Oral Bioavailability Of Drugs Research Articles

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.

In-vitro Lipolysis, Stability and Pharmacodynamic Study of Cilnidipine Loaded Self-emulsifying Drug Delivery System

Aim: The aim of this research work was to investigate the potential ability of cilnidipineloaded- Self-Emulsifying Drug Delivery System (SEDDS) to improve the solubility and oral bioavailability of cilnidipine. background: The limited oral bioavailability of BCS class II drugs restricts the clinical utility of drugs. Self-emulsifying drug delivery systems (SEDDS) are widely used for poorly water-soluble drugs to enhance their solubility and oral bioavailability. Background: The therapeutic value of drugs is constrained by the low oral bioavailability of BCS class II drugs. In order to improve the solubility and oral bioavailability of poorly water-soluble drugs, SEDDS are frequently utilised. Methods: To develop the cilnidipine-loaded-SEDDS formulation, Canola oil as the oil phase, tween 80 as the surfactant, and PEG 300 as the co-surfactant were used. The SEDDS formulation was evaluated based on stability study per ICH guidelines, drug precipitation during in-vitro lipolysis study under fasted and fed state, and in vivo pharmacodynamic study in Wistar rats. The content of the drug was determined by assay of SEDDS formulation using the official method of cilnidipine. Result: The pharmacodynamic study demonstrated that cilnidipine-loaded SEDDS formulation significantly produced a rapid antihypertensive effect (within 2 h) that lasted for 24 h in comparison to drug suspension. During the in vitro lipolysis study, the concentration of the drug recovered from the aqueous phase under both fasted and fed state was more than 90% after 10 minutes, with a minute amount of drug involved in precipitation. At stability conditions of 30±2 °C/65±5%RH for a duration of six months, the SEDDS formulation was found to be stable. The content of cilnidipine in the SEDDS formulation was found to be 98.4%. Conclusion: A BCS class-II drug's oral bioavailability and dissolution might be improved using the self-emulsifying drug delivery method.

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.

Synthesis, Computational Study, and In Vitro α-Glucosidase Inhibitory Action of 1,3,4-Thiadiazole Derivatives of 3-Aminopyridin-2(1H)-ones.

This article reports on the synthesis of nine promising new 1,3,4-thiadiazole derivatives based on 3-aminopyridones, containing various acidic linkers. The synthesis was carried out by cyclizing the corresponding thiohydrazides 4a-c and anhydrides of glutaric, maleic, and phthalic acids upon heating in acetic acid solution. The conducted bio-screening of the synthesized new 1,3,4-thiadiazole derivatives containing different acidic linkers (butanoic, acrylic, and benzoic acids) showed that they have significant inhibitory activity against α-glucosidase (up to 95.0%), which is 1.9 times higher than the value for the reference drug acarbose (49.5%). Moreover, one of the 1,3,4-thiadiazole derivatives with a benzoic acid linker-2-(5-((6-Methyl-2-oxo-4-(thiophen-2-yl)-1,2-dihydropyridin-3-yl)carbamoyl)-1,3,4-thiadiazol-2-yl)benzoic acid (9'b)-showed an IC50 value of 3.66 mM, nearly 3.7 times lower than that of acarbose (IC50 = 13.88 mM). High inhibitory activity was also shown by 1,3,4-thiadiazole derivatives with a butanoic acid linker (compounds 7b, 7c)-with IC50 values of 6.70 and 8.42 mM, respectively. A correlation between the structure of the compounds and their activity was also established. The results of molecular docking correlated well with the bioanalytical data. In particular, the presence of a butanoic acid linker and a benzoic fragment in compounds 7b, 7c, and 9b increased their binding affinity with selected target proteins compared to other derivatives 3-6 (a-c). Calculations according to Lipinski's rule of five also showed that the synthesized compounds 7b, 7c, and 9b fully comply with Ro5 and meet all criteria for good permeability and acceptable oral bioavailability of potential drugs. These positive bioanalytical results will stimulate further in-depth studies, including in vivo models.

