An Effective Absorption Behavior of Insulin for Diabetic Treatment Following Intranasal Delivery Using Porous Spherical Calcium Carbonate in Monkeys and Healthy Human Volunteers

Abstract

Porous spherical calcium carbonate (PS-CaCO(3)), in contrast to regular calcium carbonate (CaCO(3)), which has a cuboidal particle shape, has a characteristic spherical particle shape with a large number of porous, sliver crystals. The effect of PS-CaCO(3) as a drug carrier on intranasal insulin absorption was investigated in cynomolgus monkeys and healthy human volunteers. Each insulin formulation (powder) containing PS-CaCO(3) or regular CaCO(3) was administered intranasally. Serum insulin and glucose levels after administration were evaluated. The insulin absorption after intranasal administration with each CaCO(3) was found to be much more rapid than that after subcutaneous administration. The serum insulin level after intranasal insulin delivery (16 U per monkey) with PS-CaCO(3) showed a higher C(max) (403.5 microU/mL) and shorter T(max) (0.167 h) when compared with regular CaCO(3). The serum glucose level reduction rate after intranasal delivery using PS-CaCO(3) was faster than that of regular CaCO(3), reflecting the difference in absorption rates. Following repeated intranasal administrations for 4 weeks in monkeys, no toxicity was observed even with a maximum insulin dose level of 25 U. Furthermore, the intranasal insulin absorption rate with PS-CaCO(3) in healthy humans was also observed to be considerably faster than that with regular CaCO(3). Effects of PS-CaCO(3) on a more effective absorption behavior of insulin were considered to be the result of a greater affinity between the nasal mucosa layer and PS-CaCO(3), which is closely related to its structural characteristics. Thus, intranasal insulin delivery using PS-CaCO(3) is thought to be a safe and highly available system enabling more effective insulin absorption behavior with the appearance of endogenous postprandial insulin secretion in healthy humans. We believe that our intranasal insulin delivery system enabling a rapid and short-acting pharmacological effect against postprandial hyperglycemia will be more beneficial than pulmonary insulin delivery systems in the treatment of diabetes.

Pharmacokinetics and Pharmacodynamics of Intranasal Insulin Administered to Patients with Type 1 Diabetes: A Preliminary Study

“…Nevertheless, the data appear to confirm the finding in a small group of healthy volunteers 1 that this intranasal formulation has an improved bioavailability compared with published data from previous studies with intranasal insulin. [2][3][4][5] The time course of insulin absorption and concomitant attenuation of plasma glucose seen in this study was consistent with previously published data. Mean peak serum insulin levels increased as the dose of intranasal insulin increased.…”

“…A number of studies have been performed using intranasal formulations. Studies in healthy volunteers include those by Drejer et al, 2 Haruta et al, 3 Paquot et al, 4 and Newman et al 5 In addition, Nolte et al 6 8 Moses et al, 9 Salzman et al, 10 and Sinay et al, 11 have studied the use of intranasal insulin in patients with type 1 and type 2 diabetes mellitus. The development of a marketable formulation has been hampered by the poor bioavailability generally seen with this route of delivery, and by local irritation caused by these formulations.…”

“…Following administration of fastacting soluble insulin by subcutaneous injection, the maximal plasma concentration of insulin is reached after 1-2 h. 12 Studies in fasting healthy volunteers given single doses of fastacting insulin intranasally showed plasma insulin levels peaking within 15 min; however, there was high inter-individual variability in the absorption of insulin via this route. [2][3][4] Plasma glucose levels began to fall within 10 min after nasal insulin administration, with a Relative bioavailability between intranasal insulin and subcutaneous insulin has been extrapolated from mean data. nadir in blood glucose after approximately 40-50 min.…”

Obtenção E Caracterização De Nanoestruturas De Carbonato De Cálcio

“…al., 2012). Além disso, essas nanopartículas também são utilizadas em estudos de liberação controlada de moléculas bioativas (HARUTA et al, 2003). Existem relatos na literatura sobre a atividade antimicrobiana das partículas de carbonato de cálcio em sua forma nanoestruturada (JEONG et al, 2007).…”

Calcium carbonate microspheres as carriers for the anticancer drug camptothecin

“…Among these inorganic materials used as drug carriers, calcium carbonate has received considerable attention because of its slow biodegradability and low toxicity [19,20], as well as being commercially available in relatively large quantities at reasonable cost. In addition, calcium carbonate is pH-sensitive; its structure is well maintained in neutral environments, while drug release can be triggered by the acid environment in tumor tissues and lysosomes [21].…”