What is the protaminated form of short-acting insulin analogues?

Protaminated Forms of Short-Acting Insulin Analogues

Protaminated forms of short-acting (rapid-acting) insulin analogues are intermediate-acting insulin formulations created by combining rapid-acting insulin analogues with protamine to extend their duration of action, resulting in products like NPL (Neutral Protamine Lispro) and insulin aspart protamine suspension. 1, 2

Mechanism and Formulation

The addition of protamine to rapid-acting insulin analogues creates a sustained-release formulation with pharmacokinetic properties comparable to NPH (Neutral Protamine Hagedorn) insulin:

• NPL (Neutral Protamine Lispro) is created by combining insulin lispro with protamine, producing an intermediate-acting insulin with pharmacokinetics and glucodynamics comparable to human NPH insulin 2
• Insulin aspart protamine suspension is the protaminated form of insulin aspart, used in premixed formulations like NovoLog Mix 70/30 1
• The protamine binding delays absorption from the subcutaneous injection site, converting the rapid-acting analogue into an intermediate-acting insulin 2, 3

Clinical Formulations

These protaminated analogues are primarily available as premixed insulin products rather than standalone formulations:

• NovoLog Mix 70/30 contains 70% insulin aspart protamine suspension and 30% soluble insulin aspart, providing both intermediate and rapid-acting components 1
• Insulin lispro Mix 75/25 contains 75% insulin lispro protamine suspension (NPL) and 25% insulin lispro 4, 2
• Insulin lispro Mix 50/50 contains 50% NPL and 50% insulin lispro 2

Pharmacokinetic Profile

The protaminated component provides intermediate-acting insulin coverage:

• The rapid-acting component maintains its fast onset of action within the mixture, allowing injection just prior to meals 2
• The protaminated component provides sustained insulin activity comparable to NPH insulin 2, 3
• In NovoLog Mix 70/30, the addition of protamine results in insulin activity that is 30% short-acting and 70% long-acting 1
• Peak pharmacodynamic activity occurs between 1-4 hours after injection 1

Important Clinical Distinction

A critical caveat: NPL was specifically developed because direct mixing of rapid-acting insulin analogues with human NPH insulin is problematic—an exchange occurs between soluble insulin lispro and protamine-bound human insulin within human NPH, precluding prolonged storage of such mixtures 2. This is why manufactured protaminated forms were necessary rather than simply mixing rapid-acting analogues with existing NPH insulin.

Practical Application

These formulations are typically administered twice daily to cover multiple meals:

• Dosing timing: Should be administered within 15 minutes before meal initiation for type 1 diabetes; within 15 minutes before or after meal initiation for type 2 diabetes 1
• Coverage pattern: Each dose is intended to cover 2 meals or a meal and a snack 1
• Resuspension required: These are suspensions that must be visually inspected and resuspended immediately before use to ensure uniform white and cloudy appearance 1