Search Results (478)

Background: Isoconazole nitrate (ISN), an antifungal agent that inhibits ergosterol synthesis by blocking lanosterol 14α-demethylation, is widely used to treat candidiasis, and improving its skin retention and permeability can enhance its therapeutic efficacy. Therefore, we developed an ISN nanoparticle (ISN-NP) gel by wet-bead milling in the presence of methylcellulose (MC). Methods: These ISN nanoparticles were incorporated into a carboxypolymethylene hydrogel (Carbopol). The ISN concentration was measured using HPLC, and Wistar rats and Candida albicans were used to evaluate skin absorption and antifungal activity, respectively. Results: The ISN-NP gel exhibited a particle size distribution ranging from 60 to 220 nm, with the nanoparticles remaining stable. In addition, the ISN-NP gel demonstrated superior antifungal activity against Candida albicans. The Carbopol gel maintained appropriate viscosity and physical stability, and the ISN nanoparticles were released from the gel. Compared with microparticle-based gels (ISN-MP gels), the ISN-NP gel showed significantly enhanced drug release and transdermal permeation, with 1.54- and 1.7-fold increases, respectively. Conclusions: These findings indicate that incorporating ISN nanoparticles (nanocrystalline ISN) into a Carbopol-based gel matrix provides a promising strategy to enhance the topical delivery of this poorly water-soluble antifungal drug. Overall, this nanogel system represents a valuable platform for transdermal delivery in clinical applications. Full article

Tinea is a superficial fungal infection of keratinized structures caused by specific filamentous fungi called dermatophytes. Terbinafine, a drug used to treat tinea, is poorly soluble in water, and its delivery into the skin via nanoparticle formulation usingpoly(lactic-co-glycolic acid) (PLGA) has been demonstrated. In this study, we investigated the preparation conditions for nanoparticles (NPs) to achieve efficient intradermal delivery of terbinafine. Terbinafine-loaded PLGA NPs were prepared using the nanoprecipitation method, and the particle size distribution and average particle size were measured using dynamic light scattering. Skin permeability tests were conducted using mouse dorsal skin, and the amount of terbinafine delivered into the skin was measured to evaluate the release behavior in the skin. In the preparation of terbinafine-loaded PLGA NPs, under conditions where the external solution was purified water, the mean volume diameter was 40.49 ± 15.63 nm, the terbinafine-loaded content was 3.31 ± 0.29%, and the entrapment efficiency was 55.08 ± 4.88%. Under conditions of an external solution containing 1.0 × 10⁻³ w/v% arginine(Arg) aq. solution, the mean volume diameter was 41.71 ± 16.08 nm, the terbinafine-loaded content was 5.17 ± 0.37%, and the entrapment efficiency was 86.48 ± 6.01%. The entrapment efficiency and content were higher under the condition using 1.0 × 10⁻³ w/v% Arg aq. solution compared to purified water. In addition, in the skin permeability test, no drug was detected in the receptor solution sampled from both the NPs suspension group and the simple solution group, and no drug was detected in the intradermal solution in the simple solution group. The intradermal drug concentration was 77.94 ± 10.66 µg/g under conditions where purified water was used as the dialysate, and 96.42 ± 61.62 µg/g under conditions using 1.0 × 10⁻³ w/v% arginine, exceeding the reported minimum inhibitory concentration (MIC) of 8.87 µg/g, suggesting the efficacy of terbinafine-loaded PLGA NPs for the treatment of tinea versicolor. Since tinea treatment is a long-term process, it is desirable to deliver a stable amount of drug to the treatment site at all times. Therefore, the nanoparticle preparation conditions using purified water as the external solution, where the intradermal drug concentration exceeded the MIC and remained stable in the skin permeability test, were suggested to be suitable for tinea treatment. Full article

