Journal of pharmaceutical sciences最新文献

Lipid-based nanocarriers offer a promising approach to provide topical antifungal therapy through drug delivery enhancement and synergistic effect. Accordingly, the study was planned to develop a nano-lipid matrix incorporating an antifungal drug and a natural agent using a Quality by Design (QbD) approach. Several nanoemulsions (NEs) were developed with natural Cinnamon Essential Oil (CEO) and Miconazole (MCZ) that were optimized for selecting the best formula to be integrated with gel-base providing topical nanoemulgel (NEG) system. As far as we know, this is the first study to develop a nano-lipid matrix co-loading MCZ and CEO using a Quality by Design (QbD) approach. The optimization criteria based on the smallest particle size and maximum percentage of in vitro release. NEG was characterized for various parameters to emphasize its uniformity and appropriateness for topical delivery. Further, in vitro release over 6 hours, kinetic modeling and stability analysis were executed to confirm the behavior and mechanism of the release in addition to the physical and chemical stability of the formulation. Ultimately, antifungal activity assay was conducted to check the effectiveness of CEO and MCZ combination as antifungal agents and suitability of the NEG as a nano-lipid carrier. The optimized MCZ-loaded NE was successfully developed with nanosize (222.7 nm) and high in vitro release (86.46%) then incorporated into preformulated gel base providing MCZ-loaded NEG. It demonstrated promising physicochemical properties including; pH (5.9), viscosity (11650 cP), spreadability (50.7 mm), extrudability (89.3 g/cm²), and drug content (99.1 %). It favorably prolonged drug release over 6 hours (54.5 %) and confirmed its stability when stored over 6 months at two different conditions; room temperature and refrigerator. Eventually, MCZ-loaded NEG significantly improved the antifungal efficacy against Candida albicans, which suggest that NEG offer a synergistic platform for topical antifungal treatment.

Nitrite scavenging is an effective strategy to control nitrosamine formation during the shelf-life of pharmaceutical drug products, particularly when other interventions are insufficient. Here, we showed that the addition of a specific nitrite scavenger, ascorbic acid, decreased nitrosamine formation in tablets. It was found that a homogeneous distribution of ascorbic acid in the excipient blend achieved through wet blending was critical to minimizing nitrosamine formation. As an antioxidant, the use of ascorbic acid requires a validated analytical method and established acceptance limits for regulatory compliance, which is complicated by our observation that ascorbic acid was unstable during routine tablet production and on stability. Additionally, new API related substances were seen and attributed to the reaction with ascorbic acid, which necessitates structure elucidation and toxicological qualification. With these limitations in mind, implementing a nitrite scavenging system for nitrosamine control requires well-defined workflows for the data package, analytical methods, and regulatory filing strategy throughout the product lifecycle.

Amorphous solid dispersion (ASD) is a widely adopted strategy to enhance the solubility of poorly water-soluble drugs. However, disintegration delay after storage poses a significant challenge to formulation performance. This study investigates the influence of disintegrant characteristics on disintegration behavior of hydroxypropyl methylcellulose (HPMC)-based ASD tablets containing griseofulvin (GRF). Two disintegrants, croscarmellose sodium (CCS) and crospovidone (CPV), were evaluated for their effects on the physical structure and disintegration performance of HPMC-based ASDs tablets under accelerated storage conditions (40°C/75% relative humidity). Dynamic viscoelastic measurements, hardness testing and disintegration testing revealed that disintegrant type markedly affected HPMC structural reorganization after storage. Tablets with CCS exhibited plasticization and a temporary loosening of the structure initially. Over time, water retention by CCS facilitated the rearrangement of HPMC chains, leading to prolonged disintegration times. Conversely, CPV maintained a loose network structure due to its high wicking ability, which prevented significant structural changes and preserved the disintegration performance. Tablets without disintegrants showed significant disintegration delay, highlighting the critical role of disintegrant selection in ensuring effective drug absorption through rapid disintegration. These findings underscore the importance of understanding the disintegrant mechanisms for optimizing ASD formulations for improved bioavailability.

