AAPS PharmSciTech最新文献

Quercetin and α-lipoic acid are antioxidants with potential applications in the treatment of various skin conditions, such as wounds and chemoprevention of skin cancer. To enable their effective topical co-delivery and co-localization in the tissue, we developed microemulsions (ME). The selected ME (ME-50) formed a stable system with a mean droplet size of 134.4 ± 17.9 nm, increasing to 224.9 ± 19.9 nm upon antioxidants co-incorporation. The ME preserved the antioxidant capacities of the molecules, with DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging assay showing an IC₅₀ of 6.2 ± 0.1 µg/mL, similar to the solution. Skin penetration studies revealed a 2.4-fold increase in quercetin (Q) accumulation in the stratum corneum and a 3.5-fold increase in the delivery to viable epidermis and dermis (ED) after a 12 h-treatment with the ME compared to control solutions; α-lipoic acid (LA) penetration improved up to 1.9-fold in ED upon ME incorporation. Treatment with Q + LA co-loaded ME enhanced the antioxidant activity in the stratum corneum and ED by 1.3-fold and 2.0-fold, respectively, compared to solutions. Treatment with the ME for 24 h also reduced oxidative species levels by 55% in H₂O₂-exposed keratinocytes compared to the control (untreated) cells. Taken together, these results suggest that ME-50 is a promising delivery system for enhancing the cutaneous co-delivery of quercetin and α-lipoic acid and the antioxidant effects in the tissue, offering a potential topical treatment for oxidative stress-related skin conditions.

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The prognosis for patients with glioblastoma multiforme (GBM), an aggressive and deadly brain tumor, is poor due to the limited therapeutic options available. Biomimetic nanoparticles have emerged as a promising vehicle for targeted mRNA vaccine delivery, thanks to recent advances in nanotechnology. This presents a novel treatment method for GBM. This review explores the potential of using biomimetic nanoparticles to improve the specificity and effectiveness of mRNA vaccine against GBM. These nanoparticles can evade immune detection, cross the blood–brain barrier, & deliver mRNA directly to glioma cells by mimicking natural biological structures. This allows glioma cells to produce tumor-specific antigens that trigger strong immune responses against the tumor. This review discusses biomimetic nanoparticle design strategies, which are critical for optimizing transport and ensuring targeted action. These tactics include surface functionalization and encapsulation techniques. It also highlights the ongoing preclinical research and clinical trials that demonstrate the therapeutic advantages and challenges of this strategy. Biomimetic nanoparticles for mRNA vaccine delivery represent a new frontier in GBM treatment, which could impact the management of this deadly disease and improve patient outcomes by integrating cutting-edge nanotechnology with immunotherapy.

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Due to the poor solubility, permeability, stability and tumor-targeting ability of norcantharidin (NCTD), currently commercially available NCTD formulations require patients to take the medicine more frequently. Moreover, the formulation of NCTD themselves have certain toxicity, thus showing unsatisfactory therapeutic outcomes and serious systemic side effects. Based on the specific acidic environment at the tumor site, in this study, the pH-sensitive NCTD solid self-microemulsion (NCTD@CS-DMMA SSME) was prepared by introducing 2,3-dimethylmaleic acid amide modified chitosan (CS-DMMA), and it was wrapped in colon-coated capsule to achieve stable and controlled drug release in the acidic environment of colonic tumors. After self-emulsification, it had a particle size of 75.88 ± 0.85 nm and carried a negative charge. Under the condition of pH 6.5, NCTD@CS-DMMA SSME exhibited first-order release kinetics characteristics. Moreover, the cumulative release under the condition of pH 6.5 was 2.04-fold higher than that under the condition of pH 7.4. The in situ intestinal absorption assay elucidated that the prepared formulation could effectively improve the absorption rate constant and apparent permeability coefficients of NCTD in colon tumor site. The antitumor effect in vivo and in vitro showed that it could not only improve the inhibition ability of tumor growth, migration and invasion in mice, but also increase the tumor-infiltrating T lymphocytes in mice with colon cancer, thus inhibiting tumor growth. In summary, the NCTD@CS-DMMA SSME can deliver drugs to the site of colon tumors and continuously release drugs, providing new insights into improving the treatment effectiveness of colon cancer.

