Routes of administration of insulin

2.1 Current approach for the delivery of insulin

The conventional and current method for diabetic treatment is by replacement therapy, which involves the administration of insulin exogenously via the subcutaneous route to mimic pancreatic insulin secretion [1]. At present many diabetics are dependent on multiple doses of subcutaneous injections of insulin daily in order to maintain blood glucose level, and they consider this the standard treatment for diabetes [2]. Although these injections have been used for a number of years, as they avoid many complications which are really life-threatening, there are also issues related to the negative effects the delivery method itself can have on a patient's life [3]. Furthermore, poor patient compliance, pain at injection site, infection due to improper administration (self-administration), hypertrophy at the injection site due to insulin deposition, cost-effectiveness, risk and inadequate control of blood glucose level are associated with subcutaneous treatment, since multiple daily injections of insulin are needed [4]. It may also lead to diabetic micro- and macroangiopathy [5].

Although subcutaneous injection of insulin is the preferred approach, it often fails to mimic the normal insulin secretion pathway observed in a healthy individual (Figure 2.1). There are some innate problems that demand a more effective delivery system for insulin. Of these, the major problem is that insulin injections expose all of the body's tissues to an equal concentration of insulin, providing the liver with only a fraction (~20%) of what was initially injected [6]. This can cause negative effects, including overstimulation of cell growth and other metabolic events that can lead to diabetic complications [6, 7]. In contrast, under normal conditions, physiological insulin is produced in the pancreas and secreted into blood vessels. Insulin then enters the hepatic portal circulation, where it contacts the liver, in which a large first-pass extraction of portal insulin occurs; i.e. the liver acts as a regulator here [8]. The insulin may then be destroyed by the liver before entering the general circulation. When insulin is administered subcutaneously, absorption occurs directly into the peripheral circulation, bypassing hepatic extraction. Therefore, by subcutaneous insulin injections, the tissues are exposed to higher levels of insulin than if insulin were taken by the portal route [9]. Because the primary target of exogenous insulin is the liver, the most suitable mode of delivery of insulin for type 2 diabetes is through the portal vein, as in the case of intraperitoneal injection of insulin. It is obvious from this mechanistic difference in insulin delivery that it is not possible to mimic the normal pattern of basal insulin secretion, causing patients to experience hyperinsulinaemic episodes. The other drawbacks associated with subcutaneous insulin therapy include pain at site of injection; infection due to improper administration; hypertrophy at the injection site due to insulin deposition; insulin oedema; atherosclerosis, which occurs due to irregular absorption of insulin; and, lastly, it is less cost-effective and more risky [3]. Improper treatment of diabetes can have serious consequences for the patient, and may even be life-threatening in some cases. The need for large amounts of insulin in obese diabetics also demands the most appropriate methods of insulin delivery. These are important reasons why an improved delivery method for insulin is necessary to improve patient compliance and overall quality of life. Therefore, it would be beneficial to develop a better method of insulin delivery that more closely mimics the body's natural insulin pharmacokinetic profile.

2.2 Routes of administration of insulin

Various routes other than subcutaneous which are under investigation for insulin replacement include oral, pulmonary, transdermal, nasal, buccal, ocular, rectal and vaginal (Figure 2.2) [10]. Many different techniques for overcoming these ongoing problems have been developed and tested by researchers and pharmacists worldwide. A good number of pharmaceutical companies have become involved in this area of research, with a number of ideas being evaluated in clinical trials.

2.2.1 Buccal route

Due to high systemic effects, surface area and high vascularity, buccal administration of insulin is highly preferable [11]. The buccal epithelium is non-keratinous in nature and composed of multiple layers of cells. The oral mucosa is an attractive delivery site due to its large surface area for absorption (100–200 cm2), easy accessibility, limited proteolytic activity, and high degree of vascularization. However, due to the effects of the constant flow of saliva and the relatively thick, multilayered buccal barrier, the buccal and sublingual mucosa presents problems for insulin delivery [12]. A drug delivered through the buccal route enters directly into the systemic circulation, bypassing the hepatic first-pass metabolism. The two major drug transport mechanisms through the buccal mucosa involve transcellular and paracellular pathways [13]. Peptides that cross the buccal epithelium via the paracellular route come into contact with extracellular enzymes like aminopeptidases in the buccal mucosa, thereby leading to degradation of insulin [14]. Disadvantages associated with the buccal route, like low bioavailability, can be improved by the use of various permeation enhancers such as sorbitol and phosphatidylcholine.

The buccal route offers several advantages for insulin delivery [15–18] (Table 2.1).

Various approaches, including the use of absorption enhancers such as bile acid salts, sodium lauryl sulfate, detergents, etc., can be taken to increase membrane permeability. Also, the addition of enzyme inhibitors like sodium deoxycholate to increase drug stability has been undertaken to improve the buccal absorption of proteins (Figure 2.3) [19].

Absorption enhancers

A continuous hypoglycaemic effect was exhibited by Pluronic F-127 (PF-127) gel containing insulin and unsaturated...