International Journal of Pharmaceutics最新文献

This study explores the impact of drug loading (DL) on the physical stability, dissolution performance, and micellisation behaviour of binary and ternary amorphous solid dispersions (ASDs) of lumefantrine (LUM), a poorly soluble antimalarial drug. Based on preliminary evaluations, Soluplus® was chosen as the polymer for its excellent solubility enhancement and amorphous stabilisation of LUM, while Kolliphor® RH40 was employed as a surfactant additive due to its synergistic ability to improve solubility and sustain supersaturation with Soluplus®. Binary ASDs (BASDs) and ternary ASDs (TASDs) were produced via hot-melt extrusion (HME) across a DL range of 10-50%. P-XRD and DSC provided qualitative and quantitative insight into DL-dependent amorphisation loss, showing that TASDs exhibited significantly lower T_gs and poorer physical stability than BASDs, with the inferiority amplified at increased DL. In general, pH-triggered dissolution was seen to deteriorate with increasing DL in both the binary and ternary systems. TASDs outperformed BASDs at low DL (≤20%); however, TASDs were more sensitive to the increase in DL, showing a markedly sharper decline in dissolution at DL ≥ 30%, which resulted in lower drug release relative to their BASD counterparts at higher DLs. At 40% and 50% DL, TASDs even underperformed their corresponding physical mixtures. Dynamic light scattering (DLS) analysis of micelles formed during dissolution revealed that ASDs with higher DLs generated larger and less uniform micelle systems, which correlated with reduced release performance. Noticeably, the addition of RH40 may disturb Soluplus®-driven micellisation by forming small aggregates, potentially undermining its solubilisation efficiency. Overall, these findings highlight a delicate, DL-dependent balance between the addition of surfactant and formulation robustness, suggesting the need for caution when operating near a potential critical DL, particularly in surfactant-containing ASD systems for high-dose, poorly soluble drugs.

The presented work investigates critical aspects of rational formulation design through machine learning (ML) methodology to identify essential patterns in immediate release ibuprofen oral dosage products influencing its pharmacokinetic profile. Registry data were extracted and standardized into a consistent format using pandas (v1.3.5) in Python 3.9, with special attention to variant nomenclature for identical excipients. Patterns regarding the usage of dissolution-modifying excipients as well as ibuprofen variants were used to investigate their influence on clinical pharmacokinetic profile. Film coated tablets emerged as the most common immediate release dosage form of ibuprofen utilizing ibuprofen acid as the active ingredient and sodium lauryl sulfate as surfactant/wetting agent. Ibuprofen special variants, such as ibuprofen sodium dihydrate, ibuprofen lysine and ibuprofen arginine, offer more rapid drug release and onset with significantly reduced tmax and increased Cmax as well as generally lower bioavailability variance compared to standard immediate release ibuprofen oral dosage forms. The approaches presented in this article will be helpful in better understanding of rational formulation strategies and support regulatory scientific decisions ensuring predictable bioavailability and reproducible clinical responses.

Irinotecan is widely used in cancer therapy but is limited by significant toxicities due to systemic and intestinal exposure to its active metabolite, SN-38. To improve its therapeutic profile, irinotecan has been encapsulated in pegylated liposome as a nano-liposomal form (nal-IRI) to modify its pharmacokinetics (PK) and enhance tumor delivery via the enhanced permeability and retention effect. While nal-IRI has shown clinical benefits, the formulation-specific PK and pharmacodynamics (PD) underlying its efficacy and safety remain unknown. This study aimed to develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model to compare the disposition and tumor response of irinotecan and SN-38 following administration of free irinotecan (free-IRI, Camptosar®) and nal-IRI (Onivyde®) in pediatric tumor xenografts. Plasma and tissue PK data (liver, spleen, kidney, brain, lung, and tumor) were collected from healthy and tumor-bearing mice treated with various intravenous doses of both formulations. The model accurately described plasma, tissue, and tumor concentrations of irinotecan and SN-38. Key determinants of disposition included enterohepatic recycling, carboxylesterase-mediated conversion in liver/plasma, and clearance through biliary/metabolic pathways for irinotecan, and biliary/renal routes for SN-38. Nal-IRI exhibited formulation-specific characteristics, including phagocyte-mediated uptake, non-linear plasma clearance, liposomal release and permeability-limited tissue distribution, that are major determinants of nal-IRI disposition. PD modeling indicated intra-tumoral SN-38 exposure was the principal driver of antitumor efficacy. Nal-IRI achieved sustained and higher SN-38 tumor exposure, producing more rapid and durable tumor suppression than free-IRI. This integrated PBPK/PD framework provides mechanistic insights into the enhanced efficacy of nal-IRI and supports its optimized use in irinotecan-based cancer therapy.

The clinical translation of nanomedicine for non-alcoholic fatty liver disease (NAFLD) is frequently hindered by rapid hepatic clearance mediated by Kupffer cells, which are the predominant phagocytic macrophages in the liver. Conventional stealth strategies, such as PEGylation, protect host cells from phagocytosis; however, their exploitation in drug delivery is limited by the prevailing assumption that immune evasion impairs cellular uptake. Our previous study demonstrated that liposomes functionalized with a CD47-derived self-peptide (SLip) effectively evaded macrophage clearance while retaining strong interactions with non-macrophage liver cells. Leveraging the decoupling of immune evasion and cellular accessibility, we developed a mixed liposomal system (MLip) composed of conventional liposomes (Lip) and SLip at tunable ratios, which enabled modulation of macrophage uptake. By adjusting the Lip:SLip composition, phagocytic efficiency was dose-dependently regulated, as confirmed by phagocytosis index assays. In vivo, MLip exhibited prolonged hepatic retention owing to delayed Kupffer cell clearance and enhanced delivery to hepatocytes and other parenchymal liver cells. To assess its therapeutic potential, silibinin was encapsulated within MLip, and collagenase I was surface-absorbed to promote extracellular matrix remodeling (ECM). Notably, the optimized 1:1 Lip/SLip formulation significantly attenuated liver fibrosis and improved histopathological outcomes in Lep ob/ob mice. This study presents a rational strategy to balance immune evasion with target cell engagement through hybrid liposomal engineering, offering a versatile and effective platform for liver-targeted nanotherapeutics with improved pharmacokinetics and therapeutic efficacy in NAFLD.

