Summary new routes of administration for insulin

New routes of administration for insulin

Insulin
- Peptide hormone
- Regulation of carbohydrate blood levels and metabolism
- Insulin causes a.o. liver, muscle and fat cells to take up glucose as glycogen or as
triglycerides
- Insulin is produced by the pancreas as a reaction to a raise in blood glucose levels
(e.g. after food intake).
- To prevent hypo-glycaemia, there is a rapid decrease (metabolization) of insulin after
insulin has done its work

Diabetic patient type I
- No insulin production at all when glucose levels are high
- Maintenance of basal insulin levels between meals and during the night (basal
insulin)
- To generate insulin blood level peaks during/shortly after the meal adapted to the
carbohydrate intake. (pre-prandial insulin)
- Imitate natural insulin levels and profile in blood

Diabetic type II
- Still insulin production but an insufficient reaction of the body to insulin
- Generate peak levels of insulin as reaction to the meal. (pre-prandial insulin)
- Type II does have a basal insulin.

Substance insulin
- A-chain 20 amino acids
- B-chain 31 amino acids
- Between the chains two cysteine bridges
- One internal cysteine bridge in the A-chain
- 5805 Da
- Forms easily dimers and hexamers (induced by zinc ions)

Source of insulin
- Past: from the pancreas of pigs/cattle
- Now: production from recombinant micro-organisms (E. coli, S. cerevisiae)

Properties relevant to administration and dosage form
- 5808 Da
- Diameter = 2.2 nm
- Unstable in solution (fridge)
- Tendency for aggregation in solution (dimers and hexamers)
- Broken down by enzymes in the gastro-intestinal tract (proteolytic enzymes)
- Too large to pass membranes, except of the alveoli membrane.

, Subcutaneous injection
advantages disadvantages
 High bioavailability (>90%)  Sterile
 Control of dose  Pain
 Dose flexibility  Ableness to inject
 Fast effect  Expensive
 Long acting (depot) possible  Fridge required
 Not released in the portal vein
 Slow uptake in the circulation

1. Injection pen
advantages disadvantages
 “Easy” to use  Injection
 Precise and flexible dosing  Sterile
 Low change for dosing errors  More times a day
 Thin needle  Simulation of natural plasma profile is
 Reproducible injection depth difficult
 Insulin in solution (fridge)  Fridge

2. Insulin pump
indications disadvantages
 poor control of blood sugar  Mechanically fragile
 aware of hypoglycemia  Blockage of tubing
 history of severe hypoglycemia  expensive
 For pregnant women
 irregular lifestyle
 low insulin requirements

Fast acting insulin
- pre-prandial insulin
- fast onset, rapid acting
- limit duration of the effect
- Change the amino acid sequence to prevent dimers being formed. Dimers cause a
decreased diffusion rate.
- Insulin aspart (NovoRapid): B-28 proline  aspartic acid
- insulin glulisin (Apidra): B-3 aspartic acid  lysine and B-29 lysine  glutamic acid
- insulin lispro (Humalog): B-28 proline  B-29 lysine

intermediate acting
- complex of insulin with protamine (and some zinc)
- amorphous hexamer of zinc-insulin

Long actin insulin
- basal insulin
- Slow dissolution rate
- Zinc insulin, crystalline: Crystalline hexamer of zinc-insulin
- Insulin Glargine (Lantus):