Relative Oral Bioavailability Research Articles

152 Reducing the bioavailability of a mix of mycotoxins in broiler chickens with a clay- and algae-based decontaminant

Abstract Poultry feed is often contaminated with several mycotoxins that can impair animal health and performance, even at levels below the official guidance. The incorporation of mycotoxin decontaminants in the feed can limit these adverse effects. It is necessary to test the efficacy of these supplementations in vivo, but this requires specific experimental setups. The objective of this study was to test, in a validated toxicokinetic model, the ability of an algae-clay-based decontaminant to reduce the exposure of broilers to mycotoxin polycontamination (aflatoxin B1 – AFB1, ochratoxin A – OTA and deoxynivalenol, DON). The study included 16 male broiler chickens (Ross 308) of approximately 1.6 kg body weight (BW). After an acclimatization period of 1 wk, the broiler chickens were fasted for 12 h and then administered a single oral bolus with either the mycotoxins (n = 8) or the mycotoxins in combination with the decontaminant (n = 8; 2.0 mg AFB1/kg BW, 0.5 mg DON/kg BW, 0.25 mg OTA/kg BW, 2.5 g decontaminant/kg feed), administered in a parallel study design. Blood samples of the 16 broiler chickens were taken at different time points between 0 h (before administration) and 24 h (post administration; p.a.). The analysis of deoxynivalenol-3-sulphate (DON-3S, DON main metabolite), OTA and AFB1 in plasma was performed using UHPLC-MS/MS. The following parameters were calculated: area under the curve from time zero to the last point above the LOQ (AUC0→t), maximal plasma concentration (Cmax) and time at maximal plasma concentration (Tmax). Results showed that, using the oral bolus model, the mycotoxin decontaminant significantly altered the AUC0- >12h of DON-3S in broiler chicken (P = 0.012). The relative oral bioavailability [(average AUC0- >t mycotoxin + decontaminant/ average AUC0- >t mycotoxin) * 100] of DON-3S when administered with the decontaminant was 60.1%. For OTA, the decontaminant decreased the absorption of OTA as indicated by a significantly decreased AUC0- >24h (P < 0.001). Consequently, the relative oral bioavailability of OTA when administered with the decontaminant was lowered as well, namely 55.7%. For AFB1, the decontaminant affected the absorption of AFB1 with a significantly decreased AUC0- >8h (P < 0.001), Cmax (P < 0.001) and a significantly delayed Tmax (P = 0.025). Consequently, the relative oral bioavailability of AFB1 when administered with the decontaminant was 35.9%. Therefore, it can be concluded that the tested algae-clay based mycotoxin decontaminant reduces the oral absorption of multiple mycotoxins orally administered to broiler chickens in a single oral bolus model. These results are consistent with results obtained with DON in different experimental models (in vitro dynamics and in vivo performance) and confirm the efficacy of the decontaminant tested to control this mycotoxin in poultry production.

Infant formula as a solid lipid dose form for enhancement of the oral bioavailability of cannabidiol for paediatric patients

Cannabinoids can save paediatric patients from harmful psychological conditions caused by epilepsy. However, the limited aqueous solubility of the drug presents a limitation to oral absorption and bioavailability. Previous studies have shown the enhancement of oral bioavailability for poorly water-soluble drugs using milk or milk-based products like infant formula as a novel lipid-based formulation, due to digestion of the lipids to enhance drug solubility. that is particularly well suited to infants and in low economy settings. Therefore, this study has investigated the in vitro solubilization enhancement of cannabidiol (CBD) in milk-based products during digestion using synchrotron small angle X-ray scattering, followed by pharmacokinetic studies to determine the relative oral bioavailability. The in vitro results, coupled with in vivo data, demonstrate a two-fold increase in the oral bioavailability of CBD in bovine milk as well as infant formula. The results of this study indicate the potential for infant formula to be considered as a novel formulation approach for CBD. Further study is encouraged for more drugs with infant formula to strengthen the correlation between the solubilization of drug and their oral bioavailability.

An Algoclay-Based Decontaminant Decreases Exposure to Aflatoxin B1, Ochratoxin A, and Deoxynivalenol in a Toxicokinetic Model, as well as Supports Intestinal Morphology, and Decreases Liver Oxidative Stress in Broiler Chickens Fed a Diet Naturally Contaminated with Deoxynivalenol.