3D‐Printed Lipid Mesophases for the Treatment of Chronic Liver Disease

AbstractAlthough lipid‐based formulations are an attractive approach for enhancing the oral bioavailability of lipophilic drugs, their addition into solid oral dosage forms has been proven challenging due to their high viscosity and heat sensitivity. Therefore, unlike the traditional tableting process, this study employed semi‐solid extrusion 3D‐printing to produce–at room temperature–gastro‐resistant printlets containing a high percentage of bioactive lipids for the effective delivery of lipophilic drugs through self‐emulsification. The bio‐compatible lipidic mesophase ink, owing to a tunable 3D nanostructure, is employed as a starting material to produce printlets via additive manufacturing. An active lipid mixture – with antifibrotic properties – is blended with the antioxidant vitamin E and water, and the ink printability is optimized by carefully tailoring its composition, and thus its phase identity. The obtained printlets disintegrated upon contact with intestinal fluids forming colloidal structures that enhanced the solubility of a poorly water‐soluble drug. The printlets exhibited antifibrotic activity on human hepatic stellate cells, LX‐2, suggesting that the generated self‐emulsified colloidal structures made both the fibrosis‐resolving bioactive excipients and the drug promptly available, enhancing their cell uptake and, in turn, their therapeutic activity.

A56 EVALUATING THE DYNAMICS OF CYP3A11 AND REG3G MODULATION BY IL-22

Abstract 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 enzyme that accounts for roughly 70% of total drug metabolism. In addition, IL-22 induces the expression of Reg3g, the gene that encodes an antimicrobial C-type lectin that has bactericidal activity against Gram+ bacteria in the small intestine. Modulation of these proteins can influence both the oral bioavailability of drugs and microbial composition. Aims The aim of this study was to define the existence of reversible modulation of IL-22 on Cyp3a11 and Reg3g expression in the intestinal epithelium. Methods In vitro enteroids from each part of the mouse small intestine were cultured in 3D in the presence or absence of IL-22 for 5 days. Cyp3a11 and Reg3g transcript expression was evaluated by qPCR followed by protein analysis to define their modulation at varying timepoints after IL-22 treatment cessation. Results IL-22 reduced Cyp3a11 expression, an effect that normalized the day after treatment cessation. However, 4 days after treatment cessation there was rebound hyperexpression of Cyp3a11 in duodenal enteroids, which normalized the following day. IL-22 reduced the expression and activity of Cyp3a11 which normalized soon after stopping IL-22 treatment. In contrast, IL-22 induced the expression of Reg3g, an effect that lasted up to 5 days after treatment cessation. The effect of IL-22 on Cyp3a11 expression and activity was rapidly reversed in contrast to the effect on Reg3g which was more prolonged. Conclusions IL-22 suppresses the expression of Cyp3a11 and induces the expression of Reg3g. The reversible nature of these effects is different between both, with the increased expression of Reg3g 5 days after IL-22 treatment cessation. These data suggest that the regulation of gene expression, protein or enzyme activity by IL-22 may exhibit varying temporal effects and should be considered when assessing its role in intestinal mucosal biology. Funding Agencies This work was funded by the Dr. Lloyd Sutherland Chair in IBD/GI Research and the Weston Foundation.

Construction of An Oral Bioavailability Prediction Model Based on Machine Learning for Evaluating Molecular Modifications

ObjectiveThis study aims to explore the impact of ADME on the Oral Bioavailability (OB) of drugs and to construct a machine learning model for OB prediction. The model is then applied to predict the OB of modified berberine and atenolol molecules to obtain structures with higher OB. MethodsInitially, a drug OB database was established, and corresponding ADME characteristics were obtained. The relationship between ADME and OB was analyzed using machine learning, with Morgan fingerprints serving as molecular descriptors. Compounds from the database were input into Random Forest, XGBoost, CatBoost, and LightGBM machine learning models to train the OB 7prediction model and evaluate its performance. Subsequently, berberine and atenolol were modified using Chemdraw software with ten different substituents for mono-substitution, and chlorine atoms for a full range of double substitutions. The modified molecular structures were converted into the same format as the training set for OB prediction. The predicted OB values of the modified structures of berberine and atenolol were compared. ResultsAn OB database of 386 drugs was obtained. It was found that smaller molecular weight and a higher number of rotatable bonds (ten or less) could potentially lead to higher OB. The four machine learning models were evaluated using MSE, R2 score, MAE, and MFE as metrics, with Random Forest performing the best. The models' predictions for the test set were particularly accurate when OB ranged from 30% to 90%. After mono-substitution and double substitution of berberine and atenolol, the OB of both drugs was significantly improved. ConclusionsThis study found that some ADME properties of molecules do not have an absolute impact on OB. The database played a decisive role in the process of the machine learning OB prediction model, and the performance of the model was evaluated based on predictions within a range of strong generalization ability. In most cases, mono-substitution and double substitution were beneficial for enhancing the OB of berberine and atenolol. In summary, this study successfully constructed a machine learning regression prediction model that can accurately predict drug OB, which can guide drug design to achieve higher OB to some extent.

