International Journal of Pharmaceutics: X最新文献

This study evaluated the potential of poly(ethylene vinyl acetate) (EVA) copolymers as matrix formers in miniaturised implants, allowing to achieve controlled drug delivery into the inner ear. Due to the blood-cochlea barrier, it is impossible to reliably deliver a drug to this tiny and highly sensitive organ in clinical practice. To overcome this bottleneck, different EVA implants were prepared by hot melt extrusion, altering the vinyl acetate content and implant diameter. Dexamethasone was incorporated as a drug with anti-inflammatory and anti-fibrotic activity. Its release was measured into artificial perilymph, and the systems were thoroughly characterised before and after exposure to the medium by optical and scanning electron microscopy, SEM-EDX analysis, DSC, X-ray powder diffraction, X-ray microtomography and texture analysis. Notably, the resulting drug release rates were much higher than from silicone-based implants of similar size. Furthermore, varying the vinyl acetate content allowed for adjusting the desired release patterns effectively: With decreasing vinyl acetate content, the crystallinity of the copolymer increased, and the release rate decreased. Interestingly, the drug was homogeneously distributed as tiny crystals throughout the polymeric matrices. Upon contact with aqueous fluids, water penetrates the implants and dissolves the drug, which subsequently diffuses out of the device. Importantly, no noteworthy system swelling or shrinking was observed for up to 10 months upon exposure to the release medium, irrespective of the EVA grade. Also, the mechanical properties of the implants can be expected to allow for administration into the inner ear of a patient, being neither too flexible nor too rigid.

MDCK/Caco-2 assays serve as essential in vitro tools for evaluating membrane permeability and active transport, especially mediated by P-glycoprotein (P-gp). Despite their utility, challenges remain in quantifying active transport and using the efflux ratio (ER) to determine intrinsic values for active efflux. Such an intrinsic value for P-gp facilitated efflux necessitates knowing whether this transporter transports the neutral or ionic species of a compound. Utilising MDCK-MDR1 assays, we investigate a method for determining transporter substrate fraction preference by studying ER pH-dependence for basic, acidic and non-dissociating compounds. These results are compared with model fits based on various assumptions of transporter species preference. As an unexpected consequence of these assays, we also give evidence for an additional influx transporter at the basolateral membrane, and further extend our model to incorporate this transport. The combined influences of paracellular transport, the previously unaccounted for basolateral influx transporter, as well as potential pH effects on the transporter impedes the extraction of intrinsic values for active transport from the ER. Furthermore, we determined that using inhibitor affects the measurement of paracellular transport. While clear indications of transporter species preference remain elusive, this study enhances understanding of the MDCK system.

In assisted reproduction techniques, oocytes encounter elevated levels of reactive oxygen species (ROS) during in vitro maturation (IVM). Oxidative stress adversely affects oocyte quality, hampering their maturation, growth, and subsequent development. Thus, mitigating excessive ROS to safeguard less viable oocytes during IVM stands as a viable strategy. Numerous antioxidants have been explored for oocyte IVM, yielding considerable effects; however, several aspects, including solubility, stability, and safety, demand attention and resolution. In this study, we developed nanoparticles by self-assembling endogenous bilirubin and melatonin hormone coated with bilirubin-conjugated glycol chitosan (MB@GBn) to alleviate oxidative stress and enhance oocyte maturation. The optimized MB@GBn exhibited a uniform spherical shape, measuring 128 nm in particle size, with a PDI value of 0.1807 and a surface potential of +11.35 mV. The positively charged potential facilitated nanoparticle adherence to the oocyte surface through electrostatic interaction, allowing for functional action. In vitro studies demonstrated that MB@GB significantly enhanced the maturation of compromised oocytes. Further investigation revealed MB@GB's effectiveness in scavenging ROS, reducing intracellular calcium levels, and suppressing mitochondrial polarization. This study not only offers a novel perspective on nano drug delivery systems for biomedical applications but also presents an innovative strategy for enhancing oocyte IVM.

