Oral Bioavailability Of Drugs Research Articles

Recent Updates in Nanocrystal Technology: A Reference to Oral Drug Delivery System

Increasing the oral bioavailability of drugs that dissolve slowly may be possible with the use of nanocrystal technology. It is being employed for drug engineering and research after making rapid advancements in recent years. The manufacturing process for pharmaceuticals is significantly hampered by the low solubility and quick rate of dissolution of poorly soluble medications. When taken orally, medications that are poorly soluble often have low and inconsistent bioavailability, which could lead to therapeutic failure. Pure drug nanocrystals prepared via "bottom-up" or "topdown" procedu are able to significantly improve the way poorly soluble medications dissolve thanks to their enormous surface area, which in turn enhances oral absorption. Nanocrystal medications allow for the creation of various dosage formulations. The use of nanocrystal technology in pharmaceutical research, particularly for oral drug delivery systems, is the main focus of this review. First, a quick discussion on the characteristics of pharmaceutical nanocrystals and several nanocrystal technology preparation techniques is provided. The application of nanocrystal technology in pharmaceutical science is covered after a discussion of the creation of prolonged-release formulations. Next follows a brief overview of the scaling-up procedure, commercial nanocrystal drug products, and regulatory aspects of nanodrugs. This paper offers a thorough explanation of preparation techniques, their characterisation, and how they are used in oral drug delivery systems.

Biomolecular Condensates Based on Amino Acid for Enhancing Oral Bioavailability and Therapeutic Efficacy of Hydrophobic Drugs.

The oral administration of chemo- or immunotherapeutic drugs presents a compelling alternative for patients with malignant colorectal cancer, offering a convenient and patient-compliant "hospital-free" strategy. Unfortunately, the hydrophobic nature of many drug candidates, alongside the harsh conditions of the gastrointestinal tract, frequently results in suboptimal bioavailability and heightened systemic toxicity. To address these challenges, we harnessed the unique properties of biomolecular condensates, which form through a liquid-liquid phase separation mechanism, to develop a versatile platform for drug encapsulation and delivery. In this study, we introduce a reliable and effective amorphous oral drug delivery system based on biomolecular condensates derived from the amino acid derivative N-(benzyloxycarbonyl)-l-proline (ZP). These ZP condensates exhibit dynamic intermolecular interactions and possess unique physicochemical attributes such as fluidity and viscoelasticity. They significantly improve the solubility of hydrophobic drugs, ensuring enhanced stability and optimized pharmacokinetics under physiological and gastrointestinal conditions. By maintaining drugs in an amorphous state, we substantially increased drug bioavailability and markedly improved pharmacokinetics. Furthermore, the ZP condensates demonstrate potential as an integrated therapeutic platform capable of potentiating the synergies between chemotherapy and immunotherapy while concurrently reducing systemic toxicity. This has resulted in a significant enhancement of chemo-immunotherapy efficacy in the treatment of colorectal cancer, representing a notable advancement in drug delivery and oncology.

Variables Affecting the Preparation and Characterization of Axitinib as Oral Niosmoes

Axitinib is anticancer drug act on different solid tumors by inhibtion protein kinase enzyme which is responsible for support the tumors with blood demand. Due to its low solubility, it has low bioavailability when given orally also it is affected by liver metabolism. Axitinib formulated as non-ionic vesicles (niosomes) for the first time to study the effect of different variables on the in vitro behaviour of vesicles in a hope to improve drug oral bioavailability. Niosomal dispersion formulas were formulated by diverse techniques via multiple kinds of surface-active agent (tween also span), cholesterol and dicetyl phosphate then evaluated for visual appearance, efficiency of drug entrapment (EE%), size of the vesicles, poly dispersity index, zetapotential, viscosity, invitro drug release and study the vesicles morphology by FE-SEM. Many variables effect on EE% were studied such as effect of surfactant amount and type, effect of surfactant combination, impact of various ratios of cholesterol, impact of DCP in various amount , effect of preparation method and effect of sonication time. The results showed that the EE% between (50.97%-98.24%), the particle size was found within the range (64.5 nm - 530.79 nm), zeta potential which was between ( -16.6 to -31 mV), polydispersity index (PDI) <1 and viscosity between (584 – 889.6) centipoise. The niosomal dispersion F1 which contained 1:1 weight ratio (span60: cholesterol) was found with high EE% (96.5±0.16%), smallest particle size (64.5±0.5 nm), highest drug release (100%) of drug released at the end of 4 hours and FE-SEM photograph showed that niosomes were spherical with no aggregation and had a smooth surface. The results showed that thin film hydration method with sonication for four minutes was the best method for preparation of axitinib niosomes, the type and amount of surfactants used, cholesterol ratio, stabilizer and the time of sonication had a substantial effect on EE%, the size of the vesicles as well as drug release; which were investigated so as to optimize the niosomal dispersion of anti-tumour drug reaching to an optimum formula that may improve drug bioavailability. Key words: Axitinib, Anticancer, Vesicles, Surfactants, Invitro behaviour, Entrapment efficiency.

