Nishihata Toshiaki

Trials of rectal insulin suppositories in healthy humans

Abstract Administration of an insulin suppository containing adjuvant such as sodium salicylate and l -phenylalanine enamine ethylacetoacetate (enamine) to healthy male human subjects increased serum immunoreactive insulin (IRI) levels significantly. However, to decrease serum glucose concentrations significantly in humans, high serum IRI levels have to be maintained for at least about one hour in humans, rather than being transient. In comparison with enamine, sodium salicylate seems to be feasible as adjuvant in the insulin suppository since its administration to human subjects resulted in high IRI serum levels for a period long enough to lower serum glucose concentrations significantly.

An effective formulation for an insulin suppository. Examination in normal dogs

Abstract A solid dispersion of insulin with sodium salicylate or mannitol could result in the rapid release of insulin from suppositories and a significant decrease in plasma glucose concentrations in dogs after the administration of the insulin suppository even at doses as low as 0.5 U/kg or less in dogs. Furthermore, it has been shown that high plasma insulin concentrations can be maintained for more than 1 h. This results in a decrease of plasma glucose concentrations in normal dogs for more than 1.5 h, which was required for effective treatment in decreasing plasma glucose concentrations in depancreatized dogs (Nishihata et al, 1985a; Okamura et al., 1985). The addition of lecithin to the suppository base resulted in a prolonged effect of salicylate as an adjuvant in suppositories (i.e. 1.5 h.), due to the slow release of sodium salicylate. Thus, a preparation of a solid dispersion of insulin and a triglyceride base containing lecithin seems to be an effective suppository for lowering blood glucose.

The effects of complexation with hydrogenated phospholipid on the transport of salicylic acid, diclofenac and indomethacin across snake stratum corneum

Abstract Hydrogenated phospholipid (HPL) has been found to form complexes with three non-steroidal ntiinflammatory drugs: salicylic acid, diclofenac and indomethacin. The solubility of the salicylic acid complex in squalane was less than that of the plain drug, but the solubilities of the diclofenac and indomethacin complex increased upon complexation. The permeability coefficients of salicylic acid and diclofenac across shed snake skin are not affected significantly by the presence of hydrogenated phospholipid. However, the permeability coefficient for the indomethacin-HPL complex is about double that for either plain indomethacin or an indomethacin-HPL physical mixture.

Effect of gelatin in the formulation on rectal insulin absorption in the presence of enamine in normal rats and depancreatized dogs

Abstract A significant decrease in plasma glucose levels of normal rats and depancreatized dogs was observed when insulin was rectally administered in conjunction with enamine adjuvants. The enamine employed was derived from ethylacetoacetate and dl -phenylalanine. Higher bioavailability of insulin was observed when it was dissolved and dispersed in a gelatin microenema compared to the crystalline suspension of insulin in a glyceride suppository base. The lower bioavailability from glyceride suppositories has been attributed to the slow dissolution rate of crystalline insulin at the lipid/aqueous interface becoming the rate-limiting step in absorption. However, an aqueous microenema containing a solution of insulin and enamine produced lower bioavailability than gelatin formulations. This reduction in bioavailability has been attributed to greater spreading of the aqueous microenema resulting in a decrease in the amount and concentration of insulin and enamine available at the absorption site.

Bioavailability of itazigrel in dogs after oral administration of soft elastic capsules

Abstract The effect of Tween 80, a solubilizing agent, on gastrointestinal absorption was investigated in dogs after oral administration of soft elastic capsules (SEC) of itazigrel with respect to bioavailability. The bioavailability was determined from the area under the curve (AUC) of plasma itazigrel concentration after drug administration. In spite of its known low water solubility (less than 100 ng/ml), the mean absolute bioavailability of itazigrel was about 90% in six dogs under fasting conditions. Furthermore, the absolute bioavailability was also about 85% when measured 30 min after standard food was given to the dogs. The high bioavailability observed in this oral study is believed to be due to Tween 80 contained in SEC which apparently caused complete dissolution in the gastrointestinal tract.