Pharmaceutics最新文献

Background/Objectives: Ivermectin gained widespread attention as the "miracle drug" during the coronavirus disease 2019 (COVID-19) pandemic. Its inclusion in the 21st World Health Organization (WHO) List of Essential Medicines is attributed to its targeted anti-helminthic response, high efficacy, cost-effectiveness and favorable safety profile. Since the late 2000s, this bio-inspired active pharmaceutical ingredient (API) gained renewed interest for its diverse therapeutic capabilities. However, producing ivermectin formulations does remain challenging due to its poor water solubility, resulting in low bioavailability after oral administration. Therefore, the transdermal drug delivery of ivermectin was considered to overcome these challenges, which are observed after oral administration. Methods: Ivermectin was incorporated in a nano-emulsion, nano-emulgel and a colloidal suspension as ivermectin-loaded nanoparticles. The nano-drug delivery vehicles were optimized, characterized and evaluated through in vitro membrane release studies, ex vivo skin diffusion studies and tape-stripping to determine whether ivermectin was successfully released from its vehicle and delivered transdermally and/or topically throughout the skin. This study concluded with cytotoxicity tests using the methyl thiazolyl tetrazolium (MTT) and neutral red (NR) assays on both human immortalized epidermal keratinocytes (HaCaT) and human immortalized dermal fibroblasts (BJ-5ta). Results: Ivermectin was successfully released from each vehicle, delivered transdermally and topically throughout the skin and demonstrated little to no cytotoxicity at concentrations that diffused through the skin. Conclusions: The type of nano-drug delivery vehicle used to incorporate ivermectin influences its delivery both topically and transdermally, highlighting the dynamic equilibrium between the vehicle, the API and the skin.

Background: Cystic fibrosis is a hereditary disease, which causes the accumulation of dense mucus in the lungs accompanied by frequent local inflammation. The non-steroidal anti-inflammatory drug ibuprofen (IBU) and the mucolytic mannitol (MAN) can treat these symptoms. Compared to per os administration, a lower dose of these drugs is sufficient to achieve the desired effect by delivering them in a pulmonary manner. However, it is still a challenge to administer high drug doses to the lungs. We aim to develop two inhaled powder formulations, a single-drug product of MAN and a combined formulation containing IBU and MAN. Methods: MAN was dissolved in an aqueous solution of Poloxamer-188 (POL). In the case of the combined formulation, a suspension was first prepared in a planetary mill via wet milling in POL medium. After the addition of leucine (LEU), the formulations were spray-dried. The prepared DPI samples were analyzed by using laser diffraction, scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, density tests, in vitro aerodynamic studies (Andersen Cascade Impactor, Spraytec^® device), in vitro dissolution tests in artificial lung fluid, and in silico tests with stochastic lung model. Results: The DPIs showed suitability for inhalation with low-density spherical particles of appropriate size. The LEU-containing systems were characterized by high lung deposition and adequate aerodynamic diameter. The amorphization during the procedures resulted in rapid drug release. Conclusions: We have successfully produced a single-drug formulation and an innovative combination formulation, which could provide complex treatment for patients with cystic fibrosis to improve their quality of life.

Background: Zinc oxide nanobiocomposites were successfully synthesized using a green synthesis approach. The process involves the utilization of the isoflavone puerarin, resulting in the formation of PUE-ZnO NPs.

Methods: Physico-chemical and biological characterization techniques including X-ray dif-fraction (XRD), UV-vis spectroscopy, Fourier transform infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM), atomic force microscopy (AFM), and in ovo methods were employed to study the main characteristics of this novel hybrid material.

Results: The PUE-ZnO NPs were confirmed to have been successfully synthesized with a UV absorption peak at 340 nm, the XRD analysis demonstrating their high purity and crystallinity. The energy band-gap value of 3.30 eV suggests possible photocatalytic properties. Both SEM and AFM images revealed the nanoparticle`s quasi-spherical shape, roughness, and size. Good tolerability and anti-irritative effects were recorded in ovo on the chorioallantoic membrane (CAM).

Conclusions: According to these results, the synthesis of green PUE-ZnO NPs may be a promising future approach for biomedical and personal care applications.

Objective: The aim of this study was to develop quantitative structure-pharmacokinetics relationship (QSPKR) models for a group of xanthine derivatives with proven pharmacological activity and to investigate its applicability for the prediction of the pharmacokinetics of these compounds.

Methods: The SYBYL-X, KowWin, and MarvinSketch programs were employed to generate a total of fourteen descriptor variables for a series of new compounds: 7- and 7,8-substituted theophylline derivatives (GR-1-GR-8) and three well-known methylxanthines. Pharmacokinetic profiles of all compounds were determined after intravenous administration of studied compounds to cannulated male rats. Pharmacokinetic parameters were calculated using noncompartmental analysis.