Lipid nanocarriers have attracted a great deal of interest in the delivery of therapeutic molecules. Despite their many advantages, compliance with quality standards and reproducibility requirements still constrain their industrial production. The relatively high failure rate in lipid nanocarrier research and development can be attributed to immature bottom-up manufacturing practices, leading to suboptimal control of quality attributes. Recently, the pharmaceutical industry has moved toward quality-driven manufacturing, emphasizing the integration of product and process development through the principles of quality by design. Quality by design in the pharmaceutical industry involves a thorough understanding of the quality profile of the target product and involves an assessment of potential risks during the design and development phases of pharmaceutical dosage forms. By identifying essential quality characteristics, such as the active ingredients, excipients and manufacturing processes used during research and development, it becomes possible to effectively control these aspects throughout the life cycle of the drug. Successful commercialization of lipid nanocarriers can be achieved if large-scale challenges are addressed using the QbD approach. QbD has become an essential tool because of its advantages in improving processes and product quality. The application of the QbD approach to the development of lipid nanocarriers can provide comprehensive and remarkable knowledge enabling the manufacture of high-quality products with a high degree of regulatory flexibility. This article reviews the basic considerations of QbD and its application in the laboratory and large-scale development of lipid nanocarriers. Furthermore, it provides forward-looking guidance for the industrial production of lipid nanocarriers using the QbD approach.

Glabridin (Gla) has been reported to have significant effects in scar treatment, and however, the water insolubility of Gla leads to its poor transdermal absorption ability, which affects its bioactivities. Therefore, we attempted to prepare the Gla dissolving microneedles (Gla-MN) to improve the absorbtion of Gla. After investigation of the 3 factors including the needle tip matrix concentration, the prescription concentration of backing material, and the dissolution method of Gla, we finally determined the process parameters of 10% hyaluronic acid (HA) as the needle tip and 5% polyvinyl alcohol (PVA) as the backing, according to which the Gla-MN was prepared with the good characteristics of high hardness, complete appearance and good in vitro dissolution ability. We then loaded Gla onto the microneedles and measured that the average drug loading of Gla-MN was 2.26 ± 0.11 μg/mg and the cumulative transdermal release of Gla-MN was up to 76.9% after 24 h. In addition, Gla-MN had good skin penetration properties, with Gla-MN penetrating at least 4 to 5 layers of parafilm. And the skin basically could return to normal after 4 h of piercing. Importantly, our results showed that Gla-MN had higher transdermal delivery and therapeutic effects against keloid than that of Gla at the same dosage.

Process intensification involves the miniaturization of equipment while retaining process throughput and performance. The pharmaceutical industry can benefit from this approach especially during drug product development, where the availability of active pharmaceutical ingredients (API) is often limited. It reduces the need for process scale up, as equipment used during product development and commercial production is identical. However, applications of process intensification for processing pharmaceutical powders are limited so far. Here we show that semi-continuous mini-blending can be utilized for process intensification of blending of API and excipients. Uniform blending at commercially relevant throughputs was achieved through mini-blends with a volume of less than ten liters. Our results demonstrate that blending speed, cycle time and blender fill level can be optimized without compromising blending performance. Acceptable blend uniformity is obtained over a broad range of operating parameters, by choosing the right excipients. The optimized throughput of the mini-blending process is in line with the desired throughput of a commercial Continuous Direct Compression (CDC) process.

Cancer remains a major global health challenge, and despite available treatments, its prognosis remains poor. Recently, researchers have turned their attention to intelligent nanofibers for cancer drug delivery. These nanofibers exhibit remarkable capabilities in targeted and controlled drug release. Their inherent characteristics, such as a high surface area-to-volume ratio, make them attractive candidates for drug delivery applications. Smart nanofibers can release drugs in response to specific stimuli, including pH, temperature, magnetic fields, and light. This unique feature not only reduces side effects but also enhances the overall efficiency of drug delivery systems. Electrospinning, a widely used method, allows the precision fabrication of smart nanofibers. Its advantages include high efficiency, user-friendliness, and the ability to control various manufacturing parameters. In this review, we explore the latest developments in producing smart electrospun nanofibers for cancer treatment. Additionally, we discuss the materials used in manufacturing these nanofibers and the critical parameters involved in the electrospinning process.