Objectives: Surfactants are commonly incorporated into amorphous solid dispersions (ASDs) to improve manufacturing and enhance the dissolution of poorly water-soluble drugs. However, their impact on in vitro dissolution, in vivo bioavailability, and in vitro-in vivo correlation (IVIVC) remains poorly understood, impeding the rational design of ASDs. This study aimed to elucidate the impact of six surfactants: anionic sodium lauroyl glutamate (SLG), sodium taurocholate (NaTC), sodium lauryl sulfate (SLS), and non-ionic polysorbate 80 (TW80), poloxamer 188 (P188), and polyoxyethylene lauryl ether (Brij-35), on the performance of paclitaxel (PTX)/HPMC-AS ASD. Methods: Binary PTX/HPMC-AS and ternary PTX/HPMC-AS/surfactant ASDs were prepared via rotary evaporation for FT-IR study. For dissolution and pharmacokinetic studies, low drug-loading formulations were prepared by physically blending PTX/HPMC-AS ASD with surfactants. Drug–polymer–surfactant interactions were investigated using NMR and FT-IR techniques. Dissolution performance was systematically evaluated by analyzing: (1) solubility of crystalline PTX in HPMC-AS/surfactant solutions; (2) supersaturation sustaining capacity in HPMC-AS/surfactant solutions; (3) surfactant effects on ASD dissolution and supersaturation generation; and (4) phase transformation during ASD dissolution. In vivo bioavailability was assessed in rats. Results: Findings revealed surfactant-specific effects: (1) SLG and P188 minimally affected bioavailability of PTX/HPMC-AS ASD (p > 0.05), consistent with their negligible effect on dissolution, attributable to incompatibility with PTX/HPMC-AS and weak molecular interactions; (2) TW80 significantly reduced bioavailability (p < 0.001) by inducing crystallization; thereby diminishing the amorphous advantage; (3) NaTC, Brij-35, and SLS markedly increased bioavailability (p < 0.001), owing to their compatibility with PTX and HPMC-AS, which enhanced dissolution and maintained amorphous state of precipitates. Surfactants appear to modulate ASD performance by governing supersaturation generation in solution and maintaining amorphous stability in the undissolved solid. Conclusions: The dissolution and bioavailability of ASDs are fundamentally controlled by compatibility between drug, polymer, and surfactant. Surfactant selection critically impacts ASD bioavailability. Comprehensive dissolution characterization, including supersaturation kinetics and precipitate phase analysis, enables prediction of bioavailability. Integrating molecular-level interaction analysis with multidimensional dissolution profiling is therefore essential for rational ASD design. Full article

Sinomenine (SIN) is a promising candidate for the treatment of rheumatoid arthritis (RA). Although it possesses the advantage of being non-addictive, its poor aqueous solubility and low oral bioavailability have limited its clinical application. To address these issues, SIN was encapsulated into lipid cubic liquid crystal nanoparticles (LCNPs) and systematically characterized. Molecular dynamics (MD) simulations were first employed to screen suitable excipients for formulation development. Combined with single-factor optimization and Box–Behnken response surface design, the optimal composition and preparation process were determined. The resulting SIN-LCNPs exhibited a particle size of 149.7 ± 0.9 nm, a polydispersity index (PDI) of 0.223 ± 0.01, a zeta potential of −18.9 mV, and an encapsulation efficiency (EE%) of 92.2%. Spectroscopic analyses confirmed successful incorporation of SIN into the lipid matrix. Pharmacodynamic studies revealed that SIN-LCNPs enhanced targeted drug delivery to inflamed joints, significantly alleviating inflammation and suppressing disease progression in rats. In vivo single-pass intestinal perfusion (SPIP) experiments further demonstrated that SIN was primarily absorbed through the small intestine and that the LCNP carrier effectively improved its intestinal permeability. Collectively, this study provides a novel strategy and theoretical foundation for developing efficient formulations of poorly water-soluble drugs, highlighting the potential clinical application of SIN-LCNPs in RA therapy. Full article