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Intravenous routes of drug delivery are widely used in clinical practice due to the advantages of fast onset of action and avoidance of first-pass effect. Still, it is difficult to develop poorly water-soluble drugs for intravenous administration. In recent years, the application of nanocrystal technology has become more and more widespread, mainly involving reducing the particle size to the nanoparticle size range and improving its physicochemical properties to enhance the bioavailability of drugs. Intravenous nanocrystals (INCs) can show unique advantages in the vasculature, with their high drug loading capacity, low toxicity, and overcoming low solubility, which makes them a new solution in tumor therapy. In addition, INCs are mainly suspended in aqueous/oil phase media, which makes them easy to inject. Therefore, INCs may serve as a novel strategy to address poor water solubility, low bioavailability, and associated toxicity. This review contains the compositional development of INCs, and preparation methods, and provides some insights into their application in oncology.

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We investigated the experimental solubility of tofacitinib citrate (TNF) in HSPiP predicted mono solvents at varied temperature points, followed by validation with various models (computational and thermodynamic) and GastroPlus based predicted in-vivo performance in individuals (adult humans). HSPiP (Hansen software) predicted five mono solvents (N-methyl-2-pyrrolidone as NMP, ethanol, polyethylene glycol 400 as PEG400, chloroform, and water). The thermally stable drug was solubilized in these solvents. Computational (Van't Hoff and Apelblat) models were applied to validate the experimental solubility data (mole fraction solubility, X_e). The selected solvent (NMP) was used as a vehicle for subcutaneous (sub-Q) formulation development and compared against conventional tablet for high effectiveness in terms of pharmacokinetic parameters (PK) in humans. Results showed that the drug solubility in NMP was “endothermic and entropy” driven as evidenced with the applied models (computational and thermodynamic). The optimized components for sub-Q delivery were NMP (21.5% v/v), PEG400 (10.0% v/v), and PBS (phosphate buffer solution at pH 7.4). GastroPlus predicted 0.036 µg/mL and 0.042 µg/mL values of C_max (maximum drug reached in the blood) in the blood after sub-Q and oral delivery, respectively. In vivo access of the drug was maximally extended in sub-Q delivery as compared to tablets as predicted in GastroPlus considering humans (fast condition). Conclusively, the sub-Q administration of TNF can be a promising alternative to the conventional tablets.

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Pressurized metered dose inhalers (pMDI) are a vital therapy for the treatment of lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). In pMDI, the propellants used to deliver the drug to the lungs are hydrofluorocarbons (HFC). However, the current HFCs in use have large global warming potential (GWP). In order to reduce or eliminate the use of propellants with large global warming potential, efforts are underway within the pharmaceutical industry to transition to the use of low GWP propellants in pMDI, while maintaining their effectiveness in treating disease. The current switch from higher GWP propellants mirrors the switch from chlorofluorocarbon (CFC) propellants to HFCs undertaken in the 1990’s, which was driven by ozone depletion concerns. In this paper, the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) discusses aspects of the switch to low GWP propellants from the perspective of materials compatibility of pMDI components with low GWP propellants. Leveraging the learnings and advances in pMDI component materials implemented following the switch from CFCs, industry is well positioned to make the change. This paper describes the utility of the low GWP propellants being developed for use in pMDI and the learnings from the previous transition that are being leveraged by industry. The current state of development will be described, including a review of available literature supporting the transition to low GWP propellants.

Purpose

This work reports the development and characterisation of polymeric films composed of gelatin or its chemically modified derivatives (crotonoylated, itaconoylated, and methacryloylated gelatins) blended with polyvinyl alcohol (PVA). Metronidazole served as an antimicrobial drug in these formulations.

Methods

The films were produced by casting aqueous solutions of polymers, followed by solvent evaporation. Their structure and physicochemical characteristics were studied using Fourier transform infrared spectroscopy, scanning electron microscopy, and mechanical testing. The thickness of the films, their folding endurance, the surface pH, and transparency were also evaluated. The mucoadhesive performance of the films was evaluated through an ex vivo detachment technique involving freshly excised sheep vaginal tissues. In vitro cumulative drug release studies were conducted using Franz diffusion cells.

Results

The results demonstrate that incorporating unsaturated functional groups into gelatin improves its mucoadhesive properties compared to native gelatin. The drug release experiments conducted in vitro showed that the cumulative release from pure gelatin/PVA films was found to be 49 ± 2%, whereas modified gelatins/PVA (70:30) films released ~ 64–71%.

Conclusion

These findings suggest that modified gelatins could serve as effective excipients in designing mucoadhesive formulations for vaginal administration, with potential applications extending to other transmucosal drug delivery systems.

