Novel Approaches for Oral Insulin Delivery - Pharmaceutical Technology

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Novel Approaches for Oral Insulin Delivery
The authors review various oral drug delivery systems that have been explored to increase patient compliance for insulin.


Pharmaceutical Technology
Volume 33, Issue 7

In 1982, biosynthetic insulin became the first marketed human healthcare product derived from rDNA technology. This novel technology opened new ways for the development of insulin analogues. However, the pharmacokinetics following s.c. injection of rapid-, intermediate-, and long-acting preparation does not match the profile of physiological insulin secretion. The peak absorption of regular, short-acting human insulin occurs from two to four hours after the injection and usually persists for several hours, but it does not provide the early and quick rise in plasma insulin concentration required to prevent physiological postprandial hyperglycemia after a meal. The prolonged-acting formulation is intended to maintain the basal insulin levels to control blood glucose between meals and during the night when one cannot deliver insulin at a constant and reproducible low-level rate that characterizes normal insulin secretion. These shortcomings of the conventional preparation make it virtually impossible to achieve normoglycemia.

In spite of newer, more potent and highly purified insulins, development of human insulin, change of once-daily injection to twice-daily insulin therapy, and the introduction of portable insulin infusion pumps, diabetes is still a high-risk disease and is far from being controlled. The present mode of insulin administration is by the s.c. route by which insulin is presented to the body in a nonphysiological manner. The s.c. administration of insulin has many challenges. The major drawbacks of this method are local discomfort, inconvenience of multiple injections, and occasional hypoglycemia as a result of overdose. Because of these problems, novel approaches for insulin delivery are being explored, including oral, transdermal, nasal, rectal, pulmonary, uterine, and ocular delivery as well as s.c. implants. Delivery options that use dermal, nasal, and oral approaches have been explored (12–14). This review describes various oral insulin delivery systems.

Pulmonary delivery

Inhaled insulin appears to be suitable for patients with diabetes because of its high bioavailability and a pharmacokinetic profile that mimics the time kinetics of insulin secretion after a meal. Clinical studies were conducted among a small number of patients with type I or type II diabetes who had been treated with s.c. insulin. Inhaled insulin was given three times daily, just before meals, and was combined with a bedtime s.c. injection of long-acting insulin (1). In patients with type I or type II diabetes, the metabolic control achieved with inhaled insulin was similar to that obtained with a s.c. insulin regimen. Tolerance of inhaled insulin was good, and treatment satisfaction was better than that with the s.c. regimen. Insulin inhalation appears to be an interesting way of insulin delivery for elderly patients with diabetes. However, no studies have been conducted in elderly patients with diabetes to assess this route's acceptability, convenience, and ease of use in this particular population. In addition, it is necessary to conduct pharmacokinetic studies in the elderly because lung aging might reduce the bioavailability of inhaled insulin (10). Although Pfizer (New York) launched Exubra in 2006, it has been reported that it is not successful. Of the several inhaled insulin devices that are in various stages of development, the Exubera formulation was the first to be approved for use in the United States and in Europe (11).

Pulmonary delivery has emerged as the most feasible option thus far, but oral delivery is the ultimate goal. Oral insulin delivery must protect insulin from proteolytic degradation in the stomach and the upper portion of the small intestine. In addition, the absorption of insulin from the gut must be enhanced. The absorption of insulin is very poor because of the hydrophilic nature of the big molecule. Basic problems of insulin stability in the gut and absorption from the gastrointestinal tract still must be resolved (15). To achieve gastrointestinal absorption, Morishita et al. evaluated whether oligoarginine, a cell-penetrating peptide (CPP), can improve intestinal absorption of insulin in rats (16). Peptides composed of six [R(6)], eight [R(8)] and 10 [R(10)] residues of arginine were used as the CPP. No insulin absorption was observed following administration of insulin solution alone. However, insulin absorption increased dramatically after co-administration of the D-form of R(6), D-R(6), and the L-form of R(6), L-R(6), in a dose-dependent manner. The effects on insulin absorption were more pronounced for D-R(6) than for L-R(6). Among oligoarginines composed of 6, 8, or 10 arginine residues, D-R(8) showed the strongest enhancing effects on insulin intestinal absorption.


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