiton of intestinal, but not due to inhibition of hepatic first-pass metabolism. Hepatic CYP3A4 related systemic clearance was inversely related to ritonavir exposure and not only hepatic but also intestinal CYP3A4 expression contributed to systemic clearance of lopinavir.

Phase I Study of Oral Azacitidine in Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia

To determine the maximum-tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and clinical activity of an oral formulation of azacitidine in patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). Patients received 1 cycle of subcutaneous (SC) azacitidine (75 mg/m2) on the first 7 days of cycle 1, followed by oral azacitidine daily (120 to 600 mg) on the first 7 days of each additional 28-day cycle. Pharmacokinetic and pharmacodynamic profiles were evaluated during cycles 1 and 2. Adverse events and hematologic responses were recorded. Cross-over to SC azacitidine was permitted for nonresponders who received ≥ 6 cycles of oral azacitidine. Overall, 41 patients received SC and oral azacitidine (MDSs, n = 29; CMML, n = 4; AML, n = 8). Dose-limiting toxicity (grade 3/4 diarrhea) occurred at the 600-mg dose and MTD was 480 mg. Most common grade 3/4 adverse events were diarrhea (12.2%), nausea (7.3%), vomiting (7.3%), febrile neutropenia (19.5%), and fatigue (9.8%). Azacitidine exposure increased with escalating oral doses. Mean relative oral bioavailability ranged from 6.3% to 20%. Oral and SC azacitidine decreased DNA methylation in blood, with maximum effect at day 15 of each cycle. Hematologic responses occurred in patients with MDSs and CMML. Overall response rate (i.e., complete remission, hematologic improvement, or RBC or platelet transfusion independence) was 35% in previously treated patients and 73% in previously untreated patients. Oral azacitidine was bioavailable and demonstrated biologic and clinical activity in patients with MDSs and CMML.

Development and in vivo evaluation of a new oral nanoparticulate dosage form for leuprolide based on polyacrylic acid

It was the aim of this study to develop a nanoparticulate oral drug delivery system for leuprolide based on polyacrylic acid (PAA). In order to achieve formation of nanoparticles in a mild, aqueous environment, two different techniques were combined, namely hydrophobic ion pairing between leuprolide and sodium dodecyl sulphate in a first step, followed by encapsulation into nanoparticles gained by interpolymer complexation between polyacrylic acid and Pluronic F68. The obtained nanoparticles were characterized regarding particle size distribution, drug encapsulation efficiency and in vitro release profile. Additionally, the pharmacokinetic profiles of leuprolide after oral administration of PAA-nanoparticulate and PAA-control tablets to male Sprague-Dawley rats were assessed and compared. It could be shown, that hydrophobic ion pairing increased encapsulation efficacy of leuprolide and leads to a slowed drug release of nanoparticulate suspensions. Relative oral bioavailability of leuprolide could be increased by nanoparticulate tablets up to 4.2-fold. Results verify that the suggested approach is a promising strategy for the design of oral delivery systems for oral administration of peptide drugs.

Evaluation of Pharmacokinetics of Simvastatin and Its Pharmacologically Active Metabolite from Controlled-Release Tablets of Simvastatin in Rodent and Canine Animal Models

Biotransformation of pharmacologically inactive lactone prodrug simvastatin (SV) into pharmacologically active simvastatin βhydroxy acid (SVA) exhibits inter-species differences due to variations in amount and activity of esterase enzymes. In this study, we investigated the pharmacokinetics (PK) of SV and its metabolite SVA following oral doses of SV from controlled-release (CR) tablets and immediate-release (IR) tablets in rodent and canine animal models that features different esterase activity. In rat PK study, no SV was detected in plasma for both formulations due to rapid hydrolysis of SV into SVA by plasma esterase. Besides, no signifi cant differences in PK parameters of SV or SVA were observed between both species. In dog PK study, the relative oral bioavailability of CR tablets in terms of SV was 72.3% compared to IR tablets. Regarding formulation differences in dogs, CR tablets exhibited signifi cantly lower C max (p<0.05), and higher T max (p<0.01) and MRT (p<0.01) for both SV and SVA compared to IR tablets. Accordingly, CR tablets of SV with prolonged drug release profi les in both species might be a potential candidate for a more effective delivery of SV with reduced side effects. Besides, similar PK parameters of SV and SVA in both species despite variation in enzyme activities suggested involvement of equally potent biotransformation pathways in these animal species.

