Although subcutaneous (SC) delivery is the preferred way to administer an injected therapeutic, SC injections are limited
in the amount of drug substance that can be delivered. Strategies for overcoming this problem are crucial to widening the
scope of drugs that may be given subcutaneously. Using a recombinant DNA-derived hyaluronidase enzyme is an approach for possibly
changing dosing regimens and bioavailability of several types of agents, including biologics.
Intravenous, intramuscular, and subcutaneous delivery
Intravenous administration.
Therapeutic agents can be introduced into the body by several routes of administration with each having specific advantages
and disadvantages (see Table I). For many drugs, including biologics and anticancer agents, the traditional route of administration
is intravenous (IV). IV injections are given either as a 1-to-2-min-bolus or an infusion with a longer duration to facilitate
administering precise doses in a controlled manner or in providing a rapid response. IV dosing is also typical when administering
irritating agents such as cytotoxics that would otherwise cause tissue damage and pain if given by alternative routes. IV
dosing requires the skilled insertion of a needle or catheter directly into a vein, a process that can be challenging, especially
in certain patient types such as obese, palliative-care, and neonate patients. Direct IV access also carries a risk of systemic
infection. IV drugs are administered by trained medical personnel in a hospital or physician's office and, because of the
rapid effects achieved, patients are typically observed for undesired side effects following injection. This entire process
occupies both space in an office and specialized nursing time (1).
Intramuscular injections.
When therapeutic regimens require injection volumes in excess of 1 mL, intramuscular (IM) injections are generally chosen.
IM injections are given deep into skeletal muscle and usually involve the gluteal, deltoid, rectus femoris, or vastus lateralis
muscles. Volumes of 2–5 mL can be administered, and this route is particularly suited for drugs that are not readily soluble,
as a sustained depot action is possible (2, 3). Because of the distance from the skin surface into a muscle, IM injections
require a relatively long needle (1–2 in.). There is a possibility of hitting a nerve or blood vessel, leading to muscle contractures
and nerve injury (3). Because of the needle length and bore size required, IM injections are painful and can temporarily result
in limited mobility, an issue of particular concern in older patients (2). IM injections, therefore, are best performed by
trained personnel who are familiar with anatomical landmarks, which may be difficult to identify in obese or emaciated patients.
Infection is a risk with any parenteral injection because of the risk of bacteria being introduced into the tissue (2, 4–6),
which in turn can lead to abscesses and infections in the skin or soft tissue. Other complications of IM injections include
local induration, erythema, hematoma, persistent bleeding, and ultimately, drug discontinuation. Less common side effects
can include intramuscular hemorrhage, cellulitis, tissue necrosis, and gangrene (7, 8). Although several studies have shown
that there are no substantial differences between IM and SC injections in terms of absorption and drug efficacy (2), the absorption
rate from an IM injection does depend on blood flow at the injection site and the muscle mass. Also, the rate may be unpredictable
in infants because of insufficient muscle tone and vascularity of muscle tissue.
Subcutaneous delivery.
During SC administration, a needle is inserted through the epidermal and dermal layers of the skin and into the fatty subcutaneous
tissue. Following injection, the drug reaches the bloodstream via the capillaries or the lymphatic system, depending on the
molecular size of the therapeutic (2, 3, 9). Large proteins are typically not suited for oral administration, as such drugs
would be degraded in the digestive tract and poorly absorbed. Most proteins require SC administration. Large-molecule drugs
typically reach the bloodstream through the lymphatic vessels as they move very slowly from the tissues into the capillaries.
SC injections have several immediate advantages over other injection types. In contrast to the skilled personnel required
for the administration of IV and IM injections, SC injections can be administered by the patient (2, 3). A small needle is
required (length of ⅜–⅝ in.), and the injections are not generally painful and carry a reduced risk of infection and other
complications. If an infectious agent is injected subcutaneously, it is generally limited to a local infection rather than
a systemic infection. For patients requiring multiple doses, SC injections offer a broader range of alternative sites (3).
The resultant drug absorption is also slower than IV and may avoid the risks of bolus administration.
