AAPS PharmSciTech最新文献

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and remains associated with a poor five-year overall survival rate (~ 17.4%). Current therapies are limited by suboptimal efficacy and safety, underscoring the need for novel interventions. This study investigates the repurposing of amodiaquine (AQ), an anti-malarial drug, formulated into inhalable liposomes for targeted NSCLC therapy. The AQ-loaded liposomes exhibited favorable physicochemical properties, including sub-200 nm particle size, low polydispersity index (< 0.3), high drug loading (≈40%), and stability for over two months. In-vitro aerosolization studies demonstrated efficient lung-targeting potential, with > 70% of particles depositing in the deep lung regions. Cytotoxicity assays revealed significantly enhanced anticancer potency of AQ-liposomes compared to the free drug in NSCLC cell lines. Furthermore, clonogenic and wound healing assays showed a marked reduction in cancer cell proliferation and migration. Mechanistically, caspase assays indicated elevated apoptosis in AQ-liposome-treated cells. In 3D spheroid models, AQ-liposomes disrupted spheroid integrity more effectively than AQ alone, confirmed by live/dead staining. Collectively, these findings support the potential of inhalable AQ liposomes as a promising therapeutic strategy for NSCLC. Future in vivo studies and clinical evaluation are warranted to validate translational feasibility and therapeutic efficacy in NSCLC management.

In this study, a stable nanocrystalline drug delivery system for indomethacin (IND) was rapidly developed by integrating machine learning methods with Hummer Acoustic Resonance (HAR) technology. This system effectively enhanced the solubility of IND and demonstrated excellent scalability. High-throughput screening using HAR technology identified P188-PVA as the optimal composite stabilizer for IND nanocrystal suspensions. Molecular dynamics simulations were employed to thoroughly investigate the interaction mechanisms between the drug and stabilizers. Systematic design and optimization of IND nanocrystal formulation parameters and HAR process conditions were conducted using an integrated modeling approach combining Box-Behnken design (BBD) and artificial neural networks (ANN). Various statistical metrics were employed to evaluate and compare the predictive accuracy and generalization capability of BBD-RSM and ANN models, thereby identifying the optimal formulation. HAR technology was successfully used to scale up the optimal formulation by 5- and 50-fold, demonstrating its initial potential for scalability. Freeze-drying, spray-drying, and fluidized-bed drying techniques were evaluated for solidifying the prepared nanocrystal suspensions. Multiple analytical techniques were employed to characterize the particle size and solid-state properties of IND nanocrystals. PXRD and DSC analyses confirmed the crystalline nature of the IND nanocrystals. In vitro dissolution experiments indicated that IND nanocrystals exhibited significantly improved dissolution compared to raw IND. Additionally, the concepts and methodologies proposed in this study could also be applied to the development of other poorly water-soluble drugs.

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This paper provides an expert review of extant research into commercially utilized targeted drug delivery systems for brain therapeutics, with Glioblastoma Multiforme (GBM), Parkinson’s Disease (PD), Alzheimer’s Disease (AD) and Major Depressive Disorder (MDD), as case studies. While the paper highlights the progress made in developing effective drug delivery solutions, a common denominator across much of the research is the singular challenge posed by the Blood Brain Barrier (BBB) against the bulk of drug delivery options and treatments. The paper identifies critical pathways and transporting effective therapeutics through the barrier, and calls for further innovation into nano-systems, gels, and wafers with BBB-beating properties. The paper calls for the modernization of manufacturing regulatory systems, as well as increased preclinical studies and clinical trials to establish the utility of such nano-systems. Ultimately, the paper vouches for fast-tracking and even exemption of promising delivery solutions from phase IV studies but instead to accurately assess and evaluate the solutions' efficacy in a “real world" setting.

