Search Results (153)

Background/Objectives: Biorelevant in vitro dissolution testing is used increasingly to predict complex mechanisms in the gastrointestinal (GI) tract that determine oral bioavailability. However, the limited use of non-compendial systems is driven by the lack of widely accepted, standardized validation frameworks. This ongoing gap continues to restrict their adoption relative to United States Pharmacopeia (USP) apparatus. While the physiological relevance and biopredictive capabilities of the tiny-TIM and TIM-1 in vitro GI models have been demonstrated in previous studies, their inter-laboratory reproducibility has not been systematically established. Therefore, this international ring study evaluates the reproducibility of in vitro simulations of GI transit and absorption of paracetamol in fasted- and fed-state conditions in tiny-TIM and TIM-1. Methods: Three laboratories used TIM-1 and five used tiny-TIM to simulate oral administration of a 500 mg paracetamol solution to a healthy adult. Paracetamol solution was selected as a well-characterized and widely available BCS I compound to minimize formulation and solubility effects and focus on system performance, enabling the generation of a generic validation dataset for the reproducibility of TIM experiments. Results: Paracetamol bioaccessibility profiles were repeatable and reproducible (all pairwise f₂ > 50). Maximum differences in total bioaccessible paracetamol were 0.9% (TIM-1) and 2.8% (tiny-TIM) within laboratories and 3.4 and 5.9% between laboratories. Inter-lab variability at individual time points remained <4.0% (fasted) and 5.2% (fed). Both TIM models produced biopredictive metrics, correctly predicting no food effect on total paracetamol bioaccessibility and capturing delayed t_max. Gastric and intestinal environments showed repeatable pH, temperature, and GI transit characteristics, with fluctuations across transit stages that mirrored reported in vivo patterns. Conclusions: These results demonstrate that TIM systems can reproducibly simulate gastrointestinal conditions across laboratories and generate consistent measurements of drug product performance, despite the complexity of the dynamic processes involved. While this evaluation involving a single BCS I drug solution should not be directly extrapolated to experiments with poorly soluble compounds or different formulations, it supports the use of TIM systems as robust in vitro models in drug product development. This study provides a standardized, inter-laboratory, baseline performance dataset to support regulatory submissions incorporating TIM data and enable more confident interpretation of TIM experiments. Full article

Propolis is a chemically complex natural product with recognized antioxidant potential, but its compositional heterogeneity and poor aqueous solubility complicate formulation and interpretation of in vitro release behavior. In this study, a nanostructured lipid carrier (NLC) based on Gelucire^® 44/14 was developed as a physicochemical platform to modulate the accessibility of a selected Chilean ethanolic propolis extract. Propolis extracts from different origins were first screened using complementary antioxidant assays (DPPH, ABTS, ORAC, FRAP), leading to the selection of the Peñaflor extract, which exhibited the highest phenolic content (~41 mg GAE/g) and antioxidant capacity. The selected extract was incorporated into NLCs with encapsulation efficiencies above 90%, a narrow size distribution (~200 nm), and high stability over 90 days. Under simple aqueous conditions, propolis release remained limited (<15% over 6 h), consistent with diffusion- and partition-controlled transport. In simulated gastrointestinal media containing bile components, pronounced pH- and composition-dependent effects were observed. While fed-state intestinal conditions induced extensive morphological remodeling without increasing the analytically accessible fraction (<3% at 4 h), fasted-state intestinal media promoted a higher accessible fraction (~14% within 1 h) without complete carrier disruption, as confirmed by transmission electron microscopy. Preliminary cytocompatibility studies in HepG2 cells showed acceptable viability at 10–40 µg/mL and concentration-dependent effects at higher doses. Overall, this work demonstrates that bile components modulate propolis accessibility through dynamic partitioning and colloidal reorganization rather than simple carrier breakdown, providing a physicochemical framework for future digestion and absorption studies. Full article