The aims of this study were (i) to determine the effect of an algoclay-based decontaminant on the oral availability of three mycotoxins (deoxynivalenol; DON, ochratoxin A; OTA, and aflatoxin B1; AFB1) using an oral bolus model and (ii) to determine the effect of this decontaminant on the performance, intestinal morphology, liver oxidative stress, and metabolism, in broiler chickens fed a diet naturally contaminated with DON. In experiment 1, sixteen 27-day-old male chickens (approximately 1.6 kg body weight; BW) were fasted for 12 h and then given a bolus containing either the mycotoxins (0.5 mg DON/kg BW, 0.25 mg OTA/kg BW, and 2.0 mg AFB1/kg BW) alone (n = 8) or combined with the decontaminant (2.5 g decontaminant/kg feed; circa 240 mg/kg BW) (n = 8). Blood samples were taken between 0 h (before bolus administration) and 24 h post-administration for DON-3-sulphate, OTA, and AFB1 quantification in plasma. The algoclay decontaminant decreased the relative oral bioavailability of DON (39.9%), OTA (44.3%), and AFB1 (64.1%). In experiment 2, one-day-old male Ross broilers (n = 600) were divided into three treatments with ten replicates. Each replicate was a pen with 20 birds. The broiler chickens were fed a control diet with negligible levels of DON (0.19-0.25 mg/kg) or diets naturally contaminated with moderate levels of DON (2.60-2.91 mg/kg), either supplemented or not with an algoclay-based decontaminant (2 g/kg diet). Jejunum villus damage was observed on day 28, followed by villus shortening on d37 in broiler chickens fed the DON-contaminated diet. This negative effect was not observed when the DON-contaminated diet was supplemented with the algoclay-based decontaminant. On d37, the mRNA expression of glutathione synthetase was significantly increased in the liver of broiler chickens fed the DON-contaminated diet. However, its expression was similar to the control when the birds were fed the DON-contaminated diet supplemented with the algoclay-based decontaminant. In conclusion, the algoclay-based decontaminant reduced the systemic exposure of broiler chickens to DON, OTA, and AFB1 in a single oral bolus model. This can be attributed to the binding of the mycotoxins in the gastrointestinal tract. Moreover, dietary contamination with DON at levels between 2.69 and 2.91 mg/kg did not impair production performance but had a negative impact on broiler chicken intestinal morphology and the liver redox system. When the algoclay-based decontaminant was added to the diet, the harm caused by DON was no longer observed. This correlates with the results obtained in the toxicokinetic assay and can be attributed to a decreased absorption of DON.

Multi-functional Chitosan Polymeric Micelles for improving the oral bioavailability of Paclitaxel based on synergistic effect.

A novel multi-functional micelle delivery system was developed for enhancing the oral absorption of paclitaxel (PTX). The delivery carriers were constructed by modifying chitosan-stearic acid (CS-SA) micelles with L-carnitine (LC) and co-encapsulating quercetin (Que), and the PTX-loaded micelles were prepared by film-sonication dispersing technique. The as-prepared micelles showed homogeneous spherical shapes with a small particle size of 148.3 ± 1.7nm, high drug loading of 7.05% and low critical micelle concentration (CMC) of 16.89µg/ml. Compared to the in-house PTX formulation similar to the commercial injection Taxol™, the target PTX-loaded micelles had obvious sustained-release effects and exhibited an oral relative bioavailability of 168.08%. The cellular uptake studies of Caco-2 cells confirmed the micellar modification of LC and the co-loading of Que played important roles in promoting the absorption of drug loaded in micelles. The CYP3A4 enzyme test demonstrated the micelles had an inhibitory effect on the metabolic enzyme due to the presence of Que. These findings confirmed the potential of the multi-functional chitosan polymeric micelles based on synergistic effect as an effective oral delivery system.

Abstract CT167: Trial in progress: Phase 1 dose escalation study of T-1101, a first-in-class oral Hec1/Nek2 inhibitor, in patients with advanced refractory solid tumors

