Expert insights into the development of large-volume subcutaneous drugs with permeation enhancers: A survey examining challenges, alternatives, and future directions

Permeation enhancers (PE) such as hyaluronidase are increasingly incorporated into subcutaneous (SC) biologic drug formulations to improve drug absorption. However, there remain gaps in our understanding of the intricacies of their co-formulation with drugs, including their impact on formulation development, manufacturing processes, and SC administration volume limits. This global, online, anonymous survey of 100 formulation experts familiar or experienced with co-formulating drugs with PE was conducted from 25 April to 6 May 2024 to gain more insights into these gaps and explore the perspectives of drug formulation stakeholders. The survey consisted of 11 screening questions and 25 questions related to the process of developing SC drugs co-formulated with PE. The mean duration of experience was 13.7 years and 46 % of participants were currently or previously employed by a company that markets PE for co-formulation with drugs. The biophysical aspects of hyaluronidase were considered moderately/very/extremely challenging by 89 % of respondents, particularly the high drug-interaction potential, temperature sensitivity, and pH sensitivity. Incompatibility between drug and PE was reported to occur in 36 % of cases (weighted mean; mode: 31-40 %). The most common stages where challenges occurred were quality and stability testing and co-formulation development. Despite a lack of data demonstrating improvements in SC drug bioavailability with PE, 90 % of respondents believed that PE positively impacts drug bioavailability. These findings may assist stakeholders in making informed decisions regarding co-formulation of drugs with PE.