Search Results (290)

Background/Objectives: The major limitations of self-nanoemulsifying systems include complex processing and expensive instrumentation required for solidification approaches. In this study, smart poloxamer-based solidification strategies were used to develop and optimize febuxostat-loaded formulations. Methods: A self-nanoemulsifying drug delivery system (SNEDDS) component was selected based on solubility and emulsification tests. The influence of poloxamer molecular weight (low or high) and its concentration (2–10% w/w) on formulation performance was assessed through the design of experiments. Finally, in-vitro melting assessment and a comparative dissolution test were performed on the optimized SNEDDS formulation. Results: Imwitor 988 and Tween 20 were selected to prepare the formulations. Increasing the molecular weight and concentration of the poloxamer significantly increased the temperature and time required for the melting of the SNEDDS formulation. The optimized SNEDDS formulation comprised 3.98% w/w poloxamer 188, which melts at 36 °C within 111 s. In-vitro melting showed that the formulation completely converted to a liquid state upon exposure to body temperature. Finally, the optimized SNEDDS formulation exhibited superior dissolution efficiency (96.66 ± 0.28%) compared to raw febuxostat (72.09 ± 4.33%) and marketed tablets (82.23 ± 3.10%). Conclusions: The poloxamer-based approach successfully addressed the limitations associated with conventional solidification while maintaining superior dissolution performance. Therefore, it emerges as a promising alternative approach for enhancing the bioavailability of poorly water-soluble drugs. Full article

Background/Objectives: Hot-melt extrusion (HME) has gained prominence for the manufacture of sustained-release oral dosage forms, yet the application of wax-based matrices and their resilience to alcohol-induced dose dumping (AIDD) remains underexplored. This study aimed to develop and characterise wax-based sustained-release felodipine formulations, with a particular focus on excipient functionality and robustness against AIDD. Methods: Felodipine sustained-release formulations were prepared via HME using Syncrowax HGLC as a thermally processable wax matrix. Microcrystalline cellulose (MCC) and lactose monohydrate were incorporated as functional fillers and processing aids. The influence of wax content and filler type on mechanical properties, wettability, and drug release behaviour was systematically evaluated. Ethanol susceptibility testing was conducted under simulated co-ingestion conditions (4%, 20%, and 40% v/v ethanol) to assess AIDD risk. Results: MCC-containing tablets demonstrated superior sustained-release characteristics over 24 h, showing better wettability and disintegration. In contrast, tablets formulated with lactose monohydrate remained structurally intact during dissolution, overly restricting drug release. This limitation was effectively addressed through granulation, where reduced particle size significantly improved surface accessibility, with 0.5–1 mm granules achieving a satisfactory release profile. Ethanol susceptibility testing revealed divergent behaviours between the two filler systems. Unexpectedly, MCC-containing tablets showed suppressed drug release in ethanolic media, likely resulting from inhibitory effect of ethanol on filler swelling and disintegration. Conversely, formulations containing lactose monohydrate retained their release performance in up to 20% v/v ethanol, with only high concentrations (40% v/v) compromising matrix drug-retaining functionality and leading to remarkably increased drug release. Conclusions: This study highlights the pivotal role of excipient type and constitutional ratios in engineering wax-based sustained-release formulations. It further contributes to the understanding of AIDD risk through in vitro assessment and offers a rational design strategy for robust, alcohol-resistant oral delivery systems for felodipine. Full article