Abstract Background: T-1101, a novel small molecule, is the first-in-class oral agent that specifically disrupts the interaction between two commonly overexpressed, critical mitotic regulators, Hec1 and Nek2, within cancer cells. Such disruption leads to abnormal mitosis followed by apoptosis of cancer cells and provides a potential therapeutic strategy for cancer treatment. T-1101, with growth inhibition concentrations (IC50) ranging from14 to 74 nM across various human cancer cell lines, exhibited potent anti-liver and breastcancer activities in vivo, and highly active (IC50 7-19 nM) in MDR (multiple drugresistance) expressing cell lines. The effective inhibitory dose of T-1101 was determined to be between 10 and 25 mg/kg twice a day in xenograft animal models. Moreover, T-1101 has synergistic activity when combined with other anticancer drugs such as doxorubicin, topotecan and paclitaxel etc. Clinically, oral powder for constitution (OPC) form was first used in the initial study. To improve better patient compliance, the capsule (CAP) form is then deployed in current T-1101’s phase 1 study. Methods: Two T-1101 oral formulations (OPC and CAP) have been designed for the first-in-human, multi-center, open-label, dose-escalation studies to evaluate the safety, tolerability and establish the Recommended Phase 2 Dose (RP2D) in subjects with advanced refractory solid tumors. The secondary objectives are to assess the pharmacokinetics (PK) and therapeutic response after receiving treatment. DLT was determined within the first treatment cycle. Patients showing clinical benefit after first 2cycles of T-1101may enter extension cohort to continue the treatment. In OPC 3+3 escalation study (NCT03195764, NCT03349073), T-1101 was administered orally once daily, days 1 to 14 every 21 days per cycle with 8 planned dose levels at dose of 9, 18, 36, 54, 72, 90, 108 to 126 mg/m2. The OPC study was terminated at 36 mg/m2 before the primary endpoint (determination of maximum tolerated dose; MTD) was reached and subsequent dosing level will be evaluated with the CAP formulation. Based on the 52% of relative oral bioavailability (%F) of CAP versus OPC in preclinical Beagle dogs’ PK study, the starting dose of CAP form of T-1101 was determined at 100 mg daily forconsecutive 28-day per cycle for 2 cycles with dose levels of 100, 200, 225, 250, 300 and 350 mg/day. The accelerated titration and Bayesian Optimal Interval (BOIN) designs are used for the T-1101 capsule dose escalation study (NCT04685473), in which one subject will be enrolled per dose level until one subject have DLT or two subjects experience ≥ Grade 2 drug-related AE during Cycle 1 at any dose level, then the dose escalation will follow the BOIN design. Cohorts 1 (100 mg/day) 2 (200 mg/day) and 3 (225 mg/day) have been completed without DLT. As of November 2023, the trial remains open to enrollment. Citation Format: Wu-Chou Su, Li-Yuan Bai, Hui-Hua Hsiao, Her-Shyong Shiah, Yu-Min Yeh, Shang-Hung Chen, Shang-Yin Wu, Hui-Ching Wang, Hui-Jen Tsai, Kwang-Yu Chang, Jui-Hung Tsai, Chun-Hui Lee, Chieh Hua Lee, Yu-Sheng Chao, Li-Tzong Chen. Trial in progress: Phase 1 dose escalation study of T-1101, a first-in-class oral Hec1/Nek2 inhibitor, in patients with advanced refractory solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT167.

Design and therapeutic application of trans‐sodium crocetinate‐loaded cyclodextrin metal–organic frameworks as an enteric preparation for treating chronic heart failure

Chronic heart failure (CHF) arises from structural and functional changes in the myocardial tissue attributable to various etiologies. Crocetin and its derivative trans‐sodium crocetinate (TSC) have exhibited cardioprotective attributes; however, their poor aqueous solubility and bioavailability impede clinical development. This study aimed to construct a cyclodextrin metal–organic frameworks (CDMOFs)‐based oral delivery system to enhance the pharmacokinetic profile and therapeutic efficacy of TSC for CHF treatment. TSC was loaded into the synthesized γ‐CDMOFs via vacuum adsorption. The CDMOFs@TSC formulation was characterized and evaluated in vitro. Pharmacokinetic and pharmacodynamic analyses were performed in beagle dogs and CHF rats induced by coronary artery ligation, respectively. Both TSC and CDMOFs@TSC elicited no discernible toxicity or pathological changes in major organs of rats, providing preliminary evidence for their biosafety. Pharmacokinetic study in beagle dogs demonstrated that CDMOFs@TSC capsules markedly increase the relative oral bioavailability by 198% versus free TSC capsules. In rats afflicted with CHF, the administration of CDMOFs@TSC yielded notable enhancements in cardiac function. Additionally, it precipitated a reduction in biomarkers linked to myocardial injury, manifested anti‐inflammatory and antifibrotic effects, and induced alterations in myocardial energy metabolism. This is the first report of CDMOFs‐based oral delivery to improve the TSC bioavailability and efficacy. The utilization of CDMOFs@TSC resulted in superior therapeutic outcomes in comparison to standalone TSC by optimizing pharmacokinetics and precise targeted delivery. These results highlight the clinical potential of CDMOF as porous carriers to enable oral delivery of natural products for CHF therapy.

Comparative Evaluation of Bioavailability, Efficacy and Safety of MICROCORE NESC® with Calcium Carbonate and Calcium Citrate Malate in Osteopenic and Osteoporotic Patients: A Randomized Clinical Trial.