A Novel Domperidone Hydrogel: Preparation, Characterization, Pharmacokinetic, and Pharmacodynamic Properties

The purpose of the present study was to prepare a novel domperidone hydrogel. The domperidone dispersion was prepared by the solvent evaporation method. The characteristics of domperidone dispersion were measured by dynamic light scattering (DLS), scanning electronic microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffractometry, and solubility test, respectively. Domperidone hydrogel was prepared by directly incorporating the domperidone dispersion in Carbopol hydrogel to increase its mucoadhesive properties to gastrointestinal tract (GIT). The in vivo pharmacokinetic and pharmacodynamic studies were investigated to evaluate the relative oral bioavailability and the propulsion efficacy of domperidone hydrogel as compared with market domperidone tablet (Motilium tablet). The particle size of domperidone dispersion in distilled water was 454.0 nm. The results of DSC and X-ray indicated that domperidone in dispersion was in amorphous state. The solubility of domperidone in the dispersion in distilled water, pH of 1, 5, and 7 buffer solution was 45.7-, 63.9-, 13.1-, and 3.7-fold higher than that of raw domperidone, respectively. The area under the plasma concentration curve (AUC0–24) in domperidone hydrogel was 2.2-fold higher than that of tablet. The prolonged propulsion efficacy in the domperidone hydrogel group compared to that in tablet group was observed in the pharmacodynamic test.

Enhanced oral bioavailability of cyclosporine A by liposomes containing a bile salt.

The main purpose of this study was to evaluate liposomes containing a bile salt, sodium deoxycholate (SDC), as oral drug delivery systems to enhance the oral bioavailability of the poorly water-soluble and poorly permeable drug, cyclosporine A (CyA). Liposomes composed of soybean phosphatidylcholine (SPC) and SDC were prepared by a thin-film dispersion method followed by homogenization. Several properties of the liposomes including particle size, polydispersity index, and entrapment efficiency were characterized. The in vitro release of CyA from these liposomes was less than 5% at 12 hours as measured by a dynamic dialysis method. The pharmacokinetic results in rats showed improved absorption of CyA in SPC/SDC liposomes, compared with CyA-loaded conventional SPC/cholesterol (Chol) liposomes and microemulsion-based Sandimmune Neoral®. The relative oral bioavailability of CyA-loaded SPC/SDC and SPC/Chol liposomes was 120.3% and 98.6%, respectively, with Sandimmun Neoral as the reference. The enhanced bioavailability of CyA was probably due to facilitated absorption by the liposomes containing SDC rather than improved release rate.

Preparation, characterization, and in vivo evaluation of a self-nanoemulsifying drug delivery system (SNEDDS) loaded with morin-phospholipid complex

BackgroundAs a poorly water-soluble drug, the oral application of morin is limited by its low oral bioavailability. In this study, a new self-nanoemulsifying drug delivery system (SNEDDS), based on the phospholipid complex technique, was developed to improve the oral bioavailability of morin.MethodsMorin-phospholipid complex (MPC) was prepared by a solvent evaporation method and characterized by infrared spectroscopy and X-ray diffraction. After formation of MPC, it was found that the liposolubility of morin was significantly increased, as verified through solubility studies. An orthogonal design was employed to screen the blank SNEDDS, using emulsifying rate and particle size as evaluation indices. Ternary phase diagrams were then constructed to investigate the effects of drug loading on the self-emulsifying performance of the optimized blank SNEDDS. Subsequently, in vivo pharmacokinetic parameters of the morin-phospholipid complex self-nanoemulsifying drug delivery system (MPC-SNEDDS) were investigated in Wistar rats (200 mg/kg of morin by oral administration).ResultsThe optimum formulation was composed of Labrafil® M 1944 CS, Cremophor® RH 40, and Transcutol® P (3:5:3, w/w), which gave a mean particle size of approximately 140 nm. Oral delivery of the MPC-SNEDDS exhibited a significantly greater Cmax (28.60 μg/mL) than the morin suspension (5.53 μg/mL) or MPC suspension (23.74 μg/mL) (all P < 0.05). Tmax was prolonged from 0.48 to 0.77 hours and to 1 hour for MPC and MPC-SNEDDS, respectively. In addition, the relative oral bioavailability of morin formulated in the MPC-SNEDDS was 6.23-fold higher than that of the morin suspension, and was significantly higher than that of the MPC suspension (P < 0.05).ConclusionThe study demonstrated that a SNEDDS combined with the phospholipid complex technique was a promising strategy to enhance the oral bioavailability of morin.