Cutaneous leishmaniasis (CL) is a neglected tropical disease for which current chemotherapeutic options are limited by systemic toxicity (such as hepato-nephrotoxicity, arrhythmia, nausea, vomiting) and difficult administration regimens. Pentamidine (PTM), although effective, exhibits severe dose-limiting adverse effects. Polymeric micelles based on Pluronic^® F127 (F127) offer an attractive strategy to improve PTM delivery by enhancing solubility, reducing cytotoxicity, and enabling controlled release. Here, we developed PTM-loaded F127 polymeric micelles and performed a multidisciplinary evaluation combining physicochemical characterization, in vitro biological assays, and gene expression profiling. Dynamic light scattering, UV–visible absorption, fluorescence spectroscopy, and NMR confirmed micelle formation, PTM–polymer interactions, and temperature-dependent assembly. PTM-loaded micelles exhibited biorelevant nanoscale dimensions and preserved stability under physiological conditions. Biological assays demonstrated that F127 micelles markedly reduced PTM cytotoxicity in RAW264.7 macrophages while maintaining potent antileishmanial activity against Leishmania major promastigotes. RT-qPCR analysis revealed modulation of key pathways involved in redox homeostasis, oxidative stress, calcium regulation, apoptosis-like responses, and drug resistance, suggesting that micellar encapsulation influences both PTM bioavailability and parasite stress responses. Overall, PTM-loaded F127 micelles significantly improved the therapeutic index of PTM in vitro. These findings support the potential of F127 polymeric micelles as a promising nanocarrier platform for safer and more effective CL therapy. Full article

Background: Thiabendazole (TBZ), a benzimidazole with established antifungal and anthelmintic properties, has also been reported to exert antiangiogenic effects relevant to tissue remodeling and chronic inflammatory microenvironments. The present study examined how manganese coordination and cyclodextrin modify the dissolution behavior and endothelial activity of TBZ. Methods: Antiangiogenic potential was assessed through a human umbilical vein endothelial cells (HUVECs) scratch-wound migration assay. Dissolution profiles of TBZ, manganese–thiabendazole (MnTBZ), and MnTBZ/monochlorotriazynil-β-cyclodextrin (MCT-β-CD) formulation were evaluated under biorelevant pH conditions (1.2, 4.5, 6.8, 7.4) using the paddle method. Results: TBZ displayed a more rapid and extensive dissolution at pH 1.2, compared to MnTBZ. Partial dissociation at pH 4.5 modestly improved TBZ availability, while dissolution remained minimal at neutral pH. MCT-β-CD enhanced the solubility of MnTBZ at pH ≥ 6.8. In agreement with these profiles, TBZ exerted the strongest inhibition of endothelial migration, followed by MnTBZ/MCT-β-CD and MnTBZ. Conclusions: Manganese coordination and cyclodextrin formulation modulate both the dissolution behavior and endothelial migration-inhibitory activity of TBZ, suggesting that such formulation approaches may influence the delivery-related and functional properties of benzimidazole derivatives. Full article

Background/Objectives: Ocular drug delivery faces significant challenges due to anatomical and physiological barriers that limit drug bioavailability, particularly with conventional eye drops. Levofloxacin (LEVO), a broad-spectrum antibiotic, is widely used in the treatment of bacterial conjunctivitis, but its therapeutic efficacy is hindered by rapid precorneal clearance and short residence time. Methods: This study introduces a biorelevant 2 mL dissolution model to simulate ocular conditions better and evaluate the release kinetics of LEVO-loaded nanofibrous ophthalmic inserts. Compared to the conventional 40 mL setup, the 2 mL system demonstrated a slower and more sustained drug release profile, with kinetic modeling confirming a more controlled release behavior. Difference and similarity factor analysis further validated the distinct release profiles, highlighting the impact of dissolution volume on release dynamics. Results: Preliminary pharmacokinetic modeling suggested that the nanofiber inserts, particularly when applied twice daily, maintained levofloxacin concentrations above minimum inhibitory and bactericidal levels for extended durations across three bacterial strains (Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus), potentially outperforming traditional eye drops. Conclusions: These findings suggest that small-volume dissolution testing may provide a more realistic method for evaluating ophthalmic insert formulations, though in vivo validation is needed. Moreover, the nanofibrous inserts show potential as a sustained-release alternative that warrants further investigation to improve patient compliance and therapeutic outcomes in ocular disease management. Full article

In recent years, amino-gem-bisphosphonic acids and their esters have been considered a family of compounds of great chemical and pharmacological interest due to their important biological properties and their value as key synthons in the synthesis of more complex molecules with biological interest. This explains why several research groups are interested in developing new methods for the preparation of these compounds. Therefore, we would like to report here a summary of the synthetic strategies published in the last fifteen years for the synthesis of acyclic and heterocyclic α-, β- and γ-amino-gem-bisphosphonates, as well as their application in the preparation of selected compounds of chemical and pharmacological interest. This information can be of general knowledge to researchers working in this area, as it provides the starting point for new methods and applications of these compounds. Full article