Hot-melt extrusion (HME) potentially coupled with 3D printing is a promising technique for the manufacturing of dosage forms such as drug-eluting implants which might even be individually adapted to patient-specific anatomy. However, these manufacturing methods involve the risk of thermal degradation of incorporated drugs during processing. In this work, the stability of the anti-inflammatory drug dexamethasone (DEX) was studied during HME using the polymers Eudragit® RS, ethyl cellulose and polyethylene oxide. The extrusion process was performed at different temperatures. Furthermore, the influence of accelerated screw speed, the addition of the plasticizers triethyl citrate and polyethylene glycol 6000 or the addition of the antioxidants butylated hydroxytoluene and tocopherol in two concentrations were studied. The DEX recovery was analyzed by a high performance liquid chromatography method suitable for the detection of thermal degradation products. The strongest impact on the drug stability was found for the processing temperature, which was found to reduce the DEX recovery to <20% for certain processing conditions. In addition, differences between tested polymers were observed, whereas the use of additives did not result in remarkable changes in drug stability. In conclusion, suitable extrusion parameters were identified for the processing of DEX with high drug recovery rates for the tested polymers. Moreover, the importance of a suitable analysis method for drug stability during HME that is influenced by several parameters was highlighted.

The field of pharmaceutical 3D printing is growing over the past year, with Spitam® as the first 3D printed dosage form on the market. Showing the suitability of a binder jetting process for dosage forms. Although the development of inks for pharmaceutical field is more trail and error based, focusing on the Z-number as key parameter to judge the printability of an ink. To generate a more knowledgeable based ink development an approach from electronics printing was transferred to the field of pharmaceutical binder jetting. Therefore, a dimensionless space was used to investigate the limits of printability for the used Spectra S Class SL-128 piezo print head using solvent based inks. The jettability of inks could now be judged based on the capillary and weber number. Addition of different polymers into the ink narrowed the printable space and showed, that the ink development purely based on Z-numbers is not suitable to predict printability. Two possible ink candidates were developed based on the droplet momentum which showed huge differences in process stability, indicating that the used polymer type and concentration has a high influence on printability and process stability. Based on the study a more knowledgeable based ink design for the field of pharmaceutical binder jetting is proposed, to shift the ink design to a more knowledgeable based and process-oriented approach.

Forty-eight (48) drug products (DPs) containing amorphous solid dispersions (ASDs) have been approved by the U.S. Food and Drug Administration in the 12-year period between 2012 and 2023. These DPs comprise 36 unique amorphous drugs. Ten (10) therapeutic categories are represented, with most DPs containing antiviral and antineoplastic agents. The most common ASD polymers are copovidone (49%) and hypromellose acetate succinate (30%), while spray drying (54%) and hot melt extrusion (35%) are the most utilized manufacturing processes to prepare the ASD drug product intermediate (DPI). Tablet dosage forms are the most common, with several capsule products available. Line extensions of several DPs based on flexible oral solids and powders for oral suspension have been approved which provide patient-centric dosing to pediatric and other patient populations. The trends in the use of common excipients and film coating types are discussed. Eighteen (18) DPs are fixed-dose combinations, and some contain a mixture of amorphous and crystalline drugs. The DPs have dose/unit of amorphous drug ranging from <5 mg up to 300 mg, with the majority being ≤100 mg/unit. This review details several aspects of DPI and DP formulation and manufacturing of ASDs, as well as trends related to therapeutic category, dose, and patient-centricity.