Impact of Fluid Induced Distention

One obvious consequence resulting from the SC injection of a protein or peptide therapeutic is that some finite volume of displacement must occur at the site of injection. In general, best efforts are made to minimize this injection volume as excessive distention can cause discomfort, pain, and even sufficient back pressure to reflux drug through the needle track used to penetrate the epidermis/ dermis. SC injection of a 200-p.L formulation is frequently the goal, but physical/ chemical properties of protein and peptide therapeutics and the dose required sometimes demand larger volumes to be injected. If the injection site is constrained by septa associated with adipose of the SC site, a discrete, distended fluid pocket is formed. Some locations of the deeper SC space can be connected to large continuous areas that function to separate deeper fatty and muscular structures; these continuous areas are referred to as fascial planes (46). Thus, if a volume is injected into an SC site that is associated with a fascial plane, the fluid will fan out in a manner such that discrete borders of the injected volume are not discernable and no discrete, distended fluid pocket will be formed. It is not difficult to imagine the potential for different PK, PD, and metabolism outcomes for a protein or peptide therapeutic delivered into a fluid-filled pocket versus that distributed into a fascial plane.

Fluid injected into an SC site can be absorbed into both vascular and lymphatic capillary beds. The rate of fluid absorption from an SC injection site can be controlled by a number of factors, but in general, fluid from a 200-p.L injection volume can be completely cleared in a few hours. In the absence of its removal, the hydrodynamic pressure exerted by fluid introduced into an SC injection site could disrupt associations between cells and ECM components. Such an outcome would likely trigger cellular responses associated with tissue remodeling, resulting in the local release of factors from resident macrophages and mast cells (e.g., histamine). Accordingly, the SC injection site will respond according to how long that excess fluid volume exists. SC injections typically use iso-osmotic formulations, on the basis of the belief that hypo- or hyperosmotic preparations will incite a painful injection. Iso-osmotic (or slightly hypo-osmotic) formulations will also minimize the amount of water drawn into the injection site because of an imbalance in local osmotic pressure; hyper-osmotic formulation would draw water into the injection site. Whatever the nature of the formulation, the fluid volume injected can initiate a series of responses that can affect the PK of the protein or peptide being delivered.

In most cases, insignificant tissue damage results from an SC injection, and thus, there is little to trigger tissue remodeling events. As efforts are made, however, to increase the volume injected into an SC space, the potential for tissue damage and the initiation of tissue remodeling events are increased. To reduce this outcome, slow infusion methods into the SC space have been described (47). Additionally, it is possible to alleviate some issues associated with the impact of fluid-induced distention at an SC injection site by increasing the effective volume of an SC injection site. This can be achieved by altering the physical nature of this potential space by cleaving ECM elements by injection of specific enzymes, such as hyaluronidase. In doing so, the cross-linking elements that constrain the effective volume at a site of SC injection can be expanded (48,49).

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