Background/Objectives: 5-Fluorouracil (5-FU) and Irinotecan (IRT) are two of the most used chemotherapeutic agents in CRC treatment. However, achieving treatment goals has been hampered by poor drug delivery to tumor sites and associated toxicity from off-target binding to healthy cells. Though the synergism of 5-FU-IRT has provided incremental improvements in clinical outcomes, the short elimination half-life and off-target binding to healthy cells remain significant challenges. We postulated that nanoencapsulation of a combination of 5-FU and IRT in niosomes would prolong the drugs’ half-lives, while over-encapsulation lyophilized powder in Targit^® oral capsules would passively the CRC microenvironment and avoid extensive systemic distribution. Methods: Ranges of formulation and process variables were input into design of experiment (DOE Fusion One) software, to generate screening experiments. Niosomes were prepared using the thin-film hydration method and characterized by size, the polydispersity index (PDI), morphology and intrastructure, and drug loading. Blank niosomes ranged in size from 215 nm to 257 nm. Results: After loading with the 5-FU-IRT combination, the niosomes averaged 251 ± 2.20 nm with a mean PDI of 0.293 ± 0.01. The surfactant-to-cholesterol ratio significantly influenced the niosome size and the PDI. The hydrophilic 5-FU exhibited superior loading compared to the lipophilic IRT molecules, which probably competed with other lipophilic niosome components in niosomes’ palisade layers. In vitro dissolution in biorelevant media showed delayed release until lower intestinal region (IRT) or colonic region (5-FU). Conclusions: Thus, co-nanoencapsulation of 5-FU/IRT in niosomes, lyophilization, and over-encapsulation of powder in colon-specific capsules could passively target the CRC cells in the colonic microenvironment. Full article

Background/Objectives: Currently there are very few effective oral antileishmanial treatments. In this study we evaluated a new bis(pyridine-2-carboxamidine) antileishmanial drug (JNII40_base) and its hydrochloride salt (JNII40_HCl). Methods: The characterization studies performed allowed us to determine the crystallinity, hydration water, and presence of hydrogen bonds in these drugs. Different dissolution methods were employed to predict intestinal absorption. A high-performance liquid chromatography–mass spectrophotometry (HPLC-MS/MS) method was developed for the determination of JNII40 in plasma. Results: Pharmacokinetic studies in rats of JNII40_base at 100 and 20 mg/kg, and JNII40_HCl at 20 mg/kg, showed a non-linear pharmacokinetic at high doses. An innovative biorelevant medium of phosphate buffer pH 6.8 with polysorbate 80 at 0.6% (w/v) showed high concentration values for JNII40_base at 30 min, which predicts good intestinal absorption. These results were consistent with the bioavailability data, which exhibited a significant (p < 0.05) increase in maximum plasma concentration (C_max) and a slight delay in time to maximum (T_max) compared to JNII40_HCl. Furthermore, the sustained release of JNII40_base in this biorelevant media was related to high plasma concentration values at 24 h (C_24h) observed in bioavailability studies. These plasma concentrations of JNII40_base were above the half-maximal inhibitory concentration (IC₅₀) against promastigote and amastigote forms of Leishmania donovani, which is indicative of effectiveness and should reduce the occurrence of drug resistance during treatments. Conclusions: The bioavailability and pharmacokinetic data support the consideration of this drug for further in vivo studies as an oral antileishmanial treatment. Full article

Background/Objectives: This paper describes the use of physiologically based biopharmaceutics modelling (PBBM) to predict the effect of food on diclofenac and ibuprofen absorption from ultra-rapid-release Surge Dose^® tablets. Methods: Fasted-state diclofenac pharmacokinetics (PK) were used with published IV data and biorelevant dissolution data for the diclofenac tablets to develop a mechanistic PBBM model which could be used to predict absorption. Results: The resultant model that best fitted the PK data showed that, in vivo, the ultra-rapid-release tablets behaved like a solution with a median time to peak plasma concentration (T_max) of 20 min. Incorporating a well-established model for gastric emptying in the fed state, the fed T_max for these tablets was predicted to be 21 min, similar to that seen in fasted subjects. Use of a PBBM model to predict absorption of ibuprofen in the fasted and fed states again showed that ultra-rapid-release tablets produced fast and consistent absorption independent of the presence of food. Predicted mean T_max values were 31.8 and 35.4 min in the fasted and fed states, respectively. Conclusions: Therefore, even if Surge Dose^® formulations are taken after food, as frequently recommended for NSAIDs, the speed of absorption and subsequent onset of action should not be impacted. Full article