Research on prediction of human oral bioavailability of drugs based on improved deep forest

Human oral bioavailability is a crucial factor in drug discovery. In recent years, researchers have constructed a variety of different prediction models. However, given the limited size of human oral bioavailability data sets, the challenge of making accurate predictions with small sample sizes has become a critical issue in the field. The deep forest model, with its adaptively determinable number of cascade levels, can perform exceptionally well even on small-scale data. However, the original deep forest suffers unbalanced multi-grained scanning process and premature stopping of cascade forest training. In this paper, we propose a human oral bioavailability predict method based on an improved deep forest, called balanced multi-grained scanning mapping cascade forest (bgmc-forest). Firstly, the mordred descriptor method is selected to feature extraction, then enhanced features are obtained by the improved balanced multi-grained scanning, which solves the problem of missing features at both ends. And finally, the prediction results are obtained by feature mapping cascaded forests, which is based on principal component analysis and cascade forests, ensures the effectiveness of the cascade forest. The superiority of the model constructed in this paper is demonstrated through comparative experiments, while the effectiveness of the improved module is verified through ablation experiments. Finally the decision-making process of the model is explained by the shapley additive explanations interpretation algorithm.

Fabrication and Characterization of Andrographolide-loaded Microsponges to Enhance Oral Bioavailability of Drug against Colon Cancer Using HT29 Cells

Background: The current research aimed to determine ways to improve the bioavailability of andrographolide (AGP) for use in colon cancer treatment by developing and evaluating microsponges loaded with the drug. Methods: Utilising the quasi-emulsion solvent diffusion approach, microsponges containing AGP were synthesised. A total of ten formulations were prepared using different concentrations of drug, polymer and other excipients. Particle size, shape, and differential scanning calorimetry (DSC) were used to characterise the microsponges that were created. To find out the rate at which the microsponges would expel their contents, researchers measured their release dynamics. In vitro anticancer activity of formulation was determined using HT29 cells Results: Results showed that the percentage yield of the formulations ranged from 10.85-41.03%. The highest drug concentration was achieved in formulation F8 with a particle size of 33.7 nm. SEM analysis demonstrated that the particles were round and possessed a rough and porous surface. Increasing the ratio of ethyl cellulose to AGP reduces surface roughness. The microsponge's DSC difractogram reveals prominent peaks at 18°, 24°, and 38° (2 θ) with reduced intensity, suggesting that the microsponges' crystalline character has diminished. In vitro drug release study showed 93.85% release upto 12 hours. Mathematical models showed normal release of the formulations with “n” values greater than 0.90 of all the formulations. Formulation F8 decreased the HT-29 cells' ability to survive. The percentage of cell cytotoxicity was 75.54 at 100μg/ml. Since AGP microsponges had a detrimental effect on the survival of colorectal cancer cells. Conclusion: It can be concluded from the study that prepared formulations possess anticancer properties against cancerous cells and can be used as an alternative anticancer drug.

Effect of carvedilol on pharmacokinetics of sofosbuvir and its metabolite GS-331007: role of P-glycoprotein.

