AAPS PharmSciTech最新文献

Purpose: This study aimed to develop lactoferrin-coated Brexpiprazole-loaded nanostructured lipid carriers (Lf-BXP-NLCs) using a Design of Experiments (DoE) approach combined with an artificial neural network (ANN) to improve brain targetability and prolong residence time.

Method: Drug solubility and interactions of Brexpiprazole with solid lipid, liquid lipid, surfactant, and co-surfactant were evaluated using in silico molecular docking. NLCs were prepared by hot high-speed homogenization. Plackett-Burman design was employed to screen critical formulation and process variables, while the Box-Behnken design enabled optimization. A feed-forward ANN model was developed to predict particle size (PS) and drug release (DR), and to assist in selecting formulations meeting critical quality attributes (CQAs). NLCs were characterized for physicochemical properties, encapsulation efficiency, morphology, in vitro release, ex vivo studies, and stability.

Results: Brexpiprazole showed higher solubility in GMS, oleic acid, Tween®80, and Span®80, supported by favorable docking interactions (-1.6 to -2.0 kcal/mol). Liquid lipid content, homogenization speed, and sonication time significantly influenced PS and DR, with liquid lipid amount identified as the most critical factor. Optimized Lf-BXP-NLCs exhibited a PS of 132.8 ± 2.4 nm, PDI 0.249 ± 0.013, and zeta potential -26.2 ± 1.3 mV. High entrapment efficiency (87.8 ± 0.25%) and drug loading (11.71 ± 0.03%) were achieved, along with extended drug release (55.00 ± 2.26%-66.97 ± 2.25% at 12-24 h, 96.14 ± 2.96% at 28 h) and higher permeation flux (75.35 µg/cm²/h).

Conclusion: The integrated DoE-Assessment of a predicted model-based successful optimization of lactoferrin-functionalized extended release Brexpiprazole-loaded NLCs with 132.8 ± 2.4 nm, and zeta potential -26.2 ± 1.3 mV, which demonstrated strong compatibility, sustained release, and promising potential for targeted nose-to-brain delivery of Brexpiprazole.

Irritant contact dermatitis (ICD) is a common and potentially debilitating chronic skin disorder that affects a large proportion of the worldwide population. In the present work, licofelone (LF) was incorporated into poly (d,l-lactide-co-glycolide) (PLGA) nanoparticles to design a topical nanocarrier systems intended to boost its therapeutic impacts in treatment of ICD. To achieve this objective, LF-loaded PLGA nanoparticles (PLGANPs) were fabricated utilizing the nanoprecipitation technique, and the formulation parameters were statistically optimized utilizing a D-optimal experimental design. Three independent variables were investigated: PLGA amount (X₁), poloxamer amount (X₂), and poloxamer type (X₃). The encapsulation efficiency (Y₁: EE%), particle size (Y₂: PS), polydispersity index (Y₃: PDI), and zeta potential (Y₄: ZP) were selected as dependent responses. The optimized formulation (P19) exhibited spherical morphology, with a particle size of 160.45 ± 0.42 nm, an encapsulation efficiency of 93.34 ± 0.26%, a PDI of 0.24 ± 0.009, and a zeta potential of -34.8 ± 0.27 mV. When incorporated into a gel, P19 displayed a sustained drug release profile and achieved 2.72-fold higher permeation across rat skin compared to a conventional LF gel. In vivo, topical application of P19 gel effectively alleviated xylene-induced ear dermatitis in mice. It markedly suppressed the inflammatory response and consequently decreased the immune expression of proinflammatory cytokines. The histopathology further confirmed a pronounced reduction in dermal edema and inflammatory cell infiltration, corroborating the biochemical findings. Collectively, these results indicate the potential of LF-loaded PLGA nanoparticles as a novel topical therapeutic system for ICD.

Optimization of lipid-based formulations (LBF) for moderately lipophilic neutral drugs is often challenging. The low drug loading and precipitation of supersaturated state of drug after digestion and dispersion warrants attention. Herein, we attempted supersaturated LBF of olaparib (OLA) and evaluated them for lipid composition, thermal-induced supersaturation, and precipitation inhibition and its impact on biopharmaceutical performance. Conventional and supersaturated type II and type III LBFs were developed using medium-chain (MCT) lipid excipients, with and without polymeric precipitation inhibitor (PI). Formulations were characterized in terms of solubility, supersaturation stability, colloidal properties, in vitro lipolysis, permeability, and in vivo pharmacokinetics in rats. Thermal processing significantly increased drug loading in all systems, achieving two-fold increase in the apparent degrees of supersaturation. MCT based LBFs exhibited superior solubilization capacity compared to long-chain systems. Among the screened PIs, PVP-VA most effectively stabilized the supersaturated state of OLA by delaying the precipitation and hence sustain higher aqueous drug concentrations. Type III LBFs demonstrated enhanced dispersion, smaller droplet sizes, and higher negative zeta potentials, translating to higher in vitro permeability and in vivo exposure relative to Type II systems. This work establishes mechanistic relationships between lipid composition, supersaturation stabilization, and oral drug absorption in the development of LBFs of moderately lipophilic neutral drugs.