Background: The bioavailability of a drug depends, among other parameters, on solubility. One of the strategies used to enhance the solubility of sparingly soluble drugs is the use of excipients. Excipients can interact with the drug by increasing its solubility and/or stabilizing supersaturated solutions. Some of the most common excipients are cyclodextrins and hydrophilic polymers. Objectives: The effect of two cyclodextrins (captisol and cavasol) and three hydrophilic polymers (klucel, kollidon and plasdone S630) on the solubility of three ionizable drugs (benzthiazide, isoxicam, and piroxicam) is evaluated at biorelevant pH values, using two complementary techniques. Methods: The solubility enhancement was evaluated by the comparison of the solubility with and without the presence of excipients through the shake-flask and CheqSol methodology. Results: Captisol and cavasol slightly increase the concentration of the neutral species of the drugs in the solution before precipitation begins, although they do not enhance the supersaturation duration nor the thermodynamic solubility of the drugs. The increase in solubility in the presence of cyclodextrins is mainly caused by the ionization state of the drug. Hydrophilic polymers not only improve thermodynamic solubility but also the extent and the duration of the supersaturation. Some metastable forms are observed for benzthiazide and isoxicam in the presence of kollidon and plasdone S630. Conclusions: The shake-flask method enabled the evaluation of thermodynamic solubility both in the absence and presence of excipients. Meanwhile, the CheqSol method provided insights into the presence of supersaturated solutions. Different behavior is observed depending on the nature of the excipient. Full article

Background: Candesartan cilexetil, a Biopharmaceutics Classification System (BCS) II prodrug, demonstrates compromised bioavailability attributable to its limited aqueous solubility coupled with P-glycoprotein (P-gp)-mediated efflux and hepatic first-pass metabolism, thereby introducing complexities in generic drug bioequivalence assessments. With the rapid advancement of computational technologies, the integration of biorelevant dissolution methodologies with physiologically based pharmacokinetic (PBPK) modeling is emerging as a transformative paradigm in advancing bioequivalence evaluation strategies for generic drug products. This study presents a GastroPlus^®-driven framework integrating in vivo predictive dissolution (IPD) and virtual bioequivalence (VBE) to evaluate the quality consistency of generic candesartan cilexetil tablets. Methods: By developing an oral PBPK model in GastroPlus^®, we established an IPD method using a phosphate-buffer-based flow-through cell dissolution apparatus. In vitro dissolution profiles of generic tablets from four manufacturers were measured and incorporated into the model to perform VBE simulations. Results: The results demonstrated that only the product from Company A achieved virtual bioequivalence with the reference product, aligning with real-world quality consistency assessments. Conclusions: The proposed framework exhibited robust predictive capability, bridging in vitro dissolution data to in vivo bioequivalence outcomes, thereby offering a cost-effective and efficient strategy for formulation optimization and preclinical bioequivalence evaluation of generic drugs. Full article

Background/Objectives: The oral delivery of large-molecule drugs remains challenging due to poor solubility, perdemeability, and stability in the gastrointestinal tract, resulting in low bioavailability. In this study, hot melt extrusion (HME) was investigated as a solvent-free manufacturing technique for mucoadhesive bilayer films to improve drug absorption. Methods: Polyvinyl alcohol (PVA) and polyethylene oxide (PEO) were evaluated as mucoadhesive film-forming polymers, in conjunction with Eudragit^® RS as a water-insoluble backing layer. Paracetamol and lactase were utilized as small and large molecule APIs, respectively. The resulting films were assembled into bilayer film samples and examined for mechanical properties, mucoadhesion, and dissolution behavior. A novel dissolution model was developed to evaluate unidirectional drug transport. Results: The results showed that bilayer films could be successfully fabricated using HME, with different mechanical properties depending on the polymer and drug content. Tests with the newly developed dissolution model showed a unidirectional drug release. The model also confirmed the need for biorelevant dissolution test systems because of a better differentiation between polymers compared to standard test methods such as the paddle-over-disk method. Furthermore, the investigation revealed that the activity of enzymes was retained after extrusion, thus indicating the feasibility of processing biologics. Conclusions: This study highlights the potential of HME to produce bilayer films as an innovative drug delivery platform offering improved bioavailability for both small and large molecules. Full article

