AAPS PharmSciTech最新文献

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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Ion pairs represent a robust molecular force arising from the union of oppositely charged ions, held together by Coulomb attraction. Daidzein (Dai), categorized as a BCS IV drug, faces limitations in clinical application due to its relatively low solubility. To enhance the drug’s solubility, a Dai ion pair was prepared, and the mechanism underlying ion-pair formation was investigated. A comprehensive approach, combining experimental techniques and theoretical calculations, such as scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, Fourier-transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, X-ray Photoelectron Spectroscopy, and computational simulation was employed to explore the ion-pair formation mechanism. The findings indicate a significant improvement in Dai solubility through the preparation of Arg and Lys ion-pair compounds. The results revealed that the Dai–Lys ion pair exhibited more short hydrogen bonds and fewer long hydrogen bonds than did the Dai–Arg ion pair, strengthening the intermolecular interactions and improving crystal structure stability. This study effectively enhanced the solubility of Dai and offers valuable insights into the mechanisms underlying ion pair formation in ionizable drugs.

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Multidrug resistance (MDR) poses a significant challenge in cancer treatment by reducing the efficacy of therapies. This review highlights the potential of lyotropic liquid crystals (LLCs) as innovative nanocarrier systems to overcome MDR. LLCs are characterized by their highly ordered internal structures, which can self-assemble into various phases, including lamellar, hexagonal, and cubic geometries. These structures allow LLCs to encapsulate and release cargo with diverse sizes and polarities, making them promising candidates for drug delivery applications. The phase of LLCs—whether cubic, hexagonal, or lamellar—can influence the physicochemical properties of encapsulated drugs, enabling tailored release profiles such as sustained, controlled, or targeted delivery. This review also explores the transitions in molecular geometry of amphiphilic compounds, additives, and hydrotrope molecules, which affect the formation and stability of LLC phases with varying pore sizes and water channels. The conclusion underscores the importance of ongoing research into LLCs for addressing cancer treatment challenges, including MDR. The versatility of LLCs extends beyond drug delivery to theranostic and diagnostic applications. By leveraging responsive smart drug delivery systems or incorporating natural compounds, LLCs offer a multifaceted approach to cancer therapy, highlighting their potential as a breakthrough in the field.

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The pharmaceutical industry has expressed a lot of interest in site specific drug delivery & oral controlled release to increase treatment efficiency. The idea of a unique drug delivery system was developed to address several concerns with the physicochemical characteristics of drug molecules and the associated formulations. The use of gastro retentive systems for drug delivery, which focus on site-specific drug release for either systemic or local effects in the stomach, is one of these cutting-edge strategies for lengthening gastric residency time. This approach is especially useful for drugs that have a small window of upper gastro intestinal tract absorption. This review has discussed various gastro-retentive techniques, including floating & non-floating systems. With a focus on the numerous gastro retentive approaches that have lately emerged as the most efficient methods for site specific oral controlled release drug administration, the aim of this study on gastro retentive drug delivery systems was to synthesise the most current findings. We have highlighted the major reasons affecting gastric retention so that you may comprehend the many physiological challenges involved. Next, we discussed the different gastro retentive strategies that have been developed and improved to date, including floating, high density, mucoadhesive, unfoldable, expandable, super porous hydrogel, & magnetic systems. The benefits of gastro retentive medication administration techniques were then thoroughly discussed.

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This study hypothesizes that phospholipid-based naturosoomal nanocarriers can significantly enhance the oral solubility and bioavailability of naringin (NARNs) by improving its absorption and pharmacokinetic profile. The NARNs were prepared using solvent evaporation techniques employing a quality-by-design approach followed by physicochemical (UV–visible spectroscopy, FTIR, DSC, XRD, SEM, TEM, PS, ZP analysis), functional (EE, apparent solubility, in-vitro drug release study) characterization and pharmacokinetic investigation. NARNs showed 91.15 ± 1.40% EE, with 12-fold aqueous solubility than the pure drug, i.e., naringin (NAR). The size of the NARNs vesicles was between 150 and 300 nm, demonstrating the controlled vesicle size, whereas the zeta potential and polydispersity index were -32.2 mV and 0.524, respectively signifying the excellent stability and homogeneity of naturosomal suspension. The NARNs in-vitro dissolution data demonstrated a superior release profile (92.12%) compared to pure NAR (38.90%) and physical mixture (43.72%). The pharmacokinetic parameters of NARN in the rabbit showed promising results (T_max = 2.0 h, C_max = 1.76 ± 0.10 µg/mL, and AUC_0-24 = 14.22 ± 0.13 µg/mL h). Thus, overall results indicated that naturosomal drug delivery is a capable method for improving the drug release profile of NAR and oral bioavailability, reducing toxicity by minimizing dose size.

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