AAPS PharmSciTech最新文献

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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Albendazole serves as a broad-spectrum anthelmintic medication for treating hydatid cysts and neurocysticercosis. However, its therapeutic effectiveness is limited by poor solubility. Nanocrystals offer a promising technology to address this limitation by enhancing drug solubility. The objective of this study is to evaluate an effective stabilizer for creating an albendazole nanocrystal formulation to improve oral absorption. Among different surfactants and polymers examined, tea saponins were used as the stabilizer to develop a nanosuspension with the particle size of 180 nm through a wet grinding approach. The physical characteristics of the nanocrystals were assessed using SEM, DSC, and XRPD. The nanocrystals significantly enhanced solubility by 2.9–2602 fold in different media and showed significant enhancement in dissolution rate compared to albendazole crystals in both pH 1.0 and pH 6.8 medium. Everted gut sacs experiments demonstrated that the nanocrystals increased P_app by 3.60-fold in duodenum, 3.76-fold in jejunum, 3.71-fold in ileum, and 5.26-fold in colon, respectively. Furthermore, pharmacokinetic studies revealed that the nanocrystals significantly enhanced oral bioavailability, resulting in a 4.65-fold increase in plasma AUC_0−t value of albendazole sulfoxide (the primary active metabolite of albendazole) compared to the albendazole group. The present data indicates that tea saponins are potential natural stabilizers for preparing nanocrystals with enhanced oral bioavailability for insoluble drugs.

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Isoniazid (INH) and rifampicin (RIF) are the two main drugs used for the management of tuberculosis. They are often used as a fixed drug combination, but their delivery is challenged by suboptimal solubility and physical instability. This study explores the potential of active pharmaceutical ingredient-ionic liquids (API-ILs) to improve the physicochemical and pharmaceutical properties of INH and RIF. Antitubercular drugs, INH, or RIF, were paired with different counter ions (ascorbic acid (AsA), citric acid (CA), tartaric acid (TA), benzoic acid (BA), salicylic acid (SA), and p-amino salicylic acid (PAS)) using the solvent evaporation method. INH and RIF API-ILs were formed successfully using AsA and CA counter ions. IL formation was examined and analyzed using Fourier transform infrared (FTIR) spectroscopy, x-ray powder diffraction (XRPD), and polarized optical microscopy (POM). XRPD and POM confirmed their amorphous nature, while FTIR analysis demonstrated the contribution of hydrogen bonding to IL formation. IL formation enhanced the storage stability of the INH + RIF mixture in the presence of CA. Moreover, RIF-CA IL significantly increased the rate and extent of RIF dissolution. An effect that is unattainable with the RIF/CA physical mixture. Thus, API-IL formation not only enhances RIF dissolution but also facilitates the preparation of stable, compatible INH-RIF combinations.

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Poly(lactide-co-glycolide) (PLGA) is widely used in a variety of long-acting injectables. However, its biodegradable nature creates potential chemical stability challenges during melt extrusion, where PLGA is exposed to elevated temperature (100–140 °C) for several minutes. This study evaluated the thermal stability of three PLGA grades (Resomer® 502, 502H, and 505) with varying molecular weights and chain-ends using a differential scanning calorimeter and twin-screw extruder. DSC results revealed that both residual water content and chain-end groups significantly accelerate PLGA degradation. At 0.2% water content, all samples maintained good stability (less than 15% reduction in molecular weight). However, at 0.4% water content, Resomer 502H, which has acid end groups, experienced significant degradation (45% reduction in molecular weight) after 30 min at 140 °C due to catalyzed hydrolysis. The extruded samples remained stable across tested barrel temperatures (100 °C and 140 °C) and screw speeds (125 and 250 rpm). Further investigations of PLGA with 0.2% water content demonstrates that the hydrolysis rates of Resomer® 502 and 505 were comparable, indicating that molecular weight does not influence hydrolysis rate. In contrast, Resomer® 502H exhibited a higher hydrolysis rate and a slightly higher activation energy, suggesting a greater temperature dependency. Additionally, when subjected to 200 °C for one hour with less than 0.03% water content, Resomer® 505 showed a less than 7% reduction in molecular weight, indicating minimal thermal degradation. Conversely, Resomer® 502 and 502H experienced an increase in molecular weight, which was likely attributed to recombination reactions, particularly in Resomer® 502H, which has higher tin content (170 ppm).