Background/objectives: Pharmaceutical cocrystals have emerged as a promising strategy to enhance the solubility and bioavailability of poorly water-soluble drugs. Indomethacin (IND), classified as a Biopharmaceutics Classification System (BCS) Class II drug, exhibits low solubility but high permeability. This study aims to develop a synthesis method, evaluate cocrystal solubility/stability and the physicochemical properties of the pure components, and describe cocrystal solubility using a mathematical model. Methods: Cocrystals were synthesized via solvent evaporation, using ethanol, methanol, and ethyl acetate. The pure components, IND and benzoic acid (AcBz) were dissolved in each solvent and maintained in a thermostabilizer for 24 h. Cocrystal formation was confirmed by UV-V spectroscopy, differential scanning calorimetry (DSC), and infrared (IR) spectroscopy. Results: The results showed that the solubility of the cocrystals decreased with increasing benzoic acid concentration. Mathematical modelling revealed that solubility can be expressed as the product of the solubilities of the individual components and the stability constant of the solution complex. Among the solvents tested, ethanol exhibited the highest solubility and equilibrium constant (K_eq) for IND–AcBz cocrystals, suggesting a greater molecular affinity and enhanced cocrystal formation. Conclusions: These findings demonstrate that the formation of the novel INDAcBz cocrystal significantly enhances Indomethacin solubility and thermodynamic stability. These results validate benzoic acid as an effective coformer and establish phase solubility diagrams (PSD) as predictive tools for rational cocrystal design, supporting the future development of optimized pharmaceutical formulations. Full article

Background: Solid dispersions (SDs) of etodolac (ETD), a poorly water-soluble drug model, were developed to enhance its solubility and dissolution rate by employing various preparation methods and hydrophilic or amphiphilic polymers. Methods: Polyvinylpyrrolidone-poly(vinyl acetate) copolymers (PVP/VA), hydroxypropyl methylcellulose (HPMC) and poloxamer were used as carriers, while cryo-milling and lyophilization were utilized as routine methods to SDs preparation. Obtained SDs were characterized by drug content, solubility, dissolution rate and moisture content. The physical structure of SDs was estimated via scanning electron microscopy (SEM), whereas differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) were employed to assess the potential drug-carrier interactions. Results: SD formulations demonstrated enhanced solubility of ETD in aqueous media, including water and buffers (pH 5.5 and 7.4). DSC analysis confirmed that PVP/VA and poloxamer ensured better ETD dissolution and protection against recrystallization. Furthermore, FTIR indicated the formation of hydrogen bonds between ETD and polymer, particularly in lyophilized dispersions. Conclusions: The optimized SD formulation for ETD contained PVP/VA and/or poloxamer as carriers and was obtained via lyophilization. This SD formulation exhibited the most favorable properties, enhanced the solubility and dissolution of ETD in aqueous media and effectively reduced its crystallinity. Full article

Lipid-based formulations (LBFs) play a crucial role in enhancing the oral bioavailability of poorly water-soluble drugs by leveraging lipid digestion and solubilization processes. However, developing robust in vitro–in vivo correlations (IVIVCs) for LBFs presents unique challenges due to the complex interplay of digestion, permeation, and dynamic solubilization. This article reviews the construction of IVIVC in the context of LBFs, highlighting the limitations of traditional methods and the need for tailored approaches. It examines the in vitro tools commonly employed for LBF characterization, such as USP dissolution tests, lipolysis assays, and combined models, and discusses their relevance to in vivo performance prediction. The review also explores the sources of in vivo data essential for validating IVIVC and describes the most popular in silico tools for predicting in vivo performance, focusing on lipid-based formulations. This work aims to pave the way for more effective and adaptable IVIVC methodologies for lipid-based drug delivery systems. Full article

