A combined rapid acting-long acting insulin formulation has been developed
wherein the pH of the rapid acting insulin is decreased so that the long
acting glargine remains soluble when they are mixed together. In the
preferred embodiment, this injectable basal bolus insulin is administered
before breakfast, provides adequate bolus insulin levels to cover the
meal, does not produce hypoglycemia after the meal and provides adequate
basal insulin for 24 hours. Lunch and dinner can be covered by two bolus
injections of a fast acting, or a rapid acting or a very rapid acting
insulin. As a result, a patient using intensive insulin therapy should
only inject three, rather than four, times a day. Experiments have been
performed to demonstrate the importance of the addition of specific acids
to hexameric insulin to enhance speed and amount of absorption and
preserve bioactivity following dissociation into the monomeric form by
addition of a chelator such as EDTA. As shown by the examples, the
preferred acids are aspartic, glutamic and citric acid. These are added
in addition to a chelator, preferably ethylenediaminetetraacetic acid
(EDTA). The results show that the citric acid formulation was more
effective at dropping the blood glucose rapidly than the identical rapid
acting formulation prepared with HCl in swine. Charge masking by the
polyacid appears to be responsible for rapid insulin absorption. EDTA was
not effective when used with adipic acid, oxalic acid or HCl at hastening
the absorption of insulin. These results confirm the results seen in
clinical subjects and patients with diabetes treated with the rapid
acting insulin in combination with citric acid and EDTA.