Subcutaneous sustained-release drug delivery system for antibodies and proteins

Subcutaneous (SC) sustained release is an important drug delivery system (DDS) for antibody/protein drugs because it reduces dosing frequency. This review discusses formulations and biophysical parameters that affect the pharmacokinetics (PK) of DDSs. For example, SC injectable microspheres and polymeric hydrogels, as well as intradermal microneedles, suppress denaturation in loading and burst release of drugs [growth hormone, interferon-alpha 2b, bevacizumab, and single-chain antibody fragment (scFv)]. These DDSs significantly prolong half-life (t1/2) in plasma with low maximum concentration (Cmax) and low relative bioavailability after SC dosing to animals and/or humans. Formulation parameters, such as (1) drug loading amount, (2) drug diffusion in DDS, (3) interactions of drugs with polymers, and (4) microneedle design, likely contribute to their PK profiles. This review also discusses the effects of many biophysical parameters on PK, including (5) in vivo behavior of polymers (swelling, aggregation, dissolution, and accumulation), (6) drug interactions with extracellular matrix and hypodermis diffusion, (7) drug unfolding, (8) hypodermic concentration of drugs, inherent proteins, and cells, (9) drug absorption through lymphatic or blood vessels, (10) degradation of drugs/polymers by proteases/phagocytic cells, (11) FcRn-mediated recycling, (12) Fc gamma R-mediated endocytosis, and (13) target-mediated drug clearance. For safe dosing, (14) skin's thickness/viscoelastic properties and variations and (15) skin's recovery are also important factors. Consideration of these effects will increase the developmental speed and success of many SC sustained-release DDSs of antibody/protein drugs.