Background/Objectives: Pharmaceutical preparation technologies can enhance the bioavailability of poorly water-soluble drugs. Ursolic acid (UA) has been found to possess anti-cancer and hepatoprotective properties, demonstrating its potential as a therapeutic agent; however, its hydrophobicity and low solubility present challenges in the development of drug formulations. This study investigates the preparation of a nano-UA suspension by wet grinding, researches the influence of process parameters on particle size, and explores the rules of particle breakage and agglomeration by combining model fitting. Methods: Wet grinding experiments were conducted using a laboratory-scale grinding machine. The particle size distributions (PSDs) of UA suspensions under different grinding conditions were measured using a laser particle size analyzer. A single-factor experimental design was employed to optimize operational conditions. Model parameters for a population balance model considering both breakage and agglomeration were determined by an evolutionary algorithm optimization method. By measuring the degree to which UA inhibits the colorimetric reaction between salicylic acid and hydroxyl radicals, its antioxidant capacity in scavenging hydroxyl radicals was indirectly evaluated. Results: Wet grinding process conditions for nano-UA particles were established, yielding a UA suspension with a D50 particle size of 122 nm. The scavenging rate of the final grinding product was improved to three times higher than that of the UA raw material (D50 = 14.2 μm). Conclusions: Preparing nano-UA suspensions via wet grinding technology can significantly enhance their antioxidant properties. Model regression analysis of PSD data reveals that increasing the grinding mill’s stirring speed leads to more uniform particle size distribution, indicating that grinding speed (power) is a critical factor in producing nanosuspensions. Full article

Background/Objectives: Lipid-based formulations are widely used to enhance the oral bioavailability of poorly water-soluble drugs. However, for weakly basic drugs with higher solubility under acidic conditions, precipitation and recrystallisation after gastric emptying can compromise a formulation’s ability to maintain the drug in a solubilised, absorbable state. To address this, we evaluated an enteric coating strategy to preserve the biopharmaceutical performance of a silica-solidified lipid-based formulation. Methods and Results: The model weakly basic BCS Class IV drug, abiraterone acetate, was loaded into a lipid-based formulation and solidified using mesoporous silica nanoparticles. In an in vitro lipolysis model, introducing the formulation only after the onset of the intestinal phase led to lower precipitation and over 50% greater drug presence in the aqueous phase compared to a two-stage gastric–intestinal digestion. In an in vivo pharmacokinetic study in Sprague Dawley rats, the silica–lipid formulation (6 mg/kg), delivered in gelatine minicapsules enteric-coated with Eudragit L100-55, resulted in a 2.6-fold higher systemic exposure compared to the non-coated formulation (p < 0.0001). Conclusions: These findings support the use of enteric coating for lipid-based formulations and silica nanoparticles containing weakly basic drugs as a strategy to maintain formulation integrity until reaching the small intestine. Full article

Amorphous solid dispersions (ASDs) represent a promising formulation strategy for improving the solubility and bioavailability of poorly water-soluble drugs, a major challenge in pharmaceutical development. This review provides a comprehensive analysis of the physicochemical principles underlying ASD stability, with a focus on drug–polymer miscibility, molecular mobility, and thermodynamic properties. The main manufacturing techniques including hot-melt extrusion, spray drying, and KinetiSol^® dispersing are discussed for their impact on formulation homogeneity and scalability. Recent advances in excipient selection, molecular modeling, and in silico predictive approaches have transformed ASD design, reducing dependence on traditional trial-and-error methods. Furthermore, machine learning and artificial intelligence (AI)-based computational platforms are reshaping formulation strategies by enabling accurate predictions of drug–polymer interactions and physical stability. Advanced characterization methods such as solid-state NMR, IR, and dielectric spectroscopy provide valuable insights into phase separation and recrystallization. Despite these technological innovations, ensuring long-term stability and maintaining supersaturation remain significant challenges for ASDs. Integrated formulation design frameworks, including PBPK modeling and accelerated stability testing, offer potential solutions to address these issues. Future research should emphasize interdisciplinary collaboration, leveraging computational advancements together with experimental validation to refine formulation strategies and accelerate clinical translation. The scientists can unlock the full therapeutic potential with emerging technologies and a data-driven approach. Full article

