Akira Kamada

Enhancement of nasal absorption of insulin and calcitonin using polyacrylic acid gel

The effects of polyacrylic acid gel on the nasal absorption of insulin and [Asusup>1,7]‐eel calcitonin were investigated in rats. The nasal administration of insulin (1 IU kgsup>−1) in polyacrylic acid gel at 0.1 and 1% w/v showed maximum hypoglycaemic effects at 30 min and 1 h after administration, respectively. However, the nasal administration of insulin in carboxymethyl cellulose (1% w/v) solution had no hypoglycaemic effect at the same dose. When [Asu1.7]‐eel calcitonin (10 U kg−1) was administered nasally in polyacrylic acid gel (0.1% w/v), a prominent hypocalcaemic effect was observed during the first 30 min. Nasal administration of [Asu1,7]‐eel calcitonin in saline had no hypocalcaemic effect at the same dose. The results indicate that the polyacrylic acid gel base significantly enhanced the absorption of insulin and [Asu1,7]‐eel calcitonin via the nasal cavity.

Enhancement of rectal absorption of insulin using salicylates in dogs

Sodium salicylate and 5‐methoxysalicylate both increased the rectal absorption of insulin in dogs when co‐administered with insulin in various formulations. Microenema formulations containing 4% gelatin showed the highest insulin biavailability of the formulations studied whereas microenemas (without gelatin) and suppository formulations were not as effective in enhancing the rectal absorption of insulin.

Effect of non-ionic surfactants in a polyacrylic acid gel base on the rectal absorption of [Asu1,7]-eel calcitonin in rats

The effect of non‐ionic surfactants in a polyacrylic acid gel base on the rectal absorption of [Asu1,7]‐eel calcitonin, a calcitonin analogue, was studied in rats. Absorption was enhanced by a microenema which used a polyacrylic acid gel base, but it was reduced by the incorporation of polysorbate 80 (0.1‐5% v/v). The incorporation of polyoxyethylene 9 lauryl ether (0.1‐5% v/v) in the polyacrylic acid gel base enhanced the absorption. Rectal administration in the base containing 0.5% v/v polyoxyethylene 9 lauryl ether required a dose of the calcitonin 2‐3 times greater than an intramuscularly administered dose to achieve an equivalent hypocalcaemic effect.

Enhanced bioavailability of insulin after rectal administration with enamine as adjuvant in depancreatized dogs

Rectal absorption of insulin by depancreatized dogs was significantly enhanced by the coadministration of enamine as a suppository adjuvant and if this was followed by a further suppository containing enamine alone, the insulin absorption was even further enhanced. The additional enamine suppository resulted in high serum insulin concentrations for a longer time and effected a significant decrease in serum glucose concentrations. To decrease serum glucose concentrations effectively in depancreatized dogs, serum insulin levels had to remain high for a long period of time, rather than be transient.

Effect of enamine derivatives on the rectal absorption of insulin in dogs and rabbits

Enamine derivatives resulting from the reaction between ethyl acetoacetate and amino acids were found to promote rectal absorption of insulin in normal rabbits, with the enamine of sodium DL‐phenylalanate being the most effective adjuvant tested. Results of glucose tolerance tests in fasted alloxan diabetic rabbits showed that after oral administration of glucose, insulin suppositories containing enamines derived from either sodium phenylalanine or leucine were able to lower the serum glucose level to within the normal range for more than 2.5 h. The absorption‐promoting effect of the sodium DL‐phenylalanate enamine on rectal absorption of insulin in dogs was studied in two different formulations, gelatin microenema and suppository. The gelatin microenema containing the insulin solution caused a greater increase in the plasma insulin level than that obtained after administration of an insulin suppository.