Sofosbuvir (SOF) is a P-glycoprotein (P-gp) substrate, and carvedilol (CAR) is an inhibitor of P-gp, suggesting that it may affect the oral pharmacokinetics and safety of SOF. The current study investigated the pharmacokinetic interaction of CAR with SOF and its metabolite, GS-331007, and the possible consequent toxicities in rats. To assess the pharmacokinetics of SOF and GS-331007, rats were divided into three groups; all received a single oral dose of SOF preceded with saline (SAL), verapamil (VER) as a standard P-gp inhibitor, or CAR, respectively. The serosal, plasma, and hepatic tissue contents of SOF and GS-331007 were assessed using LC-MS/MS. Renal and hepatic toxicities were assessed using biochemical and histopathological tests. Serosal and plasma concentrations of SOF and GS-331007 were increased in the presence of CAR, suggesting a significant inhibitory effect of CAR on intestinal P-gp. Simultaneously, the pharmacokinetic profile of SOF showed a significant increase in the Cmax, AUC(0-t), AUC (0-∞), t1/2, and a reduction in its apparent oral clearance. While the pharmacokinetic profile of GS-331007 was not significantly affected. However, this notable elevation in drug oral bioavailability was corroborated by a significant alteration in renal functions. Hence, further clinical investigations are recommended to ensure the safety and dosing of CAR/SOF combination.

Bile salt integrated cerasomes: A potential nanocarrier for enhancement of the oral bioavailability of idarubicin hydrochloride

Cerasomes are a modified form of liposomes containing both inorganic and organic parts and due to their strong polyorganosiloxane surface have remarkably high morphological stability and provide easier functionalization compared with conventional liposomes. To investigate the potential of these nanocarriers for oral delivery, bile salt integrated cerasomes (named bilocerasomes) encapsulating idarubicin hydrochloride (IDA) were prepared and characterized. The optimum formulation showed excellent stability in the simulated gastrointestinal fluids as well as under storage conditions. The oral pharmacokinetics of the IDA solution, empty nanocarrier + drug solution, and IDA-loaded bilocerasome were evaluated. The nanoformulation significantly increased the area under the drug concentration–time curve and the mean residence time (∼14.3- and 9-fold, respectively). The results obtained from cell uptake and chylomicron flow blocking approach revealed that bilocerasomes are absorbed into the intestinal cells via a clathrin/caveolin-independent endocytosis pathway and transported to the systemic circulation extensively via the intestinal lymphatic vessels. Considering the high stability of the prepared bilocerasome, noticeable participation of lymphatic transport in its systemic absorption and marked enhancement in the oral absorption of IDA, bilocerasomes can be introduced as a capable carrier for improving the oral bioavailability of drugs, particularly those that hepatic first-pass metabolism seriously limits their oral absorption.

Computation Design: Nanostructured Lipid Carrier Formula of Pinostrobin

Nano lipid carriers (NLC) function by increasing the solubility and oral bioavailability of hydrophobic drugs. This study was conducted to estimate the solubility of pinostrobin in various types of solid and liquid lipid carriers through computational design and to select the optimal NLC formula with the best candidate lipid carriers. Pinostrobin and all lipid carriers were determined for their interactions with the AutoDockTools program. The values of the free energy binding (ΔG), the inhibition constant (Ki), and the type of interaction visibility were recorded as a result of the molecular docking. The interaction type of visualization was determined by the BIOVIA Discovery Studio program. The results showed that apocarotenal was the best liquid lipid carrier with a ΔG value of -3.57 kcal/mol and a Ki value of 2.40 mM. Cetosteryl alcohol was the best carrier for solid lipids, with a ΔG value of -2.18 kcal/mol and a Ki value of 25.35 mM. Apocarotenal and cetostearyl alcohol as lipid carrier candidates for the NLC formula of pinostrobin.