Background/Objectives: This study aimed to develop a novel amorphous solid dispersion (ASD) platform using poly(2-ethyl-2-oxazoline) (PEtOx) for the solubility enhancement of poorly water-soluble drugs. Fenofibrate (FB), a Biopharmaceutics Classification System (BCS) Class II drug, was selected as the model drug. The novelty of this work lies in the formulation of dual-matrix systems by blending PEtOx of varying molecular weights (50 kDa, 200 kDa, 500 kDa) with solubility-enhancing polymers, Soluplus^® and Kollidon^® VA64, to investigate component compatibility, synergistic solubility enhancement, and the influence of PEtOx molecular weight on drug release. Methods: ASDs were prepared via hot-melt extrusion (HME) and characterized using differential scanning calorimetry (DSC), scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and Fourier transform–infrared spectroscopy (FTIR) to confirm FB amorphization and evaluate drug–polymer interactions. In vitro dissolution testing was performed to assess drug release performance, and stability studies were conducted at ambient conditions for one month to evaluate physical stability. Results: DSC, PXRD, and FTIR confirmed the successful amorphization of FB and good miscibility between PEtOx and the selected excipients. In vitro dissolution studies showed an 8–12-fold increase in FB release from ASDs compared to crystalline drug. Lower-molecular-weight PEtOx grades yielded faster release profiles, while binary blends with Soluplus^® or Kollidon^® VA64 enabled tailored drug release. Stability testing indicated that all formulations maintained their amorphous state over one month. Conclusions: PEtOx-based ASDs represent a versatile platform for enhancing the solubility and dissolution of poorly water-soluble drugs. By adjusting polymer molecular weight and combining with complementary excipients, release profiles can be optimized to achieve improved performance and stability. Full article

Background/Objectives: Pinostilbene is a naturally occurring methoxylated stilbene with many beneficial health properties, including antioxidant, antimicrobial and neuroprotective activities. This stilbene has also been shown to possess anticancer or cytotoxic activity in some cancers. As in the case of other stilbenes, pinostilbene is very labile, degrades rapidly under stress conditions and is poorly water-soluble, which poses a drawback to its use as a drug. This work aims to provide further insights into its cytotoxicity activity in a colon cancer cell line and to overcome its physicochemical limitations by encapsulating the molecule in cyclodextrins. Methods: The anticancer activity was evaluated in vitro in Caco-2 colorectal cells using the neutral red assay. Subsequently, a screening of cyclodextrins was carried out to determine the one with the highest encapsulation constant, as well as the encapsulation stoichiometry, using fluorescence spectroscopy and molecular docking predictions. The formation of the inclusion complexes was checked by differential scanning calorimetry and scanning electron microscopy. The protective effect of cyclodextrins on pinostilbene release was monitored through spectrophotometric measurements over time. Results: Pinostilbene showed in vitro cytotoxicity activity in Caco-2 colorectal cells by the neutral red assay. This study revealed that the cyclodextrin with the highest encapsulation constant was the hydroxypropyl-β-cyclodextrin (K_F = 10,074.45 ± 503.72 M⁻¹), and the encapsulation stoichiometry was 1:1. DSC and SEM assays confirmed the formation of these inclusion complexes. Cyclodextrins were able to satisfactorily reduce pinostilbene degradation from 31% to less than 15% after 3 months, as well as increase its water solubility up to 10 times and enhance its release as a function of the pH of the medium. Conclusions: Pinostilbene is a promising drug candidate with strong in vitro antiproliferative activity. Many of its physicochemical limitations can be overcome with cyclodextrins, which opens the door to its future use in the pharmaceutical and food industries. Full article