Osteoporosis is a skeletal disease characterized by loss of bone mass, reduced bone strength and increased bone fragility predisposing to fractures. This study was planned to evaluate the efficacy, safety and relative bioavailability of Microcore NESC® (Natural Egg Shell Calcium) in osteopenia and osteoporotic patients. This was a randomized, open label, parallel group interventional clinical trial which included 60 study participants with osteopenia and osteoporosis who were randomized into three groups (20 each). Group 1-Microcore NESC®, Group 2-Shelcal and Group 3-CCM with 12weeks treatment period. The participants were evaluated for relative oral bioavailability, bone mineral density (BMD), serum osteocalcin, change in VAS pain scale and quality of life-Questionnaires. There was significant improvement in the BMD T scores-post-treatment with MICROCORE NESC® and Shelcal. Higher percentage of improvement in calcium absorption as depicted by an increase in serum calcium levels (10.23%) in the MICROCORE NESC®-treated group when compared to Shelcal (7.7%) and CCM (7.2%). The relative bioavailability of MICROCORE NESC® with respect to Shelcal was 93%. MICROCORE NESC®, has shown a better oral relative bio availability of calcium (93%), better improvement of BMD T score compared to Shelcal and CCM. The general health status has improved to very good/excellent in 83% of patients in MICROCORE NESC®-treated group. Thus, MICROCORE NESC® can be considered a better and safe calcium supplement, as there are very few side effects observed without any clinically significant abnormalities in lab parameters.

Solid self-microemulsifying drug delivery system (S-SMEDDS) prepared by spray drying to improve the oral bioavailability of cinnamaldehyde (CA)

The aim of this study was to prepare a solid self-microemulsifying drug delivery system (S-SMEDDS) of cinnamaldehyde (CA) by spray drying technique to improve the oral bioavailability of CA. The preparation of CA S-SMEDDS with maltodextrin as the solid carrier, a core-wall material mass ratio of 1:1, a solid content of 20% (w/v), an inlet air temperature of 150 °C, an injection speed of 5.2 mL/min, and an atomization pressure of 0.1 MPa was determined by using the encapsulation rate as the index of investigation. Differential scanning calorimetry (DSC) revealed the possibility of CA being encapsulated in S-SMEDDS in an amorphous form. The in-vitro release showed that the total amount of CA released by S-SMEDDS was approximately 1.3 times higher than that of the CA suspension. Pharmacokinetic results showed that the relative oral bioavailability of CA S-SMEDDS was also increased to 1.6-fold compared to CA suspension. Additionally, we explored the mechanism of CA uptake and transport of lipid-soluble drugs CA by S-SMEDDS in a Caco-2/HT29 cell co-culture system for the first time. The results showed that CA S-SMEDDS uptake on the co-culture model was mainly an energy-dependent endocytosis mechanism, including lattice protein-mediated endocytosis and vesicle-mediated endocytosis. Transport experiments showed that CA S-SMEDDS significantly increased the permeability of CA in this model. These findings suggested that CA S-SMEDDS is an effective oral solid dosage form for increasing the oral bioavailability of lipid-soluble drug CA.

Pharmacokinetic enhancement of marbofloxacin by alpha-1-monolaurin pre-treatment in broiler chickens.

The present study investigated the prospect of improvement in pharmacokinetic (PK) parameters of marbofloxacin due to alpha-1-monolaurin pre-treatment in broiler chickens. Two groups of broilers were administered a single oral dose of marbofloxacin (5.00 mg kg-1 body weight): Group-I without pre-treatment and Group-II with alpha-1-monolaurin pre-treatment (4.00 g kg-1 feed for 10 days). Blood sampling was done periodically for both groups and plasma marbofloxacin concentrations were determined using ultra-high performance liquid chromatography. Pharmacokinetic parameters using non-compartmental modelling approach were calculated with the PKSolver software. Statistical analysis revealed significant differences in plasma marbofloxacin concentrations between the two groups at 1, 2, and 24 hr. Group-II birds exhibited a higher mean maximum plasma concentration (2.43 µg mL-1) at an earlier time (Tmax: 1.38 hr) compared to Group-I. The plasma concentrations of marbofloxacin were maintained above 0.10 and 0.18 µg mL-1 up to 24 hr in Group-I and Group-II broilers, respectively. Significant differences were observed in PK parameters such as the area under the curve and total body clearance. The mean relative oral bioavailability of Group-II birds compared to Group-I was 119.61%. The findings of the study provided evidence of PK parameters enhancement of marbofloxacin in the alpha-1-monolaurin pre-treated group. The calculated PK-pharmacodynamic indices for marbofloxacin predicted clinical efficaciousness in the broiler chickens.

