AAPS PharmSciTech最新文献

The administration of surfactant aerosol therapy to preterm infants receiving continuous positive airway pressure (CPAP) respiratory support is highly challenging due to small flow passages, relatively high ventilation flow rates, rapid breathing and small inhalation volumes. To overcome these challenges, the objective of this study was to implement a validated computational fluid dynamics (CFD) model and develop an overlay nasal prong interface design for use with CPAP respiratory support that enables high efficiency powder aerosol delivery to the lungs of preterm infants when needed (i.e., on-demand) and can remain in place without increasing the work of breathing compared with a baseline CPAP interface. Realistic in vitro experiments were first conducted to generate baseline validation data, and then the CFD model, once validated, was used to explore key design parameters across a range of preterm infant nose-throat geometries and aerosol delivery conditions. The most important factors for efficient aerosol delivery were shown to be (i) maintaining the aerosol delivery flow rate below the tracheal flow rate (to minimize CPAP line loss) and (ii) concentrating the aerosol within the first portion of the inhalation waveform. An optimized design was shown to deliver approximately 37–60% of the nominal dose through the system and to the lungs with low intersubject variability (1050–2200 g infants) across two modes of device actuation (automated and manual) with room for further improvement. Ergonomic curvatures and streamlining of the prong geometries were also found to reduce work of breathing and flow resistance compared with a commercial alternative.

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Paeoniflorin is a natural pharmaceutical ingredient with a widely biological activity. However, as a hydrophilic drug, the problem of low transdermal rate limits its clinical application. To overcome this shortage, LUVs were used as biocompatible carriers of paeoniflorin in this study. We prepared paeoniflorin-loaded large unilamellar vesicles (LUVs) with W/O/W structure by microfluidics. We used four kinds of chips to prepare paeoniflorin LUVs and explored the effects of the chip structures on LUVs properties applying both experiments and numerical simulations. The difference of fluid mixing mechanisms was analyzed among four different channels, including straight and curved structures. Then we evaluated the differences in skin permeability among the three groups, paeoniflorin aqueous solution group, drug-loaded liposome group and blank liposome & drug mixture group, using the abdominal skin of male mice. The results showed that the structure of the microfluidic channel was a key factor affecting the flow rate and mixing efficiency. The mixing efficiency further affected the liposome size. The mixing efficiency of curved channel was not better than that of a straight channel due to the low flow rate and long mixing time. By the results of transdermal experiments, LUVs could reduce the transdermal time and increase the total transdermal amount. LUVs effectively improved the transdermal absorption efficiency of paeoniflorin. In conclusion, paeoniflorin LUVs with highly efficient transdermal were successfully prepared by using microfluidics. We explored the underlying fluid dynamics that lead to variations in the preparation with different chip structures. The transdermal effect of the LUVs was verified.

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The prevalence and death due to cancer have been rising over the past few decades, and eliminating tumour cells without sacrificing healthy cells remains a difficult task. Due to the low specificity and solubility of drug molecules, patients often require high dosages to achieve the desired therapeutic effects. Silica nanoparticles (SiNPs) can effectively deliver therapeutic agents to targeted sites in the body, addressing these challenges. Using SiNPs as vehicles for anti-cancer drug delivery has emerged as a promising strategy due to their unique structural properties, biocompatibility, and versatility. This review explores the various aspects of SiNPs in cancer therapy, highlighting their synthesis, functionalization, and application in delivering chemotherapeutic agents, photosensitizers, and nucleic acids. SiNPs offer advantages such as high drug loading capacity, controlled release, and targeted delivery, enhancing therapeutic efficacy and reducing systemic toxicity. Moreover, this review aims to provide an in-depth understanding of the current state and prospects of SiNPs in revolutionizing cancer treatment and improving patient outcomes.

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Continuously explored in pharmaceuticals, microemulsions and nanoemulsions offer drug delivery opportunities that are too significant to ignore, namely safe delivery of clinically relevant drug doses across biological membranes. Their effectiveness as drug vehicles in mucosal and (trans)dermal delivery is evident from the volume of published literature. Commonly, their ability to enhance skin permeation is attributed to dispersion size, a characteristic closely related to solubilization capacity. However, the literature falls short on distinctions between microemulsions and nanoemulsions for definitions, behavior, or specific differences in their mechanisms of action in (trans)dermal delivery. The focus is typically on surfactant/cosurfactant ratio and droplet size but the role of mesostructures or the effect of cosolvent (C_sol), oil (O) or water (W) on permeation profile remain poorly explained. Towards a deeper understanding of these vehicles in (trans)dermal drug delivery, this review begins with their conceptual and practical distinctions before delving into the published works for less obvious but potentially important underlying mechanisms; notably composition and the competitive positioning of system constituents in the resulting microstructures and subsequent effect(s) these may have on skin structures and drug permeability. For practical purposes, this review focuses on formulation systems based on ternary diagrams with commonly accepted non-ionic surfactants, cosurfactants, cosolvents, and oils used in pharmaceutical applications.

