Dose Volume Limitations

Instead of dividing the dose over several sites or delivering it more slowly using a continuous infusion system, the industry has focused on single-bolus strategies to simplify self-administration: efforts have been made to reduce the SC injection volume by increasing the concentration of the protein and peptide formulation being injected. Such a philosophy does reduce needle and syringe use, and this has a number of positive social and health care benefits. It also has the negative aspect of preparing formulations where the protein or peptide can be at a remarkably high concentration; antibody-based therapeutics can be formulated at concentrations of several hundred milligrams per milliliter. At such high concentrations, a protein solution can become so viscous that it can no longer be delivered by a needle and syringe. Several high-concentration antibody formulations have, however, been described where the issue of increased viscosity has been addressed (110).

Alternately, the concentration of a delivered protein or peptide can be increased by reducing its solubility—that is, delivering it as a suspended solid. Insulin is probably the best-known example of this approach, with crystallized and precipitated suspensions being injected by millions of diabetics (56). Methods have been identified to produce and stabilize a suspension of particles that can provide a fairly consistent delivery—essential for reproducible PK and PD outcomes. A depot effect for insulin can be achieved by the slow dissolution of insulin co-crystallization with zinc ions and the polycationic peptide prot-amine. While insulin is the most recognized biotherapeutic to be administered by SC injection as a particulate suspension, other proteins have been crystallized in an effort to expand this list (111,112), and some progress has been made to identify sustained-release crystalline forms of proteins other than insulin (113). In such cases, the size and characteristics of these particles and the formulation in which they are prepared must be acceptable for injection and able to pass through a needle of reasonable gauge.

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