Amisulpride effectively treats both positive and negative symptoms of schizophrenia. However, its poor aqueous solubility and low intestinal permeability limit oral bioavailability. This study developed chitosan-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) encapsulating amisulpride for intranasal delivery, thereby enhancing solubility, permeability, and bioavailability. Amisulpride-loaded chitosan-coated PLGA NPs were prepared using the oil-in-water emulsion-solvent evaporation method. Formulations were optimized based on particle size (PS), zeta potential (ZP), polydispersity index (PDI), entrapment efficiency (EE%), and loading capacity (LC%). The optimized formulation was characterized by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and X-ray diffraction (XRD). The solubility, stability, mucoadhesion, in vitro drug release, and cytotoxicity were also evaluated. The optimized formulation (F2) had a PS of 246.13 ± 2.28 nm, PDI of 0.14 ± 0.03, ZP of 41.04 ± 1.76 mV, EE% of 77.87, and LC% of 24.64. Encapsulating the drug in the NPs increased its solubility and the stability over three months showed no significant changes in the characteristics mentioned. F2 exhibited strong mucoadhesive properties and enhanced drug release at pH 5.5 and pH 7.4, with cumulative release of 77.41% at pH 7.4 and 92.17% at pH 5.5. Cytotoxicity testing confirmed biocompatibility across 0.75-10 mg/mL. Amisulpride chitosan-coated PLGA NPs demonstrated favourable physicochemical properties, solubility, stability, controlled drug release, and mucoadhesive profile with enhanced cell viability at specific concentrations across multiple epithelial cell lines compared with the drug solution and unloaded NPs. This work highlights the promising potential of Amisulpride Chitosan-coated PLGA NPs as an innovative intranasal nanocarrier for improved schizophrenia therapy.

Abiraterone acetate (ABA) belongs to low permeability low solubility class. It exhibits pH-dependent solubility with slightly better solubility at gastric pH. It may thus undergo supersaturation and precipitation after gastric emptying. ABA may undergo premature hydrolysis in intestinal lumen which decreases the amount absorbed. This can contribute to its low bioavailability. The aim was to formulate ABA in self-emulsifying drug delivery system (SEDDS), which was loaded in in situ gelling system made of alginate or alginate and chitosan. This can provide controlled release of ABA, preventing possible precipitation with SEDDS augmenting absorption. Alginate and alginate-chitosan based formulations were developed based on gelling capacity. SEDDS comprising oleic acid with Tween 80 and glycerol was fabricated and loaded into in situ gelling formulations. The release behavior was monitored using continuous pH variation. The oral bioavailability of ABA was assessed indirectly by monitoring rat total serum testosterone level. Results indicated that both increasing the concentration of alginate and adding chitosan contributed to enhanced gelation. Loading ABA in SEDDS hastened its dissolution. Loading into in situ gelling system resulted in controlled release with alginate-chitosan system showing better retention of ABA in stomach and intestinal phases. The total serum testosterone level was 8.18, 3.43, 1.51, 3.4 and 0.25 ng/ml for control rat, rats receiving ABA aqueous suspension, ABA in SEDDS, ABA SEDDS in 1% alginate and ABA SEDDS in 1% alginate/1% chitosan. The results suggested that SEDDS can prevent premature degradation and controlling the release within the stomach and intestine maximize the efficacy.

The administration of neurotherapeutics is severely hindered by the blood-brain barrier (BBB), which limits drug transport to the brain. Self-emulsifying drug delivery systems (SEDDS) offer a promising nanocarrier strategy for improving the solubility, transmembrane permeability across the BBB, and targeted delivery of lipophilic drugs to the central nervous system. This review highlights the formulation principles, excipient selection, and mechanistic insights into SEDDS-mediated enhancement of BBB transport. A critical evaluation of the translational potential and pharmacokinetic benefits of both oral and intranasal SEDDS is presented, along with discussions on innovations in ligand-functionalized, hybrid, and mucoadhesive SEDDS. Additionally, the application of AI/ML-driven optimization tools for preformulation design, along with physiologically based pharmacokinetic (PBPK) modelling, is discussed, and a comparative analysis of reported SEDDS compositions with AI-based formulation predictions is presented. Clinical readiness is assessed through an overview of preclinical outcomes, the patent landscape, and emerging innovation trajectories. This review also addresses key challenges, including excipient safety, scale-up hurdles, and regulatory compliance, providing expert insights into future directions for the clinical translation and optimization of SEDDS for neurotherapeutic delivery.

