Challenges and Opportunities for the Subcutaneous Delivery of Therapeutic Proteins

Abstract

Biotherapeutics is a rapidly growing drug class, and over 200 biotherapeutics have already obtained approval, with about 50 of these being approved in 2015 and 2016 alone. Several hundred protein therapeutic products are still in the pipeline, including interesting new approaches to treatment. Owing to patients' convenience of at home administration and reduced number of hospital visits as well as the reduction in treatment costs, subcutaneous (SC) administration of biologics is of increasing interest. Although several avenues for treatment using biotherapeutics are being explored, there is still a sufficient gap in knowledge regarding the interplay of formulation conditions, immunogenicity, and pharmacokinetics (PK) of the absorption of these compounds when they are given SC. This review seeks to highlight the major concerns and important factors governing this route of administration and suggest a holistic approach for effective SC delivery.

Influence of physiochemical properties on the subcutaneous absorption and bioavailability of monoclonal antibodies

“…The SC space varies in composition across species; 4 , 6 , 8 thus, as a means to understand if the SC PK findings in rats were meaningful in another species, we chose to evaluate the PK of a subset of molecules in cynomolgus monkeys since this species is commonly used for predictions of human antibody PK. The PK in cynomolgus monkeys was evaluated following a single 1 mg/kg IV or SC administration of Platform 1 and 3 mAbs.…”

“… 5 - 7 Currently, the SC bioavailability for marketed mAbs in humans is ~60–80%. 4 , 6 , 8 While the mechanisms related to the incomplete bioavailability observed for some mAbs are not well understood, there is a general consensus that the PK fate and absorption profile of mAbs following SC administration requires an understanding of the SC space/anatomy and composition.…”

“…The SC matrix or hypodermis has been reviewed extensively. 4 , 6 , 8 Briefly, the hypodermis is composed of connective tissue separated by fat lobules (adipose tissues) and cellular components, including adipose cells, fibroblast and macrophages. The fibroblasts are responsible for producing constituents of the extracellular matrix (ECM), including glycosaminoglycans (GAGs), elastin and collagen.…”

Antimicrobial peptides – Advances in development of therapeutic applications

“…The main challenge of this administration route is penetrating through extracellular matrix where physiological components like protein, antibody, immune cells may interact and aggregated active molecules. This way of drug administration is also limited by the injected volume [ 216 ]. The development of polymeric particles advances the delivery by controlling release, physically separating the biologic from the subcutaneous microenvironment and improved dispersion using hyaluronidases.…”

Hydrogen/deuterium exchange-mass spectrometry analysis of high concentration biotherapeutics: application to phase-separated antibody formulations

“…Subcutaneous (SC) injections can serve as an alternative drug administration strategy, allowing for patient self-administration and reducing overall costs, but very high therapeutic concentrations (>100 mg/mL) may be required to deliver high doses. 5 Despite the advantages associated with SC administration, development of mAbs formulated at such high concentrations presents many challenges in processing, manufacturing, storage, and delivery, mainly owing to the non-ideal behaviors of highly concentrated proteins, which are quite different from those observed for dilute solutions. Unusual protein behaviors at high concentrations often stem from protein self-association, leading to undesired solution properties, such as increased solution viscosity, opalescent solution appearance, and liquid-liquid phase separation.…”