Background/Objectives: Hot-melt extrusion (HME) has become a key technology in pharmaceutical formulation, particularly for enhancing the solubility of poorly soluble Active Pharmaceutical Ingredients (APIs). While horizontal HME is widely adopted, vertical HME remains underexplored despite its potential benefits in footprint reduction, feeding efficiency, temperature control, and integration into continuous manufacturing. This study investigates vertical HME as an innovative approach in order to optimize drug polymer interactions and generate stable amorphous dispersions with controlled release behavior. Methods: Extrusion trials were conducted using a vertical hot-melt extruder developed by Rondol Industrie (Nancy, France). Acetylsalicylic acid (ASA) supplied by Seqens (Écully, France) was used as a model API and processed with Soluplus^® and Kollidon^® 12 PF (BASF, Ludwigshafen, Germany). Various process parameters (temperature, screw speed, screw profile) were explored. The extrudates were characterized by powder X-ray diffraction (PXRD) and small-angle X-ray scattering (SAXS) to evaluate crystallinity and microstructure. In vitro dissolution tests were performed under sink conditions using USP Apparatus II to assess drug release profiles. Results: Vertical HME enabled the formation of homogeneous amorphous solid dispersions. PXRD confirmed the absence of residual crystallinity, and SAXS revealed nanostructural changes in the polymer matrix influenced by drug loading and thermal input. In vitro dissolution demonstrated enhanced drug release rates compared to crystalline ASA, with good reproducibility. Conclusions: Vertical HME provides a compact, cleanable, and modular platform that supports the development of stable amorphous dispersions with controlled release. It represents a robust and versatile solution for pharmaceutical innovation, with strong potential for cost-efficient continuous manufacturing and industrial-scale adoption. Full article

Bariatric surgery involves major changes in the anatomy and physiology of the gastrointestinal tract, which may alter oral drug bioavailability and efficacy. Phosphodiesterase-5 inhibitor (PDE5i) drugs are the first-line treatment of erectile dysfunction, a condition associated with a higher BMI. In this paper, we examine the PDE5i vardenafil for possible post-bariatric changes in solubility/dissolution and absorption. Vardenafil solubility was determined in vitro, as well as ex vivo using aspirated gastric contents from patients prior to vs. following bariatric procedures. Dissolution was tested in vitro under unoperated stomach vs. post-gastric sleeve/bypass conditions. Lastly, the gathered solubility/dissolution data were used to produce an in silico physiologically based pharmacokinetic (PBPK) model (GastroPlus^®), where gastric volume, pH, and transit time, as well as proximal GI bypass (when relevant) were all adjusted for, evaluating vardenafil dissolution, gastrointestinal compartmental absorption, and pharmacokinetics before vs. after different bariatric procedures. pH-dependent solubility was demonstrated for vardenafil with low (pH 7) vs. high solubility (pH 1–5), which was confirmed ex vivo. The impaired dissolution of all vardenafil doses under post-gastric bypass conditions was demonstrated, contrary to complete (100%) dissolution under pre-surgery and post-sleeve gastrectomy conditions. Compared to unoperated individuals, PBPK simulations revealed altered pharmacokinetics post-gastric bypass (but not after sleeve gastrectomy), with 30% lower peak plasma concentration (C_max) and 40% longer time to C_max (T_max). Complete absorption after gastric bypass is predicted for vardenafil, which is attributable to significant absorption from the large intestine. The biopharmaceutics and PBPK analysis indicate that vardenafil may be similarly effective after sleeve gastrectomy as before the procedure. However, results after gastric bypass question the effectiveness of this PDE5i. Specifically, vardenafil’s onset of action might be delayed and unpredictable, negatively affecting the practicality of the intended use. Full article

Cellulose nanocrystals possess unique properties such as high surface area and excellent biocompatibility. They can disrupt strong hydrogen bonds and other intermolecular forces that hinder the solubility of certain molecules thus enhancing the solubility of poorly soluble materials. The main challenge in formulating poorly soluble drugs lies in their limited therapeutic efficacy due to inadequate solubility and bioavailability. Therefore, an innovative approach such as using cellulose nanocrystals to enhance the solubility is highly needed. The aim of this research is to study the potential of ramie (Boehmeria nivea L. Gaud) as a source of cellulose nanocrystals in the development of microspheres for the solubility enhancement of poorly soluble drugs. Nanocrystalline cellulose was isolated from the ramie (Boehmeria nivea L. Gaud) by optimizing hydrolysis conditions with varying acid concentrations and reaction times. Characterizations were performed by measuring particle size, pH, and sulfate content, followed by morphological study by SEM, functional group analysis, and thermal analysis. The use of sulfuric acid in the hydrolysis process of flax cellulose at 45 °C, as the type of acid that gives the best results, at 50% acid concentration for 60 min produces cellulose nanocrystallines with a particle size of 120 nm, sulfate concentration density of 133.09 mmol/kg, crystallinity of 96.2%, and a yield of 63.24 ± 8.72%. Furosemide was used as the poorly soluble drug model and its solubility enhancement in the form of furosemide/RNCC microspheres was evaluated through saturated solubility testing and in vitro dissolution. This study demonstrated that RNCC could improve the solubility of furosemide, which contributes to developing sustainable drug formulations and eco-friendly delivery systems for poorly soluble drugs. Full article