In Vitro and In Vivo Evaluation of a Novel Water-Soluble N-Glycyl Prodrug (N-GLY-CBZ) of Carbamazepine

The synthesis and characterization of N-glycyl-carbamazepine (N-Gly-CBZ), an N-acyl urea derivative of carbamazepine (CBZ) designed to act as a prodrug and convert to CBZ and glycine in vivo by enzymatic cleavage of the glycyl-urea bond was recently reported. The rate and extent of conversion of N-Gly-CBZ to CBZ in a whole animal model is reported here along with supporting in vitro data. Pharmacokinetic parameters were determined for N-Gly-CBZ and CBZ following IV and oral administration of N-Gly-CBZ and CBZ control to rats using a crossover design. The in vivo elimination of N-Gly-CBZ following IV administration in rats was biphasic in nature with a t(1/2) of about 1.1 min, which was very similar to the t(1/2) for appearance of CBZ. The mean value for the relative AUC ratio for CBZ from N-Gly-CBZ and CBZ from a cyclodextrin solution showed that N-Gly-CBZ delivered a (± SD) 98 ± 16% (± SD) equivalent dose of CBZ in six rats. The results of the IV dosing pharmacokinetics investigation were consistent with N-Gly-CBZ acting as a prodrug with rapid and complete conversion to CBZ in vivo. The overall absolute oral bioavailability of CBZ from N-Gly-CBZ was determined to be 41 ± 14% in three rats. The relative oral bioavailability of CBZ from N-Gly-CBZ compared to an oral CBZ control was 1.72 ± 0.54. That is, the prodrug, N-Gly-CBZ, demonstrated superior oral bioavailability of CBZ over the CBZ control, which was likely due to its greater aqueous solubility.

Polyamidoamine dendrimers as potential drug carriers for enhanced aqueous solubility and oral bioavailability of silybin

Purpose: In this study, the effect of polyamidoamine (PAMAM) dendrimers on the solubility of silybin was investigated. The in vitro drug release and the pharmacokinetics of silybin–dendrimer complex were also investigated. Methods: The solubilization of silybin by PAMAM dendrimers of generation G1.5, G2, G2.5, and G3 with different concentrations was determined and compared in different pH conditions. The in vitro release of silybin from the silybin–dendrimer complex was compared with pure silybin. Twelve rats randomized into two groups were separately orally administered silybin and silybin–PAMAM complex. Results: The water solubility of silybin was significantly improved by PAMAM dendrimers of generations G1.5, G2, G2.5, and G3 with different concentrations in different pH conditions (P < 0.05). The in vitro release of silybin from the silybin–dendrimer complex was significantly slower compared with pure silybin (P < 0.05). The pharmacokinetics parameters Tmax, Cmax, and AUC0–∞ of silybin and silybin–dendrimer complex were 10 minutes, 134.2 ng/mL, 654.6 (ng·h)/mL and 15 minutes, 182.4 ng/mL, 1298.7 (ng·h)/mL, respectively. The relative oral bioavailability of silybin–dendrimer complex calculated on the basis of AUC0–∞ was about 178% as compared with silybin. Conclusion: These results indicated that PAMAM dendrimers could increase the water solubility of silybin and improve its oral bioavailability.

