Insulin formulations

Question 1

3 principles of insulin formulation

Answer 1

Insulin
Excipients
Device

Question 2

What would call each insulin molecule?

Answer 2

Monomer

Question 3

What would call 2 insulin molecules?

Answer 3

Dimer

Question 4

What would call 6 insulin molecules (3 dimers)?

Answer 4

Hexamer

Question 5

How are dimers stabilized?

Answer 5

Hydrophobic interactions between GluB21 and GlyB23 of one monomer and ProB28 on another monomer.

Question 6

How are hexamer formulation stabilized?

Answer 6

By Zn2+ and phenol

Question 7

Faster acting insulin

Answer 7

Bolus
Stabilized monomeric form (easily break off from multimeric form)
Increased absorption rate (more soluble)

Question 8

Longer acting insulin

Answer 8

Basal
Stabilized multimeric form (takes longer to break off)
Reduced absorption rate. (Chunkier and less soluble)

Question 9

More soluble insulin analogues (rapid)

Answer 9

Lispro
Aspart
Glulisine

Question 10

Less soluble insulin analogues (Intermediate/long)

Answer 10

Degludec
Detemir
Glargine

Question 11

What was changes in Insulin lispro (Humalog)?

Answer 11

ProB28 and LysB29 are swapped

Question 12

What is the effect of the changes in insulin lispro?

Answer 12

Proab28 is responsible for stabilizing the insulin dimer. So the swap is enough to destabilase the dimer and less likely to bind to zinc.
Most stable in monomer form and more soluble than native insulin.

Question 13

What was changes in Insulin Aspart (NovoRapid)?

Answer 13

ProB28 switched with Asp

Question 14

What is the effect of the changes in Insulin Aspart?

Answer 14

Proab28 is responsible for stabilizing the insulin dimer. So the swap is enough to destabilase the dimer and less likely to bind to zinc.
Most stable in monomer form and more soluble than native insulin.

Question 15

What was changes in Insulin glulisine?

Answer 15

AsnB3 to Lys

LysB29 to Glu

Question 16

What is the effect of the changes in Insulin glulisine?

Answer 16

Decreased hexamer formation
Monomer stabilization
Enhance solubility.

Question 17

What was changes in Insulin glargine?

Answer 17

AsnA21 to Gly

Add ArgB31 and 32

Question 18

What is the effect of the changes in Insulin glargine?

Answer 18

Less soluble at physiological pH

Question 19

What was changes in Insulin dugledec?

Answer 19

Remove ThrB30 and attach a longer chain molecule at LysB29.

Question 20

What is the effect of the changes in Insulin deugledec?

Answer 20

The long chain attachment helps to stabilize the insulin in hexametric structure. Once the zinc diffuses out, the hexamers disassemble releasing monomer. Monomers diffuse into circulation from depot.

Question 21

What was changes in Insulin detemir?

Answer 21

ThrB30 removed

Add myristic acid at LysB29.

Question 22

What is the effect of the changes in Insulin detemir?

Answer 22

Long hydrocarbon chain reduces solubility of the insulin analogue. But its main action is to help it bind to albumin in the blood.

Question 23

Two types of inulin formulations

Answer 23

Solutions

Suspensions

Question 24

Insulin Solutions action

Answer 24

Rapid onset

Shorter acting

Question 25

Insulin Suspensions action

Answer 25

Slower onset

Longer acting

Question 26

NPH (isophane) insulin

Answer 26

Neutral protamine hagedorn

Question 27

What is Neutral protamine Hagedorn (NPH)

Answer 27

Protamine complexes with insulin to form aggregates through ionic
interactions – suspension.
Prolongs insulin release – Intermediate-acting formulations.