Insulin Formulations Flashcards
What does it mean if it is more soluble?
Faster acting = shorter-acting
What is insulin self-association?
Monomers form dimers form hexamers
What is the most soluble?
Monomers = most
Dimers
Hexamers = least
How are subunits linked together?
By disulphide bridges
What are the interactions between?
Subunit B
What is insulin self-association linked with?
Equilibrium
What factors affect insulin self-association?
Relative concentration of each form
Excipients
What happens if there are more hexamers?
Equilibrium shifts so less hexamers = more monomers
What can modifying insulin structure cause?
High absorption rate = faster-acting
Lower absorption rate = lower-absorption rate
What is animal insulin?
Extracted + purified from bovine + porcine pancreas
What are the cons of animal insulin?
Some cultures NOT accepted
What is recombinant human insulin?
Structurally identical to human insulin
BUT produced in bioreactor using recombinant DNA technology
What is an example of recombinant human insulin?
Insuman
What is an example of animal insulin?
Hypurin
What do solutions tend to be?
Rapid onset, shorter-acting
What do suspensions tend to be?
Slower onset, longer-acting
How do excipients influence duration?
Zinc + phenolic compounds promote self-association of insulin into hexamers
What is NPH?
Neutral Protamine Hagedorn
= Isophane insulin (intermediate)
How does NPH (isophane) insulin work?
Protamine complexes with insulin to form aggregates through ionic interactions = suspension
= prolongs insulin release
What are the more soluble forms of insulin?
Lispro
Aspart
Glulisine
What are the less soluble forms of insulin?
Degludec
Detemir
Glargine
How does the change in Insulin Lispro make it faster-acting?
Destabilises dimers + hexamers
= monomers favoured
ALSO binds to zinc less avidly = doesn’t form dimers + hexamers
How is Insulin Lispro formed?
Proline is swapped for lysine
Lysine is swapped for proline
How is Insulin Aspart formed?
Proline swapped for aspartic acid
How does the change in Insulin Aspart make it faster-acting?
Destabilisers dimers + hexamers
= monomers favoured
How is Insulin Glulisine formed?
Asparagine swapped for lysine
Lysine swapped for glutamic acid
How does the change in Insulin Glulisine make it faster-acting?
Decreased hexamer formation
Monomer stabilisation
Enhanced solubility
How is Insulin Degludec formed?
Threonine removed
Attach hexadecandioyl through glutamic acid spacer at lysine
What is an example of Insulin Degludec?
Tresiba
How does the change in Insulin Degludec make it longer-acting?
Injected
As phenol from vehicle diffuses = insulin degludec hexamers link up via single side-chain contacts
= less soluble than hexamers
= long chain dissociates = releases insulin
How is Insulin Detemir formed?
Remove threonine
Attach myristic acid at lysine
How does the change in Insulin Detemir make it longer-acting?
Binds albumin
= makes it stay longer in blood
= prolonging t1/2
How is Insulin Glargine formed?
Swap asparagine for glycine
Then add 2 arginine’s
How does the change in Insulin Glargine make it longer-acting?
Changes isoelectric point to 6.7
= reduced solubility at physiological pH
What is an example of Insulin Glargine?
Toujeo
What is an example of Insulin Detemir?
Levemir
What devices are there?
Insulin pen
Insulin pumps
Closed-loop systems
Inhaled insulin - Exubera (discontinued) + Afrezza
