Improvement of Subcutaneous Bioavailability of Insulin by Sulphobutyl Ether β-Cyclodextrin in Rats

Abstract

The objective of this study was to examine and compare how hydrophilic beta-cyclodextrin derivatives (beta-CyDs) improve the bioavailability of insulin following subcutaneous injection of insulin solution in rats. When insulin solutions in the absence of beta-CyDs were injected into the dorsal subcutaneous tissues of rats, the absolute bioavailability of insulin calculated from plasma immunoreactive insulin (IRI) levels was approximately 50%. When maltosyl-beta-cyclodextrin was added to the solutions, there was no change in the plasma IRI levels and hypoglycaemia compared with those of the insulin-alone solution. Dimethyl-beta-cyclodextrin decreased the bioavailability of insulin, although it increased the maximal concentration of IRI in plasma and the capillary permeability of the fluorescein isothiocyanatedextran 40, a non-degraded permeation marker. When insulin solutions containing sulphobutyl ether-beta-cyclodextrin with a degree of substitution of the sulphobutyl group of 3.9 (SBE4-beta-CyD) were injected, the IRI level rapidly increased and maintained higher IRI levels for at least 8 h. The bioavailability of the insulin/SBE4-beta-CyD system was about twice that of insulin alone and approached 96%. The enhancing effects of SBE4-beta-CyD may be in part due to the inhibitory effects of SBE4-beta-CyDs on the enzymatic degradation and/or the adsorption of insulin onto the subcutaneous tissue at the injection site, although this does not apparently facilitate capillary permeability. These results suggest that SBE4-beta-CyD in aqueous insulin injection for subcutaneous administration is useful for improving the bioavailability and the hence the pharmacological effects of insulin.

Design and Evaluation of Cyclodextrin-Based Drug Formulation

“…[17][18][19][20] Among these compounds, hydrophilic CyDs such as HP-b-CyD, SBE-b-CyD, and branched b-CyD have received special attention, because their toxicity is very low and aqueous solubility is very high, promising a parenteral use. [63][64][65][66][67][68] The glucuronyl-glucosyl-b-CyD (GUG-b-CyD) is a new entry of branched CyDs, which contains a carboxyl group in the branched maltosyl residue. 69) In fact, the hemolytic activity of GUG-b-CyD on rabbit erythrocytes is lower than that of b-CyD and G2-b-CyD (see Fig.…”

“…Among the CyDs tested, HP-bCyD and G 2 -b-CyD significantly inhibited the adsorption to containers and self association of insulin at neutral pH, whereas DM-b-CyD had only a moderate effect on the aggregation. 175,176) In addition, SBE-b-CyDs showed different effects on insulin aggregation, depending on the degree of substitution of sulphobutyl group: i.e., the inhibition at relatively low substitution (SBE4-b-CyD) and acceleration at higher substitution (SBE7-b-CyD). In fact, sulfated b-CyD (b-CyD-sul) significantly accelerated the insulin aggregation.…”

Synthesis of New Carnosine Derivatives ofβ-Cyclodextrin and Their Hydroxyl Radical Scavenger Ability

“…Cyclodextrin complexation has proved promising in stabilizing and increasing the absorption of growth hormones [19], interleukin-2 [19], aspartame [20], albumine [21], g-globuline [21], cyclosporine A [22], calcitonin [23], and insulin [6] [24] [25]. Rapid plasma clearance and problems regarding immunogenicity [6 ± 8] may limit the practical use of peptides or proteins of therapeutic importance.…”

In situforming poly(lactic acid-co-glycolic acid) implants containing leuprolide acetate/β-cyclodextrin complexes: preparation, characterization, andin vitrodrug release

“…Such a study is required to gain insight into their suitability for subcutaneous injection. Although other derivatives of β-CD such as hydroxyl propyl-β-cyclodextrin (HP-β-CD) and sulfobutyl ether-β-cyclodextrin (SBE-β-CD) are more safe for subcutaneous injection [39][40][41][42][43] and β-CD are known to be cytotoxic at high concentrations [44,45], β-CD-containing formulations have been used for subcutaneous administration [46][47][48][49][50]. The morphology of fibroblast cells in contact with implants after 24 hours were monitored via an optical microscope ( Figure 6).…”