Abstract
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.
Highlights
Syringeability and injectability are two very important constraints in handling highly concentrated and complex formulations of recombinant biologics, proteins, and biopharmaceutical drugs often not experienced with conventional small molecule simple parenteral [1]
The typical force distance-plot is shown in Fig. 6, which shows the profile of 4% (w/v) hydroxypropyl methylcellulose (HPMC) in 3-and 6-mL syringes without a needle attached
Due to the large amount of data collection per run and variations in needle gauges and syringe body materials, we have determined that the total work of injection (WT) more accurately characterizes extrusion of syringe content rather than simple measurement of force used to extrude the content
Summary
Syringeability (i.e., ease of withdrawal from vial to syringe) and injectability (i.e., formulation performance during injection including pre-filled syringes) are two very important constraints in handling highly concentrated and complex formulations of recombinant biologics, proteins, and biopharmaceutical drugs often not experienced with conventional small molecule simple parenteral [1]. Biologics having high molecular weights (i.e., insulin 5.8 kDa; Humira consisting of 1330 amino acids, and MW 148 kDa) and high concentrations per milliliter (mg/mL) and their means of delivery as opposed to small molecular weight drugs (i.e., epinephrine 183 Da) are associated with many challenges including their rheology. Peptides and proteins have high specificity and potency, in many cases, concerns related to the high dose of proteins with varying viscosities as often concentrated formulations with several hundred milligrams per milliliter are required especially to satisfy the limited volume allowed for subcutaneous injection as often preferred by FDA and patients. The high viscosity of the formulation affects both syringeability and formulation performance during
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