Relative Oral Bioavailability Research Articles

Formulation and optimization of fisetin nanoemulsion for the treatment of Alzheimer's disease in rats: Pharmacokinetic and pharmacodynamic assessment

Fiestin (FS) is a polyphenolic flavonoid that possesses various neuroprotective effects by attenuating the levels of AChE enzyme, accumulated amyloid β, free radicals and neuroinflammation against Alzheimer's disease (AD). It is also helpful in reducing cellular senescence. However, FS suffers from a dissolution rate-limited oral bioavailability, and poor blood-brain barrier (BBB) permeability leading to decreased therapeutic efficacy. To address these challenges, an attempt has been made to formulate a nanoemulsion (NE) of FS using Box-Behnken design (BBD) as optimization tool. The optimized NE contained 10 mg of FS, 164 μL of Capmul MCM EP/NF® (oil), 618 μL of T80 (surfactant), 218 μL of Transcutol P®, (co-surfactant) and 4000 μL of distilled water. The optimized formulation resulted in a mean droplet size, drug loading, polydispersity index (PDI), and zeta potential (ZP) of 32 nm, 95.5 %, 0.26, and −15.99 mV, respectively. In the pharmacokinetic studies, FS-NE showed 9.2-fold increase in Cmax as compared to naïve FS. Relative oral bioavailability FS loaded in FS-NE was 842.93 %. Further the concentration of FS loaded in FS-NE was 8.81-fold higher in brain than naive FS. To evaluate pharmacodynamic effects, an aluminum chloride (AlCl3)-induced AD rat model was used. Cognitive functions were assessed using the Morris water maze and open field tests. The formulation showed dose-dependent effects. Rats treated with both, low and high doses of FS-NE (groups VI and VII) showed significant improvements (P < 0.001) in cognitive functions in AD-induced rats. The biochemical studies showed that FS-NE at both doses attenuated the levels of AChE enzyme, amyloid β, oxidative stress, and neuroinflammation. Results of histopathology indicated that FS-NE attenuated the degeneration of neurons in the cerebral cortex and hippocampus parts of the brain.

Mesoporous silica-based amorphous solid dispersions to enhance the oral bioavailability of Neratinib maleate

Neratinib maleate (NM) used in the treatment of breast cancer, has a low and variable oral bioavailability due to its pH-dependent solubility and gut-wall metabolism-restricted permeability. Mesoporous silica based solid dispersion of NM (SD-NM-MSi) was designed to improve its solubility and dissolution rate. SYLOID XDP 3050 was selected as a mesoporous silica carrier based on its higher drug loading (15.7 %) and good flow properties. The extensive surface area of the Mesoporous silica offered a suitable site for drug adsorption. Thermal and diffractometry analysis indicated that NM was adsorbed in an amorphous form. In vitro dissolution studies revealed that the optimized SD-NM-MSi showed a higher rate and extent of drug dissolution compared to plain NM in pH 3.0, pH 4.5, and 6.8, respectively. Similarly, an oral pharmacokinetic study (10 mg/kg) resulted in significantly higher plasma exposure for SD-NM-MSi compared to plain NM, with a 73 % (P < 0.01) increase in the relative oral bioavailability of NM.

Preparation, Pharmacokinetics and Anti-Liver Injury Pharmacodynamic Study of Esculin Loaded Liposomes Modified by TPGS

In this study, Esculin (ES)-loaded liposomes modified with TPGS (ES-TPGS-Ls) were successfully prepared to enhance bioavailability and hepatoprotective activity of this coumarin glucoside. We utilize thin-film dispersion to fabricate ES-TPGS-Ls. The size, polydispersed index (PDI), Zeta potential (Z-potential), morphology, and encapsulation effectiveness of the liposomes were all evaluated afterwards. The storage stability of ES-TPGS-Ls at 4 °C was investigated. The findings showed that ES-TPGS-Ls had spherical nanoparticles with 194.47±8.54 nm as the mean size, 0.239±0.011 as PDI, and −21.16±0.97) mV as Z-potential coupled with encapsulation efficiency (EE) of 91.85±0.44%. Storage stability of liposomes at 4 °C was maintained within one week. Pharmacokinetic study showed that the relative oral bioavailability of ES-TPGS-Ls increased by 2.38 times. Pharmacodynamic studies showed that the developed liposomes could enhance the hepatoprotective activity of ES. Overall, the ES-TPGS-Ls significantly enhanced the bioavailability of esculin, thereby enhancing the in vivo hepatoprotective effect of ES.

Solubilization of Paclitaxel with Natural Compound Rubusoside toward Improving Oral Bioavailability in a Rodent Model.

