Insulin Products

There are a number of variants of insulin products that are available as a drug , namely  

It is available as a sterile, acidified or neutral solution of insulin. The solution has a potency of 40, 80, 100 or 500 USP Insulin Units in each ml. 

Mechanism of Action. It is a rapid-action insulin. The time interval from a hypodermic injection of this drug until its action may be observed ranges between 1/2 to 1 hour. It has been observed that the duration of action is comparatively short but evidently a little longer than the plasma half-life that stands at nearly 9 minutes. Importantly, the duration of action is not linearly proportional to the size of the dose, but it is a simple function of the logarithm of the dose i.e., if 1 unit exerts its action for 4 hours then 10 units will last 8 hours. In usual practice the duration is from 8 to 12 hour after the subcutaneous injection, which is particularly timed a few minutes before the ingestion of food so as to avoid any possible untoward fall in the prevailing blood-glucose level. 

The drug is a sterile suspension of Zinc-insulin crystals and protamine sulphate in buffered water for injection, usually combined in such a fashion that the solidphase of the suspension essentially comprises of crystals composed of insulin, protamine and zinc. 

Each mL is prepared from enough insulin to provide either 40, 80, or 100 USP Insulin units of insulin activity. 

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Fig. 1. (a) Process flow sheet for human insulin production, recovery, and purification (12) (b) corresponding steps in recovery of biosynthetic human... 

Insulin is one of the important pharmaceutical products produced commercially by genetically engineered bactera. Before this development, commercial insulin was isolated from animal pancreatic tissue. Microbial insulin has been available since 1982. The human insulin gene is introduced into a bacterium like E. coli. Two of the major advantages of insulin production by microorganisms are that the resultant insulin is chemically identical to human insulin, and it can be produced in unlimited quantities. 

MODY is a type of non-insulin-dependent diabetes mellitus caused by rare autosomal-dominant mutations. Presently there are six known forms of the disease which are all due to ineffective insulin production or... 

Diabetes mellitus is a complicated, chronic disorder characterized by either insufficient insulin production by the beta cells of die pancreas or by cellular resistance to insulin. Insulin insufficiency results in elevated blood glucose levels, or hyperglycemia As a result of the disease, individuals with diabetes are at greater risk for a number of disorders, including myocardial infarction, cerebrovascular accident (stroke), blindness, kidney disease, and lower limb amputations. 

Those with type 1 diabetes mellitus produce insulin in insufficient amounts and tiierefore must have insulin supplementation to survive Type 1 diabetes usually has a rapid onset, occurs before die age of 20 years, produces more severe symptoms tiian type 2 diabetes, and is more difficult to control. Major symptoms of type 1 diabetes include hyperglycemia, polydipsia (increased thirst), polyphagia (increased appetite), polyuria (increased urination), and weight loss. Treatment of type 1 diabetes is particularly difficult to control because of the lack of insulin production by die pancreas. Treatment requires a strict regimen tiiat typically includes a carefully calculated diet, planned physical activity, home glucose testing several times a day, and multiple daily insulin injections. 

Immune complex enhancement. Beta-cells activation and Increased insulin production (Btuni, 1988). Neuro-regulatory effect (Nakazawa et al., 1977 Btuni, 1988 Hiraga et al., 1993). 

Improvement of peripheral insulin utilization, beta-cells activation and increased insulin production. 

Strict avoidance of hypoglycemia. Ensure an adequate source of dextrose in any patient receiving an insulin product... 

Previous protamine exposure (e.g., during coronary artery bypass graft, or NPH insulin products containing protamine zinc)... 

A pancreas with normal (3-cell function is able to adjust insulin production to maintain normal blood glucose levels. 

Insulin is the one agent that can be used in all forms of DM for blood sugar control. Insulin is the essential treatment for patients with type 1 DM and can overcome insulin resistance in patients with type 2 DM. Insulin is available commercially in various formulations that vary markedly in terms of onset and duration of action and the source from which a product is obtained. Insulins can be divided into four separate classes based on their length of action. Most formulations are available as U-100, indicating a concentration of 100 units/mL. Insulin is typically refrigerated, and most vials are good for 28 days at room temperature. Specific details of insulin products are listed in Table 40-9. 

NPH insulin can be mixed with regular insulin and used immediately or stored for future use up to 1 month at room temperature or 3 months in refrigeration. NPH insulin can be mixed with either aspart or lispro insulins, but it must be injected immediately after mixing. Whenever mixing insulin products with NPH insulin, the shorter-acting insulin should be drawn into the syringe first. 

A number of combination insulin products are available commercially. NPH is available in combinations of 70/30 and 50/50 with regular insulin. Two short-acting insulin analog mixtures are also available. Humalog Mix 75/25 contains 75% insulin lispro protamine suspension and 25% insulin lispro. Novolog Mix 70/30 contains 70% insulin aspart protamine suspension and 30% insulin aspart. The lispro and aspart insulin protamine suspensions were developed specifically for these mixture products and will not be commercially available separately. 

Virtually all therapeutic proteins must enter the blood in order to promote a therapeutic effect. Such products must usually be administered parenterally. However, research continues on the development of non-parenteral routes which may prove more convenient, less costly and obtain improved patient compliance. Alternative potential delivery routes include transdermal, nasal, oral and bucal approaches, although most progress to date has been recorded with pulmonary-based delivery systems (Chapter 4). An inhaled insulin product ( Exubera , Chapters 4 and 11) was approved in 2006 for the treatment of type I and II diabetes. 

Pulmonary delivery currently represents the most promising alternative to parenteral delivery systems for biopharmaceuticals. Delivery via the pulmonary route moved from concept to reality in 2006 with the approval of Exubera, an inhalable insulin product (Chapter 11). Although the lung is not particularly permeable to solutes of low molecular mass (e.g. sucrose or urea), macromolecules can be absorbed into the blood via the lungs surprisingly well. In fact, pulmonary... 

Such issues and concerns underpinned the development of recombinant human insulin products, now routinely used in the management of diabetes. 

Human insulin produced by recombinant DNA technology was first approved for general medical use in 1982, initially in the USA, West Germany, the UK and The Netherlands. As such, it was the first product of recombinant DNA technology to be approved for therapeutic use in humans. From the 1990s on, several engineered insulin products (discussed later) also gained approval (Table 11.3). 

The initial approach to recombinant insulin production taken entailed inserting the nucleotide sequence coding for the insulin A- and B-chains into two different E. coli cells (both strain K12). These cells were then cultured separately in large-scale fermentation vessels, with subsequent chromatographic purification of the insulin chains produced. The A- and B-chains are then incubated together under appropriate oxidizing conditions in order to promote interchain disulfide bond formation, forming human insulin crb ... 

The RP-HPLC polishing step not only removes E. coli-derived impurities, but also effectively separates modified insulin derivatives from the native insulin product. The resultant extremely low levels of impurities remaining in these insulin preparations fail to elicit any significant immunological response in diabetic recipients. 

Insulin production takes place in the islet tissue of the pancreas, and the individual variation in the amount of this tissue is large. It is estimated that a substantial percentage of the pancreases in a population (78 per cent in one study) 13 have from 0.9 to 3.5 per cent of islet tissue. Those individuals having less than 0.9 per cent are likely to be diabetics, and those having more than 3.5 per cent are likely to be actual or potential sufferers from hyperinsulinism. 14... 

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