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Transdermal drug delivery (TDD) represents a transformative paradigm in drug administration, offering advantages such as controlled drug release, enhanced patient adherence, and circumvention of hepatic first-pass metabolism. Despite these benefits, the inherent barrier function of the skin, primarily attributed to the stratum corneum, remains a significant impediment to the efficient permeation of therapeutic agents. Recent advancements have focused on macromolecular-assisted permeation enhancers, including carbohydrates, lipids, amino acids, nucleic acids, and cell-penetrating peptides, which modulate skin permeability by transiently altering its structural integrity. Concurrently, innovative methodologies such as iontophoresis, electroporation, microneedles, ultrasound, and sonophoresis have emerged as potent tools to enhance drug transport by creating transient microchannels or altering the skin's microenvironment. Among the novel approaches, the development of nanocarriers such as Liposome, niosomes, and transethosomes etc. has garnered substantial attention. These elastic vesicular systems, comprising lipids and edge activators, exhibit superior skin penetration owing to their deformability and enhanced payload delivery capabilities. Furthermore, the integration of nanocarriers with physical enhancement techniques demonstrates a synergistic potential, effectively addressing the limitations of conventional TDD systems. This comprehensive convergence of macromolecular-assisted enhancers, advanced physical techniques, and next-generation nanocarriers underscores the evolution of TDD, paving the way for optimized therapeutic outcomes.

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Over the last two years the idea that the principles presented in Kirchhoff’s circuit and voltage laws also pertain to pharmacokinetics (1–3). It is claimed that these principles make the elimination in the liver and kidney more straight forward to model and provide a rationale for understanding why sometimes during bioavailability studies one arrives at bioavailability values greater than 100%. In this paper it will be shown that these claims are based on incorrect translations of the Kirchhoff’s Laws to pharmacokinetics.

The current study aims to establish a novel ultra-deformable vesicular system to enhance the drug penetration across the skin by preparing the ketoconazole-loaded menthosomes. It was achieved through regular thin-film evaporation & hydration techniques. To examine the effect of formulation parameters on menthosome characteristics, a 2³ full factorial design was used using Design-Expert® software. The optimized batch exhibited a vesicle size (107.6 nm), a polydispersity index (PDI) (0.248), entrapment efficiency (% EE) (76.9%), and a zeta potential (-33.7 mV). Results from ex vivo skin permeation studies and in vitro drug release demonstrated enhanced improved skin permeation and drug release compared to other formulations. An in vitro antifungal and in vivo pharmacodynamic study, elucidated the enhanced effectiveness of the optimized formulation against Candida albicans. In summary, menthosomes could serve as a potent vehicle to enhance drug penetration via the skin to improve its antifungal activity.

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Nimodipine (NIMO) is used to treat ischemic nerve injury from subarachnoid hemorrhage (SAH), but its low aqueous solubility limits clinical safety and bioavailability. This study aims to improve NIMO's solubility by preparing inclusion complexes with sulfobutylether-β-cyclodextrin (SBE-β-CD), reducing the limitations of Nimotop^® injection, including vascular irritation, toxicity, and poor dilution stability. The NIMO-SBE-β-CD inclusion complex (NIMO-CD) was characterized in both liquid and solid states through phase solubility studies and methods including DSC, FT-IR, XRD, and SEM. Dilution stability, hemolysis, vascular irritation, and acute toxicity tests were performed, with pharmacokinetic and pharmacodynamic studies using Nimotop^® as the control. Physical characterization confirmed the successful formation of the inclusion complex. NIMO’s solubility improved by 1202-fold (from 0.82 to 986.19 μg/mL at 25℃). NIMO-CD showed stability for 24 h when diluted, exhibited no hemolytic activity, reduced vascular irritation, and its median lethal dose (LD₅₀) was 2.49 times higher than that of Nimotop^®. Both NIMO-CD and Nimotop^® displayed similar pharmacokinetic profiles. Behavioral assessments (mNSS scoring and CT), along with evaluations of hematoma area and histopathology, demonstrated that NIMO-CD significantly improved outcomes in intracerebral hemorrhage, greatly enhancing neurological recovery, reducing hematoma and edema, and achieving treatment effects comparable to those of Nimotop^® injection. NIMO-CD significantly improves NIMO's solubility and stability while maintaining bioequivalence with Nimotop^®. Furthermore, its enhanced safety profile indicates its potential as a superior formulation for treating ischemic nerve injuries.

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Acrylic pressure-sensitive adhesives (PSAs) are widely applied in transdermal drug delivery systems (TDDS). However, the molecular mechanisms underlying the effect of functional groups of PSAs on drug release and transdermal permeation properties remain insufficiently clear. In this study, we investigated the effect of acrylic PSAs' functional groups on the in vitro release and transdermal permeation properties of a model drug guanfacine (GFC). The rates of release and permeation were hydroxyl PSA (PSA-OH) > non-functional group PSA (PSA-None) > carboxyl PSA (PSA-COOH). Thermal analysis, molecular modeling, Raman spectroscopy, and FTIR were employed to characterize the drug-PSA interactions. The strength of the interaction force between GFC and PSA-None was determined to be negligible. The primary amino of GFC formed a medium-strength hydrogen bond with the hydroxyl of PSA-OH and a strong ionic interaction with the carboxyl of PSA-COOH. Compared to PSA-None, PSA-OH featured a weaker mechanical strength, a higher rheological phase shift angle (δ), and a lower glass transition temperature (T_g), resulting in improved molecular mobility. Furthermore, PSA-OH exhibited higher tack, viscosity, and polarity, providing superior skin adhesion. Overall, it has been demonstrated that drug release and permeation were determined by a combination of interaction strength, molecular mobility, and skin adhesion. The novel discovery expands our understanding of the molecular mechanism of drug-PSA-skin interactions, offering a crucial point of reference for the development‌ of GFC transdermal patches.

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