Urease catalyzed high-density sodium alginate microspheres enable high oral bioavailability of macromolecular drugs.

Destruction of insulin caused by the gastric microenvironment and rapid deactivation pose inevitable barriers to oral macromolecular absorption, especially for most peptide and protein drugs. In this study, we developed high-density sodium alginate microspheres composed of magnesium oxide and urease to address these challenges. These microspheres aim to anchor the gastric mucus layer and induce microenvironmental liquefaction, thereby enhancing gastric retention and the protection of insulin. The sedimentation test confirmed the capability of the Ins/Ur/MgO@SA microsphere to rapidly traverse the gastric juice under the influence of gravity. Additionally, the urease immobilized on the Ins/Ur/MgO@SA microspheres catalyzes the hydrolysis of urea in the gastric mucus and promotes the liquefaction of mucus, which is beneficial for microsphere retention. The inclusion of MgO particles and urease, acting as pHM modifiers, helps in adjusting the local pH to avoid gastric acid-induced damage. Subsequently, an in vivo pharmacokinetic experiment verified that the relative bioavailability of the p.o. Ins/Ur/MgO@SA treated group was 15-fold higher than that of the p.o.insulin treated group. Meanwhile, satisfactory blood glucose level (BGL) reduction was observed in diabetic animals. In conclusion, Ins/Ur/MgO@SA microspheres demonstrate high biocompatibility as insulin carriers with prolonged drug release time and increased gastric retention properties, showing a far-reaching strategy for oral macromolecular drug delivery.

Improved gastric residence time of famotidine by raft-forming drug delivery system using DOE.

This study investigated the raft-forming suspension of famotidine as an anti-reflux formulation to improve the oral bioavailability of narrow absorption window drugs by enhancing gastric residence time (GRT) and preventing gastro-esophageal reflux disease (GERD). Various combinations of raft-forming agents, such as Tragacanth gum (TG), guar gum (GG), and xanthan gum (XG), were evaluated alongside sodium alginate (SA) to develop an effective raft. Preformulation studies and preliminary screening were conducted to identify the most suitable raft-forming agent, and GG was chosen due to its mucilaginous properties. The formulation was optimized using a 32 full factorial design, with the quantities of GG and SA as independent factors and apparent viscosity and in-vitro drug release (%) as dependent factors. The in vivo floating behavior study was performed for optimized and stabilized formulation. Among the tested batches, F6 was selected as the optimized formulation. It exhibited desirable characteristics such as adequate raft weight for extended floating in gastric fluid, improved apparent viscosity, and a significant percentage of drug release at 12h. A mathematical model was applied to the in-vitro data to gain insights into the drug release mechanism of the formulation. The stability of the suspension was assessed under accelerated conditions, and it demonstrated satisfactory stability. The formulation remains floating in the Rabbit stomach for more than 12h. It concludes that the developed formulation has enhanced bioavailability in the combination of GG and SA. The floating layer of the raft prevents acid reflux, and the famotidine is retained for an extended period of time in the gastric region, preventing excess acid secretion. The developed formulations are effective for stomach ulcers and GERD, with the effect of reducing acid secretion by H2 receptor antagonists.

Solusomes (novel soluplus® enriched nano-vesicular carriers) for improving the oral bioavailability of Candesartan cilexetil

