Subcutaneous injection (revision 26)

Subcutaneous injection delivers a substance into the adipose layer beneath the dermis. Absorption from this compartment is slower and more sustained than from muscle, because the tissue is less vascular, and it is the route used for almost every peptide therapeutic that is not given orally.^[1]

The route suits peptides for two reasons. Absorption is largely by capillary and lymphatic uptake, which handles large molecules that would be destroyed in the gut; and the depot behaviour of the tissue smooths the concentration profile, which is desirable for a drug intended to act over days.^[2]

Absorption rate varies with site, with depth, with local blood flow and with the physicochemical properties of the injected material. For an albumin-binding peptide with a half-life of days these variations are negligible against the dosing interval; for a short-acting preparation they are not.^[2]

The subcutaneous layer lies between the dermis and the muscle fascia, and its thickness varies greatly by site and by individual — from a few millimetres to several centimetres. Needle length is chosen so that the tip reaches this layer without passing into muscle, which is why short needles of 4–8 mm are used in current practice.^[1]

Injection into muscle rather than fat accelerates absorption, sometimes substantially. For insulin this is a well-documented cause of unexpected hypoglycaemia; for long-acting peptides the consequence is smaller because the absorption step is not rate-limiting.

Volume is limited by the compliance of the tissue. More than about 1.5 mL at one site produces discomfort and a visible bleb, and larger volumes are split. Peptide doses in this field are usually well under that, since a few milligrams of peptide occupy a very small volume at ordinary reconstitution concentrations.^[2][3]

Differences of this kind are established for insulin and are commonly extrapolated to other subcutaneous preparations. The extrapolation is reasonable but is an extrapolation: for a peptide whose absorption half-life is long relative to its elimination half-life, site differences are absorbed into the profile and become clinically undetectable.^[2]

Local blood flow modifies all of these. Heat, exercise and massage increase it; cold reduces it. These effects are largest for preparations whose absorption is fast to begin with.^[1]

Repeated injection at one site produces local changes — lipohypertrophy, in which the subcutaneous tissue thickens, and less commonly lipoatrophy. Absorption from affected tissue is erratic and generally reduced, which makes the resulting exposure unpredictable.^[1]

Rotation between and within sites is the established response. Rotation within a region preserves the region's absorption characteristics while spreading the mechanical insult; rotation between regions changes both.

Transient injection-site reactions — redness, itching, a small wheal — are common with several peptide preparations and generally resolve without intervention. Persistent nodules are a different phenomenon and, for the microsphere formulation of exenatide, are attributable to the polymer matrix rather than to the peptide.^[2] Sterile technique at the point of administration is a separate matter again, treated in the compounding literature.^[4] Nothing here is medical advice.

• Injection site rotation
• Insulin syringe
• Syringe dead space
• Sharps disposal
• Albumin binding half-life extension