International Journal of Pharmaceutics最新文献

Biotinidase deficiency is a rare inherited disorder characterized by biotin metabolism issues, leading to neurological and cutaneous symptoms that can be alleviated through biotin administration. Three-dimensional (3D) printing (3DP) offers potential for personalized medicine production for rare diseases, due to its flexibility in designing dosage forms and controlling release profiles. For such point-of-care applications, rigorous quality control (QC) measures are essential to ensure precise dosing, optimal performance, and product safety, especially for low personalized doses in preclinical and clinical studies. In this work, we addressed QC challenges by integrating a precision balance into a direct powder extrusion pharmaceutical 3D printer (M3DIMAKER™) for real-time, in-line mass uniformity testing, a critical quality control step. Small and large capsule-shaped biotin printlets (3D printed tablets) for immediate- and extended-release were printed. The integrated balance monitored and registered each printlet's weight, identifying any deviations from acceptable limits. While all large printlet batches met mass uniformity criteria, some small printlet batches exhibited weight deviations. In vitro release studies showed large immediate-release printlets releasing 82% of biotin within 45 min, compared to 100% for small immediate-release printlets. For extended-release formulations, 35% of the drug was released from small printlets, whereas 24% was released from large printlets at the same time point. The integration of process analytical technology tools in 3DP shows promise in enhancing QC and scalability of personalized dosing at the point-of-care, demonstrating successful integration of a balance into a direct powder extrusion 3D printer for in-line mass uniformity testing across different sizes of capsule-shaped printlets.

This study investigates the simultaneous prediction of active pharmaceutical ingredient (API) concentration and mass gain in film-coated tablets using Partial Least Squares (PLS) regression combined with three data fusion (DF) techniques: Low-Level (LLDF), Mid-Level (MLDF), and High-Level (HLDF). Near-Infrared (NIR) and Raman spectroscopy were utilized in both reflection and transmission modes, providing four types of spectral data per tablet. Transmission models proved more effective for API prediction by capturing data from the entire tablet, while reflection models excelled in assessing mass gain by focusing on the surface layer. Among the DF strategies, MLDF with Principal Component Analysis (PCA) offered the most significant improvements in predictive accuracy by filtering out irrelevant information. Variable selection methods further enhanced model performance by reducing the number of latent variables required. Overall, the integration of multiple spectral datasets and DF techniques resulted in models that gave predictions for evaluation samples with lower errors, demonstrating their potential to optimize quality control in pharmaceutical manufacturing.

Indocyanine green (ICG) J-aggregates (IJA) are a unique form of aggregation that exhibits superior properties to monomeric ICG. Despite their higher photoacoustic (PA) signals for imaging and heating stability during photothermal therapy (PTT), they exhibit low stability under a biological milieu. Our group previously proposed a simple procedure for in-situ preparation of IJA into liposomes, accelerating their formation and optical properties. To comprehend their potential applications, we systematically investigated the effect of the lipid bilayer composition on ICG J-aggregation and stability. Moreover, their in vitro compatibility and photothermal toxicity in monolayers and cancer spheroids, besides their in vivo biodistribution and clearance were evaluated. Our findings revealed the importance of high cholesterol and PEG-lipid content and low charged lipids (∼ 5 mol %) in liposomes to promote a high IJA/ICG ratio and, thus, high heating stability. More importantly, IJA-liposomes revealed high biocompatibility in monolayer and cancer spheroids with efficient photothermal toxicity. Finally, IJA-liposomes were cleared from the body without toxicity. Interestingly, IJA-liposomes mainly showed lower affinity to the liver than monomeric ICG, resulting in higher renal clearance. Overall, our biodegradable IJA-liposomes could be an excellent alternative to gold-based agents suitable for PA imaging and cancer PTT.