Vancomycin remains a key therapeutic option for central nervous system (CNS) infections caused by Gram-positive bacteria, yet its limited and variable penetration into the cerebrospinal fluid (CSF) poses challenges for optimal dosing. This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model to predict vancomycin exposure in both plasma and CSF following intravenous administration in patients with CNS infections. The CNS PBPK model incorporated blood, brain mass, cranial and spinal CSF compartments, and assumed passive permeability across CNS barriers. Clinical data from healthy subjects and CNS-infected patients were used for validation. Model performance was assessed by fold error analysis. Virtual simulations were performed to compare intermittent versus continuous infusion regimens. The developed CNS PBPK model reliably predicted vancomycin concentrations in plasma and cerebrospinal fluid. For 96.51% of predicted values, deviations from observed data fell within a range of 0.5 to 2 times the measured concentration, with a mean fold difference of 1.25. Specifically, 96.28% of predicted plasma concentrations fell within 0.5 to 2 times the observed values, while all predicted CSF concentrations remained within 0.5 to 2 times the observed values. Scaling factor of 4 for permeability yielded a satisfactory fit to CSF vancomycin concentrations in infected patients. Model simulations indicated that, at the same daily dose, continuous infusion achieved more stable and higher CSF trough levels than intermittent dosing. This study presents the CNS PBPK model for vancomycin capable of accurately predicting drug disposition in CSF and plasma. The model supports individualized dosing strategies and provides a quantitative framework for optimizing vancomycin therapy in CNS infections.

The present study investigated dose-dependent effects on the oral absorption of cilostazol (CIL) from cocrystals with 4-hydroxybenzoic acid (4HBA) and attempted to mitigate these effects by adding an excess amount of intact 4HBA. With increasing CIL-4HBA doses in rats, the relative maximum plasma concentration (C_max) decreased and the time to C_max (T_max) was prolonged. Although the supersaturation and precipitation of CIL were noted in fasted-state simulated gastric fluid, their extent was not dependent on its dose. However, the dissolved fraction of 4HBA, an indicator of cocrystal dissolution, significantly decreased with increasing doses. An analysis of solubility products indicated that at high doses, both components rapidly reached the equilibrium solubility of CIL-4HBA, markedly reducing the dissolution rate. These in vitro results support the reduced absorption rate of CIL. To mitigate dose-dependent effects, a physical mixture of CIL-4HBA with excess 4HBA was evaluated. Cocrystal dissolution in the stomach was strongly suppressed, which led to the disappearance of differences in relative C_max and T_max. These results suggest that solubility products in the stomach govern CIL absorption from cocrystals and also that the addition of an excess amount of an intact coformer effectively mitigates dose-dependent absorption behavior.

Microneedles represent a novel transdermal drug delivery technology that relies on micron-sized needle structures. This approach effectively penetrates the stratum corneum to achieve localized or systemic therapeutic effects, addressing the pain associated with traditional injections and the low bioavailability issues of oral administration. It addresses the pain associated with traditional injections and the low bioavailability of oral administration. Dissolving microneedles have emerged as a research hotspot in microneedle technology due to their distinctive advantages, including dissolvability, ease of operation, and absence of sharp waste. They have garnered widespread attention and application in the pharmaceutical field as an efficient means to enhance transdermal drug absorption. However, many drugs (particularly poorly soluble ones) require higher transdermal absorption enhancement factors, which traditional dissolving microneedles struggle to meet. In light of this, this paper will compare dissolving microneedles with other types of microneedles, propose optimization strategies for dissolving microneedle technology, discuss existing challenges, and outline future research directions, aiming to provide valuable references for the further development of dissolving microneedles.

As medicinal products and their manufacturing processes evolve, biopharmaceutical companies must continuously manage, document, and submit post-approval chemistry, manufacturing, and controls (CMC) changes to global health authorities. Traditionally, this process is time consuming, administratively burdensome, and hindered by region-specific requirements, often delaying the implementation of critical updates and improvements. In response, regulators and industry stakeholders are increasingly collaborating to enhance efficiency and expedite patient access to critical therapeutics. This article describes the initiation and organization of a pilot project focused on post-approval change (PAC) reliance/collaboration and digital authoring as part of an end-to-end process improvement initiative. The pilot aimed to demonstrate time savings in authoring, review, and approval by leveraging automation, cloud-based collaboration, and a common core CMC dossier. Of the target 37 National Regulatory Authorities (NRAs), 27 (73%) agreed to participate in the pilot, with 26 also utilizing a novel third-party collaboration platform. In this pilot, 85% (23/27) of participating NRAs reached approval within 9 months, compared with approximately 36 months typically required using a conventional post-approval submission process for comparable changes. These results underscore an emerging interest to embrace innovative regulatory practices and support the development of formal, scalable reliance/collaboration pathways.