Risedronate, a bisphosphonate widely prescribed for osteoporosis, suffers from poor oral bioavailability and gastrointestinal adverse effects. To overcome these limitations, risedronate-laden cubosomes were developed for transdermal delivery. Cubosomes were fabricated using the top-down approach and optimized via Central Composite Design to assess the influence of glyceryl monooleate, Poloxamer 407, and the impact of sonication time on critical quality attributes. The optimized formulation exhibited a particle size of 61.45 ± 7.26 nm, PDI of 0.312 ± 0.04, zeta potential of -24.27 ± 2.27 mV, and entrapment efficiency of 90.65 ± 0.06%. In vitro release demonstrated 90.81 ± 3.17% drug release over 24 h. FTIR analysis confirmed the absence of drug-excipient interactions and successful drug encapsulation, while SAXS verified a cubic D-type (Pn3m) structure. Transmission electron microscopy further revealed uniform nano-sized cubic particles. The optimized cubosomes were incorporated into a Carbopol 934-based gel to facilitate transdermal application. Ex vivo permeation across rat skin showed a flux of 0.184 ± 0.005 mg/cm².h for the cubosomal gel, markedly higher than plain risedronate (0.0069 ± 0.002 mg/cm²/h). Skin irritation studies confirmed biocompatibility, and drug deposition studies revealed a 2-fold increase in skin retention with the cubosomal gel compared to plain gel. In vivo pharmacokinetic evaluation demonstrated a 1.39-fold enhancement in bioavailability relative to plain risedronate and a 3-fold improvement compared to marketed oral tablets. Collectively, these findings establish risedronate-laden cubosomal gel as a promising patient-friendly transdermal delivery system for long-term management of osteoporosis.

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Effective management of acute wounds, particularly those caused by burns and trauma, remains a significant clinical challenge. Conventional formulations, such as ointments, creams, and hydrogels, often face challenges related to stability, portability, and patient compliance. To address these limitations, we developed a novel bi-layered skin tablet system using direct compression for immediate application to topical wounds. The upper protective layer contains konjac glucomannan as a gelling agent and oleic acid as a permeability enhancer. The lower therapeutic layer includes a synergistic combination of clindamycin hydrochloride (CLC), benzalkonium chloride (BKC), and recombinant human mitsugumin 53 (rhMG53), a membrane repair protein. rhMG53 was repurposed for acute wound healing at a reduced dosage to maintain therapeutic efficacy while improving cost efficiency. The formulation was optimized to achieve controlled release of rhMG53 for wound repair and of CLC and BKC for antibacterial activity. The synergistic interaction between CLC and BKC (Index 1.2) enhanced broad-spectrum antibacterial efficacy. The prepared tablets underwent in-vitro testing for hardness, swelling index, content uniformity, drug release, and stability. The rhMG53 containing formulation demonstrated consistent drug loading (98.5%, RSD < 6%), prolonged release, and effective wound healing in cell-based tests. The tablet form improves portability, stability, and ease of application compared with conventional remedies. This bi-layered skin tablet system represents a promising therapeutic strategy for acute wound management, particularly in emergency and military settings where lightweight, ready-to-use treatments are critically needed.

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Despite advances in mesothelioma treatment, malignant pleural mesothelioma (MPM) continues to present a poor prognosis due to its aggressive progression and resistance to conventional therapies. Current treatment modalities, including surgery, chemotherapy, radiation, and immunotherapy, offer limited efficacy, with a five-year survival rate of approximately 12%. To address the limitations of systemic drug delivery, this study investigates the therapeutic potential of osimertinib (OSI), a third-generation tyrosine kinase inhibitor, delivered via inhalation using poly(lactic-co-glycolic acid) (PLGA) nanoparticles. The optimized PLGA-OSI formulation exhibited an encapsulation efficiency of 43.1 ± 4.8%, drug loading of 4.4 ± 0.4%, particle size of 198.5 ± 9.3 nm, and zeta potential of -17.6 ± 1.2 mV. In vitro cytotoxicity assays revealed IC₅₀ values of 13.5 ± 0.1 µM (MSTO-211H), 27.7 ± 0.3 µM (H2452), and 8.1 ± 0.2 µM (H226) after 48 h. Compared to free OSI, PLGA-OSI enhanced cellular uptake, increased GFP-positive cells by 1.7-fold, and elevated fluorescence intensity by 5.3-fold. Clonogenic and scratch assays confirmed significant inhibition of cell proliferation and migration. Moreover, spheroid models demonstrated superior tumor suppression with multi-dose treatments. These findings highlight the potential of inhaled PLGA-OSI nanoparticles to improve drug delivery and therapeutic outcomes in MPM, supporting their further development as a targeted treatment strategy against this challenging malignancy.