Bacterial Influence on Pharmacokinetics of Tacrolimus and Sulfasalazine through Regulation of Host Metabolism

AbstractThe unpredictable oral bioavailability of established drugs like tacrolimus and sulfasalazine presents a significant clinical challenge. This variability can lead to either toxicity or insufficient therapeutic effect. It is known that alterations in drug transporters and metabolic enzymes influence drug bioavailability. Recent evidence suggests that the indirect metabolism by gut microbes could influence transporters and enzymes which can affect the bioavailability of oral drugs. In this study, the pharmacokinetics of tacrolimus and sulfasalazine are modeled under varying host colonic conditions induced by the bacteria E. coli Nissle 1917 and Bifidobacterium adolescentis. Insight is provided into the sensitivity of pharmacokinetics to the bacterial influence on expression of intestinal drug transporters and cytochrome p450 enzymes. Our findings demonstrate that bacterial modulation reduces tacrolimus peak blood concentration compared to healthy renal transplant patients. Conversely, bacterial presence leads to a two‐fold increase in sulfasalazine's peak plasma concentration compared to healthy subjects. These results suggest that incorporating the gut bacteria's influence on colonic transporters and enzymes can improve the explanation of pharmacokinetic variability. This approach has the potential to refine pharmacokinetic models and ultimately address the challenge of variable oral drug bioavailability.

The Controlled Preparation of a Carrier-Free Nanoparticulate Formulation Composed of Curcumin and Piperine Using High-Gravity Technology.

Carrier-free nanoparticulate formulations are an advantageous platform for the oral administration of insoluble drugs with the expectation of improving their bioavailability. However, the key limitation of exploiting carrier-free nanoparticulate formulations is the controlled preparation of drug nanoparticles on the basis of rational prescription design. In the following study, we used curcumin (Cur) and piperine (Pip) as model water-insoluble drugs and developed a new method for the controlled preparation of carrier-free drug nanoparticles via multidrug co-assembly in a high-gravity environment. Encouraged by the controlled regulation of the nucleation and crystal growth rate of high-gravity technology accomplished by a rotating packed bed, co-amorphous Cur-Pip co-assembled multidrug nanoparticles with a uniform particle size of 130 nm were successfully prepared, exhibiting significantly enhanced dissolution performance and in vitro cytotoxicity. Moreover, the hydrogen bonding interactions between Cur and Pip in nanoparticles provide them with excellent re-dispersibility and storage stability. Moreover, the oral bioavailability of Cur was dramatically enhanced as a result of the smaller particle size of the co-assembled nanoparticles and the effective metabolic inhibitory effect of Pip. The present study provides a controlled approach to preparing a carrier-free nanoparticulate formulation through a multidrug co-assembly process in the high-gravity field to improve the oral bioavailability of insoluble drugs.

Microfluidics-on-a-chip for designing celecoxib-based amorphous solid dispersions: when the process shapes the product

AbstractThe fundamental idea underlying the use of amorphous solid dispersions (ASDs) is to make the most of the solubility advantage of the amorphous form of a drug. However, the drug stability becomes compromised due to the higher free energy and disorder of molecular packing in the amorphous phase, leading to crystallization. Polymers are used as a matrix to form a stable homogeneous amorphous system to overcome the stability concern. The present work aims to design ASD-based formulations under the umbrella of quality by design principles for improving oral drug bioavailability, using celecoxib (CXB) as a model drug. ASDs were prepared from selected polymers and tested both individually and in combinations, using various manufacturing techniques: high-shear homogenization, high-pressure homogenization, microfluidics-on-a-chip, and spray drying. The resulting dispersions were further optimized, resorting to a 32 full-factorial design, considering the drug:polymers ratio and the total solid content as variables. The formulated products were evaluated regarding analytical centrifugation and the influence of the different polymers on the intrinsic dissolution rate of the CXB-ASDs. Microfluidics-on-a-chip led to the amorphous status of the formulation. The in vitro evaluation demonstrated a remarkable 26-fold enhancement in the intrinsic dissolution rate, and the translation of this formulation into tablets as the final dosage form is consistent with the observed performance enhancement. These findings are supported by ex vivo assays, which exhibited a two-fold increase in permeability compared to pure CXB. This study tackles the bioavailability hurdles encountered with diverse active compounds, offering insights into the development of more effective drug delivery platforms. Graphical Abstract

Perfluoropolyether-Based Gut-Liver-on-a-Chip for the Evaluation of First-Pass Metabolism and Oral Bioavailability of Drugs.