Background: Automated semi-solid extrusion (SSE) material deposition is a promising new technology for preparing personalized medicines for different patient groups and veterinary applications. The technology enables the preparation of custom-made oral elastic gel tablets of active pharmaceutical ingredient (API) by using a semi-solid polymeric printing ink. Methods: An automated SSE material deposition method was used for generating chewable gel tablets loaded with propranolol hydrochloride (-HCl) at three different API content levels (3.0 mg, 4.0 mg, 5.0 mg). The physical appearance, surface morphology, dimensions, mass and mass variation, process-derived solid-state changes, mechanical properties, and in-vitro drug release of the gel tablets were studied. Results: The inclusion of API (1% w/w) in the semi-solid CuraBlend^TM printing mixture decreased viscosity and increased fluidity, thus promoting the spreading of the mixture on the printed (material deposition) bed and the printing performance of the gel tablets. The printed gel tablets were elastic, soft, jelly-like, chewable preparations. The mechanical properties of the gel tablets were dependent on the printing ink composition (i.e., with or without propranolol HCl). The maximum load for the final deformation of the CuraBlend™-API (3.0 mg) gel tablets was very uniform, ranging from 73 N to 80 N. The in-vitro dissolution test showed that more than 85% of the drug load was released within 15–20 min, thus verifying the immediate-release behavior of these drug preparations. Conclusions: Automated SSE material deposition as a modified 3D printing method is a feasible technology for preparing customized oral chewable gel tablets of propranolol HCl. Full article

Background/Objectives: Chronic lung diseases are among the leading causes of death worldwide. In the treatment of these diseases, non-steroidal anti-inflammatory drugs can be effective. We have previously developed an excipient formulation alongside a modern manufacturing protocol, which we aim to further investigate. We have chosen two new model drugs, meloxicam (MX) and its water-soluble salt, meloxicam-potassium (MXP). The particles in dry powder inhaler (DPI) formulation were expected to have a spherical shape, fast drug release, and good aerodynamic properties. Methods: The excipients were poloxamer-188, mannitol, and leucine. The samples were prepared by spray drying, preceded by solution preparation and wet grinding. Particle size was determined by laser diffraction, shape by scanning electron microscopy (SEM), crystallinity by powder X-ray diffraction (PXRD), interactions by Fourier-transform infrared spectroscopy (FT-IR), in vitro drug dissolution by paddle apparatus, and in vitro aerodynamic properties by Andersen cascade impactor and Spraytec^® device. Results: We achieved the proper particle size (<5 μm) and spherical shape according to laser diffraction and SEM. The XRPD showed partial amorphization. FT-IR revealed no interaction between the materials. During the in vitro dissolution tests, more than 90% of MX and MXP were released within the first 5 min. The best products exhibited an aerodynamic diameter of around 4 µm, a fine particle fraction around 50%, and an emitted fraction over 95%. The analysis by Spraytec^® supported the suitability for lung targeting. Conclusions: The developed preparation process and excipient system can be applied in the development of different drugs containing DPIs. Full article

