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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