Results: Multiple linear regression revealed that logD was the main determinant of the variability in V_ss, λ_z, and CL of the studied compounds. Moreover, λ_z and CL depended on LUMO and HEFO, while for V_z COAR was the only explanatory variable. The developed QSPKR models accounted for most of the variation in V_ss, λ_z, CL, and fraction unbound (f_u) (R² ranged from 0.68 to 0.91). Cross-validation confirmed the predictive ability of the models (Q² = 0.60, 0.71, 0.34, and 0.32 for V_ss, λ_z, CL, and f_u, respectively).

Conclusions: The multivariate QSPKR models developed in this study adequately predicted the overall pharmacokinetic behavior of xanthine derivatives in rats.

The failure of immunotherapies in cancer patients is being widely studied due to the complexities present in the tumor microenvironment (TME), where regulatory T cells (Treg) appear to actively participate in providing an immune escape mechanism for tumors. Therefore, therapies to specifically inhibit tumor-infiltrating Treg represent a challenge, because Treg are distributed throughout the body and provide physiological immune homeostasis to prevent autoimmune diseases. Characterization of immunological and functional profiles could help to identify the mechanisms that need to be inhibited or activated to ensure Treg modulation in the tumor. To address this, quantitative in silico approaches based on mechanistic mathematical models integrating multi-scale information from immune and tumor cells and the effect of different therapies have allowed the building of computational frameworks to simulate different hypotheses, some of which have subsequently been experimentally validated. Therefore, this review presents a list of diverse computational mathematical models that examine the role of Treg as a crucial immune resistance mechanism contributing to the failure of immunotherapy. In addition, this review highlights the relevance of certain molecules expressed in Treg that are associated with the TME immunosuppression, which could be incorporated into the mathematical model for a better understanding of the contribution of Treg modulation. Finally, different preclinical and clinical combinations of molecules are also included to show the trend of new therapies targeting Treg.

Background/Objectives: Thymoquinone (TQ) exhibits diverse biological activities, but its poor solubility and bioavailability limit its cancer efficacy, requiring innovative solutions. This study explores the development of an oral delivery system targeting colon cancer based on TQ pectin beads (TQ-PBs) produced through an adjustable electrospray technique. This study hypothesised that adjusting bead diameter through the electrospray technique enables precise control over water absorption and erosion rates, thereby achieving a controlled release profile for encapsulated TQ, which enhances targeted delivery to the colon. Methods: TQ-PBs were synthesised and optimised using an electrospray technique based on the ionic gelation method. The prepared beads were characterised based on particle size, sphericity, encapsulation efficiency (EE), water uptake, erosion, surface morphology, molecular interactions, and texture. The cumulative TQ release studies, an accelerated stability test, and cytotoxicity evaluation against the colon cancer HT-29 cell line were also assessed. Results: The optimised TQ-PB formulation demonstrated an average bead size of 2.05 ± 0.14 mm, a sphericity of 0.96 ± 0.05, and an EE of 90.32 ± 1.04%. The water uptake was 287.55 ± 10.14% in simulated gastric fluid (SGF), 462.15 ± 12.73% in simulated intestinal fluid (SIF), and 772.41 ± 13.03% in simulated colonic fluid (SCF), with an erosion rate of 45.23 ± 5.22%. TQ release was minimal in SGF (8.13 ± 1.94% after 2 h), controlled in SIF (29.35 ± 3.65% after 4 h), and accelerated in SCF (94.43 ± 2.4% after 3 h). Stability studies over one month showed a size reduction of 17.50% and a 6.59% decrease in TQ content. Cytotoxicity assessments revealed significant anticancer activity of TQ-PB, with an IC50 of 80.59 ± 2.2 μg/mL. Conclusions: These findings underscore the potential of TQ-PB as an effective oral drug delivery system for targeted colorectal cancer therapy.

Background/Objectives: Skin injuries are common in the equine clinical practice, requiring effective treatment to support natural healing. Bacuri butter is gaining attention for its potential in wound healing and its anti-inflammatory, antimicrobial, and antioxidant properties. Natural polymers such as onion (Allium cepa) bioplastics have been investigated for their potential as occlusive dressings and for tissue regeneration. Methods: This study evaluated the healing process of experimentally induced skin wounds on horses treated with bacuri butter, washed onion film, and unwashed onion film. Clinical and histopathological analyses of the wounds were conducted in six clinically healthy horses over 28 days, with a control group receiving Ringer's lactate solution. The onion films were produced and characterized for their chemical structure and properties, while the bacuri butter was sourced and prepared for application. Results: All treatments, including the control group, promoted wound healing without relevant differences in wound contraction rates, gross aspect, or histopathological parameters. Conclusions: Therefore, despite minor variations observed in the clinical evaluations between the treatment groups, the bacuri butter or onion biopolymer showed no significant healing effect on skin wounds in horses. Additionally, this study showed the potential of equine models in testing novel therapeutic approaches for wound healing, benefiting both veterinary and human medicine.