Relative Oral Bioavailability and Food Effects of Two Sepiapterin Formulations in Healthy Participants.

Sepiapterin is an orally administered drug in development for the treatment of phenylketonuria, an inborn error of metabolism characterized by the deficiency of the phenylalanine-metabolizing enzyme phenylalanine hydroxylase. This study characterized the pharmacokinetics, safety, and tolerability of 2 clinical sepiapterin formulations (Phase 1/2, Phase 3) and the effects of food on the pharmacokinetics of the Phase 3 formulation in healthy participants. In Part A, 18 participants were randomized to one of 2 treatment sequences, each with 4 dosing periods comprising a single dose (20 or 60mg/kg) of the Phase 1/2 or the Phase 3 formulation with a low-fat diet. In Part B, 14 participants were randomized to one of 2 sequences, each comprising 4 dosing periods of a single dose (20 or 60mg/kg) of the Phase 3 formulation under fed (high-fat) or fasted conditions. Following oral administration, sepiapterin was quickly absorbed and rapidly and extensively converted to tetrahydrobiopterin (BH4). BH4 was the major circulating active moiety. Under low-fat conditions, the Phase 3 formulation was bioequivalent to the Phase 1/2 formulation at 20mg/kg, while slightly lower BH4 exposure (approximately 0.81×) for the Phase 3 formulation was observed at 60mg/kg. BH4 exposure increased to approximately 1.7× under the low-fat condition and approximately 2.8× under the high-fat condition at a dose of either 20 or 60mg/kg for the Phase 3 formulation, compared with the fasted condition. Both sepiapterin formulations were well tolerated, with no serious or severe adverse events reported. All treatment-emergent adverse events were mild or moderate in severity.

Dual strategy to improve the oral bioavailability of efavirenz employing nanomicelles and curcumin as a bio-enhancer

The present investigation was focused on the development of Soluplus®-based nanomicelles (NMs) (10 % w/v) loaded with Efavirenz (EFV) (5 mg/mL) and Curcumin (natural bio-enhancer) (CUR) (5, 10 and 15 mg/mL) to improve the oral bioavalability of EFV. Micellar formulations were obtained employing an acetone-diffusion technique. Apparent aqueous solubility was increased up to ∼1250-fold and 25,000-fold for EFV and CUR, respectively. Drug-loaded nanoformulations showed an excellent colloidal stability with unimodal size distribution and PDI values < 0.30. In vitro drug release was 41.5 % (EFV) and 2.6 % (CUR) from EFV-CUR-NMs over 6 h in simulated gastrointestinal fluids. EFV-CUR-loaded NMs resulted as safe nanoformulations according to the in vitro cytocompatibility assays in Caco-2 cells. Furthermore, CUR bio-enhancer activity was demonstrated for those nanoformulations. A CUR concentration of 15 mg/mL produced a significant (p < 0.05) increment (2.64-fold) of relative EFV oral bioavailability. Finally, the active role of the lymphatic system in the absorption process of EFV, after its oral administration was assessed in a comparative pharmacokinetic study in presence and absence of cycloheximide, a lymphatic transport inhibitor.Overall our EFV-CUR-NMs denoted their potential as a novel nanotechnological platform, representing a step towards an optimized “nano-sized” therapy for AIDS patients.

Chitosan-based oral nanoparticles as an efficient platform for kidney-targeted drug delivery in the treatment of renal fibrosis

There is increasingly keen interest in developing orally delivered targeted drugs, especially for diseases that require long-term medication. Hence, we manufactured nanoparticles derived from methoxypolyethylene glycol-chitosan (PCS) to enhance the oral delivery and kidney-targeted distribution of salvianolic acid B (SalB), a naturally occurring renoprotective and anti-fibrotic compound, as a model drug for the treatment of renal fibrosis. Orally administered SalB-loaded PCS nanoparticles (SalB-PCS-NPs) maintained good stability in the gastrointestinal environment, improved mucus-penetrating capacity, and enhanced transmembrane transport through a Caco-2 cell monolayer. The relative oral bioavailability of SalB-PCS-NPs to free SalB and SalB-loaded chitosan nanoparticles (SalB-CS-NPs) was 367.0 % and 206.2 %, respectively. The structural integrity of SalB-PCS-NPs after crossing the intestinal barrier was also validated by Förster resonance energy transfer (FRET) in vitro and in vivo. Fluorescein isothiocyanate (FITC)-labeled SalB-PCS-NPs showed higher kidney accumulation than free FITC and FITC-labeled SalB-CS-NPs (4.6-fold and 2.1-fold, respectively). Significant improvements in kidney function, extracellular matrix accumulation, and pathological changes were observed in a unilateral ureter obstruction mouse model of renal fibrosis after once daily oral treatment with SalB-PCS-NPs for 14 days. Thus, oral administration of SalB-PCS-NPs represents a promising new strategy for kidney-targeted drug delivery.