Background: Physiologically based biopharmaceutics modeling (PBBM) models can help to predict drug release and in vivo absorption behaviors. Colon drug delivery systems have gained interest over the past few years due to the advantages they provide in treating certain diseases in a local way. The objectives of this work were to simulate the biopharmaceutical and pharmacokinetic behavior of metronidazole hydrophilic matrices coated with different enteric polymers and to highlight the factors with a significant impact on the simulated pharmacokinetic parameters. Methods: Physicochemical properties of metronidazole were introduced into Simcyp^® simulator platform, and the Advanced Dissolution Absorption Model (ADAM) was employed to simulate the in vivo intestinal absorption and colonic concentrations of metronidazole using a PBBM model. A Kruskal–Wallis test was carried out in order to determine which one of the factors studied has a statistically significant impact on the pharmacokinetic parameters (AUC, C_max, and T_max) simulated. Results: Enteric-coated matrix tablets are capable of avoiding metronidazole absorption in the small intestine and releasing it in the colonic region. The release and absorption rates of metronidazole depend largely on the percentage of weight gain of the coating and also on the coating agent. Coated tablets with a time-dependent coating show less variability. Conclusions: PBBM models can help predict the release from drug delivery systems and the pharmacokinetics in vivo of metronidazole from data obtained in vitro, although complementary in vivo studies should be needed. Full article

The main aim of this study was to develop a diclofenac-loaded, orodispersible formulation prepared by double-needle electrospinning. For the use of two needles, one above the other, a new needle holder was designed and 3D printed. During the optimization of the drug-free PVP carrier, the effect of the polymer concentration on the morphology and average fiber diameter was investigated. Electrospinning was possible for solutions with a PVP concentration between 7.5 and 15 w/w%. Too low viscosity led to smooth-surfaced nanoparticles, since electrospraying occurred. The optimal material properties and process parameters were used to prepare drug-loaded nanofibers. The morphology, crystallinity, chemical interactions, encapsulation efficiency, drug distribution, in vitro disintegration, in vitro dissolution, cytocompatibility, and 6-month stability were tested. According to the results, the electrospun formulation was an amorphous solid dispersion with excellent encapsulation efficiency. The drug distribution was homogeneous within the nanofiber matrix. The disintegration was completed in about 5 s in artificial saliva and about 41 s on an artificial tongue. The dissolution in artificial saliva was complete within 10 min. Overall, a promising formulation was developed with rapid disintegration, immediate drug release, and good stability. Additionally, a new in vitro dissolution method (“AS-to-FaSSGF”) was developed to obtain a bigger picture of drug dissolution throughout the gastrointestinal tract. Full article

Cyclodextrins (CDs) enhance the solubility of poorly water-soluble drugs like ibuprofen (IBU), making them promising carriers for pulmonary drug delivery. This route lowers the required dose, minimizing side effects, which could be beneficial in treating cystic fibrosis. In this study, a nano-spray-drying technique was applied to prepare CD/IBU complexes using sulfobutylether-β-cyclodextrin (SBECD) or (2-Hydroxy-3-N,N,N-trimethylamino)propyl-beta-cyclodextrin chloride (QABCD) as carriers as well as mannitol (MAN) and leucine (LEU) as aerosolization excipients. Various investigation techniques were utilized to examine and characterize the samples, including a Master Sizer particle size analyzer, scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FT-IR). We applied in vitro Andersen Cascade Impactor measurements and in silico simulation analysis to determine the sample’s aerodynamic properties. We also performed in vitro dissolution and diffusion tests. Applying formulations with optimal aerodynamic properties, we achieved an improved ~50% fine particle fraction values based on the Andersen Cascade Impactor measurements. The in vitro dissolution and diffusion studies revealed rapid IBU release from the formulations; however, the QABCD-based sample exhibited reduced membrane diffusion compared to SBECD due to the formation of electrostatic interactions. Full article