In the evolving field of drug discovery and development, multiorgans-on-a-chip and microphysiological systems are gaining popularity owing to their ability to emulate in vivo biological environments. Among the various gut-liver-on-a-chip systems for studying oral drug absorption, the chip developed in this study stands out with two distinct features: incorporation of perfluoropolyether (PFPE) to effectively mitigate drug sorption and a unique enterohepatic single-passage system, which simplifies the analysis of first-pass metabolism and oral bioavailability. By introducing a bolus drug injection into the liver compartment, hepatic extraction alone could be evaluated, further enhancing our estimation of intestinal availability. In a study on midazolam (MDZ), PFPE-based chips showed more than 20-times the appearance of intact MDZ in the liver compartment effluent compared to PDMS-based counterparts. Notably, saturation of hepatic metabolism at higher concentrations was confirmed by observations when the dose was reduced from 200 μM to 10 μM. This result was further emphasized when the metabolism was significantly inhibited by the coadministration of ketoconazole. Our chip, which is designed to minimize the dead volume between the gut and liver compartments, is adept at sensitively observing the saturation of metabolism and the effect of inhibitors. Using genome-edited CYP3A4/UGT1A1-expressing Caco-2 cells, the estimates for intestinal and hepatic availabilities were 0.96 and 0.82, respectively; these values are higher than the known human in vivo values. Although the metabolic activity in each compartment can be further improved, this gut-liver-on-a-chip can not only be used to evaluate oral bioavailability but also to carry out individual assessment of both intestinal and hepatic availability.

Exploring pectin-casein micelles as novel carriers for oral drug delivery of artesunate in the treatment of systemic lupus erythematosus

The oral route of administration is considered the optimal choice for treating chronic diseases due to its convenience and non-invasiveness, which can help prevent physical and mental harm to patients undergoing long-term treatment. However, challenges such as safety, gastrointestinal stability, and bioavailability of oral drugs often limit their effectiveness. Natural biomacromolecule micelles, known for their safety, stability, biocompatibility, and diverse functions, have emerged as promising carriers for oral treatment of chronic diseases like systemic lupus erythematosus (SLE) with fat-soluble drugs. This study introduces an innovative approach by developing an oral delivery system using chemically synthesized natural biomacromolecules to load artesunate for treating SLE. By synthesizing amphiphilic polymer micelles from pectin and casein through a carbodiimide reaction, a more stable structure is achieved. The hydrophobic core of these micelles encapsulates artesunate, resulting in the formation of an oral delivery system (PC-AS) with several advantages, including high drug loading and encapsulation efficiency, small particle size, negative potential, strong stability in the gastrointestinal tract, low toxicity and side effects, strong adhesion in the small intestine, and high bioavailability. These advantages facilitate efficient absorption of artesunate in the gastrointestinal tract, leading to improved bioavailability and effective alleviation of SLE-like symptoms in MRL/lpr mice. By utilizing chemically synthesized natural macromolecular micelles for delivering artesunate in the treatment of SLE, this study overcomes the oral barriers associated with the original drug and presents a novel solution for the long-term oral treatment of chronic diseases.

Water in nigella oil microemulsion for enhanced oral bioavailability of linagliptin.

Linagliptin is hydrophilic antidiabetic with poor oral bioavailability due to poor permeability and pre-systemic metabolism. The objective was to assess w/o microemulsion for enhanced oral bioavailability of linagliptin. Nigella oil was used as oily phase based on its reported antidiabetic effect. Isopropyl myristate (IPM) or capryol were combined with nigella oil to impart intestinal membrane permeabilizing abilities. Pseudoternary phase diagrams were constructed utilizing nigella oil in presence and absence of isopropyl myristate or capryol as oily phase using Tween 60 as surfactant. W/O microemulsion formulations were selected from the constructed phase diagrams and linagliptin was loaded in the internal aqueous phase at a concentration of 0.5mg/ml. The prepared formulations were physically evaluated and linagliptin in vitro release was monitored. Eventually, the in vivo hypoglycemic effect was assessed using diabetic rats. The developed microemulsions were of w/o type and exhibited Newtonian flow behavior with nigella/capryol microemulsion recording the lowest viscosity. The recorded droplet size values were 104.9, 121.2 and 86.4nm for nigella, nigella/IPM and nigella/capryol microemulsions, respectively. All microemulsion formulations showed slower drug release rate compared with aqueous suspension with nigella/capryol microemulsion showing the highest release rate compared to other microemulsions. Release data from microemulsion best fitted to Higuchi model. In vivo oral hypoglycemic activity measurement reflected a more intensified hypoglycemic effect with rapid onset after oral ingestion of microemulsion compared to linagliptin dispersion. Nigella oil/IPM-based microemulsion was ranked as the most effective. The investigation highlighted the feasibility of w/o microemulsion for enhanced oral bioavailability of hydrophilic drugs like linagliptin.

