Insulin administration: present strategies and future directions for a noninvasive (possibly more physiological) delivery

Abstract

Insulin is a life-saving medication for people with type 1 diabetes, but traditional insulin replacement therapy is based on multiple daily subcutaneous injections or continuous subcutaneous pump-regulated infusion. Nonphysiologic delivery of subcutaneous insulin implies a rapid and sustained increase in systemic insulin levels due to the loss of concentration gradient between portal and systemic circulations. In fact, the liver degrades about half of the endogenous insulin secreted by the pancreas into the venous portal system. The reverse insulin distribution has short- and long-term effects on glucose metabolism. Thus, researchers have explored less-invasive administration routes based on innovative pharmaceutical formulations, which preserve hormone stability and ensure the therapeutic effectiveness. This review examines some of the recent proposals from clinical and material chemistry point of view, giving particular attention to patients’ (and diabetologists’) ideal requirements that organic chemistry could meet.

Oral insulin delivery: existing barriers and current counter-strategies

“…Despite all the initial excitement, delivery of insulin through MDI or CSII still did not mimic the physiology of the endogenously secreted human insulin, where the insulin is reversely distributed between portal and systemic circulation which has driven researchers to develop less invasive and more physiological routes of insulin administration such as transdermal, inhaled, nasal, buccal, ocular, rectal and the highly preferred oral insulin …”

“…Due to their biocompatibility and low toxicity, gold nanoparticles have been used to deliver insulin orally and intranasally. Hypoglycaemia has been recorded when given to diabetic Wistar rats …”

“…[7] Diabetic patients treated with injectable insulin preparations are subjected to the side-effects of hyperinsulinaemia, weight gain and hypoglycaemic risks. [7] A step towards normal physiology…”

“…Despite all the initial excitement, delivery of insulin through MDI or CSII still did not mimic the physiology of the endogenously secreted human insulin, where the insulin is reversely distributed between portal and systemic circulation which has driven researchers to develop less invasive and more physiological routes of insulin administration such as transdermal, inhaled, nasal, buccal, ocular, rectal and the highly preferred oral insulin. [7] While stability requirements for formulation of a protein hormone as well as making sure of its therapeutic efficacy were taken into consideration by researchers, most of the developed formulations have failed to demonstrate satisfying bioavailability results. [7,10] Oral insulin and rationale for its use…”

Tissue barriers and novel approaches to achieve hepatoselectivity of subcutaneously-injected insulin therapeutics

“…A substantial amount of INS is degraded in the liver after IR mediated endocytosis, 3 with a hepatic clearance of 50~80%. The remaining INS is circulated systemically, where the range of INS is 10 to 30 pM at basal conditions, 4 and then reaches peripheral tissues including skeletal muscle and adipose tissue. Different from the microvessels aligning hepatocytes, peripheral blood capillaries are considered as continuous and tight (fenestration 6-12 nm).…”