Candesartan cilexetil (CAN) is administered for treating hypertension and heart failure. CAN suffers poor oral bioavailability, owing to limited aqueous solubility, and first-pass metabolism. Solusomes (novel Soluplus® enriched nano-vesicular carriers) combine the merits of Soluplus®, and the traditional liposomes. They were explored to increase CAN solubility, allow a high drug release rate, and improve the oral drug bioavailability. Solusomes were developed via thin film hydration technique utilizing lipid (phosphatidylcholine; PC) and polymeric solubilizer (Soluplus®; Solu). S6 system comprising PC (0.1% w/v), CAN and Soluplus® (at 1:5 ratio; w/w), following a 5 min sonication period, was the optimum one with respect to drug entrapment efficiency (83.5 ± 2.6%), drug loading (11.9 ± 0.3%), particle size and shape (377.2 ± 12.1 nm, spherical), zeta-potential (−19.6 ± 2.1 mV), saturated drug solubility (32.09 ± 0.71 µg/mL), drug released % after 1 h (68 ± 0.9%), and stability. Significantly higher Cmax (969.12 ± 46.3 ng/mL), shorter median Tmax (1h), and improved relative bioavailability (≈ 6.8 folds) in rabbits could evidence the potential of S6 system in enhancing oral CAN bioavailability. S6 solusomes act as dual platform to improve the oral drug bioavailability and maintain effective drug concentration for a prolonged period.

Nanocrystalline solid dispersions: an emerging approach for oral bioavailability enhancement of anticancer drugs using lapatinib ditosylate as the case drug

The bioavailability of lapatinib ditosylate, an active anticancer agent against breast neoplasms, is constrained by its poor bioavailability due to poor aqueous solubility. So, the study’s objective was to develop its nanocrystalline solid dispersion (NSD) in order to improve its oral bioavailability. The process of wet media milling followed by lyophilization was used to prepare NSDs of the drug. Using polyvinyl pyrrolidone (PVP), and sodium dodecyl sulfate (SDS) as combination stabilizers, the resultant NSD demonstrated the smallest particle size and a sufficient stability during formulation screening. Differential scanning calorimetry, and powder X-ray diffraction techniques confirmed the crystalline state of the dispersion. Scanning electron microscopic analysis of optimized NSD revealed evenly distributed rod-shaped crystals of lapatinib ditosylate. The molecular-level interaction in the formulated dispersion was confirmed by NMR analysis. The formulated NSD has enhanced aqueous solubility of lapatinib ditosylate, by 3.68 folds. It also exhibited improved drug release as well as enhanced in vitro anticancer activity in the MCF-7 cell line. Similar findings were derived from in vivo pharmacokinetic investigations, where, compared to pure drug, the maximum plasma drug concentration (Cmax), and area under the curve (AUC), of formulated NSD, increased by 2.45, and 2.56, times respectively for lapatinib ditosylate. All these pharmacokinetic parameters were found to be improved in formulation LP, when compared to the marketed formulation, Tykerb. Thus, this study demonstrated a commercially viable method for increasing the oral bioavailability of anticancer drug, lapatinib ditosylate through the screening and optimization of stabilizers in nanocrystalline solid dispersion.

Self-microemulsifying system of an ethanolic extract of Heliopsis longipes root for enhanced solubility and release of affinin

Self-microemulsifying or self-nanoemulsifying drug delivery systems (SMEDDS/SNEDDS) are well known to improve the dissolution and increase the oral bioavailability of hydrophobic drugs, including herbal extracts. Organic extracts of Heliopsis longipes root and affinin, its main component, induce a vasodilator effect; however, they are poorly water soluble and therefore are difficult to administer and dose by the oral route. This research aimed to develop, through pseudo-ternary phase diagrams, a self-microemulsifying system prepared from an ethanolic extract of H. longipes root (HL-SMDS). In addition, the optimized lipid-based formulation was characterized and its in vitro gastrointestinal simulated dissolution was determined. The formulation composed of Transcutol, 55% (solubilizer); Tween80/PG, 10% (surfactant/co-solvent); Labrasol, 35% (surfactant); and the herbal extract was selected as optimal and identified as a SMEDDS, since when coming into contact with water, it forms a micro-emulsion with droplet sizes less than 100 nm. The stability tests showed that HL-SMDS remained stable over time under extreme conditions. Furthermore, the amount of affinin released from HL-SMDS at pH 1 and 6.8 was higher than that of the ethanolic extract from H. longipes root. These results indicate that HL-SMDS is a novel alternative to improve the aqueous solubility and therefore the oral bioavailability of the ethanolic extract of H. longipes root.

