Hepatic-Directed Vesicle Insulin: A Review of Formulation Development and Preclinical Evaluation

Abstract

Hepatic-directed vesicle insulin (HDV-I), a novel investigational vesicle (<150 nm diameter) insulin delivery system that carries insulin and a specific hepatocyte-targeting molecule (HTM) in its phospholipid bilayer and has the ability to mimic a portal vein insulin infusion remotely [subcutaneous (SC) HDV-I] and noninvasively (oral HDV-I), has been developed. This review summarizes formulation development, subsequent refinements, and results of preclinical evaluation studies, including biodistribution, mechanistic, and toxicology studies of predominantly SC HDV-I, in various animal models. Studies conducted to date have confirmed the hepatocyte specificity of HDV and HDV-I and revealed that HDV-I can stimulate the conversion of hepatic glucose output to uptake at a dose that is <1% of the dose of regular insulin (RI) required for liver stimulation; suggest that the enhanced antihyperglycemic effect of HDV-I is due to hepatic glucose uptake; and in pancreatectomized dogs during an oral glucose tolerance test, HDV-I normalized blood glucose curves when compared to control curves in intact dogs and prevented secondary hypoglycemia in contrast to the same dose of RI. A 28-day SC HDV toxicity study in rats revealed no clinical, clinical laboratory, or histopathological findings, and the battery of three genetic toxicology studies was negative. Results support the hypothesis that HDV-I works by stimulating hepatic glucose uptake and/or glycogen storage in insulin-deficient animals. The ability to target the delivery of HDV-I to the liver reestablishes the liver as a major metabolic modulator of glucose metabolism. The future of HDV-I depends on the results of ongoing development and longer term clinical trials.

Oral Delivery of Insulin: Novel Approaches

“…The vesicles contain a specific proprietary hepatocyte-targeting molecule -biotinphosphatidylethanolamine -in their phospholipid bilayer. Clinical trials in adult patients with type 1 diabetes mellitus demonstrated that the postprandial glycaemic control produced by 0.1 and 0.2 U/kg oral HDV-I was similar to that produced by 0.07 U/kg SC Humulin R [7].…”

“…All these effects are due to the fact that oral route provide insulin directly to the liver through portal circulation, resembling that which occurs in the non-diabetic individual [6]. The achievement of an adequate level of insulin in portal circulation has been associated with more a rapid and significant lowering of plasma glucose and haemoglobin A1c levels, the normalization of the plasma levels of three carbon precursors -such as lactate, pyruvate and alanine -and the hormones cortisol, growth hormone and glucagon [7].…”

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

“…Still, the vast majority of HDV-I was the free form encapsulated inside of vesicles (99% free INS). 25 In addition, vesicles with increased diameter over 90 nm exhibit increased uptake by nonparenchymal cells which decreases the specificity to hepatocytes. 26 The final example of active liver targeting is Proinsulin-transferrin (ProINS-Tf) fusion protein, which consists of the inactive human INS precursor, ProINS, and Tf.…”

“…INS is then dissociated from the lipid complex over time and exerts INS action in the liver. 24,25 HTM is composed of molecules targeted either the asialoglycoprotein (galactose) receptor, hepatobiliary receptor or biotin receptor on hepatocytes. The amount of INS delivered to liver has been enhanced in the HDV-I formulation.…”

The Importance of the Liver in Insulin Replacement Therapy in Insulin-Deficient Diabetes

“…Hepatic targeted insulin has been demonstrated to significantly reduce the postmeal hyperglycemic area under the curve (AUC) by using oral glucose tolerance tests (OGTTs) in dogs (5). Postmeal blood glucose AUCs in dogs are elevated after pancreatectomy due to insulin deficiency, but blood glucose AUCs are not normalized after pancreatectomy when treated with replacement SC insulin.…”