Preparation, characterization and in vivo pharmacokinetic study of ginsenoside Rb1-PLGA nanoparticles

This study aimed to construct a Ginsenoside Rb1-PLGA nano drug delivery system, optimize its preparation process, characterize and evaluate the resulting Ginsenoside Rb1-PLGA Nanoparticles (GRb1@PLGA@NPs). GRb1@PLGA@NPs were prepared using the emulsion solvent evaporation method. The optimal preparation process was determined using Plackett–Burman design combined with Box-Behnken experiments. Physical characterization and in vitro release studies were conducted. LC–MS/MS technique was employed to investigate the pharmacokinetic characteristics of GRb1 and GRb1@PLGA@NPs in rat plasma. The optimal preparation process yielded GRb1@PLGA@NPs with a particle size of 120.63 nm, polydispersity index (PDI) of 0.172, zeta potential of − 22.67 mV, encapsulation efficiency of 75%, and drug loading of 11%. In vitro release demonstrated sustained drug release. Compared to GRb1, GRb1@PLGA@NPs exhibited a shortened time to peak concentration by approximately 0.72-fold. The area under the plasma concentration–time curve significantly increased to 4.58-fold of GRb1. GRb1@PLGA@NPs formulated using the optimal process exhibited uniform distribution and stable quality, its relative oral bioavailability was significantly improved compared to free GRb1.

Mucus-penetrating and permeation enhancer albumin-based nanoparticles for oral delivery of macromolecules: Application to bevacizumab

The oral administration of therapeutic proteins copes with important challenges (mainly degradation and poor absorption) making their potential therapeutic application extremely difficult. The aim of this study was to design and evaluate the potential of the combination between mucus-permeating nanoparticles and permeation enhancers as a carrier for the oral delivery of the monoclonal antibody bevacizumab, used as a model of therapeutic protein. For this purpose, bevacizumab was encapsulated in PEG-coated albumin nanoparticles as a hydrophobic ion-pairing complex with either sodium deoxycholate (DS) or sodium docusate (DOCU). In both cases, complex formation efficiencies close to 90% were found. The incorporation of either DS or DOCU in PEG-coated nanoparticles significantly increased their mean size, particularly when DOCU was used. Moreover, the diffusion in mucus of DOCU-loaded nanoparticles was significantly reduced, compared with DS ones. In a C. elegans model, DS or DOCU (free or nanoencapsulated) disrupted the intestinal epithelial integrity, but the overall survival of the worms was not affected. In rats, the relative oral bioavailability of bevacizumab incorporated in PEG-coated nanoparticles as a complex with DS (B-DS-NP-P) was 3.7%, a 1000-fold increase compared to free bevacizumab encapsulated in nanoparticles (B-NP-P). This important effect of DS may be explained not only by its capability to transiently disrupt tight junctions but also to their ability to increase the fluidity of membranes and to inhibit cytosolic and brush border enzymes. In summary, the current strategy may be useful to allow the therapeutic use of orally administered proteins, including monoclonal antibodies.Graphical

Pharmacokinetic profiles and egg residue patterns of levamisole in laying hens at two dosing rates and two routes of administration

The levamisole maximum residue limit for edible fat, kidney, and muscle of chickens is 0.01 mg/kg. However, no maximum residue limit has been established for eggs. In the present study, the pharmacokinetic profile and levamisole residue in the eggs from laying hens were investigated using ultra-performance liquid chromatography-tandem mass spectrometry. A single dose of levamisole (30 mg/kg) was administered via the intramuscular or oral route, and an additional egg residue study was performed with 300 or 600 mg/kg commercial LEV drug (30 or 60 mg/kg as levamisole) orally. The limit of quantification was 0.0056 μg/mL and 0.0015 mg/kg for plasma and eggs, respectively. The plasma concentration was below the limit of quantification 10 and 12 h after intramuscular and oral administration, respectively. The half-life of the absorption phase was comparable between the intramuscular and oral routes, which was approximately 1 h, and the mean maximum concentration value was significantly higher in intramuscular (2.29 ± 0.30 μg/mL) than in oral (1.45 ± 0.38 μg/mL) route. The relative oral bioavailability after intramuscular administration was 92.3%. In the egg residue study, dose-dependent area under concentration and maximum concentration were observed after single oral administration of 30 and 60 mg/kg egg residue, and the calculated withdrawal period for both 30 and 60 mg/kg groups based on the positive list system standard (0.01 mg/kg) was 7 d after the treatment.