Background: Ciprofloxacin (CIP) is a poorly water-soluble fluoroquinolone-type antibiotic that can be useful in the treatment of lung infections. When the drugs are delivered directly to the lungs, a smaller dosage is needed to achieve the desired effect compared to the oral administration. Moreover, the application of nanoparticles potentially enhances the effectiveness of the treatments while lowering the possible side effects. Therefore, we aimed to develop a “nano-in-micro” structured dry powder inhaler formulation containing CIP. Methods: A two-step preparation method was used. Firstly, a nanosuspension was first prepared using a high-performance planetary mill by wet milling. After the addition of different additives (leucine and mannitol), the solid formulations were created by spray drying. The prepared DPI samples were analyzed by using laser diffraction, nanoparticle tracking analysis, scanning electron microscopy, X-ray powder diffraction, and differential scanning calorimetry. The solubility and in vitro dissolution tests in artificial lung fluid and in vitro aerodynamic investigations (Spraytec^® device, Andersen Cascade Impactor) were carried out. Results: The nanosuspension (D50: 140.0 ± 12.8 nm) was successfully prepared by the particle size reduction method. The DPIs were suitable for inhalation based on the particle diameter and their spherical shape. Improved surface area and amorphization after the preparation processes led to faster drug release. The excipient-containing systems were characterized by large lung deposition (fine particle fraction around 40%) and suitable aerodynamic diameter (between 3 and 4 µm). Conclusions: We have successfully formulated a nanosized antibiotic-containing formulation for pulmonary delivery, which could provide a potential treatment for patients with different respiratory infections. Full article

Bacterial infections caused by resistant strains have emerged as one of the most significant life-threatening challenges. Developing alternatives to conventional antibiotic formulations is crucial to overcoming these challenges. Vancomycin HCl (VCM) is a glycopeptide antibiotic used for Gram-positive bacterial infections that must be given intravenously for systemic infections since it cannot pass through the gut wall due to its chemical structure and characteristics. The aim of this research is to develop VCM in a niosomal nanoform to then be encapsulated in fast-disintegrating oral films for effective delivery to enhance the application of vancomycin-loaded niosomes for treating oral infections and to be used in dental treatments. The formulation of niosomes encapsulating VCM was conducted with various ratios of Span 40, Span 60, and cholesterol as well as Kolliphor RH40 and Kolliphor ELP as co-surfactants using the microfluidic technique. The prepared niosomes were characterised using dynamic light scattering (DLS) for their size determination; high-pressure liquid chromatography, HPLC, for drug encapsulation efficiency determination; and the agar diffusion method for the determination of the antibacterial efficacy of the VCM niosomes against Bacillus subtilis. The niosomal formulation was then incorporated into polyvinyl alcohol (PVA) film, and the properties of the oral film were characterised by in vitro assays. The vancomycin-loaded niosomes produced with optimal conditions exhibited small diameter with acceptable polydispersity index, and drug encapsulation efficiency. This study presents multifunctional niosomes loaded with VCM, which demonstrated efficient in vitro activity against Gram-positive bacteria upon the slow release of VCM from niosomes, as demonstrated by the dissolution test. Oral films containing VCM niosomes demonstrated uniform weights and excellent flexibility with high foldability and a rapid disintegration time of 105 ± 12 s to release the niosomal content. This study showed that the microfluidic approach could encapsulate VCM, a peptide in salt form, in surfactant-based niosomal vesicles with a narrow size distribution. The incorporation of niosomes into fast-disintegrating film provides a non-invasive and patient-friendly alternative for treating bacterial infections in the oral cavity, making it a promising approach for dental and systemic applications. Full article