Evaluating the Dynamics of Cyp3a11, MRP2 and MDR1 Modulation by IL-22

Background: IL-22 is a cytokine produced by a number of immune cell populations, including type 3 innate lymphoid cells. We have shown previously that IL-22 suppresses the expression Cyp3a11 in the mouse intestine, a gene that encodes a drug metabolizing. In addition, IL-22 reduces the expression of MRP2 and MDR1, the gene that encodes as Multidrug resistance protein 2 or 1 involve in the drug detoxification. Modulation of these proteins can influence the oral bioavailability of drugs. Aims: The aim of this study was to define the existence of reversible modulation of IL-22 on Cyp3a11, MRP2 and MDR1 expression and protein level or activity in the intestinal epithelium. Methods: In vitro enteroids of the mouse small intestine were cultured in 3D in the presence/absence of IL-22 for 5 days. Cyp3a11, MRP2 and MDR1 transcript expression was evaluated by qPCR followed by protein analysis to define their modulation and activity at varying timepoints after IL-22 treatment cessation. Results: IL-22 reduced the expression and activity of Cyp3a11 which normalized soon after stopping IL-22 treatment. This action of IL-22 are made without any modulation of protein level of Cyp3a11. In the same way, IL-22 reduces the expression and the protein level of MRP2 and MDR1, an effect normalizes after treatment cessation. Conclusions: IL-22 suppresses the expression and the activity of Cyp3a11 without any modulation of the protein level unlike at the level of MRP2 and MDR1 which are reduced. These data suggest that regulation of gene expression, protein or enzyme activity by IL-22 may have variable effects: Cyp3a11 is ATP-independent, whereas MRP2 and MDR1 are ATP-dependent. This direct or indirect enzymatic modulation of these proteins must be taken into account when assessing the role of the drug in the biology of the intestinal mucosa. Dr. Lloyd Sutherland Chair in IBD/GI Research/Weston Foundation. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Dissolution and antioxidant potential of apigenin self nanoemulsifying drug delivery system (SNEDDS) for oral delivery

Self-nanoemulsifying drug delivery systems (SNEDDS) have been used to improve the oral bioavailability of various drugs. In the current study, apigenin was developed as SNEDDS to solve its dissolution problem and enhance oral bioavailability and antioxidant potential. SNEDDS were prepared by mixing Gelucire 44/14, Tween 80, and PEG 400 under controlled conditions. The droplet of diluted SNEDDS demonstrated a spherical shape with a size of less than 100 nm and a neutral charge. The very fast self-emulsification was obtained within 32 s, and the transmittance values exceeded 99%. The highest drug loading was 90.10 ± 0.24% of the initial load with the highest %encapsulation efficiency of 84.20 ± 0.03%. FT-IR and DSC spectra showed no interaction between components. The dissolution in buffer pH 1.2, 4.5, and 6.8 showed significantly higher dissolved apigenin than the apigenin coarse powder. The dissolution profiles were fitted to the Korsmeyer–Peppas kinetics. The cellular antioxidant activities in Caco-2 cells were approximately 52.25–54.64% compared to no treatment and were higher than the apigenin coarse powder (12.70%). Our work highlights the potential of SNEDDS to enhance the dissolution and permeability of apigenin and promote antioxidant efficacy, which has a strong chance of being developed as a bioactive compound for nutraceuticals.