Oral metronomic therapy of pancreatic cancer with gemcitabine and paclitaxel co-loaded in lecithin-based Self-Nanoemulsifying preconcentrate (LBSNEP)

This study aimed to evaluate gemcitabine (GEM)/paclitaxel (PTX) co-loaded into a lecithin-based self-nanoemulsifying preconcentrate (LBSNEP) orally administered in a metronomic therapeutic manner against pancreatic cancer. LBSNEP was developed and evaluated, composed of Caproyl 90, Tween80, lecithin, TPGS, and propyl glycol at a ratio of 20:20:30:5:25, resulting in a droplet diameter of approximately 180 nm. Cell viability studies on MIA PaCa-2 demonstrated a synergetic effect at a proportion of 1:2 between PTX and GEM. Additionally, LBSNEP and baicalein (BAI) were demonstrated to prevent GEM from being deaminated by cytidine deaminase. The combination of GEM, PTX, and BAI in the LBSNEP showed good dissolution in simulated gastric fluid. The pharmacokinetic study conducted on rats showed that co-administration of GEM, PTX, and BAI in the LBSNEP enhanced the respective relative oral bioavailability levels of GEM and PTX by 1.5- and 2-fold, respectively, compared to the solution group. The tumor inhibition study was conducted with metronomic therapy at a low daily dose compared to conventional therapy at a higher dose every 3 days. Results indicated that oral metronomic delivery of GEM/PTX/BAI LBSNEP could inhibit tumor growth during administration phase, and that there were similar tumor volumes compared to traditional chemotherapy at day 28 even if the dose of metronomic chemotherapy was 2.2-fold less than that of the latter. In conclusion, a self-nanoemulsifying drug-delivery system for the oral delivery of GEM, PTX, and BAI in a metronomic manner enhanced the therapeutic effect on pancreatic cancer, providing an alternative option for chemotherapy.

Curcumin amorphous solid dispersions benefit from hydroxypropyl methylcellulose E50 to perform enhanced anti-inflammatory effects

The solubility and permeability enhancement of curcumin (Cur) is crucial for its manufacture and application in medical field. Herein, Cur amorphous solid dispersions (ASDs) with enhanced drug solubility and permeability was formulated by Eudragit EPO (EuD) and biological macromolecules of hydroxypropyl methylcellulose E50 (HPMC), and significant functions of HPMC for Cur ASDs were mainly studied. The results showed that the mean particle size of Cur decreased from more than 300 nm to less than 200 nm with the addition of HPMC in excipient aqueous solution evidenced by dynamic light scattering result, confirming that HPMC had the ability to inhibit crystallization by lowering drug-rich droplets in the initial mixing process. Innovatively for molecular dynamic modeling study, crystalline Cur molecules in EuD medium trended to aggregate while not for EuD/HPMC 1:1 and EuD/HPMC 3:1 medium. HPMC functioned as surfactant converted the arrangement of phospholipid bilayers to un-ordered, and un-ordered state of phospholipids lead to the enhancement of Cur transmembrane using HPMC as auxiliary excipient. Cur-EuD/HPMC 3:1 contributed greatly to the Cur permeability, leading to obtain superior relative oral bioavailability and anti-inflammatory effect. Cur ASDs with proper amount of HPMC can be rendered as outstanding therapeutic strategy for medical application.

Formulation and Characterization of Ursodeoxycholic Acid Nanosuspension Based on Bottom-Up Technology and Box-Behnken Design Optimization.