Sorafenib is an oral tyrosine kinase inhibitor which inhibits the growth of cancer cells by inhibiting several tyrosine kinase receptors taking part in the perpetuation and pathogenesis of breast tumours. Sorafenib was approved in 2005 for the treatment of liver and prostate cancers. In recent years, focused studies have explored the drugs clinical potential in breast cancer. There are several clinical trials (ongoing and completed) of sorafenib to treat metastatic breast cancer patients. Interestingly, these have shown encouraging results in particular in combination with other clinically-used drugs. However, effective clinical use has been somewhat hampered due to the drug's hydrophobicity, rapid first pass metabolism, short half-life, low oral bioavailability and side effects including hand and foot reaction as well as hypersensitivity. In attempts to overcome some of these drawbacks, nanotechnology-based delivery systems have been explored including nanocarriers like liposomes, niosomes, lipid-polymer hybrid nanoparticles, solid lipid nanocarriers, microemulsions, nanovectors and gel matrices. We will describe current state-of-the-art nanocarrier-based strategies, and discuss how such approaches can be harnessed to enhance the clinical efficacy of sorafenib for breast cancer treatment.

Oxidative stress is regarded as a major pathogenic key factor in chronic idiopathic pulmonary fibrosis (IPF), a disease with high mortality and an unclear cause. Gallic acid (GA) is a natural polyphenolic compound that shows significant antioxidant potential. However, its therapeutic effectiveness is limited due to low oral bioavailability, rapid metabolism, and poor aqueous solubility. To overcome such barriers, lecithin-polymer hybrid micelles (LPHM) were engineered as a nanocarrier platform for GA delivery. This study investigated the formulation and optimization of GA-loaded LPHM for pulmonary fibrosis therapy. LPHM were optimized using a D-optimal experimental design, assessing the drug amount (X₁) and polymer type (X₂: Pluronic® P123 or D-α-tocopheryl polyethylene glycol succinate, TPGS) on entrapment efficiency (Y₁), particle size (Y₂), and zeta potential (Y₃). The optimized formula, comprising TPGS with 17 mg GA, showed an entrapment efficiency of 96.78 ± 1.45%, a particle size of 120.22 ± 1.45 nm, and a zeta potential of - 32.12 ± 0.97 mV. In-vitro release demonstrated a biphasic sustained-release profile. In-vivo pharmacokinetics showed a 7.35-fold increase in oral bioavailability of the optimized formula as compared to free GA. In a bleomycin-induced IPF model, the optimized formula significantly mitigated fibrotic progression, as evidenced by reductions in transforming growth factor-β, matrix metalloproteinase-7, hydroxyproline, and collagen-1. Overall, GA-loaded LPHM represent a promising oral drug delivery strategy for IPF, with broader potential in managing chronic diseases that demand sustained release and enhanced systemic exposure.

This research focuses on creating a novel Brijaluronic-based terpesomal system capable of transporting quercetin (QER) efficiently to the brain. The vesicles were fabricated through an ethanol-injection method and then refined using a structured optimization approach in Design-Expert® software. The influence of three main formulation parameters: terpene-to-drug ratio, surfactant type, and hyaluronic acid amount were evaluated. The optimization process was designed to maximize EE%, minimize VS, and maintain ZP within an acceptable stability range. The optimal formula hit a desirability target of 0.957. It achieved an 88.66% EE%, featured nano-carriers sized at 72.09 nm, and had a stable charge of - 26.5 mV. Physicochemical characterization studies revealed a spherical morphology, an in-vitro release defined by a biphasic profile, and a secure structural integrity which was validated using FTIR analysis. Moreover, over the course of three months, the formulation did not degrade or change significantly, demonstrating its high degree of stability. Notably, terpesomes demonstrated a ~ 3.5-fold enhancement in antioxidant activity, reducing the IC₅₀ from 12.98 ± 0.82 µg/mL to 3.68 ± 0.20 µg/mL, representing a statistically and pharmacologically significant improvement. Radio-kinetic assessments further supported its potential for precise brain targeting. The brain/blood was highest for the optimized formulation at all-time points. Compared with the nasal QER solution, Technetium-99m ([^99mTc]Tc)-QER-loaded terpesomes exhibited superior brain-targeting efficiency, as evidenced by higher AUC, shorter T_max, and greater C_max values in the brain. Taken together, the Brijaluronic terpesomes represent a highly promising, innovative nano-platform. This engineered system appears poised to boost the effectiveness of QER in neurotherapeutic applications.

Lung cancer (LC) is one of the major causes of mortality due to cancer throughout the world, primarily due to difficulties in early detection and the restricted efficacy of conventional therapies. Inhalation drug delivery systems provide a potential strategy for targeted LC therapy by allowing direct deposition of drugs into the lungs, therefore improving therapeutic effectiveness and reducing systemic side effects. This review offers a comprehensive outlook on different inhalation formulations, highlighting their benefits in enhancing drug bioavailability and patient outcomes. It also explores the molecular pathways involved in LC progression and identifies critical LC treatment targets. Although substantial progress has been made in the field of LC treatment, numerous challenges hamper the clinical translation of inhalation therapeutic systems, such as formulation instability, physiological barriers, patient-specific variations, and immune responses. The strategies to deal with these problems are discussed, aiming at the modification of nanocarriers, stimuli-sensitive systems, and immunomodulatory approaches. In conclusion, the review underscores the potential of inhalation systems in the treatment of LC with special emphasis on the promise of personalized medicine and combination therapies to transform LC management.