Self-microemulsifying drug delivery system improves curcumin dissolution and bioavailability

Background: Curcumin has a wide spectrum of biological and pharmacological activities, but it has not yet been approved as a therapeutic agent because of its low solubility and stability in aqueous solution, and the relatively low bioavailability in vivo. To overcome these limitations, self-microemulsifying drug delivery system (SMEDDS) of curcumin was developed. Method: Various oils, surfactants, and cosurfactants were selected to optimize the formulation. Pseudoternary phase diagrams were constructed and orthogonal design was used to compare the oil-in-water (o/w) microemulsion-forming capacity of different oils/surfactants/cosurfactants. The solubility of curcumin in various oils and cosurfactants was determined to find suitable ingredients with a good solubilizing capacity. Droplet size was measured to obtain the concentration of oil, surfactant, and cosurfactant for forming stable microemulsion. Furthermore, its quality and bioavailability in mice were assessed. Results: Pseudoternary phase diagrams and solubility test showed that the formulation of SMEDDS composed of 20% ethanol, 60% Cremophor RH40®, and 20% isopropyl myristate, in which the concentration of curcumin reached 50 mg/mL. Curcumin was released completely from SMEDDS at 10 minutes. The developed SMEDDS formulation improved the oral bioavailability of curcumin significantly, and the relative oral bioavailability of SMEDDS compared with curcumin suspension was 1213%. Conclusion: The SMEDDS can significantly increase curcumin dissolution in vitro and bioavailability in vivo.

Preparation, characterization and relative bioavailability of oral elemene o/w microemulsion

The objective was to develop an elemene oil/water (o/w) microemulsion and evaluate its characteristics and oral relative bioavailability in rats. Elemene was used as the oil phase and drug, polysorbate 80 as a surfactant along with ethanol, propylene glycol, and glycerol as the cosurfactants. The microemulsion was prepared by mixing method, or ultrasonication method in an ultrasonic bath. Its three-dimensional response surface diagram was drawn by Mathcad software. The microemulsion was characterized by visual observation, cross-polarized microscopy, size, zeta potential, acidity, viscosity, and surface tension measurement. The drug content and entrapment efficiency were determined by ultra fast liquid chromatography (UFLC) and liquid surface method. Blood was drawn from rats at different time points after oral administration of an elemene microemulsion or a commercial elemene emulsion for measurement of the drug in plasma by UFLC to establish the pharmacokinetic parameters and relative bioavailability. The elemene microemulsion as a clarified and isotropic system containing 1% elemene (w/v), 5% ethanol (v/v), 15% propylene glycol (v/v), 15% glycerol (v/v), and 5% polysorbate 80 (w/v), was characterized as (57.7 ± 2.8) nm in size, 0.485 ± 0.032 in polydispersity index, (3.2 ± 0.4) mv in zeta potential, (5.19 ± 0.08) in pH, 6 mpa·s in viscosity, (31.8 ± 0.3) mN·m(-1) in surface tension, (8.273 ± 0.018) mg·mL(-1) in content of β-elemene, and (99.81 ± 0.24)% in average entrapment efficiency. The area under the concentration-time curves from 0 h to 24 h (AUC(0→24h)) of the elemene microemulsion and commercial elemene emulsion were integrated to be 3.092 mg·h·L(-1) and 1.896 mg·h·L(-1) respectively, yielding a relative bioavailability of 163.1%. The present study demonstrates the elemene microemulsion as a new formulation with ease of preparation, high entrapment efficiency, excellent clarity, good stability, and improved bioavailability.

Cyclosporin A-Loaded Poly(ethylene glycol)-b-poly(d,l-lactic acid) Micelles: Preparation, in Vitro and in Vivo Characterization and Transport Mechanism across the Intestinal Barrier

To improve the oral bioavailability of poorly water-soluble cyclosporin A (CyA), polymeric micelles based on monomethoxy poly(ethylene glycol)-b-poly(d,l-lactic acid) (mPEG-PLA) were prepared. In vitro release test showed that the cumulative release percentage, about 85%, of CyA from polymeric micelles within 24 h was comparable to that from Sandimmun Neoral, the currently available oral formulation of CyA. A relative oral bioavailability of 137% in rats compared with Sandimmun Neoral was demonstrated for CyA-loaded polymeric micelles. The other aim of the current work was to study the transport mechanism of mPEG-PLA micelles across the intestinal barrier. It was found that polymeric micelles could significantly increase the permeability of CyA across Caco-2 monolayers without significantly affecting transepithelial electrical resistance values, and the apparent permeation coefficient (P(app)) of CyA was significantly higher in the AP-BL direction compared to that in the BL-AP direction, suggesting that polymeric micelles might undergo an active AP to BL transport that probably involved endocytosis which was confirmed by confocal microscope observation. The permeation of CyA through Caco-2 monolayers showed that the P(app) was significantly increased when CyA was formulated with the copolymer below its critical association concentration (CAC) and no significant difference was found above its CAC, implying that mPEG-PLA monomers affected the intestinal P-gp efflux pumps. Therefore, the mPEG-PLA micelles seemed to be a good candidate for oral delivery of poorly soluble drugs.