We have demonstrated the efficacy of a novel strategy for achieving the prolonged and sustained release of vancomycin as a prophylaxis against surgical site infection (SSI). This strategy uses hydrophobic ion pairing (HIP), joining vancomycin with counter ions and efficiently encapsulating the antibiotic in biodegradable polymer nanospheres. To complete the process, vancomycin-complexes were formed in an aqueous acidic medium, and then they were encapsulated in poly(lactic-co-glycolic) acid (PLGA), polylactic acid (PLA), and polycaprolactone (PCL) nanospheres via the double-emulsion solvent-evaporation method. Our results show that sulfate and sulfonate-based counter ions provide the most effective structure for vancomycin-HIP formation, achieving 95% complexation efficiency at a 1:2 molar ratio. Once formed, the vancomycin-dioctyl sodium sulfosuccinate (Van-DOSS) complex achieved a 3.7-fold increase in lipophilicity (LogP _{octanol/water}), which significantly improved encapsulation efficiency in comparison to unmodified vancomycin. Encapsulation efficiency increased by 2.7-fold in PLGA (64.7% ± 0.4%) and by 5.5-fold in PLA (46.7 ± 5.9%) and PCL (47.7 ± 6.9%). The Van-HIP nanospheres achieved an in-vitro release of vancomycin that was three-to-five times the minimum inhibitory concentration required for S. aureus over the critical 28-day window indicated for post-operative care after spine surgery. Consequently, these findings support a sustained-release option for antibiotic formulation to improve surgical outcomes.

Tablet mechanical strength is governed by both the intrinsic mechanical properties of the constituent materials and the applied compaction conditions. In this work, we investigated the relationships among tablet tensile strength, tablet brittleness, quantified by the tablet brittleness index, and powder plasticity, quantified by in-die mean yield pressure. Seven common excipients and twelve binary mixtures were selected to represent materials spanning a wide range of mechanical behaviors. For a given material, tablets become more brittle and weaker as porosity increases, following an exponential decay relationship. At a fixed tablet porosity, in-die mean yield pressure shows a positive correlation with tablet brittleness index that follows a power-law function. This relationship enables prediction of tablet brittleness index at a specified porosity directly from in-die mean yield pressure. Because in-die mean yield pressure can be readily obtained from in-die compression data using only small quantities of material, it offers an efficient means to estimate tablet brittleness early in development and provides valuable guidance for designing robust tablets.

Glatiramer acetate (GA) electrostatically complexes with cytosine-guanine oligodeoxynucleotides (CpG ODN), forming ∼100 nm cationic nanoparticles that localize this potent immunostimulant to the injection site. We previously reported GA-CpG nanoparticles retained the anti-tumor activity of CpG while mitigating systemic immune-related adverse events. Nonetheless, nanoparticulate systems like polypeptide-oligonucleotide complexes pose challenges with reproducible production, in-use stability, and storage stability, which must be solved before translation for clinical use. In this study, we systematically investigated a microfluidic mixing process to define reproducible production of GA-CpG nanoparticles. Dynamic light scattering measurements revealed significantly smaller and more uniform nanoparticles for microfluidic processing versus traditional mixing via pipette. We screened a range of buffer systems to determine the pH and ion types that could maintain colloidal stability and CpG potency. Buffer screening tests indicated that amino acid buffers, particularly glutamic acid, better maintained particle consistency than commonly used parenteral buffers. Finally, formulations of potential lyoprotectants and GA-CpG nanoparticles were developed. Freeze-thaw and freeze-drying experiments were conducted to assess the effects of buffers and lyoprotectants. Formulations with 5% HP-β-CD or trehalose yielded mean particle sizes of less than 127 nm and retained even after storage for 6 months at 40 °C/75% relative humidity. The work on electrostatic complexes reported here may provide valuable guidance to formulators aiming to optimize polypeptide-based oligonucleotide polyplex products for in-use or long-term stability.

The pH-mediated effect of drug ionization on solubility is well-described. However, pH can also indirectly influence solubility by altering the colloidal structures in human intestinal fluids. This study investigates the indirect pH effect on the apparent solubility of 13 uncharged drugs across a pH range of 4.5 to 7.5 in fed-state simulated intestinal fluids (SIF) composed of taurocholate and lecithin, with or without added lipids (monoolein and/or sodium oleate). A pronounced indirect pH effect on drug solubility was observed when oleate was present in the SIF, whereas monoolein had only a minor effect. Below pH 6.5, sodium oleate was converted to oleic acid, resulting in lipid droplet formation that enhanced lipophilic compound solubility in the total sample (lipid phase + micellar phase), while the micellar solubility remained similar to the reference SIF (without oleate). This resulted in an up to 50-fold increase of the ratio total/micellar drug solubility, which correlated well with drug lipophilicity or its combination with total polar surface area (R² ≈ 0.8). At higher pH, a lipid phase was not formed because the ionized sodium oleate partitioned in the micellar phase, where it significantly increased drug solubilization. These findings highlight the importance of considering indirect pH effects in solubility assessments by tuning simulated intestinal fluids composition to better reflect in vivo reality.