Paclitaxel, which features low water solubility and permeability, is an efflux pump substrate. The current paclitaxel drugs are given intravenously after resolving the solubility issue. Yet, oral delivery to achieve therapeutic bioavailability is not effective due to low absorption. This study evaluated a natural compound, rubusoside, to improve oral bioavailability in an animal model. Free paclitaxel molecules were processed into nano-micelles formed in water with rubusoside. The particle size of the nano-micelles in water was determined using dynamic light scattering. The oral bioavailability of paclitaxel in nano-micelles was determined against Cremophor/alcohol-solubilized Taxol after oral and intravenous administration to pre-cannulated Sprague Dawley rats. When loaded into the rubusoside-formed nano-micelles, paclitaxel reached a supersaturated concentration of 6 mg/mL, 60,000-fold over its intrinsic saturation of 0.1 µg/mL. The mean particle size was 4.7 ± 0.7 nm in diameter. Compared with Taxol®, maximum blood concentration was increased by 1.5-fold; the time to reach maximum concentration shortened to 0.8 h from 1.7 h; and, relative oral bioavailability increased by 88%. Absolute oral bioavailability was 1.7% and 1.3% for the paclitaxel nano-micelles and Taxol®, respectively. Solubilizing paclitaxel with rubusoside was successful, but oral bioavailability remained low. Further inhibition of the efflux pump and/or first metabolism may allow more oral paclitaxel to enter systemic circulation.

Functionalized xanthohumol nanoemulsion: fabrication, characterization and bioavailability enhancement of bioactive compounds.

Xanthohumol is an isopentadienyl flavonoid in hops, which have several pharmacological effects. However, due to the poor bioavailability of xanthohumol, it cannot be widely used. In this study, solvent extraction combined with preparative liquid chromatography was used to separate and purify xanthohumol in hop residue. And the purity, yield and recovery of xanthohumol was 983.0 ± 2.1 g kg-1, 921.61 ± 5.65 g kg-1, and 5.41 ± 0.07 g kg-1, respectively. Response surface methodology optimization revealed that 216.75 g kg-1 ethyl oleate, 574.1 g kg-1 polyoxyl-35 castor oil (EL35) and 209.15 g kg-1 polyethylene glycol 200 (PEG200) produced the xanthohumol nanoemulsion with a loading capacity of 85.40 ± 0.33 g kg-1, mean droplet diameter of 42.35 ± 0.06 nm, and zeta potential of -21.78 ± 0.18 mV. Xanthohumol nanoemulsion has better relative stability. The relative oral bioavailability of xanthohumol nanoemulsion was increased by 1.76 times. These results provide a theoretical basis for the application of nanoemulsion containing xanthohumol in food and pharmaceutical industry. © 2024 Society of Chemical Industry.

Preparation, characterization, in vitro and in vivo studies of liposomal berberine using novel natural Fiber Interlaced Liposomal technology

Berberine hydrochloride (BBR), used in various traditional medicinal practices, has a variety of pharmacological effects. It is a plant-derived quaternary isoquinoline alkaloid with a low water solubility and can be used in the treatment of various conditions. However, the therapeutic use of BBR has been compromised because of its hydrophobic characteristics, in addition to its low stability and poor bioavailability. To overcome these drawbacks of BBR’s oral bioavailability, technologies like liposomal delivery systems have been developed to ensure enhanced absorption. But conventional liposomes have low physical and chemical stability due to delicate liposomal membranes, peroxidation and rapid clearance from the bloodstream. Surface modification of liposomes could be a solution and creating a liposome with plant-based fibers as surface material will provide enhanced stability, aqueous solubility and protection against degradation. Consequently, the aim of this study is to create and describe a Fiber Interlaced Liposome™ (FIL) as a vehicle for an enhanced bioavailability platform for BBR and other biomolecules. This optimised FIL-BBR formulation was analysed for its structural and surface morphological characteristics by using FTIR, SEM, TEM, XRD, zeta potential and DSC. Encapsulation efficiency, stability, and sustained release studies using an in vitro digestion model with simulated gastric and intestinal fluids were also examined. FIL formulation showed a sustained release of BBR at 59.03 % as compared to the unformulated control (46.73 %) after 8 h of dialysis. Furthermore, the FIL-BBR demonstrated enhanced stability in the simulated gastric fluid (SGF) in addition to a more sustained release in the simulated intestinal fluid (SIF). The efficacy of FIL-BBR were further anlaysed by an in vivo bioavailability study using male Wistar rats and it demonstrated a 3.37−fold higher relative oral bioavailability compared to the unformulated BBR. The AUC 0-t for BBR in FIL-BBR was 1.38 ng.h/mL, significantly greater than the unformulated BBR (0.41 ng.h/mL). Similarly, the Cmax for BBR in FIL-BBR (50.98 ng/mL) was discovered to be far greater than unformulated BBR (15.54 ng/mL) after the oral administration. These findings imply that fruit fiber based liposomal encapsulation improves the stability and slows down BBR release, which could be advantageous for applications requiring a higher bioavailability and a more sustained release.