Relative oral bioavailability of morphine and naltrexone derived from crushed morphine sulfate and naltrexone hydrochloride extended-release capsules versus intact product and versus naltrexone solution: A single-dose, randomized-sequence, open-label, three-way crossover trial in healthy volunteers

Background: Morphine sulfate/sequestered naltrexone hydrochloride (HCl) (MS-sNT) extended-release fixed-dose combination capsules, approved by the US Food and Drug Administration (FDA) in August 2009 for chronic moderate to severe pain, contain extended-release morphine pellets with a sequestered core of the opioid antagonist naltrexone. MS-sNT was designed so that if the product is tampered with by crushing, the naltrexone becomes bioavailable to mitigate morphine-induced subjective effects, rendering the product less attractive for tampering. Objectives: The primary aim of this study was to compare the oral bioavailability of naltrexone and its metabolite 6-β-naltrexol, derived from crushed pellets from MS-sNT capsules, to naltrexone solution. This study also assessed the relative bioavailability of morphine from crushed pellets from MS-sNT capsules and that from the whole, intact product. Methods: This single-dose, randomized-sequence, open-label, 3-period, 3-treatment crossover trial was conducted in healthy volunteers. Adults admitted to the study center underwent a 10-hour overnight fast before study drug administration. Each subject received all 3 of the following treatments, 1 per session, separated by a 14-day washout: tampered pellets (crushed for ≥2 minutes with a mortar and pestle) from a 60-mg MS-sNT capsule (60 mg morphine/2.4 mg naltrexone); 60-mg whole, intact MS-sNT capsule; and oral naltrexone HCl (2.4 mg) solution. Plasma concentrations of naltrexone and 6-β-naltrexol were measured 0 to 168 hours after administration. Morphine pharmaco-kinetics of crushed and whole pellets were determined 0 to 72 hours after administration. The analysis of relative bioavailability was based on conventional FDA criteria for assuming bioequivalence; that is, 90% CIs for ratios of geometric means (natural logarithm [In]-transformed C max and AUC) fell within the range of 80% to 125%. Subjects underwent physical examinations, clinical laboratory tests, and ECG at screening and study discharge and were monitored for adverse events (AEs) throughout the study. Results: Of the 24 subjects enrolled in the study, 23 completed it. Most subjects were white (79%) and male (63%); the mean (SD) age was 39.3 (11.2) years and the mean weight was 77.6 (13.5) kg (range, 55.0102.5 kg). Plasma C max and AUC 0-t of naltrexone after the administration of crushed pellets of MS-sNT (579 pg/mL and 1811 h · pg/mL, respectively) and naltrexone solution (584 pg/mL and 1954 h · pg/mL) were not significantly different; 90% CIs were 83.8% to 116% and 83.3% to 102%, meeting the regulatory requirements for assuming bioequivalence in this study population. Plasma naltrexone concentration was below the lower limit of quantitation (4.0 pg/mL) in 23 of 24 subjects (96%) after whole MS-sNT administration. Morphine AUC 0-t was not significantly different whether MS-sNT was crushed (163 h · ng/mL) or administered whole (174 h · ng/mL), but C max was numerically higher (24.5 vs 7.7 ng/mL) and T max was numerically shorter (2.00 vs 7.03 hours) with MS-sNT crushed versus whole. The most commonly reported AEs were nausea (8/23 [35%], 10/24 [42%], and 3/23 [13%] subjects in the crushed, whole, and naltrexone groups, respectively) and emesis (6 [26%], 7 [29%], and 2 [9%]). Conclusions: In this single-dose study, when pellets from MS-sNT were crushed, naltrexone appeared to be completely released and available to mitigate morphine-induced effects. When MS-sNT was administered whole, morphine was released in an extended-release fashion while naltrexone remained sequestered.