Ursodeoxycholic acid (UDCA) is a therapeutic agent used for the treatment of cholestatic hepatobiliary diseases in pediatric patients. It is a bile acid that presents high lipophilicity, and it belongs to Class II of the Biopharmaceutical Classification System (BCS), which exhibits low water solubility and high intestinal permeability, which leads to poor oral absorption. The objective of this work was to design and optimize UDCA nanosuspensions by means of the precipitation-ultrasonication method to improve the solubility, dissolution, and oral bioavailability of UDCA. A three-level, three-factor Box-Behnken design was used to optimize formulation variables and obtain uniform, small-particle-size UDCA nanosuspensions. The independent variables were: stabilizer percentage (X1), amplitude (X2), and sonication time (X3), and the dependent variable was the particle size (Y1). In the precipitation-ultrasonication method, UDCA was dissolved in acetone:PEG 400 (1:1 v/v) and quickly incorporated into the antisolvent (pre-cooled aqueous dispersion of HPMC E-15 0.3%), by means of intense sonication at 50 W for 5 min, controlling temperature through an ice water bath. The lyophilization efficacy was evaluated by means of a cryoprotective efficacy test, working with 10% maltose at -80 °C. The nanosuspensions were characterized by dynamic light scattering (DLS), X-ray diffraction, and scanning electron microscopy (SEM). The physicochemical stability was determined at 25 °C and 4 °C at 7, 14, 30, and 60 days, and the UDCA content was analyzed via HPLC-UV. An in vitro dissolution assay and an oral bioavailability study were performed in male Wistar rats. A significant impact was achieved in the optimized nanosuspension with 0.3% (stabilizer), 50 W (amplitude), and 5 min (sonication time), with a particle size of 352.4 nm, PDI of 0.11, and zeta potential of -4.30 mV. It presented adequate physicochemical stability throughout the study and the UDCA content was between 90% and 110%. In total, 86% of UDCA was dissolved in the in vitro dissolution test. The relative oral bioavailability was similar without significant statistical differences when comparing the lyophilized nanosuspension and the commercial tablet, the latter presenting a more erratic behavior. The pharmacokinetic parameters of the nanosuspension and the commercial tablet were Tmax (1.0 ± 0.9 h vs. 2.0 ± 0.8 h, respectively), Cmax (0.558 ± 0.118 vs. 0.366 ± 0.113 µM, respectively), ΔCmax (0.309 ± 0.099 vs. 0.232 ± 0.056, respectively), AUC (4.326 ± 0.471 vs. 2.188 ± 0.353 µg/mL.h, respectively, p < 0.02), and IAUC0-24h (2.261 ± 0.187 µg/mL.h vs. 1.924 ± 0.440 µg/mL.h, respectively). The developed nanosuspension presents an appropriate dosage and administration for pediatric patients. On the other hand, it exhibits an adequate absorption and UDCA oral bioavailability.

Zein-based nanospheres and nanocapsules for the encapsulation and oral delivery of quercetin

In this study, the ability of zein nanospheres (NS) and zein nanocapsules containing wheat germ oil (NC) to enhance the bioavailability and efficacy of quercetin was evaluated. Both types of nanocarriers had similar physico-chemical properties, including size (between 230 and 250 nm), spherical shape, negative zeta potential, and surface hydrophobicity. However, NS displayed a higher ability than NC to interact with the intestinal epithelium, as evidenced by an oral biodistribution study in rats. Moreover, both types of nanocarriers offered similar loading efficiencies and release profiles in simulated fluids. In C. elegans, the encapsulation of quercetin in nanospheres (Q-NS) was found to be two twice more effective than the free form of quercetin in reducing lipid accumulation. For nanocapsules, the presence of wheat germ oil significantly increased the storage of lipids in C. elegans; although the incorporation of quercetin (Q-NC) significantly counteracted the presence of the oil. Finally, nanoparticles improved the oral absorption of quercetin in Wistar rats, offering a relative oral bioavailability of 26% and 57% for Q-NS and Q-NC, respectively, compared to a 5% for the control formulation. Overall, the study suggests that zein nanocarriers, particularly nanospheres, could be useful in improving the bioavailability and efficacy of quercetin.

PH-triggered dynamic erosive small molecule chlorambucil nano-prodrugs mediate robust oral chemotherapy

Currently, the dynamic erosive small molecule nano-prodrug is of great demand for oral chemotherapy, owing to its precise structure, high drug loading and improved oral bioavailability via overcoming various physiologic barriers in gastrointestinal tract, blood circulation and tumor tissues compared to other oral nanomedicines. Herein, this work highlights the successful development of pH-triggered dynamic erosive small molecule nano-prodrugs based on in vivo significant pH changes, which are synthesized via amide reaction between chlorambucil and star-shaped ortho esters. The precise nano-prodrugs exhibit extraordinarily high drug loading (68.16%), electric neutrality, strong hydrophobicity, and dynamic large-to-small size transition from gastrointestinal pH to tumoral pH. These favorable physicochemical properties can effectively facilitate gastrointestinal absorption, blood circulation stability, tumor accumulation, cellular uptake, and cytotoxicity, therefore achieving high oral relative bioavailability (358.72%) and significant tumor growth inhibition while decreasing side effects. Thus, this work may open a new avenue for robust oral chemotherapy attractive for clinical translation.