Cholic Acid-Grafted Thiolated Chitosan-Enveloped Nanoliposomes for Enhanced Oral Bioavailability of Azathioprine: In Vitro and In Vivo Evaluation.

The purpose of the present study was to develop a cholic acid-grafted thiolated chitosan (CA-CS-TGA) polymeric biomaterial for attaining improved permeation via attaching thiol groups and cholic acid moieties. For this purpose, a CA-CS-TGA graft was prepared, and modification was confirmed via FTIR analysis. The prepared CA-CS-TGA graft was used to coat the azathioprine-loaded nanoliposomes (ENLs), with subsequent characterization in terms of zeta size, zeta potential, and SEM analysis. Pharmaceutical evaluation was carried out in terms of drug release studies, and ex vivo permeation and in vivo oral bioavailability were studied. The particle size and zeta potential of CA-CS-TGA coated nanoliposomal formulation CA-CS-TGA-NLs were found to be 245 ± 15.6 and +22.4 ± 0.58, respectively, compared to that of nonenveloped nanoliposomal formulation 165.7 ± 12.3 and -21.8 ± 0.14, respectively, indicating successful coating. CA-CS-TGA-NLs indicated 64% of drug release in 24 h at pH 7.4. Ex vivo permeation enhancement and relative oral bioavailability studies indicated a 2.84-fold enhanced permeation and 6-fold enhanced oral bioavailability of CA-CS-TGA-NLs compared to Azathioprine suspension. Based on the results, it can be concluded that grafting the CA-CS-TGA polymer onto nanoliposomes seems to be a promising strategy to enhance the oral bioavailability of Azathioprine.

Rerouting cardiovascular management following gastric bypass surgery: Dose optimization of carvedilol using population-based analysis.

A population-based pharmacokinetic (PK) modeling approach (PopPK) was used to investigate the impact of Roux-en-Y gastric bypass (RYGB) on the PK of (R)- and (S)-carvedilol. We aimed to optimize carvedilol dosing for these patients utilizing a pharmacokinetic/pharmacodynamic (PK/PD) link model. PopPK models were developed utilizing data from 52 subjects, including nonobese, obese, and post- RYGB patients who received rac- carvedilol orally. Covariate analysis included anthropometric and laboratory data, history of RYGB surgery, CYP2D6 and CYP3A4 in vivo activity, and relative intestinal abundance of major drug- metabolizing enzymes and transporters. A direct effect inhibitory Emax pharmacodynamic model was linked to the PK model of (S)- carvedilol to simulate the changes in exercise- induced heart rate. A 2-compartmental model with linear elimination and parallel first-order absorptions best described (S)-carvedilol PK. RYGB led to a twofold reduction in relative oral bioavailability compared to nonoperated subjects, along with delayed absorption of both enantiomers. The intestinal ABCC2 mRNA expression increases the time to reach the maximum plasma concentration. The reduced exposure (AUC) of (S)-carvedilol post-RYGB corresponded to a 33% decrease in the predicted area under the effect curve (AUEC) for the 24-hour β-blocker response. Simulation results suggested that a 50-mg daily dose in post-RYGB patients achieved comparable AUC and AUEC to 25-mg dose in nonoperated subjects. Integrated PK/PD modeling indicated that standard dosage regimens for nonoperated subjects do not provide equivalent β-blocking activity in RYGB patients. This study highlights the importance of personalized dosing strategies to attain desired therapeutic outcomes in this patient cohort.

Preparation, Optimization, and Anti-Pulmonary Infection Activity of Casein-Based Chrysin Nanoparticles.

Chrysin has a wide range of biological activities, but its poor bioavailability greatly limits its use. Here, we attempted to prepare casein (cas)-based nanoparticles to promote the biotransfer of chrysin, which demonstrated better bioavailability and anti-infection activity compared to free chrysin. Cas-based chrysin nanoparticles were prepared and characterized, and most of the preparation process was optimized. Then, the in vitro and in vivo release characteristics were studied, and anti-pulmonary infection activity was evaluated. The constructed chrysin-cas nanoparticles exhibited nearly spherical morphology with particle size and ζ potential of 225.3 nm and -33 mV, respectively. These nanoparticles showed high encapsulation efficiency and drug-loading capacity of 79.84% ± 1.81% and 11.56% ± 0.28%, respectively. In vitro release studies highlighted a significant improvement in the release profile of the chrysin-cas nanoparticles (CCPs). In vivo experiments revealed that the relative oral bioavailability of CCPs was approximately 2.01 times higher than that of the free chrysin suspension. Further investigations indicated that CCPs effectively attenuated pulmonary infections caused by Acinetobacter baumannii by mitigating oxidative stress and reducing pro-inflammatory cytokines levels, and the efficacy was better than that of the free chrysin suspension. The findings underscore the advantageous bioavailability of CCPs and their protective effects against pulmonary infections. Such advancements position CCPs as a promising pharmaceutical agent and candidate for future therapeutic drug innovations.

