A novel insulin formulation can keep providing steady levels of insulin for much longer periods in-vivo

Abstract

We have recently succeeded in preparing insulin-loaded microcapsules that release the insulin in a strictly controlled manner with little initial rapid release in-vitro or in-vivo. We show here the superiority of the best formulation prepared with co-poly(D,L-lactic/glycolic) acids (PLGA) (mean MW 5800, L/G ratio 50:50) with a main diameter of 15 approximately 30 microm in-vivo. When 3.2 % insulin-loaded PLGA microcapsules were subcutaneously given as a single dose to streptozotocin-induced hyperglycaemic rats (250 U kg(-1)), plasma insulin levels gradually increased and constant levels (30.3-94.1 microU mL(-1)) were sustained. Rats receiving the formulation once a week showed not only steady plasma insulin levels, but also gained weight at a similar speed to normal rats. Meanwhile, daily treatment with Humulin U (25 U kg(-1)) caused a transient high insulin level (2723.9 microU mL(-1) at 1 h) in plasma, but the body weight of the rats was little changed. A pharmacological study in female Cynomolgus monkeys also revealed that the microcapsular formulation provided a flat release of insulin for longer periods and showed no immunogenic activity. In the near future, therefore, this insulin formulation could become very beneficial as a provider of basal insulin levels for insulin-dependent diabetic patients.

Preparation, in vitro release, in vivo absorption and biocompatibility studies of insulin-loaded microspheres in rabbits

“…A body weight gain in diabetic rats was observed as fast as normal rats after single injection of insulin-loaded microspheres in 28 days. 16 The above study also found very little body weight gain of diabetic rats by daily injection of insulin solution. large number of macrophages and a few polymorphonuclear (PMN) cells were observed infiltrating into the connective tissue.…”

Controlled Delivery of Basal Level of insulin From Chitosan–Zinc–Insulin-Complex-Loaded Thermosensitive Copolymer

“…Some of the approaches that have been tried in order to reduce the initial burst of insulin and to control the release duration and stabilization of insulin are PEGylation of insulin and addition of zinc salts, ethanol and/or glycerol, hydroxypropyl-$-cyclodextrins, sugars, salts, cationic polyelectrolyte, and nonionic and ionic surfactants to insulin. 2,[7][8][9][10][11][12][13][14] A combination approach of two or more delivery systems such as nanoparticle-microsphere or microsphere-hydrogel has also been tried to control and prolong the release behavior of various proteins. [15][16][17][18] However, development of microparticleor nanoparticle-based delivery systems involve complicated manufacturing procedure, low drug loading, and low protein stability due to the presence of organic solvents, heat, and agitation.…”

In vivo evaluation of a conjugated poly(lactide-ethylene glycol) nanoparticle depot formulation for prolonged insulin delivery in the diabetic rabbit model

“…12,13 For proteins to be used as drugs, delivery via polymer particles overcomes many of the associated unfavorable pharmacokinetics and side effects. 14 Multiple emulsion solvent evaporation methods are considered to be simple and versatile, so have been widely used for the preparation of protein-entrapped polymer particles. 15,16 However, major limitations for successful utilization of this modality of protein delivery include the instability of proteins during formulation, lyophilization, storage, and polymer degradation.…”