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Human time activity profile for r-DNA/GE/GM lente insulin.

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Lente insulins information.


The lente types of Semilente, Lente and Ultralente are also called zinc suspension insulins.

In 1952 Hallas-Moller developed lente insulin when they discovered that the addition of zinc and an acetate buffer crystallized insulin and prolonged its duration. [1][2]

Technical detailsEdit

Lente insulin is actually a combination of two other lente-type insulins in the fractions 30% semilente insulin and 70% Ultralente insulin. And so the short-acting semilente and the slow-acting ultralente combined produce an insulin that is intermediate-acting. [3]

When reading a description of Lente insulin, the word amorphous [4] is often used. The description is often used interchangably with the semilente term, in speaking of the 30% fraction of Lente that is semilente insulin. The word crystalline is also used in connection with describing the composition of Lente insulins; this is the Ultralente 70% fraction.

Why Lente doesn't equal 70/30Edit

Lente-70 30

Direct comparison of insulin activity profiles for Lente and 70/30 insulins. The early strong action from the non-suspended R/neutral/normal insulin is seen at the "bump" from hours 0-6.

Let's look at the differences in the two insulins. Lente is comprised of 70 % long-acting Ultralente insulin and 30% short-acting Semilente insulin. So proportions of a long-acting and short-acting insulin are being combined to produce a intermediate-acting insulin. Both Ultralente and Semilente insulin are suspended by adding zinc and the size of their respective insulin crystals. The largest insulin crystals are those of Ultralente, while Semilente contains the smallest, or microcrystals. Simply put, you're combining a long insulin and a short insulin to make an intermediate-acting one.[5]

70/30 insulin starts with 70% NPH/isophane insulin, an intermediate-acting insulin which is suspended by protamine. To that, 30% R/neutral/normal insulin, which is short-acting and soluble, meaning there is no suspension; nothing is added to this insulin to delay its action. In this case, you are taking an intermediate-acting insulin with a suspension and adding to it a short-acting one with no suspension to create an intermediate-acting insulin.

So we have an insulin (Lente), made up of a long-acting and short-acting insulin, both with zinc suspensions, and a mixed insulin (70/30), made from an intermediate-acting protamine suspended insulin and a short-acting one without any suspension. Because of these differences, the insulin action profile for these two insulins is going to be quite different, even though both insulins are classed as intermediate-acting.

What Lente Is NotEdit

No Lente-type insulin regardless of species can contain any NPH/isophane insulin [6] or any R/Neutral insulin. [7][8]

Both are chemically impossible: the phenol preservative present in NPH/isophane alters the action of Lente-type insulins, creating a mixture with an approximate action of R/Neutral. [9][10]

The zinc suspension of Lente-type insulin binds R/Neutral, causing the short-acting insulin to slow, losing its short-acting effect. [11][12]

Before the invention of VetPen, Lente-type insulins could not be dispensed in pen or cartridge form because the glass ball formerly used to mix the insulin in these devices shattered the Lente crystals. [13]

Combining Lente Family InsulinsEdit

None of the Lente family of insulins (semilente, Lente, Ultralente) can be combined with [9] NPH/isophane insulins. The phenol preservatives present in NPH-type insulins alters the Lente-types to the point where they become a close approximation of R/neutral, with regard to action. [9][14]

Keeping the phenol preservatives in mind, all protamine-suspended insulin mixes would be "off limits" regarding same syringe mixing with any Lente-type insulins. [14]

Insulin manufacturers [15] indicate that R/neutral and semilente, Lente, ultralente insulins are able to be combined in the same syringe, but only just before injection. In pre-filled syringes, the zinc suspension of the Lente-type insulins binds the R/neutral, causing it to lose its short-acting effect. Various studies have documented this, and some doctors advise against using R/neutral in the same syringe with the Lente family of insulins. [8][16][17][14]

Lente-family membersEdit

The following insulins are classed as Lente-family insulins, a subset of intermediate-acting insulins with a particular combination of ultralente and semilente. The entire Lente family includes Ultralente, a Long-acting insulin and Semilente, a Short-acting one.

Trade names:

These fall into the category of short-acting insulins.

The following are lente type zinc suspension insulins but since they are produced for use in animals, they are not found in BNF, but in its sister veterinary formulary.

These fall into the category of intermediate-length insulins.

British Pharmacopia [20] defines Ultralente-type insulins as: A sterile neutral (neutral used here refers to the pH, not to the fast-acting insulin known as neutral or R) suspension of bovine insulin or of human insulin in the form of a complex obtained by the addition of a suitable zinc salt; consists of rhombohedral crystals (10-40 microns).

Trade names:


These fall into the category of long-acting insulins.

Specifications of lente insulinsEdit

Monotardhm

Novo Nordisk Monotard HM--GE Human Lente Insulin.

British Pharmacopia [23] defines a lente insulin as: A sterile neutral(neutral used here refers to pH, not to the type of insulin known as neutral or R) suspension of bovine and/or porcine insulin or of human insulin in the form of a complex obtained by the addition of a suitable zinc salt; consists of rhombohedral crystals (10-40 microns) and of particles of no uniform shape (not exceeding 2 microns).
4592

Novolin L--Novo Nordisk's GE Lente insulin was sold in North America under this brand name until the end of 2003.


British Pharmacoepia: [23]

Sterile buffered suspension of mammalian insulin in the form of a complex obtained by addition of zinc chloride. Insulin is in a form insoluble in water. Prepared by mixing 3 volumes of insulin zinc suspension (amorphous) and 7 volumes of insulin zinc suspension (crystalline). Contains 40, 80, or 100 units/ml. White suspension available in multidose containers. pH 6.9 - 7.5. Complies with a test for prolongation of insulin effect.

