Table 2.

Factors related to the insulin preparation and their effect on insulin pharmacokinetics.

Factor	Effect on insulin pharmacokinetics
Physical status (i) Soluble insulin (ii) Insulin suspensions (iii) Biphasic insulin mixtures	Although insulin glargine molecule is soluble in formulation, the reduced solubility at neutral pH results in the formation of microprecipitates upon SC injection with delayed absorption as a result [84]. Adding protamine to the insulin formulation results in formation of insulin crystals in the formulation which are injected into the SC tissue, thus prolonging the pharmacokinetic profile of NPH insulin (insulin suspension) [34, 79]. Suspensions and biphasic insulin mixtures are often associated with a larger pharmacokinetic variability between injection compared to insulin preparations in homogenous solution [10, 18, 80–82, 111]
Concentration	There exists an inverse relationship between insulin concentration and the insulin absorption of soluble insulin from the SC tissue, reflected by a delayed absorption with increasing insulin concentration [34, 64, 98, 99]. The effect of concentration on insulin pharmacokinetics does not apply to all soluble insulin preparations, for example, the 200 U insulin degludec and insulin lispro [103, 104]. The pharmacokinetics of insulin suspensions is also affected by insulin concentration. For NPH insulin, the concentration of insulin crystals increases with insulin concentration with delayed SC absorption as a result [34]. Finally, for soluble insulin that precipitates in SC tissue, that is, the 300 U insulin glargine formulation, increasing the concentrations will result in decreased depot surface area from which dissolution and absorption can occur resulting in delayed absorption from the SC tissue [37, 102]
Injection volume	Soluble insulin that does not precipitate in the SC tissue will diffuse and increase in volume upon SC injection, resulting in depot dilution. The relative increase in depot volume and consequently depot dilution occurs faster for small- compared to large-volume depots [34]. Smaller depots will also have a relatively larger surface-to-volume ratio that increases the diffusion area of the injection depot [101]. The result is a relatively faster absorption with smaller injection volumes [34, 98, 107]
Size	Decreased molecular size, such as the formation of insulin monomers, increases the rate of absorption [66] while increases in size of the insulin molecule by means of PEGylation [87, 90] or the self-association of insulin molecules into larger structures such as di- or multihexamers [20, 33] delay insulin absorption from the SC tissue. Furthermore, the large insulin molecules achieved by PEGylation or albumin binding of insulin reduces the insulin clearance rate and subsequently prolongs the half-life in the circulation [20, 40, 87, 89–91]
Excipients	The pharmacokinetic profile of insulin can be modified by excipients added to the formulation. Excipients such as niacinamide [112], BioChaperone [76], hyaluronidase [77, 78], citrate, and treprostinil [72–74] enhance the absorption rate of insulin by a variety of mechanisms, including effects on association state of insulin, subcutaneous blood flow, vascular permeability, insulin diffusion, or depot distribution in the SC tissue, while protamine, zinc, and phenol [32, 34] can also influence the absorption of certain insulin molecules by altering the association state of insulin