International Journal of Pharmaceutics: X最新文献

Amorphous solid dispersion (ASD) formulations are preferred enabling formulations for poorly water soluble active pharmaceutical ingredients (API) as they reliably enhance the dissolution behavior and solubility. Balancing a high stability against unwanted transformations such as crystallization and amorphous phase separation during storage on the one hand and optimizing the dissolution behavior of the formulation (high supersaturation and maintenance for long time) on the other hand are essential during formulation development. This study assessed the potential of ternary ASDs (one API and two polymers) containing the polymers hydroxypropyl cellulose together with poly(vinylpyrrolidone-co-vinyl acetate) (PVP VA64) or hydroxypropyl cellulose acetate succinate to stabilize the amorphously embedded APIs fenofibrate and simvastatin during storage and to enhance the dissolution performance. Thermodynamic predictions using the PC-SAFT model revealed for each combination of polymers the optimal polymer ratio, maximum API load that is thermodynamically stable as well as miscibility of the two polymers. The stability predictions were validated by three months enduring stability tests, followed by a characterization of the dissolution behavior. The thermodynamically most stable ASDs were found to be the ASDs with deteriorated dissolution performance. Within the investigated polymer combinations, physical stability and dissolution performance opposed each other.

Pharmaceutical 3D printing (3DP) is one of the emerging enabling technologies of personalised medicines as it affords the ability to fabricate highly versatile dosage forms. In the past 2 years, national medicines regulatory authorities have held consultations with external stakeholders to adapt regulatory frameworks to embrace point-of-care manufacturing. The proposed concept of decentralized manufacturing (DM) involves the provision of feedstock intermediates (pharma-inks) prepared by pharmaceutical companies to DM sites for manufacturing into the final medicine. In this study, we examine the feasibility of this model, with respect to both manufacturing and quality control. Efavirenz-loaded granulates (0–35%w/w) were produced by a manufacturing partner and shipped to a 3DP site in a different country. Direct powder extrusion (DPE) 3DP was subsequently used to prepare printlets (3D printed tablets), with mass ranging 266–371 mg. All printlets released more than 80% drug load within the first 60 min of the in vitro drug release test. An in-line near-infrared spectroscopy system was used as a process analytical technology (PAT) to quantify the printlets' drug load. Calibration models were developed using partial least squares regression, which showed excellent linearity (R² = 0.9833) and accuracy (RMSE = 1.0662). Overall, this work is the first to report the use of an in-line NIR system to perform real-time analysis of printlets prepared using pharma-inks produced by a pharmaceutical company. By demonstrating the feasibility of the proposed distribution model through this proof-of-concept study, this work paves the way for investigation of further PAT tools for quality control in 3DP point-of-care manufacturing.

This study aimed to formulate and optimize an anti-acne drug namely tazarotene (TZR) in essential oil-based microemulsion (ME) using either Jasmine oil (Jas) or Jojoba oil (Joj). TZR-MEs were prepared using two experimental designs (Simplex Lattice Design®) and characterized for droplet size, polydispersity index, and viscosity. Further in vitro, ex vivo, and in vivo investigations were performed for the selected formulations. Results revealed that TZR-selected MEs exhibited suitable droplet size, homogenous dispersions, and acceptable viscosity, in addition to spherical-shaped particles in morphology. The ex vivo skin deposition study showed a significant TZR accumulation in all skin layers for the Jas-selected ME over the Joj one. Further, TZR didn't show any antimicrobial activity against P. acnes, however, it was boosted when it was incorporated into the selected MEs. The in vivo study results of the infected mice ears induced by P. acnes revealed that our selected MEs successfully reached a high level of ear thickness reduction of 67.1% and 47.4% for Jas and Joj selected MEs, respectively, versus only 4% for the market product. Finally, the findings confirmed the ability to use essential oil-based ME, particularly with Jas, as a promising carrier for topical TZR delivery in the treatment of acne vulgaris.

Corneal neovascularization (CoNV)-induced blindness is an enduring and challenging condition with limited management options. Small interfering RNA (siRNA) is a promising strategy for preventing CoNV. This study reported a new strategy using siVEGFA to silence vascular endothelial growth factor A (VEGFA) for CoNV treatment. To improve the efficacy of siVEGFA delivery, a pH-sensitive polycationic mPEG_2k-PAMA₃₀-P(DEA₂₉-D5A₂₉) (TPPA) was fabricated. TPPA/siVEGFA polyplexes enter cells via clathrin-mediated endocytosis, resulting in higher cellular uptake efficiency and comparable silencing efficiency than that of Lipofectamine 2000 in vitro. Hemolytic assays verified that TPPA safe in normal physiological environments (pH 7.4) but can easily destroy membranes in acidic mature endosomes (pH 4.0). Studies on the distribution of TPPA in vivo showed that it could prolong the retention time of siVEGFA and promote its penetration in the cornea. In a mouse model induced by alkali burn, TPPA efficiently delivered siVEGFA to the lesion site and achieved VEGFA silencing efficiency. Importantly, the inhibitory effect of TPPA/siVEGFA on CoNV was comparable to that of the anti-VEGF drug ranibizumab. Delivering siRNA using pH-sensitive polycations to the ocular environment provides a new strategy to efficiently inhibit CoNV.