Amorphous solid dispersions (ASDs) hold promising potential towards modulating the solubility of poorly soluble drugs. However, their use is limited by poor understanding of release mechanism and kinetics, especially with Soluplus®. In this study, we explored loratadine-Soluplus® ASDs with different drug loadings (DLs) from 3% to 15% to unveil drug content impact on dissolution, colloidal behavior, and surface composition. All formulations were fully amorphous and showed a single, composition-dependent glass transition temperature. Intrinsic dissolution testing revealed fast, nearly complete release and stable supersaturation for low-load ASDs (3-5% DL), while higher-load ASDs (10-15% DL) released more slowly, generated larger nanodroplets on liquid-liquid phase separation (LLPS), and showed precipitation upon standing. SEM imaging suggested similar surface morphology before and after partial dissolution, but EDX elemental analysis revealed congruent drug-polymer release at low DL and incongruent (polymer-first) release at high DL. These findings identify an optimum drug-loading window where ASD generates and sustains supersaturation status for loratadine, and highlight mechanistic links between DL, LLPS droplet size, and incongruent release that explain reduced performance at higher loadings.

A physiologically-based pharmacokinetic (PBPK) model was successfully developed to describe the absorption, distribution, metabolism, and excretion processes for the upadacitinib 15 mg, 30 mg, and 45 mg extended-release (ER) formulations. A prior numerical in vitro-in vivo correlation (IVIVC) was established for the 15 mg and 30 mg ER formulations. A novel dissolution method had to be developed to achieve adequate in vitro upadacitinib release from the 45 mg ER formulation. A PBPK model was developed and an IVIVC using the 15 mg, 30 mg, and 45 mg ER formulations was incorporated to establish a mechanistic IVIVC framework. Importantly, the more comprehensive mechanistic IVIVC model demonstrated robustness through both internal and external validation and was able to accurately predict in vivo upadacitinib exposures in a distinct clinical trial data set using the 45 mg ER tablet in vitro dissolution data. Further, the model was able to discriminate between 15 mg, 30 mg, and 45 mg exposures. As outlined and encouraged by regulatory guidances, this validated Level A mechanistic IVIVC can serve as a surrogate for bioavailability testing, be a screening tool for future upadacitinib formulation dissolution, and set clinically relevant dissolution acceptance criteria.

Cutaneous Candidiasis, a widespread opportunistic fungal infection primarily caused by Candida albicans, accounts for 1% of outpatient and 7% of inpatient dermatology consultations. The rise in antifungal resistance due to genetic mutations in Candida species has complicated therapeutic outcomes and increased mortality rates. This study aimed to develop a more effective topical therapy by formulating Luliconazole (LCZ), a potent imidazole antifungal limited by poor solubility and skin penetration, into a Transethosomal gel (LCZ-TEG) for enhanced delivery and efficacy. LCZ-loaded Transethosomes (LCZ-TESs) were developed and subsequently incorporated into a hydroxypropyl methylcellulose (HPMC) gel base. Utilizing a Box-Behnken design (BBD) within a Quality by Design (QbD) framework, the formulation was optimized by evaluating the impact of LCZ load, Tween 80 concentration, and ethanol content. The optimized LCZ-TEG formulation demonstrated a high correlation between predicted and experimental values, with a particle size (PS) of 111.90 nm, a polydispersity index (PDI) of 0.072, a zeta potential (ZP) of +49.40 mV, and a 95.00% drug entrapment efficiency (EE), with a sustained-release profile. Ex vivo studies indicated that the LCZ-TESs significantly outperformed free LCZ in skin permeation. This was corroborated by confocal laser scanning microscopy (CLSM), which revealed that LCZ-TESs exhibited stronger and deeper fluorescence signals, reaching a skin depth of 179 µm compared to only 84 µm for the rhodamine B-free solution. Furthermore, in vitro antifungal testing demonstrated a 1.40-fold increase in the zone of inhibition (ZOI) compared to the marketed Lucoz® cream. In vivo studies in a Candida-infected rat model showed a 1.50-fold reduction in treatment duration with the LCZ-TEG formulation. These findings suggest that the developed LCZ-TEG significantly improves the solubility, skin penetration, and antifungal efficacy of luliconazole, supporting its potential as a promising, efficient, and targeted therapy for Cutaneous Candidiasis.