Tissue Damage due to Needle Introduction

Depending on the needle gauge size used to introduce a protein or peptide formulation into the SC site, varying degrees of damage will be sustained by components of the interstitial space: blood vessel breakage, disorganization of cellular and acellular structures of the SC space, etc. Consequently, events of the coagulation cascade (to stop further loss of blood from damaged vessel) and initiation of tissue repair mechanisms (to return SC tissue to its pre-trauma condition) could be activated. Disruption of blood vessels releases platelets that function in sealing vessel breaks, facilitating the generation of thrombin; events that could entrap and/or destroy an injected protein or peptide therapeutic. It is important to appreciate that platelet-driven blood clotting is a complex process (99). Collagen is one element of the basement membrane recognized by platelets, although there are a variety of signals that can activate platelets: adenosine diphosphate, serotonin, thromboxane A2, and fibrinogen receptors. Links between platelets and extravascular structures are mediated by the glycoprotein known as von Willebrand factor. A series of clotting factors, famous for their absence in hemophiliac populations (e.g., factor VII, factor IX, etc.), convert soluble plasma fibrinogen to insoluble fibrin polymer—processes that trap additional platelets and complete the formation of a clot plug (99).

Following clot formation, three stages of wound repair mechanisms occur: inflammation, new tissue formation, and remodeling (100). Only inflammation occurs in a time frame that would likely affect the PK, PD, or metabolism of a formulation designed for rapid systemic absorption; the latter two phases would affect slow-release or depot outcomes that are beyond the scope of this chapter. Inflammation, driven by the infiltration of immune-associated cells, can potentially be augmented by the biological activity of an injected protein or peptide therapeutic. Inflammatory signals frequently increase local vascular permeability, and this can alter the overall absorption rate from the SC site through modulation of the parameters discussed above. Inflammation-associated cells (monocytes, neutrophils, etc.) can result in local increases in not only proteolytic activity but also reactive oxygen species in the extracellular SC space environment, applying physical and chemical stresses on an injected protein or peptide. Additionally, the immune cells that infiltrate the SC space are effective at nonselective phagocytosis. Thus, proteins and peptides that may be slow to leave the SC injection site may also be taken up and destroyed locally by these cells.

The overall point to be made here is that when a needle damages tissues to deliver a protein or peptide to an SC site, it is likely that some level of blood clotting processes and subsequent inflammatory events will ensue. Small gauge needles used for most SC injections result in minimal tissue damage. Thus, it is unclear how much impact these events might have on the PK, PD, and metabolism of an injected protein or peptide, particularly if large gauge needles required to deliver viscous, high-concentration formulations are used. What is known is that many of the factors and events associated with tissue damage associated with the introduction of a needle are becoming better understood and one can now anticipate some of the potential events that might affect the physical, chemical, and biological stability of a biopharmaceutical at an SC injection site.

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