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The available literature indicates that amino acids can stabilize proteins. Our experimental data demonstrated that lysine and glutamic acid can stabilize recombinant human erythropoietin (rhEPO) at 40°C for at least 1 month, as measured by RP-UPLC. Studies with different excipient concentrations demonstrated optimal concentrations of these amino acids within 10–12 mM. The results suggest that a lower concentration of amino acids may not be sufficient to stabilize formulations, while a higher concentration of amino acids can lead lower stability. In silico studies highlighted the importance of the FA4G4S4 model in experimental glycosylation determination, particularly in glycoprotein analysis. We obtained insights into the interactions between the glycosylated ligands of rhEPO and amino acids, as well as their impact on protein behavior and stability. We observed different interactions between the amino acids glycine, glutamic acid, and lysine and the rhEPO protein using this model in docking experiments. They also made it easier to find specific interaction areas by analyzing ligand‒protein interaction fingerprints (PLIFs). This demonstrated how the ligands bind to the proteins or remain outside their vicinity. Furthermore, this study revealed specific places where ligands and rhEPO residues can interact, which helps us learn more about how they stabilize rhEPO.

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Microneedles (MNs) appear as a transformative and minimally invasive platform for transdermal drug delivery, representing a highly promising strategy in wound healing therapeutics. This technology, entailing the fabrication of micron-scale needle arrays, enables the targeted and efficient delivery of bioactive agents into the epidermal and dermal layers without inducing significant pain or discomfort. The precise penetration of MNs facilitates localized and sustained drug release, which significantly enhances tissue regeneration and accelerates wound closure. Furthermore, MNs can be engineered to encapsulate essential bioactive compounds, including antimicrobial agents, growth factors, and stem cells, which are critical for modulating the wound healing cascade and mitigating infection risk. The biodegradable nature of these MNs obviates the need for device removal, rendering them particularly advantageous in the management of chronic wounds such as diabetic ulcers and pressure sores. The integration of nanotechnology within MNs further augments their drug-loading capacity, stability, and controlled-release kinetics, offering a sophisticated therapeutic modality. This cutting-edge approach has the potential to redefine wound care by optimizing therapeutic efficacy, reducing adverse effects, and enhancing patient adherence. As MN technology advances, its application in wound healing exemplifies a dynamic frontier within biomedical engineering and regenerative medicine.

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Delivery of therapies into skin is attractive for medical indications including vaccination and treatment of dermatoses but is highly constrained by the stratum corneum barrier. Microneedle (MN) patches have emerged as a promising technology to enable non-invasive, intuitive, and low-cost skin delivery. When combined with biodegradable polymer formulations, MN patches can further enable controlled-release drug delivery without injection. Herein, we sought to expand on the capability of MN patches to deliver therapies into skin by providing improved spatiotemporal control. Polylactic-co-glycolic acid (PLGA) microspheres were used to encapsulate model dye and then loaded into MN patches through a layer-by-layer fabrication method that created multiple layers of different composition within each MN. MN patches were loaded with up to 5 μg/MN of PLGA microspheres. Mechanical testing demonstrated that mechanical strength of MNs decreased with increasing number of microsphere layers. Microsphere-loaded MN patches inserted into porcine skin ex vivo and murine skin in vivo fully dissolved within 15 min, administering drug-loaded microspheres for controlled release lasting over 45 days. These data support the feasibility of multi-layered, microsphere-loaded MN patches designed for spatially targeted and sustained delivery of therapies into skin.

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