Abstract CT064: Impact of food and high gastric pH on the bioavailability of the WEE1 inhibitor Debio 0123 assessed in a phase 1 dose escalation study

Abstract Debio 0123 (D0123), an oral, brain-penetrant, highly selective WEE1 inhibitor, is currently in clinical development, both in combination and as monotherapy, for the treatment of patients with solid tumors. Food and gastric acid-reducing agents e.g. proton pump inhibitors (PPIs) may modify the solubility, bioavailability, safety and efficacy of oral cancer drugs. Polymedication in cancer patients is common and food restrictions can impact patient compliance and wellbeing. In order to adequately inform drug dosing in clinical trials, effects of food and high gastric pH on D0123 bioavailability were studied over three cycles in patients treated in the dose escalation of a Phase 1 study of D0123 in combination with Carboplatin (CTID NCT03968653).D0123 was given on Days 1-3 and 8-10 of each 21-day cycle in combination with carboplatin on Day 1. Current standard administration of D0123 is in fasted conditions and PPIs are prohibited. Dose-limiting toxicities were evaluated in cycle 1. The effect of food and high-gastric pH were assessed in cycles 2 and 3, respectively. In cycle 2 on Day 10, patients were receiving a high-fat meal and in cycle 3, the PPI lanzoprazole 30 mg BID was administered from Day 7 to 11. PK parameters (area under the curve (AUC), maximum concentration (Cmax)) were determined post-Day 10 dose and compared between cycle 1 (fasted) and cycle 2 (fed) or 3 (high gastric pH). Preliminary data from 3 cohorts, 3 dose levels (n=10) resulted in about 5 pairwise comparisons for food and for high gastric pH effects. Absence of D0123 accumulation between cycles was confirmed, allowing for inter-cycle comparison. Oral bioavailability of D0123 appears pH-dependent, suggesting that co-medication with PPIs should be avoided. In contrast, food intake has a limited impact on drug absorption, at all doses tested. Furthermore, D0123 administration with food may increase treatment convenience and tolerability, leading to its implementation in other D0123 trials. TABLE 1. NAND Mean change [ min ; max ] Effect of food (cycle 2 versus cycle 1) Effect of high gastric pH (cycle 3 versus cycle 1) AUC24 -3% [ -17% ; +8% ] -31% [ -39%; -23% ] Cmax -10% [ -26% ; 0% ] -33% [ -41% ; -20% ] Citation Format: Anne Bellon, Omar Saavedra, Ingrid M. Desar, Mathilde Jalving, Jourik A. Gietema, Carla van Herpen, Stefan van Ravensteijn, Esteban Rodrigo Imedio, Sylvia van Haren, Melanie Wirth, Sandrine Micallef, Vito Dozio, Rikke Frederiksen Franzen, Marie-Claude Roubaudi-Fraschini, Valerie Nicolas-Metral, Hans Gelderblom. Impact of food and high gastric pH on the bioavailability of the WEE1 inhibitor Debio 0123 assessed in a phase 1 dose escalation study [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 CT064.

Design, Optimization, and Evaluation of Chitosan-2-mercaptobenzoic Acid as a Dual-functionalized Thiomer

Aims: This study aimed to develop and evaluate mucoadhesive microspheres for the controlled release of zidovudine using a novel dual-functionalized polymer. Background: Mucoadhesive polymers have recently been widely used to prolong the GI residence time and to modulate the release impact of various mucoadhesive dosage forms. In the present study, a recently synthesized chitosan derivative, chitosan-2-mercapto benzoic acid, was used as a mucoadhesive polymer, which was further developed as a dosage form for improving oral bioavailability of zidovudine drug. Objective: The objective of this study is to evaluate the impact of a novel thiolated derivative, chitosan-2-mercaptobenzoic acid, on the oral bioavailability of the drug zidovudine. Methods: The microspheres were prepared using an emulsification crosslinking method with TPP as the crosslinking agent. Techniques such as FTIR, and DSC were employed to analyze the microspheres, along with drug content, entrapment efficiency, dissolution studies, mucoadhesion, ex vivo permeation, and in vivo evaluations. Results: Results from FTIR spectroscopy and DSC analysis revealed no interaction between the drug and polymers. The release kinetics and characterization assessments indicated a zero-order release profile with anomalous and super case-II transport types. Ex vivo permeation studies on goat intestinal mucosa demonstrated enhanced mucoadhesive properties and permeability with the optimized microspheres fabricated using thiomers compared to conventional oral therapy. Pharmacokinetic investigations showed higher zidovudine plasma levels and Cmax with the administration of microspheres, particularly those composed of thiomers. The AUC0-24h values for thiomer microspheres were significantly greater than controls and chitosan microspheres, indicating improved oral bioavailability potential. Conclusion: In conclusion, zidovudine-loaded thiomer-based mucoadhesive microspheres showed promising results with the ability to enhance the drug's oral bioavailability.