Transmucosal drug products, such as aerosols, films, semisolids, suppositories, and tablets, have been developed for the treatment of various human diseases and conditions. Transmucosal drug absorption is highly influenced by the biological structures of the mucosa and the physiological environment specific to the administration route (e.g., nasal, rectal, and vaginal). Over the last few decades, in vitro permeation testing (IVPT) using animal tissues or in vitro cell cultures have been utilized as a cost-effective and efficient tool for evaluating drug release and permeation behavior, assisting in formulation development and quality control of transmucosal drug delivery systems. This review summarizes the key mucosal permeation barriers associated with representative transmucosal administration routes, as well as considerations for IVPT method development. It highlights various IVPT methods, including vertical diffusion cell, flow-through diffusion cell, Ussing chamber, and transwell systems. Additionally, future perspectives are discussed, such as the use of optical methods to study in vitro drug permeation and the development of in vitro–in vivo correlation (IVIVC) for transmucosal drug development. The potential of IVPT as part of in vitro bioequivalence assessment strategies for locally acting transmucosal drug products is also highlighted. Full article

Objectives: Tacrolimus, a Biopharmaceutics Classification System (BCS) class II drug, is widely used for transplant patients to prevent graft rejection. To enhance its bioavailability, amorphous solid dispersion (ASD) formulations were developed and evaluated. The release properties of several ASD-based tacrolimus formulations were studied using an in-house USP IV dissolution method. Methods: The pharmacokinetics of a promising test product were compared with the commercially available Advagraf^® in a pilot clinical bioequivalence study with 12 healthy subjects. A previously published PBPK model for tacrolimus was validated using in vivo data and then applied to predict the human pharmacokinetics of several ASD-based tacrolimus formulations. Results: This study compares the pharmacokinetic (PK) parameters—AUC, Cmax, and Tmax—of Advagraf^® and a test formulation using two methodologies: one incorporating the dissolution profile directly into the PBPK model and the other utilizing the DLM approach. The results show that both methods provided accurate predictions for Cmax and Tmax, with the dissolution profile approach underestimating AUC slightly, while the DLM method predicted AUC adequately. Sensitivity analysis refining the DLM scalars in the Ileum and Colon led to optimized predictions of PK parameters. Furthermore, this study explores the use of PBPK modeling to predict in vivo behavior for additional tacrolimus formulations, highlighting the influence of formulation composition, such as the inclusion of Eudragit-S100, on dissolution profiles and bioavailability. Conclusions: This study evaluates formulations with different compositions and manufacturing characteristics; key factors that could influence their performance in the body were identified. These insights—spanning qualitative, quantitative, and manufacturing aspects—can greatly simplify the development of generic drugs, offering strong evidence of the critical role that physiologically based pharmacokinetic (PBPK) modeling can play in the early phases of generic drug development, especially in designing and assessing biopredictive dissolution methods. Full article

Background: Cannabidiol (CBD) shows interesting therapeutic properties but has yet to demonstrate its full potential in clinical trials partly due to its low solubility in physiologic media. Two different formulations of CBD (amorphous and lipid-based) have been optimized and enable an increase in bioavailability in piglets. In vivo studies are time-consuming, costly and life-threatening. Therefore, we need to develop in vitro tests that can predict what will happen in vivo. Methods: Comparisons in terms of dissolution were made especially by using different media (FaSSGF, FaSSIF, FeSSIF, HCl 0.1N with or without SLS, phosphate buffer pH 6.8 with or without SLS) and different conditions (sink or non-sink conditions). These in vitro results were confronted with in vivo results to select the most appropriate dissolution test conditions. Results: The importance of the presence of surfactants to enable solubilization of CBD was demonstrated. Neutral media enabled a relatively good prediction of the extent of absorption observed in vivo, whereas the rate of absorption was more complicated to predict. Conclusions: FeSSIF media, and FaSSIF sink media to a lesser extent, were the only compositions enabling predictions of both extent and rate, indicating that emulsification is possibly a major contributor to the in vivo availability of the drug. Full article