Background/Objectives: Conventional solid dispersion methods face significant industrial limitations, including thermal degradation, residual organic solvents, and complex preparation processes. This study presents a novel decrystallizing formulation using poloxamer and propylene glycol that remains solid during storage but liquefies at physiological temperature (37 °C). Methods: Decrystallizing formulations containing various poloxamer types (407 and 188) at different concentrations (5–25% w/w) were prepared and assessed for decrystallization temperature, decrystallization time, and drug solubility. The optimal formulation was further characterized using FTIR analysis, as well as in vitro liquefaction performance and dissolution studies. Finally, the industrial sustainability of the decrystallizing formulation was assessed against conventional methods. Results: Poloxamer 407 exhibited higher decrystallization temperature, longer decrystallization time, and superior solubilization capacity compared to Poloxamer 188. Maximum drug solubility (5.51 ± 0.08 mg/g) was achieved at 20% w/w of poloxamer 407 with a decrystallization temperature of 37 °C, and it took 216 s for decrystallization. FTIR spectroscopy confirmed hydrogen bonding interactions, which are responsible for temperature-dependent phase transitions. The decrystallizing formulation showed remarkable improvement in dissolution efficiency (80.6 ± 3.9%) compared to the raw drug (1.8 ± 0.8%), a physical mixture (11.1 ± 6.0%), and a marketed tablet (30.8 ± 2.2%). Conclusions: The current decrystallizing formulation offers a promising approach for improving the bioavailability of poorly water-soluble drugs and tackling the limitations of conventional methods. Moreover, it provides additional advantages in terms of industrial sustainability for continuous production compared to conventional approaches. Full article

Objective: This article investigated the structural characteristics, powder properties, and performance variations of co-processed pregelatinized starch (PS) and microcrystalline cellulose (MCC) at varying ratios. Methods: Scanning Electron Microscopy (SEM) revealed the embedding of MCC within the PS matrix. Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) analysis indicated no chemical interaction between the starch and MCC during processing. The physical properties of the co-processed materials were evaluated using multiple indicators, such as the Carr index, and their properties in pharmaceutical applications were evaluated using multiple indicators, such as tensile strength and dilution capacity. Results: The absence of new chemical substances during co-processing, as confirmed by FTIR/XRD analyses, coupled with SEM evidence of a physically interlocked MCC-PS architecture, conclusively demonstrates that structural reorganization occurred via physical mechanisms. An increase in the MCC proportion enhanced the tensile strength of the co-processed material while decreasing the Carr’s index, particle size, tapped density, bulk density, swelling, and water-soluble content. A co-processed sample (PS:MCC = 7:3) was selected for application in formulations. The co-processed material exhibited superior compactibility compared to a physical mixture and demonstrated favorable dilution capacity in poorly compactible model drugs, including Linaoxin and Lingzhi spore powder, as well as higher biological inertness. Conclusions: These findings suggest that the co-processed PS and MCC possess excellent compactibility and dilution capacity. The co-processed excipient demonstrates applicability in direct compression manufacturing of oral solid dosage forms (e.g., tablets), offering distinct advantages for high drug-loading formulations. Full article

Polymeric-based amorphous solid dispersions (ASDs) represent a widely employed strategy for enhancing the oral bioavailability of poorly water-soluble drugs, but their successful implementation in solid dosage forms requires careful optimization of both formulation composition and compaction parameters. In this study, the performance of polymeric-based ASD tablets were investigated using two model active pharmaceutical ingredients (APIs) with distinct glass-forming abilities (GFAs) and physicochemical characteristics: (1) indomethacin (IND, a good glass former) and (2) carbamazepine (CBZ, a poor glass former). ASDs were prepared at various API-to-polyvinylpyrrolidone (PVP) ratios (10:90, 20:80 and 40:60 w/w) and incorporated into round-shaped tablets at different ASD loadings (20% and 50% w/w). The impact of compaction pressure and dwell time on the mechanical properties, disintegration, and supersaturation performance was assessed, both immediately after preparation and following three months of storage at 25 °C and 60% relative humidity. Solid-state analysis confirmed the amorphous state of the APIs and revealed the development of API–polymer molecular interactions. Supersaturation studies under non-sink conditions demonstrated that dissolution behavior was strongly influenced by drug loading, polymer content, and compaction conditions, with CBZ formulations exhibiting faster release but greater susceptibility to performance loss during storage. The comparative evaluation of IND and CBZ highlights the critical role of API properties in determining the physical stability and dissolution performance of ASD tablets, underscoring the need for API-specific design strategies in ASD-based formulation development. Full article