Insulin suppository: enhanced rectal absorption of insulin using an enamine derivative as a new promoter

basic solution. One of the major degradation products of triamcinolone in basic media is the D-homosteroid I11 (Timmins & Gray, unpublished observations) and this reaction is therefore not dependent on an enolization step. D-homosteroids were not observed as major degradation products of triamcinolone acetonide. In summary, it may be seen that in neutral and basic media the presence of the acetonide function stabilizes the steroid ketal in comparison with the parent 1601hydroxysteroid, preventing hydroxide ion-catalysed decomposition to the D-homosteroid. Below pH 7 the shape of the pH-rate profile for the steroid ketal is almost identical to that for the parent 1601-hydroxy steroid. The shape of the pH-rate profile for the steroid ketal can be explained in terms of enol formation ionization of the enol whereas this has little influence on the decomposition of the parent 16a-hydroxysteroid. The decomposition of the steroid ketal thus parallels that of steroids possessing no C16 hydroxyl such as hydrocortisone.

Salicylate-promoted permeation of cefoxitin, insulin and phenylalanine across red cell membrane. Possible mechanism.

Uptake of sodium cefoxitin, D-phenylalanine and insulin into human red blood cells was significantly enhanced by the presence of salicylate and 5-methoxysalicylate in the medium. The mechanism of adjuvant action appeared to depend on an affinity between the adjuvant and the protein fraction in the erythrocyte membrane. The inhibitory effect of DIDS and phlorizin on the salicylate-enhanced uptake of these compounds strongly suggests that the ability of salicylate to permeate the membrane may be essential for it to act as an adjuvant.

Investigation of sustained-release suppository of sodium diclofenac in humans

Abstract A sustained-release suppository of sodium diclofenac prepared with a mixed base of glyceride and natural soya lecithin sustained the plasma diclofenac concentrations significantly in human subjects, with a three-times slower apparent absorption rate (absorption half-life: 2.9 h) in comparison with that after administration of a commercial suppository of sodium diclofenac (absorption half-life; 0.9 h). The addition of a high-melting point glyceride or hydrogenated soya lecithin in the suppository caused a slower apparent absorption rate of diclofenac with an absorption half-life of 6.3 h. Dissolution of diclofenac from the sustained-release suppository used in this study may occur according to the apparent leaching type mechanism proposed by Higuchi; i.e. the permeating rate of rectal fluid into the suppositorys matrix may regulate the release of diclofenac from the suppository.

Sustained-release of sodium diclofenac from suppository

Abstract The increased solubility of sodium diclofenac in a suppository base in the presence of lecithin resulted in a slow release of sodium diclofenac from the base. In a study using dogs, the administration of a sodium diclofenac suppository prepared from triglyceride and lecithin as bases (lecithin suppository) at a dose of 2 mg of the drug/kg dog weight maintained the plasma diclofenac concentration within an effective pharmacological range for relatively long periods without a transient high diclofenac concentration in the plasma. The bioavailability of diclofenac after administration of the suppository containing lecithin was equivalent to that observed following the administration of a conventional suppository prepared with only a triglyceride as the base. Rat rectal mucosal damage caused by sodium diclofenac was moderated by the administration of the lecithin suppository, probably due to the low concentration of sodium diclofenac in the rectal fluid due to a slow release of sodium diclofenac from the lecithin suppository.

The effect of adjuvants on the colonie absorption of cefmetazole and [Asu1,7]-eel calcitonin in rats: concentration dependent absorption pathways

Rat colonie absorption of cefmetazole and [Asu1,7]-eel calcitonin was enhanced by coadministration of sodium salicylate, disodium ethylenediaminetetraacetic acid, diethyl ethoxymethylenemalonate or trifluoperazine. Colonie absorption of cefmetazole and eel calcitonin, enhanced by various concentrations of either EDTA or trifluoperazine, appeared to occur via a paracellular pathway. Diethyl maleate did not enhance colonie absorption of eel calcitonin, but it did significantly enhance colonie absorption of cefmetazole, demonstrating the importance of a paracellular absorption pathway for eel calcitonin. Although low concentrations of DEEMM and salicylate enhanced the colonie absorption of only cefmetazole (having a low molecular weight of 471), those adjuvants at high concentrations remarkably enhanced the colonie absorption of both cefmetazole and the macromolecular peptide, eel calcitonin (mol. wt. 3363). This observation suggests two different adjuvant mechanisms, depending on the concentration of the adjuvant.