MEDICINAL CHEMISTRY

non-crystalline insulin as far as onset, duration and rate of blood sugar reduction are
concerned.
(b) Intermediate and long-acting Insulin preparations
(i)Protamine- Insulin preparations:The longer duration of action is due to protamine, a
basic protein that leaves the site of injection more slowly.
(ii)Protamine zinc insulin preparations: Prolonged duration of action of insulin, a long
time objective, was finally achieved with protamine zinc insulin. Developed in 1936,
these suspensions were proved to be better than 'prolamine insuline'duration of action.
This is prepared by complexing insulin with zinc and protamine. The products are
available with 40 – 80 units/ml.
(iii)Globin zinc Insulin preparation: Developed in 1939, its duration of action (I 2 -1 8
hours) is less than protamine zinc insulin preparations (24 - 36 hours).
(iv)lsophane Insulin suspensions: Developed in 1946, the se suspensions contain
protamine, zinc and insulin. It differs from protamine zinc insulin' in the method of
preparation and contains less prolamine than protamine zinc insulin'. This preparation has
time activity' best adopted to the requirements of majority of diabetic patients. This has a
blood sugar lowering effect usually lasting over 24 hours.
(v)Lante lnsulins :The solubility pattern of insulin (and hence its absorption) is mainly
governed by its physical state. For example, large crystals of insulin with high zinc
content will be less soluble in body fluids and naturally produce long duration of action
due to slow absorption. Such preparations are known as ultralante insulin. This concept
was utilized to develop such preparations which do not need a protein modifier (e.g.,
protamine or globin) to prolong their action. Stretching the same concept ahead,
amorphous insulin exhibits rapid absorption and hence rapid onset of action. Such insulin
cells zinc suspension I known as semilante insulin. A proper combination of ultralante
insulin (7 parts) and semilante insulin (3 parts) will naturally constitute a preparation
having a rapid onset and intermediate duration of action; both the properties desirable for
well clinical acceptance of the preparation.
(c)Very long- acting Insulin preparations: Attempts to formulate insulin preparations
with very long duration of action are made, The solubility of insulin at physiological pH
7.4 is mainly controlled by the amount of ZnCl2 which is increased to 5 - 10 times than
normally required to prepare 'soluble zinc insulin'. The increased concentration of zinc
ions form low solubility complexes with insulin molecules if the buffer is changed from
phosphate to acetate. Such suspensions are reported in U.S.P.
SAR studies
The structure of animal insulin has minor but potentially important differences from
human insulin: Porcine insulin differs by one amino acid (alanine instead of threonine at
the carboxyterminal of the B-chain, i.e., position B 30), and beef insulin differs by two
additional alterations in the sequence of the A - chain (instead of threonine and isoleucine