Omeprazole is the first in a class medication that inhibits gastric secretion. However, it has a low stability, low bioavailability, and a short half-life after peroral administration. In the current study, nonionic microemulsions containing omeprazole were formulated and characterized for transdermal and intranasal administration as alternative application routes. The droplet size, rheological characteristics, polydispersity index, permeability through rat and human skin, rat epidermis, and in vivo bioavailability in rats were studied. With these formulations with droplet sizes below 100 nm, an omeprazole permeation with fluxes ranging from 0.86 to 9.945 µg·cm⁻² h⁻¹ was observed for excised rat epidermis. However, the full-thickness human and rat skin exhibited drug entrapment. The in vivo study demonstrated that the relative bioavailabilities of the intranasal and transdermal administration were 332% and 103%, respectively, compared to an oral solution. Overall, the formulated microemulsions were stable and could serve as effective carriers, making them promising delivery systems for omeprazole delivery via transdermal and intranasal routes.

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The rheological properties of pharmaceutical mixtures are exceedingly difficult to understand and control. Despite their impact on final product quality, no generally valid approach to define and predict mixture rheology has been discovered so far. The cause is a complexity of factors affecting the particulate mixture behaviour. This study aimed at addressing part of this problem by suggesting an approach to evaluate and subsequently predict flow properties of binary particulate mixtures from parameters of individual components to better guide the formulation development. This study investigated several parameters of powder flowability under conditions with different stress levels using the FT4 powder rheometer. Studied mixtures contained ibuprofen as a model active pharmaceutical ingredient with a variety of common fillers. Results revealed that mixture behaviour varies according to given flow conditions and cannot be characterised by a single parameter and parameters appropriate to unit operations of the intended process should be used. Outputs confirmed the complexity of rheological properties of mixtures that are not always the linear combination of rheological properties of starting materials. On the other hand, developed multilinear regression models could predict studied mixture behaviour quite well by accounting for interdependencies between critical parameters, composition, and particle characteristics capturing the complexity of particle interaction interplay beyond the simple additivity of pure material properties. The prediction is valid for model ibuprofen and the other active APIs with similar characteristics. Thus, models could streamline selection of suitable mixtures for direct compression or highlight potentially problematic rheological aspects of a mixture to be addressed.

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Understanding the complex relationship between drug deposition, pulmonary pharmacokinetics, and clinical efficacy is essential to developing effective inhaled therapies. Harnessing formulation physicochemical properties can improve aerodynamic properties and enhance lung retention, yet predictive in vitro and in silico models remain essential for advanced formulation development. A range of in vitro lung epithelial models has been explored to study transepithelial transport. However, these systems often lack physiological complexity. Advanced platforms such as organoids and lung-on-a-chip models attempt to replicate the structural and mechanical features of the lung, though they face limitations in airflow simulation, aerosol characterization, and operational complexity. Consequently, preclinical in vivo rodent studies continue to play a key role due to their ability to capture systemic interactions. However, several challenges remain, particularly in isolating lung-specific pharmacokinetics. The review focuses on the use of the isolated perfused rat lung (IPL), an ex vivo model that emerged as a valuable tool allowing for the direct measurement of pulmonary absorption while minimizing systemic confounding variables. This model supports accurate control of lung dosing and enables evaluation of local metabolism, clearance, and drug retention. The review outlines IPL setup, applications, and its role in supporting the 3Rs principles (Replace, Reduce, Refine) in animal testing. As an innovative tool, IPL enhances the understanding of pulmonary drug behaviour and holds promise for improving inhaled drug development through more ethical and precise preclinical research.

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