Preparation and Characterization of Carvedilol Solid Dispersion by Kneading Method

Solid dispersion using hydrophilic carrier is one of the approaches that has a potential to increase solubility, dissolution rate and consequently the oral bioavailability of poorly-water soluble drugs. In this study, class II drug "Carvedilol" (CVD) was used because of its poor solubility, it serves as a model drug that contributes to irregular dissolution and limited bioavailability. CVD: PVP K30 solid dispersion formulations SD1, SD2 and SD3 were prepared by kneading method at different weight ratios ,1:1; 1:2 and 1:4 respectively and evaluated for drug content, solubility and dissolution rate. Kneading method enhances the stability of drugs and suitable for processing thermolabile substances. The optimum solid dispersion ratio was characterized also for drug-carrier interaction by FTIR spectroscopy, and crystallinity by SEM and PXRD and compared with physical mixture and pure drug powder.
 The results showed that the solubility of carvedilol increased by increasing the proportion of PVP K30 used in the dispersion of the drug. On the other hand, dissolution study revealed a significant enhancement in the dissolution rate of the drug using solid dispersion compared to pure drug and physical mixture. X-ray diffraction of the solid dispersion suggest that the drug's transformation from crystalline to amorphous form may be responsible for the observed improvement in dissolving rate. The carvedilol solid dispersion improved the solubility and dissolution, which depend on the carrier concentration ratio. The dissolution of drugs increased with an increase in carrier content. The studies of PXRD, SEM, and FTIR revealed the amorphous nature of the drug in solid dispersion. The solid dispersion by kneading approach using PVP K30 as a carrier is a potential method for improving CVD's solubility and dissolution rate.

Comparative Intra-Subject Analysis of Gene Expression and Protein Abundance of Major and Minor Drug Metabolizing Enzymes in Healthy Human Jejunum and Liver.

First pass metabolism by phase I and phase II enzymes in the intestines and liver is a major determinant of the oral bioavailability of many drugs. Several studies analyzed expressions of major drug-metabolizing enzymes (DMEs), such as CYP3A4 and UGT1A1 in the human gut and liver. However, there is still a lack of knowledge regarding other DMEs (i.e., "minor" DMEs), although several clinically relevant drugs are affected by those enzymes. Moreover, there is very limited intra-subject data on hepatic and intestinal expression levels of minor DMEs. To fill this gap of knowledge, we analyzed gene expression (quantitative real-time polymerase chain reaction) and protein abundance (targeted proteomics) of 24 clinically relevant DMEs, that is, carboxylesterases (CES), UDP-glucuronosyltransferases (UGT), and cytochrome P450 (CYP)-enzymes. We performed our analysis using jejunum and liver tissue specimens from the same 11 healthy organ donors (8 men and 3 women, aged 19-60 years). Protein amounts of all investigated DMEs, with the exception of CYP4A11, were detected in human liver samples. CES2, CYP2C18, CYP3A4, and UGT2B17 protein abundance was similar or even higher in the jejunum, and all other DMEs were found in higher amounts in the liver. Significant correlations between gene expression and protein levels were observed only for 2 of 15 jejunal, but 13 of 23 hepatic DMEs. Intestinal and hepatic protein amounts only significantly correlated for CYP3A4 and UGT1A3. Our results demonstrated a notable variability between the individuals, which was even higher in the intestines than in the liver. Our intrasubject analysis of DMEs in the jejunum and liver from healthy donors, may be useful for physiologically-based pharmacokinetic-based modeling and prediction in order to improve efficacy and safety of oral drug therapy.

Improving on in-silico prediction of oral drug bioavailability

ABSTRACT Introduction Although significant development has been made in high-throughput screening of oral drug absorption and oral bioavailability, in silico prediction continues to play an important role in prediction of oral bioavailability and assisting in the proper selection of potential drug candidates. Areas covered This review describes the improvements and latest modeling methods and algorithms available for the prediction of this important parameter. We performed a PubMed database search with a focus on the literature published in the last 15 years. Expert opinion A tremendous efforts have been done in the past several years to develop reliable prediction tools that can provide accurate prediction for oral bioavailability. Several studies demonstrated new methodologies and techniques to develop either web-based in silico predictive tools or integrated PBPK models to predict oral bioavailability for new molecules. Improvements in the databases and the computational power will enhance the in silico prediction accuracy and reliability. Finally, introducing artificial intelligence to the drug development process will help improve the prediction tools.

Cyclodextrin Inclusion Complexes for Improved Drug Bioavailability and Activity: Synthetic and Analytical Aspects.

