Performance and paroxetine stability in tablets manufactured by fused deposition modelling-based 3D printing

Objectives The objective of this study was to develop a method for the preparation and characterization of paroxetine (PRX) tablets, obtained by coupling hot-melt extrusion and fused deposition modelling (FDM)-based three-dimensional printing (3DP) technology. The impact of the printing process parameters on the drug stability and on the tablets performance was assessed. Methods Tablets were obtained by FDM of hot-melt extruded PRX-loaded filaments. Physicochemical, thermal, spectroscopic, diffractometric analysis and in-vitro dissolution tests of the intermediate products and the finished dosage forms were performed. Key findings The characterization of printed tablets evidenced mass and dimensions uniformity, and consistency of drug content and dissolution profile. The formation of amorphous solid dispersions and interaction of formulation components throughout the manufacturing process were demonstrated. Layer thickness, printing temperature, printing and travelling speeds, and infill were the most impacting process parameters on both the physicochemical properties and the in-vitro performance of the 3D-printed tablets. Conclusions PRX tablets, meeting compendial limits, were manufactured by 3DP, envisaging their clinical use as individually designed dosage forms. The assessment of the impact of processing parameters on the printed tablets provided insights, which will ultimately allow streamlining of the 3D process set-up for quicker and easier production of patient-centric medicines.

Pharmacokinetics and brain distribution studies of 6-hydroxykynurenic acid and its structural modified compounds

Objectives 6-Hydroxykynurenic acid (6-HKA) is an organic acid component in extracts of Ginkgo biloba leaves and acts as a major contributor to neurorestorative effects, while its oral bioavailability was low. Therefore, using prodrug method to improve the bioavailability and brain content of 6-HKA is significant. Methods Three structural modified compounds of 6-HKA were synthesized, and ultra performance liquid chromatography-tandem mass spectrometry methods for quantification of these structural modified compounds in rat plasma and rat brain homogenate were established and comprehensively validated. The methods were effectively applied to investigate the effects of structural modification on apparent permeability coefficients in cells, the pharmacokinetics and the brain distribution in rats. Key findings The results illustrated that esterification can greatly improve the apparent permeability coefficient and bioavailability of 6-HKA. Comparing with direct oral administration of 6-HKA, the bioavailability of isopropyl ester was greatly improved (from 3.96 ± 1.45% to 41.8 ± 15.3%), and the contents of 6-HKA in rat brains (49.7 ± 9.2 ng/g brain) were significantly higher after oral administration. Conclusions The bioavailability and the brain content of 6-HKA can be improved by the prodrug method. Among three structural modified compounds, isopropyl-esterified 6-HKA was the most promising treatment.

Ganoderma lucidum polysaccharides protect against sepsis-induced cardiac dysfunction by activating SIRT1

Objective To investigate whether the silent information regulator 1 (SIRT1) was involved in the protective effects of Ganoderma lucidum polysaccharides (GLP) against sepsis-induced cardiac dysfunction. Methods Lipopolysaccharide (LPS)-induced sepsis model was constructed in C57/BL6J mice. Mice were randomly divided into LPS + GLP + EX-527, LPS + EX-527, LPS + GLP, LPS or control group). The levels of serum inflammatory factor markers were examined by ELISA. H&E staining was performed to assess the inflammation. TUNEL staining and bromodeoxyuridine staining were used to observe cell apoptosis and proliferation, respectively. Expression of apoptosis and proliferation-related proteins was detected by western blot. Key findings GLP treatment could significantly increase the expression of SIRT1, reduce levels of serum inflammatory factors (TNF-α, IL-1α and IL-6) and inflammatory cells in mice heart tissue of sepsis models (all Ps < 0.01). Compared with LPS group, GLP treatment inhibited apoptosis and promoted proliferation of myocardial tissues (all Ps < 0.01). Besides, EX-527 (SIRT1 inhibitor) treatment could partially reverse the protective effects of GLP against sepsis-induced cardiac dysfunction (all Ps < 0.01). Conclusions GLP might play a protective role in sepsis-induced cardiac dysfunction through regulating inflammatory response, apoptosis and proliferation via activating SIRT1. Therefore, GLP is expected to be a probable novel strategy for treatment of sepsis.

3D Printing: an appealing technology for the manufacturing of solid oral dosage forms

Objectives The traditional manufacturing methods of solid oral dosage forms (SODFs) are reported to be time-consuming, highly expensive and not tailored to the patient’s needs. Three-dimensional printing (3DP) is an innovative emerging technology that can help to overcome these issues. The aim of this review is to describe the most employed 3DP technologies, materials and the state of the art on 3DP SODFs. Characterization techniques of 3DP SODFs, challenges and regulatory issues are also discussed. Key findings The interest in the investigation of the suitability of 3DP as an alternative strategy for the fabrication of SODFs is growing. Different 3DP technologies and starting materials have been investigated for the development of SODFs. Numerous SODFs with complex geometries and composition, and with different release patterns, have been successfully manufactured via 3DP. Despite that, just one 3DP SODF has reached the market. Summary 3DP can be a promising alternative to the classical SODFs manufacturing methods. However, numerous technically and regulatory challenges still need to be addressed in order 3DP to be extensively used in the pharmaceutical sector.