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Study explored the synergistic anti-tumor effects of a combination of compounds from Traditional Chinese Medicine, including rosmarinic acid (RA), chlorogenic acid (CA), and scoparone (SCO), in the formulation of multivesicular liposomes (MVLs). Optimization of formulations and process parameters was essential to achieve effective liposomal encapsulation and optimal release profiles for these three compounds with diverse properties. Traditional trial-and-error approaches are inefficient for the optimization of complex multi-compound MVLs. We developed a new formulation optimization model, which could address this issue by predicting the optimal multi-compound MVLs formulation. Our machine learning model integrated support vector machine regression (SVR) algorithm and cuckoo search (CS) algorithm, resulting in three CS-SVR models to predict single-compound MVLs. The CS algorithm, with various weighting rules, was then applied to search the best formulation parameters across three CS-SVR models and to maximize the encapsulation efficiency for all three compounds. The multi-compound MLVs were subsequently prepared under the predicted conditions, achieving an optimized particle size of 15.12 µm, with encapsulation efficiencies of 82.93 ± 2.43% for CA, 82.22 ± 1.25% for RA, and 95.60 ± 0.18% for SCO. The predicted optimal multi-compound MVLs were further validated through in vitro characterization and in vivo anti-tumor experiments, showing a promising synergistic anti-tumor effect consistent with in vitro results. This model accurately predicted optimal encapsulation conditions, which were validated experimentally, demonstrating improved encapsulation efficiencies and reduced trial-and-error iterations. Collectively, our model provides a predictive pathway for multi-compound MVLs formulation, indicating the ability of this model to significantly reduce experimental burden and accelerate formulation development.

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Capecitabine, an oral prodrug of 5-fluorouracil, is increasingly being loaded into various drug delivery system to enhance its bioavailability and cytotoxicity. This study aimed to prepare and evaluate capecitabine-loaded niosomes as a drug delivery system for breast cancer treatment. The niosomes were prepared by thin film hydration method using Span 60 and cholesterol. Optimization was done using 3² factorial design with the responses of particle size and entrapment efficiency. Scanning electron microscopy (SEM) was used to observe the morphology. Fourier transform infrared spectroscopy (FTIR) and ultraviolet (UV) spectrophotometry were used to confirm the nature of the interactions. The optimized batch was further assessed for percent cumulative drug release, nature of crystallinity using the X-ray diffraction method, and drug excipient compatibility using FTIR and Differential Scanning Calorimetry (DSC). The optimized batch (F8) exhibited a particle size of 118 nm, a zeta potential of 24.1 mV, an entrapment efficiency of 93%, and a polydispersibility index (PDI) of 0.25. The cumulative drug release in a pH of 6.8 indicated that 86.46 ± 0.45% of the drug was released in 24 h. Cytotoxicity testing using MTT assay on MCF-7 breast cancer cell lines showed that the capecitabine niosomes were 2.6 times more cytotoxic than the pure drug. The study demonstrates that capecitabine-niosomes significantly enhanced the anticancer activity of capecitabine, suggesting a promising approach for breast cancer treatment.

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Gefitinib (GB), an oral tyrosine kinase inhibitor suffers major setbacks in clinical application due to limited aqueous solubility leading to poor oral bioavailability. Nanosuspension serves as a promising formulation strategy to overcome the above-mentioned drawbacks. Hence, the present study involves the development of gefitinib nanosuspension (GB-NS) using High-pressure homogenization (HPH) to increase its aqueous solubility and maximize oral bioavailability. GB-NS was optimized by utilizing the quality-by-design strategy to optimize independent variables such as homogenization pressure, drug-to-stabilizer ratio, and number of cycles. Lecithin was found to stabilize the nanosuspension with optimal particle size, PDI, and zeta potential of 157 ± 18.77 nm, 0.296 ± 0.040, and -33.25 respectively. Intriguingly, a drug-to-stabilizer ratio significantly influenced (p < 0.005) particle size and PDI, establishing its crucial role in optimization. The morphological characterization by SEM of GB-NS revealed a rod-shaped structure. Thereafter, the thermal and powder X-ray analysis depicted the crystalline nature of gefitinib in GB-NS. Additionally, GB-NS exhibited enhanced saturation solubility (~ 2.4- and ~ 3.4-fold) and dissolution rate (~ 2.5- and ~ 3.5-fold) compared to pure GB in 0.1 N HCl and PBS 6.8 respectively. GB-NS remained stable under both storage conditions ( 25°C and 4°C). Finally, the pharmacokinetic study depicted a considerable increase in C_max (~ 2.84-fold) and AUC_(0-t) (~ 3.87-fold) of GB-NS when compared to free GB. Therefore, developed formulations showed a competent solution for enhancing the oral bioavailability of poor water-soluble drugs.

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