Irbesartan (IRB) is a commonly used BCS Class II antihypertensive drug requiring dissolving capacity enhancement to address oral bioavailability limitations. In this work, seven new IRB salts were successfully synthesized, including one carboxylate (IRB-MAL) and six sulfonate salts (IRB-TOSA, IRB-BSA, IRB-4-CBSA, IRB-2, 5-CBSA, IRB-MSA, and IRB-CPSA). Their vitro dissolution, intrinsic dissolution rates (IDRs), thermal/hygroscopic stability (via thermal analysis, dynamic vapor sorption, and accelerated stability tests), and phase transition process (monitored by in situ Raman spectroscopy) were evaluated. The results revealed that IRB-TOSA, IRB-MAL, IRB-BSA, IRB-4-CBSA, and IRB-MSA salts exhibited IDRs of 0.3194–0.7383 mg/(cm²·min), all significantly higher than IRB, with dissolution concentrations increased by 14.9–113.6%. IRB-TOSA and IRB-4-CBSA salts demonstrated excellent hydrothermal stability. Single crystal structure analysis confirmed proton transfer from coformers’ sulfonic/carboxylic acids (deprotonation site, H-out) to IRB’s diazaheterocycles (protonation site, H-in) in IRB salts. Six sulfonate salts exhibited N_H-in–H···O_H-out and N_non-H-in–H···O_H-out hydrogen bonds, with the former absent in IRB-MAL. Furthermore, supramolecular synthon studies revealed distinct hydrogen-bonding patterns (e.g., bifurcated bonds in 2,5-CBSA and CPSA salts) that correlate with moisture resistance. Quantitative analysis of IRB salts suggested hydrogen bond strengths may influence their melting points (decomposition temperatures). This study demonstrates that IRB salts hold promise for advanced pharmaceutical applications. Full article

The aim of this study was to investigate the influence of solid dispersion (SD) formulation factors on improvement of the bioavailability and pharmacokinetic profile of clopidogrel after peroral administration using an in vitro–in silico approach. A clopidogrel-specific, physiologically based biopharmaceutical model (PBBM) was developed and validated to predict absorption and distribution of clopidogrel after peroral administration of the tested formulations. Clopidogrel solid dispersions were prepared using two polymers (poloxamer 407 and copovidone) and a drug-to-polymer ratio of 1:5 and 1:9. The results of the in vitro dissolution test under pH–media change conditions showed that the type and ratio of polymers notably influenced the release of clopidogrel from the SDs. It can be observed that an increase in the polymer content in the SDs leads to a decrease in the release of clopidogrel from the SDs. The predictive power of the constructed clopidogrel-specific PBBM was demonstrated by comparing the simulation results with pharmacokinetic data from the literature. The in vitro dissolution data were used as inputs for the PBBM to predict the pharmacokinetic profiles of clopidogrel after the peroral administration of SDs. SDs with copovidone (1:5) and poloxamer (1:9) showed the potential to achieve the highest drug absorption and bioavailability, with an improvement of over 100% compared to an immediate-release (IR) tablet. The sample with poloxamer (1:9) may have the potential to reduce inter-individual variability in clopidogrel pharmacokinetics due to absorption in the cecum and colon and associated lower first-pass metabolism in the liver. This suggests that distal intestine may be the targeted delivery site for clopidogrel, leading to improved absorption and bioavailability of the drug. This study has shown that an in vitro–in silico approach could be a useful tool for the development and optimization of clopidogrel formulations, helping in decision making regarding the composition of the formulation to achieve the desired pharmacokinetic profile. Full article

Objectives: This study explores the development and evaluation of a bilayer sustained-release (SR) tablet formulation of ruxolitinib. As a BCS Class 1 drug, ruxolitinib requires twice-daily dosing due to its short half-life. We designed a bilayer tablet that integrates immediate-release (IR) and SR components in varying ratios to achieve sustained plasma concentrations, which we evaluated using discriminative analysis. Methods: Bilayer tablets combining IR and SR components were prepared in different ratios. In vitro dissolution tests and pharmacokinetic studies were conducted using Beagle dogs, followed by the evaluation of in vivo–in vitro correlation (IVIVC), along with a discriminative pharmacokinetic analysis focused on the SR layer. Results: A discriminative pharmacokinetic and IVIVC analysis was applied to all bilayer tablets, offering clearer insights into the plasma concentration and dissolution profiles. Pharmacokinetic studies showed that test formulation F4, which has a 20:20 IR-to-SR ratio, is expected to provide a similar area under the curve (AUC) while prolonging exposure compared to the reference IR tablet. Conclusions: This study highlights the potential of a bilayer tablet approach, combined with discriminative pharmacokinetic and IVIVC analysis, for creating a sustained-release dosage form of ruxolitinib. Full article