Towards more tolerable subcutaneous administration: Review of contributing factors for improving combination product design.

Subcutaneous (SC) injections can be associated with local pain and discomfort that is subjective and may affect treatment adherence and overall patient experience. With innovations increasingly focused on finding ways to deliver higher doses and volumes (≥2 mL), there is a need to better understand the multiple intertwined factors that influence pain upon SC injection. As a priority for the SC Drug Development & Delivery Consortium, this manuscript provides a comprehensive review of known attributes from published literature that contribute to pain/discomfort upon SC injection from three perspectives: (1) device and delivery factors that cause physical pain, (2) formulation factors that trigger pain responses, and (3) human factors impacting pain perception. Leveraging the Consortium's collective expertise, we provide an assessment of the comparative and interdependent factors likely to impact SC injection pain. In addition, we offer expert insights and future perspectives to fill identified gaps in knowledge to help advance the development of patient-centric and well tolerated high-dose/high-volume SC drug delivery solutions.

Preclinical Pharmacokinetic Study on Caffeine as an Excipient for Monoclonal Antibody Formulations.

Caffeine is a novel excipient that effectively reduces viscosity of high concentration mAb formulations intended for subcutaneous (SQ) delivery. Two preclinical studies were conducted in rats to evaluate pharmacokinetic (PK) parameters of caffeine as well as its effects on the PK profile of a model mAb, namely ipilimumab. Results show that SQ absorption and elimination of caffeine was rapid, with the average Tmax of 0.4 h and T1/2 of 1.6 h, administered with or without ipilimumab. Furthermore, caffeine did not affect ipilimumab SQ PK profiles. Independent of caffeine concentration, ipilimumab serum T1/2 was between 2 and 3 days, Tmax was between 3 and 4 days and SQ bioavailability was about 64%. In addition, SQ injection of caffeine at different dose levels showed no irritation at the injection site or adverse effects. Results from the current PK studies warrant further development of caffeine as a viscosity reducing excipient for mAb SQ formulations.

Caffeine as a Viscosity Reducer for Highly Concentrated Monoclonal Antibody Solutions.

Many monoclonal antibody (mAb) solutions exhibit high viscosity at elevated concentrations, which prevents manufacturing and injecting of concentrated mAb drug products at the small volumes needed for subcutaneous (SC) administration. Addition of excipients that interrupt intermolecular interactions is a common approach to reduce viscosity of high concentration mAb formulations. However, in some cases widely used excipients can fail to lower viscosity. Here, using infliximab and ipilimumab as model proteins, we show that caffeine effectively lowers the viscosity of both mAb formulations, whereas other common viscosity-reducing excipients, sodium chloride and arginine, do not. Furthermore, stability studies under accelerated conditions show that caffeine has no impact on stability of lyophilized infliximab or liquid ipilimumab formulations. In addition, presence of caffeine in the formulations does not affect in vitro bioactivities of infliximab or ipilimumab. Results from this study suggest that caffeine could be a useful viscosity reducing agent that complements other traditional excipients and provides viscosity reduction to a wider range of mAb drug products.