Inkjet printing has been extensively explored in recent years to produce personalised medicines due to its low cost and versatility. Pharmaceutical applications have ranged from orodispersible films to complex polydrug implants. However, the multi-factorial nature of the inkjet printing process makes formulation (e.g., composition, surface tension, and viscosity) and printing parameter optimization (e.g., nozzle diameter, peak voltage, and drop spacing) an empirical and time-consuming endeavour. Instead, given the wealth of publicly available data on pharmaceutical inkjet printing, there is potential for a predictive model for inkjet printing outcomes to be developed. In this study, machine learning (ML) models (random forest, multilayer perceptron, and support vector machine) to predict printability and drug dose were developed using a dataset of 687 formulations, consolidated from in-house and literature-mined data on inkjet-printed formulations. The optimized ML models predicted the printability of formulations with an accuracy of 97.22%, and predicted the quality of the prints with an accuracy of 97.14%. This study demonstrates that ML models can feasibly provide predictive insights to inkjet printing outcomes prior to formulation preparation, affording resource- and time-savings.

Freeze-drying is a time and cost-intensive process. The primary drying phase is the main target in a process optimization exercise. Biopharmaceuticals require an amorphous matrix for stabilization, which may collapse during primary drying if the critical temperature of the formulation is exceeded. The risk of product collapse should be minimized during a process optimization to accomplish a robust process, while achieving an economical process time. Mechanistic models facilitate the search for an optimal primary drying protocol. We propose a novel two-stage shelf temperature optimization approach to maximize sublimation during the primary drying phase, without risking product collapse. The approach includes experiments to obtain high-resolution variability data of process parameters such as the heat transfer coefficient, vial dimensions and dried layer resistance. These process parameters variability data are incorporated into an uncertainty analysis to estimate the risk of failure of the protocol. This optimization approach enables to identify primary drying protocols that are faster and more robust than a classical approach. The methodology was experimentally verified using two formulations which allow for either aggressive or conservative freeze-drying of biopharmaceuticals.

Nowadays, a high number of pipeline drugs are poorly soluble and require solubility enhancement by e.g., manufacturing of amorphous solid dispersion. Pharmaceutical 3D printing has great potential in producing amorphous solid oral dosage forms. However, 3D printing techniques differ greatly in terms of processing as well as tablet properties. In this study, an amorphous formulation, which had been printed via Fused Deposition Modeling and drop-on-powder printing, also known as binder jetting, was characterized in terms of solid-state properties and physical stability. Solid state assessment was performed by differential scanning calorimetry, powder X-ray diffraction and polarized microscopy. The supersaturation performance of the amorphous solid dispersion was assessed via non-sink dissolution. We further evaluated both 3D printing techniques regarding their processability as well as tablet uniformity in terms of dimension, mass and content. Challenges and limitations of each 3D printing technique were discussed. Both techniques are feasible for the production of amorphous formulations. Results indicated that Fused Deposition Modeling is better suited for production, as the recrystallization tendency was lower. Still, filament production and printing presented a major challenge. Drop-on-powder printing can be a viable alternative for the production of amorphous tablets, when a formulation is not printable by Fused Deposition Modeling.

The potential gain in efficacy of pulmonary administration over IV administration of some antibiotics such as ciprofloxacin (CIP) may be limited by the short residence time of the drug at the site of infection after nebulization. Complexation of CIP with copper reduced its apparent permeability in vitro through a Calu-3 cell monolayer and greatly increased its pulmonary residence time after aerosolisation in healthy rats. Chronic P. aeruginosa lung infections in cystic fibrosis patients result in airway and alveolar inflammation that may increase the permeability of inhaled antibiotics and alter their fate in the lung after inhalation compared to what was seen in healthy conditions. The objective of this study was to compare the pharmacokinetics and efficacy of CIP-Cu²⁺ complex-loaded microparticles administered by pulmonary route with a CIP solution administered by IV to model rats with chronic lung infection. After a single pulmonary administration of microparticles loaded with CIP-Cu²⁺ complex, pulmonary exposure to CIP was increased 2077-fold compared to IV administration of CIP solution. This single lung administration significantly reduced the lung burden of P. aeruginosa expressed as CFU/lung measured 24 h after administration by 10-fold while IV administration of the same dose of CIP was ineffective compared to the untreated control. This better efficacy of inhaled microparticles loaded with CIP-Cu²⁺ complex compared with CIP solution can be attributed to the higher pulmonary exposure to CIP obtained with inhaled CIP-Cu²⁺ complex-loaded microparticles than that obtained with IV solution.

Infliximab is a monoclonal antibody that plays an important role in the management and treatment of chronic inflammatory bowel diseases (IBD). Due to its macromolecular structure, its delivery through the oral route is challenging, limiting its administration to only via the parenteral route. The rectal route offers an alternative way for administering infliximab, allowing it to be localised at the disease site and circumventing its passage across the alimentary canal and thus, maintaining its integrity and bioactivity. Three-dimensional (3D) printing is an advanced production technology that permits the creation of dose-flexible drug products from digital designs. The current study assessed the feasibility of utilising semi-solid extrusion 3D printing for the fabrication of infliximab-loaded suppositories for the local treatment of IBD. Various printing inks composed of Gelucire® (48/16 or 44/14) mixed with coconut oil and/or purified water were investigated. It was shown that following reconstitution in water, the infliximab solution can be directly incorporated into the printing ink of Gelucire® 48/16 and can withstand the extrusion process, resulting in well-defined suppositories. Since water content and temperature are critical for safeguarding infliximab's potency, the effect of changing the composition of the printing inks and printing parameters on infliximab's biologic efficiency was evaluated by measuring its binding capacity (i.e., the amount of infliximab that actively binds to its antigen to exert an effect). Despite drug loading assays showing that infliximab remains intact following printing, it was found that the incorporation of water in isolation results in only ∼65% binding capacity. However, when oil is added to the mixture, infliximab's binding capacity increases up to ∼85%. These promising results demonstrate that 3D printing has the potential to be exploited as a novel platform for fabricating dosage forms containing biopharmaceuticals, avoiding patients' compliance issues observed with injectables and addressing their unmet needs.