Many active pharmaceutical ingredients show low oral bioavailability due to factors such as poor solubility and physical and chemical instability. The formation of inclusion complexes with cyclodextrins, as well as cyclodextrin-based polymers, nanosponges, and nanofibers, is a valuable tool to improve the oral bioavailability of many drugs. The microencapsulation process modifies key properties of the included drugs including volatility, dissolution rate, bioavailability, and bioactivity. In this context, we present relevant examples of the stabilization of labile drugs through the encapsulation in cyclodextrins. The formation of inclusion complexes with drugs belonging to class IV in the biopharmaceutical classification system as an effective solution to increase their bioavailability is also discussed. The stabilization and improvement in nutraceuticals used as food supplements, which often have low intestinal absorption due to their poor solubility, is also considered. Cyclodextrin-based nanofibers, which are polymer-free and can be generated using environmentally friendly technologies, lead to dramatic bioavailability enhancements. The synthesis of chemically modified cyclodextrins, polymers, and nanosponges based on cyclodextrins is discussed. Analytical techniques that allow the characterization and verification of the formation of true inclusion complexes are also considered, taking into account the differences in the procedures for the formation of inclusion complexes in solution and in the solid state.

Recent Progress in the Oral Delivery of Therapeutic Peptides and Proteins: Overview of Pharmaceutical Strategies to Overcome Absorption Hurdles.

Proteins and peptides have secured a place as excellent therapeutic moieties on account of their high selectivity and efficacy. However due to oral absorption limitations, current formulations are mostly delivered parenterally. Oral delivery of peptides and proteins (PPs) can be considered the need of the hour due to the immense benefits of this route. This review aims to critically examine and summarize the innovations and mechanisms involved in oral delivery of peptide and protein drugs. Comprehensive literature search was undertaken, spanning the early development to the current state of the art, using online search tools (PubMed, Google Scholar, ScienceDirect and Scopus). Research in oral delivery of proteins and peptides has a rich history and the development of biologics has encouraged additional research effort in recent decades. Enzyme hydrolysis and inadequate permeation into intestinal mucosa are the major causes that result in limited oral absorption of biologics. Pharmaceutical and technological strategies including use of absorption enhancers, enzyme inhibition, chemical modification (PEGylation, pro-drug approach, peptidomimetics, glycosylation), particulate delivery (polymeric nanoparticles, liposomes, micelles, microspheres), site-specific delivery in the gastrointestinal tract (GIT), membrane transporters, novel approaches (self-nanoemulsifying drug delivery systems, Eligen technology, Peptelligence, self-assembling bubble carrier approach, luminal unfolding microneedle injector, microneedles) and lymphatic targeting, are discussed. Limitations of these strategies and possible innovations for improving oral bioavailability of protein and peptide drugs are discussed. This review underlines the application of oral route for peptide and protein delivery, which can direct the formulation scientist for better exploitation of this route.

Evaluation of microstructure, dissolution rate, and oral bioavailability of paclitaxel poloxamer 188 solid dispersion.

Poor solubility is a major challenge for enhancing the oral bioavailability and clinical application of many drugs, including the broad-spectrum chemotherapy drug paclitaxel (PTX). A practical approach to improving the solubility of insoluble drugs is through the use of solid dispersion (SD).This study aimed to investigate the potential of the triblock copolymer, poloxamer 188 (P188), as a carrier for preparing solid dispersion of paclitaxel using spray drying technology. We systematically studied its microstructure, dissolution behavior in vitro, and pharmacokinetics. Our findings demonstrate that PTX exists in an amorphous state in copolymer composed of polyoxyethylene-polyoxypropylene-polyoxyethylene (PEO-PPO-PEO) P188, with stronger miscibility with hydrophobic PPO segments. All three in vitro dissolution models revealed that the release rate of drugs in SD was significantly higher compared to that of physical mixtures (PM) as well as raw drugs. Furthermore, our pharmacokinetic results showed that the area under the curve(AUC) of PTX in SD was 6 times higher than that of active pharmaceutical ingredient(API), 4.5 times higher than PM, and the highest blood drug concentration (Cmax) reached 357.51 ± 125.54 (ng/mL), approximately 20 times higher than API.Overall, our findings demonstrate that the dissolution rate of amorphous PTX in SD significantly improves, effectively enhancing the oral bioavailability of PTX.