Antihyperglycemic Effect of Insulin from Self-Dissolving Micropiles in Dogs

Abstract

Many drug delivery systems (DDSs) including chemical enhancers, electric fields, ultrasound and thermal methods have been challenged to increase the skin permeability of poorly-absorbable drugs like insulin through the percutaneous route. [1][2][3][4][5] However, the success of these transdermal DDSs has been limited because of the strong barrier function of the skin i.e. low membrane permeability of drugs through the skin. However, micron-scale needles including micropiles made of stainless steel showed an increase of the transdermal permeability of drugs. [6][7][8] Among them, the permeability of insulin through the skin was dramatically increased in rats. 9)However, these microneedles are made of iron, i.e. stainless steel, there is a possibility of side effect like metallic allergy.On the other hand, we have been studying a new delivery system, self-dissolving micropiles (SDMP), for the percutaneous administration of macromolecular drugs using threadforming biopolymers such as dextrin and chondroitin sulfate. These polymers were used as a base polymer of SDMP. Dextrin was used for the base polymer of insulin SDMP in mice study.10) However, there were some problems in fragility as a SDMP. Chondroitin sulfate could keep the viscosity in a SDMP and was selected as a base polymer because of the hardness and sharpness of the top of SDMP.11) In our feasibility studies using mice and rats, insulin, human growth hormone (hGH) and erythropoietin (EPO) were used as representatives of peptide/protein drugs. 10,11) With insulin, the efficiency was evaluated by measuring the hypoglycemic effect of insulin after administration of insulin SDMP to mice. The pharmacological availability (PA) of SDMP was over 90% as compared to intravenously injected insulin solution.10) Also, SDMP containing EPO and hGH showed high bioavailabilities (BA) of EPO, 80-90%, after percutaneous administration to mice and rats.11) Through these proof-of-concept (POC) experiments, SDMP was found out to be useful for the percutaneous administration of peptide/protein drugs. Although the POC experiments were performed in small animals, the results cannot be directly applied to human, i.e. patients. Therefore, as a second step of the POC study, insulin SDMP was prepared and its pharmacological availability has been studied in large animal, beagle dogs, in relation to the oral glucose tolerance test (OGTT). ExperimentalMaterials Insulin sodium salt was prepared from bovine pancreas insulin (25 IU/mg) in our laboratory.12) Glucose CII-Test kit was purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). D-(ϩ)-Glucose and chondroitin sulfate were obtained from Nacalai Tesque, Ltd. (Kyoto, Japan). Male beagle dogs, 10.2-12.6 kg, were obtained from Nippon SLC Co., Ltd. (Hamamatsu, Japan). All other materials used were of reagent grade and were used as received.Preparation of Insulin Micropiles To 8.0 or 4.0 mg of sodium insulin, 60 ml of 0.1 M phosphate buffered saline (PBS, pH 7.4) was added and completely dissolved. By adding 92 mg of chondroiti...

Laser-Engineered Dissolving Microneedle Arrays for Transdermal Macromolecular Drug Delivery

“…delivery of molecules across the skin is overcoming the stratum corneum barrier. Thus, a number of enhancement methods have been proposed and investigated to improve bioavailability of peptides/proteins administered transdermally, including chemical, electrical and physical methods such as penetration enhancers (25), drug carriers such as transfersomes (30) or biphasic lipid vesicles (31), iontophoresis (6,27), ultrasound (8,28), MNs (26,29,34,36), electroporation (7), thermal ablation (9) or radiofrequency ablation (32).…”

Effect of Lipophilicity on the Bioavailability of Drugs After Percutaneous Administration by Dissolving Microneedles

“…17 Relative pharmacological availability of insulin was 90%-99% in dogs. 18 These protein drugs have MW of less than 2.5 kDa. However, FITC-dextran of higher MW showed MW dependency on their BAs.…”

Two-Layered Dissolving Microneedles for Percutaneous Delivery of Peptide/Protein Drugs in Rats

“…The relative BA of interferon (IFN) against subcutaneous injection of IFN solution was 79.9-117.8% in rats (32). Relative PA of insulin was 90-99% in dogs (33). However, those pen-type dissolving microneedles needed an applicator to be inserted into the rat skin.…”