Improving Oral Bioavailability of Meloxicam: Development and Characterization of Solid Dispersions

This study investigated the development of a solid dispersion to improve the solubility and dissolution of meloxicam, a poorly water-soluble drug. Meloxicam is used to treat pain and inflammation in various conditions. The challenge was to enhance the drug's oral bioavailability by overcoming its low solubility. Two approaches were explored:
 
 1. Kneading method with Poloxamer 407: This method resulted in a formulation with significantly improved solubility compared to the pure drug.
 Solvent evaporation method with PVP K-30: While this method offered satisfactory solubility enhancement, it was not as effective as the kneading method with Poloxamer 407.Following the development of the optimized solid dispersion, a suspension formulation was prepared using various suspending agents. The optimized drug formula was then incorporated into the suspension mix. Characterization studies confirmed compatibility between the drug and excipients. FT-IR analysis showed no interaction between the drug and the carriers. Scanning electron microscopy (SEM) revealed a change in meloxicam particle morphology from crystalline to a more amorphous form, indicating a reduction in particle size and a potential explanation for the improved dissolution profile. The dissolution profile of the solid dispersion suspension prepared by the kneading method with Poloxamer 407 outperformed the one prepared with the solvent evaporation method and PVP K-30.This study demonstrates the effectiveness of the kneading method with Poloxamer 407 in developing a solid dispersion of meloxicam with enhanced solubility and dissolution. The optimized formulation exhibited good stability, acceptable drug content and release, and satisfactory rheological properties. This approach has the potential to improve the bioavailability of meloxicam and lead to a more effective oral dosage form.
 
 Keywords: Oral Bioavailability, Meloxicam:, Solid Dispersions , FT-IR analysis, SEM

Enhancement of the Dissolution and Solubility of Canagliflozin Using Nanodispersion Systems

Background: Self-nanomicellizing solid dispersion is a new formulation that combines the advantages of solid dispersion with nanomicelle methods to increase drug oral bioavailability. The technique employs an appropriate carrier to produce a solid dispersion that self-assembles into nanomicelles when in contact with gastrointestinal fluids, improving medication solubility and absorption. Objective: The study aims to develop a self-nanomicellizing solid dispersion of canagliflozin and compare it to non-nanomicellizing formulations. Methods: The solvent evaporation approach was chosen to create a solid dispersion system with soluplus and poloxamer 407 as carriers. Different canagliflozin-to-carrier ratios were investigated in order to develop nanomicellar systems with improved canagliflozin dissolving characteristics. Solid-state analysis was used to characterize the optimum self-nanomicellizing and non-self-nanomicellizing formulations. Results: The physicochemical tests revealed that canagliflozin's crystalline structure transitioned to an amorphous state in the solid dispersion system of both carriers, as evidenced by powder X-ray diffraction and differential scanning calorimetry. Particle size analysis reveals that only soluplus, in all ratios tested, produces a self-nanomicellizing solid dispersion of canagliflozin, whereas poloxamer 407 does not. Self-nanomicellizing systems incorporating Soluplus had a faster dissolving profile than pure drug and non-self-nanomicellizing formulas. Conclusions: Canagliflozin nanodispersion systems with Soluplus as a carrier may improve solubility, dissolving rate, and bioavailability.