BCS III drugs exhibit high solubility and low permeability, and some excipients were reported to increase their permeability. Although some permeability-enhancing excipients were investigated, permeability-enhancing strategy still need to be improved. Firstly, we established a database and analyzed the possible effects of excipients. Sodium lauryl sulfate (SLS) was found to be the most-used permeability-enhancing excipients. Moreover, the quantitative models for predicting P_app and P_eff of BCS III drugs with SLS were developed, and statistically meaningful descriptors include molecular weight (MW), pKa, logP, solubility, hydrogen bond (HB) count, rotatable bond count (RBC), and topological polar surface area. The models demonstrated a good fit and effective predictive capability with all the correlation R² values over 0.7. Hydrogen bonding remains the most significant factor in enhancing drug permeability with SLS, while hydrophilicity is also vital in this process. It was also found that MW, logP, pKa, and RBC play significant roles in paracellular transport. In summary, current research did the systematic and quantitative analysis of BCS III drugs and their excipients, which may accelerate formulation research on BCS III products.

Immunotherapy has made excellent breakthroughs in the field of cancer treatments, but faces challenges with low immunogenicity of tumor cells and an immunosuppressive tumor microenvironment (ITME). The emerging chemodynamic therapy (CDT) based on the Fenton/Fenton-like reaction can induce immunogenic cell death (ICD) to enhance tumor immunogenicity, facilitating the transition from immune-cold to immune-hot tumors. Synergistic CDT and immunotherapy based on advanced nanotechnology have shown immense promise for improving therapeutic efficacy while minimizing side effects in cancer treatment. This review summarizes and discusses recent advances in the field, with the goal of designing a high-quality nanoplatform to enhance synergistic CDT in combination with immunotherapy and lay the foundation for its future clinical translation.

Due to high lipophilicity and extensive first-pass metabolic loss, cannabidiol (CBD) has low oral bioavailability. Co-administration of CBD and long-chain lipids facilitates the intestinal lymphatic delivery, resulting in higher systemic bioavailability, as well as high levels of the drug within the intestinal lymphatic system. However, despite previous attempts with various lipid-based formulations, the oral bioavailability of CBD is still limited. In this work, we have developed a novel formulation of CBD based on natural rapeseed oleosomes. In vivo studies in rats demonstrated that oral administration of CBD-loaded rapeseed oleosomes leads to substantially higher oral bioavailability and intestinal lymphatic targeting of CBD in comparison with rapeseed oil or artificial emulsion made of rapeseed oil and lecithin. In vitro mechanistic assessments, including in vitro lipolysis and peroxide value determination suggest that the lower oxidative state of the oil in oleosomes in comparison to crude oil or artificial emulsion is likely to be the main factor responsible for the superior performance of the CBD-loaded rapeseed oleosomes in vivo. Although further investigation will be needed, the data suggest that natural seeds-derived oleosomes can be used as a promising lipid-based drug delivery platform promoting the bioavailability and lymphatic delivery of lipophilic drugs.

Cocrystallization has emerged as a promising formulation strategy for modulating transdermal drug absorption by enhancing solubility and permeability. However, challenges related to cocrystal dissociation in the semi-solid state need to be addressed to mitigate regulatory concerns before the widespread implementation of topical cocrystal products in clinical practice. This study aimed to develop oil-based topical formulations incorporating cocrystals with distinct thermodynamic stabilities, followed by investigating the roles of different structurally similar coformers and oily vehicles on their physicochemical properties. Three pharmaceutical cocrystals of poorly water-soluble flufenamic acid (FFA) were synthesized with isomeric pyridine carboxamides in a 1:1 stoichiometry via rapid solvent removal. These included the reported flufenamic acid-nicotinamide cocrystal (FFA-NIC), the long-elusive flufenamic acid-isonicotinamide cocrystal (FFA-IST) and flufenamic acid-picolinamide cocrystal (FFA-PIC). The resulting cocrystals, which exhibited different hydrogen bonding patterns, were characterized using powder X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy, and structural analysis through single crystal X-ray diffraction. The cocrystals were further formulated in a series of oleaginous and absorption bases, including liquid paraffin, Vaseline, lanolin, and theobroma oil, for topical delivery. The cocrystal dissociation, content uniformity, and in vitro membrane diffusion were assessed. Notably, although all FFA cocrystals exhibited thermodynamic instability in aqueous solution, a significantly reduced propensity for cocrystal dissociation was observed in the ointment bases. Integrated computational analyses of packing efficiency and interaction energy revealed that the thermodynamic stability of cocrystals followed a descending order of FFA-NIC > FFA-PIC > FFA-IST. Compared with raw FFA, FFA-IST and FFA-PIC, which had larger positive ΔV_non-H and ΔE_cocryst, achieved superior cumulative diffusion of FFA from Vaseline, with a 4.3-fold (p = 0.0003) and 3.3-fold (p = 0.0029) increase at 6 h in a Franz diffusion cell model, respectively. The diffusion of all FFA cocrystals mainly followed the Higuchi kinetic model and was positively correlated with the intrinsic dissolution rate.