Background: The aryl hydrocarbon receptor (AhR) plays a crucial role in immune and metabolic processes. The large molecular diversity of ligands capable of activating AhR makes it impossible to determine the structural features useful for the design of new potent modulators. Thus, in the field of drug discovery, the intricate nature of AhR activation necessitates the development of novel tools to address related challenges. Methods: In this study, quantitative structure-activity relationship (QSAR) models of classification and regression were developed with the objective of identifying the most effective method for predicting AhR activity. The initial dataset was obtained by combining the ChEMBL and WIPO databases which contained 978 molecules with EC₅₀ values. The predictive models were developed using the automated machine learning platform mljar according to a 10-fold cross validation (10-CV) testing procedure. Results: The classification model demonstrated an accuracy value of 0.760 and F1 value of 0.789 for the test set. The root-mean-squared error (RMSE) was 5444, and the coefficient of determination (R²) was 0.208 for the regression model. The Shapley Additive Explanations (SHAP) method was then employed for a deeper comprehension of the impact of the variables on the model's predictions. As a practical application for scientific purposes, the best performing classification model was then used to develop an AhR web application. This application is accessible online and has been implemented in Streamlit. Conclusions: The findings may serve as a foundation in prompting further research into the development of a QSAR model, which could enhance comprehension of the influence of ligand structure on the modulation of AhR activity.

Background/Objectives: Trans-resveratrol (Res) has been reported to possess many biological activities, including neuroprotective effects, owing to its anti-inflammatory and antioxidant properties. However, Res has very low water solubility, which limits its therapeutic application. In this work, we formulated water-soluble micellar formulations incorporating Res using polyethylene glycol monostearate (stPEG). Methods: These formulations (stPEG/Res) were developed using five types of stPEG containing 10, 25, 40, 55 and 140 PEG repeat units. The formulations were characterized for Res content, water solubility, particle size, zeta potential, precipitation, biodistribution, and efficacy against neuronal and motor dysfunction in intracerebral hemorrhage (ICH). Results: Intravenous administration of stPEG40/Res, which demonstrated particle size, water solubility, and biodistribution properties suitable for intravenous administration, suppressed neurological and motor dysfunction following in a collagenase-induced ICH mouse model. These effects were inhibited by zinc protoporphyrin-9, an inhibitor of the antioxidant enzyme heme oxygenase-1, suggesting that Res contributes to antioxidant enzyme expression and anti-inflammatory activity. Conclusions: The stPEG/Res micellar formulation developed in this study may offer a promising therapeutic approach for ICH treatment.

Targeted radionuclide therapy (TRT) for internal pathway-directed treatment is a game changer for precision medicine. TRT improves tumor control while minimizing damage to healthy tissue and extends the survival for patients with cancer. The application of theranostic-paired TRT along with cellular phenotype and genotype correlative analysis has the potential for malignant disease management. Chelation chemistry is essential for the development of theranostic-paired radiopharmaceuticals for TRT. Among image-guided TRT, ⁶⁸Ga and ^99mTc are the current standards for diagnostic radionuclides, while ¹⁷⁷Lu and ²²⁵Ac have shown great promise for β- and α-TRT, respectively. Their long half-lives, potent radiobiology, favorable decay schemes, and ability to form stable chelation conjugates make them ideal for both manufacturing and clinical use. The current challenges include optimizing radionuclide production processes, coordinating chelation chemistry stability of theranostic-paired isotopes to reduce free daughters [this pertains to ²²⁵Ac daughters ²²¹Fr and ²¹³Bi]-induced tissue toxicity, and improving the modeling of micro dosimetry to refine dose-response evaluation. The empirical approach to TRT delivery is based on standard radionuclide administered activity levels, although clinical trials have revealed inconsistent outcomes and normal-tissue toxicities despite equivalent administered activities. This review presents the latest optimization methods for chelation-based theranostic radiopharmaceuticals, advancements in micro-dosimetry, and SPECT/CT technologies for quantifying whole-body uptake and monitoring therapeutic response as well as cytogenetic correlative analyses.