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

Abstract

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.

Introduction

Biologic drugs such as monoclonal antibodies (mAbs) have revolutionized the treatment of cancer and autoimmune diseases, with a rapid increase in the number of options in recent years and expansion into multiple therapeutic areas (Martins et al., 2023). While most biologics are administered intravenously (IV) by healthcare professionals, there has been an increasing focus on subcutaneous (SC) formulations. Compared to IV formulations, these SC formulations may have several advantages, such as faster administration, better tolerability (particularly by reducing infusion-related reactions), potential for fewer dosing errors, self-administration, and patient preference (Desai et al., 2023, Jackisch et al., 2015, Overton et al., 2021, Pivot, et al., 2014, Usmani et al., 2022).

SC formulations are delivered to the SC extracellular space, where they disperse into the local area before being absorbed into the lymphatic system or local capillaries. As such, bioavailability with SC may be lower than with IV formulations (Richter et al., 2012), so the total dose is usually adjusted to compensate for this (Desai et al., 2023). A larger dose requirement often necessitates a larger drug volume for delivery, especially when the drug cannot be highly concentrated. While several options exist for SC biologic drug delivery, fewer options are available for volumes exceeding 3 mL. Common approaches to large-volume SC delivery include pumps, on-body injectors (OBIs), and co-formulations with permeation enhancers (PEs). PEs such as hyaluronidase (recombinant human hyaluronidase [rHuPH20]) temporarily break down hyaluronan, a gel-like substance in the skin, creating more space in the SC tissue (Kang et al., 2021). This enhances drug dispersion and allows for faster injection. It should be noted that hyaluronidase is referred to here as a PE due to familiarity with this term within the industry and drug development community, as well as the widespread adoption of the term, largely influenced by the educational narratives promoted by hyaluronidase developers over the past decade. However, to be precise, hyaluronidase facilitates dispersion through the SC space rather than increasing permeability across a membrane. Companies licensing modified hyaluronidase for large-volume SC delivery include Halozyme, the first company to initiate co-formulations with PEs, as well as Alteogen and Huonslab (Jacquot et al., 2024, Kim and Byun, 2024, Takeda Pharmaceuticals Inc., 2024). Fortunately, large-volume SC delivery technologies can be combined. By using an OBI with a drug co-formulated with hyaluronidase, manufacturers can strike a balance between delivery speed and patient comfort, optimizing the SC administration of biologic therapies.

Co-formulations of biologics and PEs may present specific challenges due to the sensitivity of hyaluronidase to pH and temperature. While hyaluronidase is active at a neutral pH (∼7), its peak enzymatic performance occurs at a pH range of 4.5–5.5 (Chen et al., 2016). However, most mAb formulations require a narrow pH range near neutral to maintain stability and prevent issues like aggregation or chemical degradation (Ghosh et al., 2023). This balance becomes even more critical given that even brief exposure of an IgG1 antibody to a pH outside of its optimal range can cause small amounts of aggregation (Ghosh et al., 2023). Excipient and buffer compatibility add another layer of complexity, as mAbs and hyaluronidase may require distinct stabilizers, such as surfactants, sugars, or buffers. The excipients optimal for one component might negatively affect the other, necessitating iterative testing to identify a stable formulation. This further complicates the development of these combination formulations.

In regards to the temperature stability of hyaluronidase, a 2015 patent highlights that the “uber-thermophile” modified variant retains at least 50 % of its enzymatic activity after incubation at 52 °C (125.6 °F) for 10 min at a neutral pH (Halozyme Inc., 2015), whereas the unmodified variant exhibits significantly reduced activity under similar conditions (Chen et al., 2016). However, the patent does not provide information on how temperature stability changes outside of a neutral pH, and it is not currently clear which variant is used in commercialized formulations. As a temperature-sensitive enzyme, hyaluronidase requires careful handling during manufacturing to prevent heat-induced denaturation. Processes like sterilization, which may involve elevated temperatures, could inactivate the enzyme, necessitating stringent temperature controls to preserve the functionality of the final product.

Despite the drug absorption benefits of PEs, evidence supporting their impact on drug bioavailability is inconsistent or incomplete (Dolton et al., 2021, Nolan and Printz, 2024). The belief that co-formulation with hyaluronidase increases the bioavailability of SC drugs appears to be mainly based on the mechanism of action of hyaluronidase rather than robust clinical data. A recent publication investigating whether there are bioavailability improvements with hyaluronidase reported a range of 0–20 % improvement for 10 monoclonal antibodies co-administered with hyaluronidase (Nolan & Printz, 2024). However, these findings were derived from computational modelling rather than clinical studies in humans for five of the 10 antibodies; moreover, for five of the 10 antibodies, bioavailability data were only available for the SC formulation with hyaluronidase, with no comparative data for formulations without it, making comparison in these antibodies impossible. Table 1 summarizes the publicly available bioavailability data for these 10 antibodies, including modelled and experimental data. While modelling provides valuable insights, exclusive reliance on modelling rather than clinical data diminishes the credibility and practical utility of the results, as computational predictions cannot fully replicate the complexities of human physiological processes influencing bioavailability.

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Mehul Desai, Srini Tenjarla, Michael Hageman, Hao Lou, Changquan Calvin Sun, Feng Zhang, Omar Rahman, Wei Chen,
Expert insights into the development of large-volume subcutaneous drugs with permeation enhancers: A survey examining challenges, alternatives, and future directions, International Journal of Pharmaceutics, Volume 689, 2026, 126515, ISSN 0378-5173,
https://doi.org/10.1016/j.ijpharm.2025.126515.