Delivery Considerations of Highly Viscous Polymeric Fluids Mimicking Concentrated Biopharmaceuticals: Assessment of Injectability via Measurement of Total Work Done "WT".

An account is given of the recent development of the highly viscous complex biopharmaceuticals in relation to syringeability and injectability. The specific objective of this study is to establish a convenient method to examine problem of the injectability for the needle-syringe-formulation system when complex formulations with diverse viscosities are used. This work presents the inter-relationship between needle size, syringe volume, viscosity, and injectability of polymeric solutions having typical viscosities encountered in concentrated biologics, by applying a constant probe crosshead speed on the plunger-syringe needle assembly and continuously recording the force-distance profiles. A computerized texture analyzer was used to accurately capture, display, and store force, displacement, and time data. The force-distance curve and area under the curve are determined, and total work done for complete extrusion of the syringe content was calculated automatically by applying an established Matlab program. Various concentrations (i.e., 0.5-4% w/v of polymeric fluids/dispersions) of polyethylene oxide (PEO) and hydroxypropyl methylcellulose (HPMC) with viscosity ranges of 5-100 cP mimicking concentrated monoclonal antibody solutions and complex biopharmaceutical formulations are investigated. Results indicate that calculated values of total work done to completely extrude the syringe content are the most appropriate parameter that describes viscosity-injection force of dispersed formulations. Additionally, the rheological properties of HPMC and PEO fluids in the context of syringeability and injectability are discussed.

Development of an amorphous based sustained release system for apremilast a selective phosphodiesterase 4 (PDE4) inhibitor.

Apremilast is a selective PDE4 inhibitor and has been approved for several inflammatory disorders. It is classified as a BCS-IV drug and has 7 polymorphic forms. In this research we report the development of an ASD based sustained-release (SR) drug delivery system. A simplified material sparing ASD formulation approach was employed to identify ideal carrier polymers for optimum drug loadings. HPMCAS-M at 20% and Copovidone at 40% drug loadings were selected as the lead formulations. A stable single-phase amorphous system of apremilast via spray drying was created and fully characterized by mDSC, XRPD, DMA, micro-dissolution, dissolution, and accelerated stability analysis. Micro-dissolution study of ASD confirmed attainment and maintenance of supersaturated state over 3 h. ASD showed 8-fold higher solubility relative to its crystalline counterpart. Novel monolithic and bilayer SR HPMC tablet matrices containing 30 mg or 60 mg of ASD system were manufactured. Tablets during dissolution exhibited gradual swelling, erosion, and disentanglement over 15-20-hours with over 90% drug released. The designed SR amorphous based matrix system showed ability to increase apremilast solubility, dissolution rate, and inhibit recrystallization or polymorphic interconversion by stabilizing its amorphous form. This new development may allow for once-daily drug administration and improve both bioavailability and patient compliance.

Release rate determination from in situ gel forming PLGA implant: a novel 'shape-controlled basket in tube' method.

OBJECTIVES: This study aimed to examine the impact of syringe-needle assembly differences in making implants of different shapes as well as its influence on the release kinetics and investigate the release kinetics of the in situ forming implant under various release arrangements. METHODS: PLGA in situ forming implant was prepared in different shape and then subjected to in vitro release testing. Mathematical modelling was used to investigate drug release mechanisms. KEY FINDINGS: The in situ forming implant was investigated for the first time how implant shapes can affect release results. It was demonstrated that implant shape differences could lead to significant variation in the release data. Here, we addressed this issue by developing a shape-controlled method to provide a consistent surface to volume ratio and, therefore, a reliable release result. Injectability in the in vitro release was discussed for the first time. Comparisons between various release methods were also evaluated. The release arrangement was found to be of great importance in release kinetics. CONCLUSIONS: The developed 'shape-controlled basket in tube' method can provide the most reproducible release profiles by minimizing implant adhesion to the release vessels or movement without sacrificing full contact between the release medium and the implant surface.

Interfacially Engineered Pyridinium Pseudogemini Surfactants as Versatile and Efficient Supramolecular Delivery Systems for DNA, siRNA, and mRNA.

This article presents the synthesis, self-assembly, and biological activity as transfection agents for pDNA, siRNA, and mRNA of novel pyridinium pseudogemini surfactants, interfacially engineered from the most efficient gemini surfactants and lipids generated in our amphiphile research program. Formulation of novel amphiphiles in water revealed supramolecular properties very similar to those of gemini surfactants, despite their lipidlike charge/mass ratio. This dual character was found also to enhance endosomal escape and significantly increase the transfection efficiency. We were also successful in identifying the parameters governing the efficient delivery of pDNA, siRNA, and mRNA, drawing valuable structure-activity and structure-property relationships for each nucleic acid type, and establishing DNA/siRNA/mRNA comparisons. Several supramolecular complexes identified in this study proved to be extremely efficient nucleic acid delivery systems, displaying excellent serum stability and tissue penetration in three-dimensional organoids.