Amniotic Mesenchymal Stem Cells Metabolite Products (AMSC-MP) contain growth factors that benefit human health. This study aims to evaluate the use of transfersomal serum (Trans) with hyaluronic acid (HA) addition to deliver large molecules of AMSC-MP for skin regeneration. Trans is composed of L-α-phosphatidylcholine and surfactants, i.e., sodium cholate (SC) or stearylamine (SA), at the weight ratio of 85:15, prepared by the thin film method with or without HA addition. The results showed that HA addition increased the particle size of Trans-SA and Trans-SC, from 261.9 ± 1.9 and 105.3 ± 0.9 nm respectively, to 317.7 ± 9.1 and 144.3 ± 0.8 nm for Trans-SA-HA and Trans-SC-HA. In contrast, no significant changes in the zeta potential occurred. The relative deformability indexes of Trans-SA, Trans-SA-HA, Trans-SC, and Trans-SC-HA compared to liposome were 0.43 ± 0.09, 0.46 ± 0.09, 1.58 ± 0.17, and 1.40 ± 0.17 respectively. The addition of HA successfully increases the in vivo skin hydration, collagen density, and number of fibroblast cells, reflecting the capacity for skin regeneration in UV-induced aged mice. Furthermore, no erythema or skin rash was observed at the 24-hour post-topical application sites. AMSC-MP transfersomal serum with HA addition successfully enhanced skin regeneration and proved safe during the in vivo study using UV aging-induced mice models, thereby enabling its potential use as skin-aging therapy.

Melanoma is the most aggressive type of skin cancer and recently approved drugs are often associated with resistance and significant adverse effects. Therefore, the design of more effective and safe options remains imperative. Photothermal therapy (PTT) using gold nanoparticles (AuNPs) presents a promising and innovative approach. In this work, the efficacy of combining a previously optimized formulation of AuNPs coated with a mixture of hyaluronic and oleic acids (HAOA-AuNPs) with near-infrared (NIR) laser irradiation in melanoma cell lines was explored. Coated and uncoated AuNPs formulations were characterized in physicochemical, morphological and elemental terms. Next, the cellular uptake efficiency as well as antiproliferative activity of the combination of each formulation with laser irradiation was evaluated. Subsequently, HAOA-AuNPs were selected to assess the underlying mechanism of combined therapy by cell cycle and Annexin V/PI assays. An in vivo syngeneic murine melanoma model was also conducted. In vitro studies demonstrated that 24 h after incubation and in the absence of laser, HAOA-AuNPs did not exhibit cytotoxic effects on the melanoma cell lines tested, similar to the laser alone. On the contrary, the combination therapy resulted in a large reduction in cell viability. Furthermore, it has been shown to promote S-phase cell cycle arrest and increase in the percentage of late apoptotic cells. Finally, the in vivo proof-of-concept showed that the intratumoral administration of HAOA-AuNPs followed by three laser irradiations impaired tumor progression. Collectively, AuNP-based PTT holds significant potential to improve treatment efficacy and safety, offering a versatile and potent tool against cancer.