United States Pharmacoepia (USP), [23] which describes the amorphous (semilente) and crystalline (ultralente) fractions separately:

Specifications of semilente fraction--30%Edit

Insulin Zinc Suspension BP (Amorphous) [24]

Sterile buffered suspension of mammalian insulin in the form of a complex obtained by addition of zinc chloride. Prepared from crystalline insulin containing not less than 23 u almost colourless suspension in which the particles have no uniform shape and rarely exceed 2 m in dimension; pH 6.9 - 7.5. Iso-osmotic with blood. Containing suitable bactericide, the preparation contains 40 and 80 units/ml.

(Note: semilente insulin alone has not been available in most markets for many years, thus the lack of notation for U100 strength insulin. It is presently available in porcine form from Polfa Tarchomin in Poland. Novo Nordisk recently discontinued its version of this insulin.)

U.S.P. describes a sterile suspension of insulin U.S.P. in buffered water for injection is modified by addition of zinc chloride so that the solid phase of suspension is amorphous. Contains 40, 80 or 100 units/ml. Also contain sodium acetate 0.15 - 0.17%, sodium chloride 0.65 - 0.75%, methyl hydroxy benzoate 0.09 - 0.11% and for each 100 units of insulin, 120 - 250 g of zinc. pH 7.2-7.5

Specifications of ultralente fraction--70%Edit

00002841 101

Iletin II Lente-U100 pork insulin by Lilly. This was discontinued in 2003.

Insulin zinc suspension (crystalline) BP [24]

Sterile buffered suspension of bovine insulin to which zinc chloride is added. Crystalline form is insoluble in water. Prepared from crystalline insulin containing not more than 23 units/mg.

White or almost colourless suspension. Particles are mainly crystalline. Majority of crystals having a maximum diameter greater than 10 m.pH 6.9 - 7.5 Iso-osmotic with blood. Preparation contains 40 and 80 units/ml.

(Note: the BP definition should be "mammalian", not "bovine" insulin, as r-DNA/GE/GM ultralente insulin was available in the UK until recently; Lilly's Humulin Zn and Ultratard were the brand names. The definition of strength should include U100, as both of the above-mentioned insulins were of U100 strength.)

U.S.P. - Sterile suspension of insulin contain 40, 80, 100 units/ml. Contains sodium acetate, sodium chloride and methyl hydroxybenzoate (Concentration same as for amorphous insulin) and zinc 120 - 250 ug. pH 7.2 - 7.5.

ReferencesEdit

  1. Gordon. Jana (April 2008). Insulin therapy: Past, present and future. DVM 360.
  2. Dumitriu, Severian (2001). Polymeric Biomaterials, Revised and Expanded 1104. CRC Press.
  3. Better Medicine-E-Newsletter. Intervet (June 2006).
  4. Definition of Amorphous. Dorlands Medical Dictionary.
  5. Greco, Deborah (2010). Treating Diabetes Mellitus in Dogs and Cats. Western Veterinary Conference.
  6. Combining Lente-type Insulins with Phenol-Preserved Insulins. National Federation for the Blind.
  7. Lente Zinc Suspension Causes Loss Of R/Neutral Short-Acting Effect. Endotext.org.
  8. 8.0 8.1 Huffman DM, Garber AJ. (1991). Availability of Soluble (R/Neutral) Insulin in Mixed Preparations With Crystalline (Lente) & Ultralente GE Insulin. Clinical Therapeutics.
  9. 9.0 9.1 9.2 Lente-Type Insulins & NPH/Isophane Insulins-A Bad Combination. National Federation for the Blind.
  10. Havlik I, Galasko G, Alberts E, Furman KI, Seftel HC. (1988). Solubility Changes on Mixing Short- and Long-acting Insulin Preparations. South African Medical Journal.
  11. Deckert, T. (1980). Intermediate-Acting Insulin Preparations: NPH (Isophane) & Lente. Diabetes Care.
    Note--in 1980, there were no r-DNA/GE/GM insulins
  12. Resource Guide. American Diabetes Association (2005).
  13. Hanas, Ragnar (1999). Insulin-Dependent Diabetes-Page 10. ChildrenWithDiabetes.
  14. 14.0 14.1 14.2 Insulin Therapy-Mixing Precautions. RxEd.org.
  15. Insulin Producers vs Doctors Re:Combining R/Neutral & Lente-type Insulins. Endotext.org.
  16. Bilo HJ, Heine RJ, Sikkenk AC, van der Meer J, van der Veen EA. (1987). Absorption Kinetics & Action Profiles-Single Subcutaneous Administration of Human Soluble (R/Neutral) & Lente Insulin. Diabetes Care.
  17. Heine RJ, Sikkenk AC, Eizenga WH, van der Veen EA. (1983). Delayed Onset of Action of Soluble (R/Neutral) Insulin After Premixing With Lente Insulin Diabetes. Research & Clinical Practice.
  18. Iletin I Lente-Beef/Pork Insulin Shown at Right.
  19. Carton Image-Iletin II Lente.
  20. British Pharmacopia-Ultralente Insulin. InChem.
  21. discussion of differences between r-DNA Ultralente and beef Ultralente insulins. Free Patents Online.
  22. Insulin Preparations. UK Committee on Safety of Medicines (1976).
  23. 23.0 23.1 23.2 British Pharmacopia-Lente Insulin. InChem.
  24. 24.0 24.1 Physical Properties--Insulin. InChem.

More InformationEdit

Subcategories

This category has the following 5 subcategories, out of 5 total.

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