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 solubilisation 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 solubilisation of drug and their oral bioavailability.

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- &amp;gt;12h of DON-3S in broiler chicken (P = 0.012). The relative oral bioavailability [(average AUC0- &amp;gt;t mycotoxin + decontaminant/ average AUC0- &amp;gt;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- &amp;gt;24h (P &amp;lt; 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- &amp;gt;8h (P &amp;lt; 0.001), Cmax (P &amp;lt; 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.

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.

Supersaturated Drug Delivery System of Oxyberberine Based on Cyclodextrin Nanoaggregates: Preparation, Characterization, and in vivo Application.

Oxyberberine (OBB), one of the main metabolites of berberine derived from intestinal and erythrocyte metabolism, exhibits appreciable anti-hyperuricemic activity. However, the low water solubility and poor plasma concentration-effect relationship of OBB hamper its development and utilization. Therefore, an OBB-hydroxypropyl-β-cyclodextrin (HP-β-CD) supersaturated drug delivery system (SDDS) was prepared and characterized in this work. OBB-HP-β-CD SDDS was prepared using the ultrasonic-solvent evaporation method and characterized. Additionally, the in vitro and in vivo release experiments were conducted to assess the release kinetics of OBB-HP-β-CD SDDS. Subsequently, the therapeutic efficacy of OBB-HP-β-CD SDDS on hyperuricemia (HUA) was investigated by means of histopathological examination and evaluation of relevant biomarkers. The results of FT-IR, DSC, PXRD, NMR and molecular modeling showed that the crystallized form of OBB was transformed into an amorphous OBB-HP-β-CD complex. Dynamic light scattering indicated that this system was relatively stable and maintained by formation of nanoaggregates with an average diameter of 23 nm. The dissolution rate of OBB-HP-β-CD SDDS was about 5 times higher than that of OBB raw material. Furthermore, the AUC0-t of OBB-HP-β-CD SDDS (10.882 μg/mL*h) was significantly higher than that of the raw OBB counterpart (0.701 μg/mL*h). The oral relative bioavailability of OBB-HP-β-CD SDDS was also enhanced by 16 times compared to that of the raw material. Finally, in vivo pharmacodynamic assay showed the anti-hyperuricemic potency of OBB-HP-β-CD SDDS was approximately 5-10 times higher than that of OBB raw material. Based on our findings above, OBB-HP-β-CD SDDS proved to be an excellent drug delivery system for increasing the solubility, dissolution, bioavailability, and anti-hyperuricemic potency of OBB.

Co-Delivery of Docetaxel and Curcumin Functionalized Mixed Micelles for the Treatment of Drug-Resistant Breast Cancer by Oral Administration.

Chemotherapeutic drugs have some drawbacks in antineoplastic therapy, mainly containing seriously toxic side effects caused by injection and multi-drug resistance (MDR). Co-delivery with two or more drugs via nanomicelles is a promising strategy to solve these problems. Oral chemotherapy is increasingly preferred owingto its potential to enhance the life quality of patients. The study intended to develop mixed micelles using D-α-Tocopherol poly(ethylene glycol) 1000 succinate (TPGS) and soluplus for the co-encapsulation of docetaxel (DTX) and curcumin (CUR), marked as (DTX+CUR)-loaded mixed micelles, treating drug-resistant breast cancer by oral administration. The (DTX+CUR)-loaded mixed micelles had a uniform particle size (~64 nm), high drug loading and encapsulation efficiency, in vitro sustained-release properties and good pH-dependent stability. In vitro cell study, the (DTX+CUR)-loaded mixed micelles displayed the highest cellular uptake, cytotoxicity, cell apoptosis-inducing rates and cell ROS-inducing levels on MCF-7/Adr cells. Notably, in vivo pharmacokinetic studies, (DTX+CUR)-loaded mixed micelles enhanced markedly the oral absorption of DTX compared to pure DTX, with a relative oral bioavailability of 574%. The (DTX+CUR)-loaded mixed micelles by oral administration had the same anticancer efficacy as taxotere by injection in resistant breast cancer bearing mice. (DTX+CUR)-loaded mixed micelles could provide a potential formulation for treating drug-resistant breast cancers by oral administration.

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.