Insulin Formulations

Insulin is synthesized in the B- (or β-) cells of the pancreatic islets of Langerhans. It is a protein (MW 5800) consisting of two peptide chains linked by two disulfide bridges; the A chain has 21 and the B chain 30 amino acids. Upon ingestion of carbohydrates, insulin is released into the blood and promotes uptake and utilization of glucose in specific organs, namely, the heart, adipose tissue, and skeletal muscle.

Insulin is used in the replacement therapy of diabetes mellitus.

Sources of therapeutic insulin preparations

(A). Porcine insulin differs from human insulin by one B-chain amino acid. Owing to the slightness of this difference, its biological activity is similar to that of human hormone.

Human insulin is produced by two methods: biosynthetically from porcine insulin, by exchanging the wrong amino acid; or by gene technology involving synthesis in E. coli bacteria.

Recombinant insulin is produced to modify pharmacokinetic properties (see below). It is important in these insulin analogues that specificity for the insulin receptor is preserved (e.g., also toward the receptor for IGF-1 = somatomedin C, which promotes proliferation of cells; p.238).

Control of delivery from injection site into blood (B). As a peptide, insulin is unsuitable for oral administration (owing to destruction by gastrointestinal proteases) and thus needs to be given parenterally. Usually, insulin preparations are injected subcutaneously. The duration of action depends on the rate of absorption from the injection site.

Variations in Dosage Form

Insulin solution. Dissolved insulin is dispensed as a clear neutral solution known as regular (R) insulin or crystalline zinc insulin. Inemergencies,suchashyperglycemiccoma,

it can be given intravenously (mostly by infusion because i.v. injections have too short an action; plasma t½ ~ 9 minutes). With the usual subcutaneous application, the effect is evident within 15–20 minutes, reaches a peak after ~ 3 hours, and lasts for ~ 6 hours.

Insulin suspensions. When it is injected as a suspension of insulin-containing particles, dissolution and release of the hormone in subcutaneous tissue is retarded (extendedaction insulins). Suitable particles can be obtained by precipitation of apolar, poorly water-soluble complexes consisting of anionic insulin and cationic partners, e.g., the polycationic protein protamine. In the presence of zinc ions, insulin crystallizes; crystal size determines the rate of dissolution. Intermediate-acting insulin preparations (NPH or isophane; Lente) act for 18–26 hours, slow-acting preparations (protamine zinc, ultralente) for up to 36 hours.

Variation in Amino Acid Sequence

Rapidly acting insulin analogues. After injection of a regular insulin solution, insulin molecules exist at the injection site in the form of hexameric aggregates. Only after disintegration into monomers can rapid diffusion into the bloodstream occur. In insulin lispro, two amino acids are exchanged, resulting in a diminished propensity toward aggregate formation. Thus, diffusion from the injection site is faster, with rapid onset and short duration of action. Insulin aspart hassimilarproperties.Fast-actinginsulinsare injected immediately before a meal, whereas regularinsulinrequiresa15–30minuteinter- val between injection and food intake.

Long-acting insulin analogues. The more extensive alteration of amino acids in insulin glargine changes the electric charge of the molecule. At pH 4 of the injectate, it is dissolved; however, at the pH of tissue it is poorly water-soluble and precipitates. Resolubilization and diffusion into the bloodstream take about one day.

Treatment of Insulin-dependent Diabetes Mellitus

Pathogenesis and complications (A). Type I diabetesmellitustypicallymanifestsinchildhood or adolescence (juvenile onset diabetes mellitus); it is caused by the destruction of insulin-producing B cells in the pancreas. A genetic predisposition together with a precipitating factor (viral infection) could start an autoimmune reaction against B-cells. Replacement of insulin (daily dose ~ 40 U, equivalent to ~ 1.6 mg) becomes necessary.

Therapeutic objectives. (1) prevention of life-threatening hyperglycemic (diabetic) coma; (2) prevention of diabetic sequelae arising from damage to small and large blood vessels, precise “titration” of the patient being essential to avoid even shortterm spells of pathological hyperglycemia;

(3) prevention of insulin overdosage leading to life-threatening hypoglycemic shock (CNS disturbance due to lack of glucose).

Therapeutic principles. In healthy subjects, the amount of insulin is “automatically” matched to carbohydrate intake, hence to blood glucose concentration. The critical secretory stimulus is the rise in plasma glucose level. Food intake and physical activity (increased glucoseuptakeinto musculature,decreased insulindemand) areaccompanied by corresponding changes in insulin secretion.

Methods of insulin replacement (B). In the diabetic, insulin can be administered as it is normally secreted. For instance, administration of a long-acting insulin in the late evening generates a basal level, whereas a fast acting insulin is used before meals. The dose needed is determined on the basis of the actual blood glucose concentration mea- suredbythepatientandthemeal-dependent demand. This regimen (so-called intensified insulin therapy) provides the patient with much flexibility in planning daily activities. A well-educated, cooperative, and compe-

tent patient is a precondition. In other cases, a fixed-dosage schedule (conventional insulin therapy) will be needed, e.g., with morning and evening injections of a combination insulin (a mixture of regular insulin plus insulin suspension) in constant respective dosage (A). To avoid hypoglycemia or hyperglycemia, dietary carbohydrate (CH) intake must be synchronized with the time course of insulin absorption from the s.c. depot: diet control! Caloric intake is to be distributed (50% CH, 30% fat, 20% protein) in small meals over the day so as to achieve a steady CH supply—snacks, late night meal. Rapidly absorbable CH (sweets, cakes) must be avoided (hyperglycemic peaks) and replaced with slowly digestible ones.

Undesirable Effects

Hypoglycemia is heralded by warning signs: tachycardia, unrest, tremor, pallor, profuse sweating. Some of these are due to the release of glucose-mobilizing epinephrine. Counter-measures: glucose administration, rapidly absorbed CH orally (diabetics should always have a suitable preparation within reach)or10–20 gglucosei.v.incaseofunconsciousness; if necessary, injection of glucagon, the pancreatic hyperglycemic hormone.

Allergic reactions are rare; locally, redness may occur at the injection site and atrophy of adipose tissue; lipodystrophy). A possible local lipohypertrophy can be avoided by alternating injection sites.

Evenwithoptimalcontrolofbloodsugar,s. c. administration of insulin cannot fully replicate the physiological situation. In healthy subjects, absorbed glucose and insulin released from the pancreas simultaneously reach the liver in high concentrations, whereby effective presystemic elimination of both substances is achieved. In the diabetic, s.c. injected insulin is uniformly distributed in the body. Since insulin concentration in blood supplying the liver cannot rise, less glucose is extracted from portal blood. A significant amount of glucose enters extrahepatic tissues, where it has to be utilized.