Insulin Suppository Research Articles

In vitro characteristics of an insulin suppository developed using palm oil base (HAMIN®) and its hypoglycaemic effect on rabbits

The long-term administration of insulin requires the development of new delivery routes. Using a base developed in-house, called HAMIN®, an insulin suppository containing 100 units (U) of insulin was formulated. The suppository was subjected to stability testing at various temperatures and the assay value was monitored. Other physical factors such as hardness, disintegration time, thermal analysis and dissolution were also tested. The suppository released more than 80% of its drug content in 30 min, and was stable for up to 11 months at −20°C. The suppository effect was studied on 11 New Zealand white rabbits, with body weight ranging from 1.6 to 2.1 kg. The results show that there was a marked reduction in glucose content when the suppository was inserted. The average drop in glucose content was 2.7 mmol/L in 15 min from the time of insertion. The maximum drop in glucose content reached 3.9 mmol/L in 2 h. Plasma insulin level, quantified using an enzyme-linked immunosorbent assay, showed a value of more than 100 µIU insulin/ml blood after 30 min. Although the insulin bioavailability was expectedly low, the rate at which the hypoglycaemic effect took place and the percentage of glucose reduction were comparable to results after subcutaneous injection.

Effectiveness of insulin suppositories in diabetic patients.

Experimental insulin suppositories regulated postprandial hyperglycaemia in diabetic patients. The insulin suppositories seemed also to avoid hyperinsulinaemia. The formulation with more rapid dissolution of insulin, which contained a solid dispersed form of insulin, effectively reduced the insulin dose required.

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.

Rectal absorption of insulin suppositories in rabbits.

When insulin solutions (100 U kg-1) at various pH values were placed in the rectum of rabbits, a large decrease in blood glucose concentration was observed except at the pH close to the iso-electric point of insulin. The effect of surface-active agents on the rectal absorption of insulin was examined by measuring the blood glucose concentration after the administration of 2 or 5 U kg-1. Non-ionic ether type, anionic, cationic and amphoteric surfactants as well as bile acids increased the absorption. The optimal effect with suppositories was reached with the addition of 1% polyoxyethylene (9) lauryl alcohol ether. Insulin suppositories containing agents enhancing rectal absorption were compared with the insulin for intravenous, intramuscular and subcutaneous injection. The changes of blood glucose and plasma immuno-reactive insulin concentration after rectal administration of insulin were similar to those after intravenous injection.

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

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

Increased intestinal absorption of insulin: an insulin suppository.

Increased intestinal absorption of insulin: an insulin suppository.

Effect of insulin suppositories in type I diabetic patients (preliminary communication).

Eight type I diabetic patients received a subcutaneous injection of 10 IU regular insulin, or--after a one week interval--a suppository containing 75 IU crystalline insulin, the surfactant Brij 58, and the basic mass. In all patients there was a disease in blood glucose (onset after 20 min, maximum effect after 50 min, end of the effect after 90 min), and the plasma IRI level increased. However, the effect was attenuated in relation to the control test employing s.c. administration. The ratio of subcutaneous to rectal doses required to achieve the same effect was between 1:18 and 1:26.

Effect of Different Bile Salts on the Relative Hypoglycemia of Witepsol W35 Suppositories Containing Insulin in Diabetic Beagle Dogs

Insulin suppositories were formulated using Witepsol W35 as a base to investigate the effect of various bile salts/acids on the plasma glucose concentration of diabetic beagle dogs. Comparison of the effect of these formulations was made with that produced by insulin subcutaneous injections. Of the bile salts/acids studied, incorporation of 100 mg of deoxycholic acid (DCA), sodium cholate (NaC), or sodium deoxycholate (NaDC) with insulin (10 U/Kg) showed that suppositories containing NaDC produced the highest area under the curve (AUC) and relative hypoglycemia (RH) of 290 ± 83 mg%h and 28% ± 8.1%, respectively. To study the optimum amount of NaDC in insulin suppositories to produce the highest RH, 50–200 mg/suppository were used, and we found that 150 mg NaDC produced 35% ± 13% RH. We also studied the influence of different doses of insulin (5–20 U/kg) in the presence of NaDC (100 mg). It was found that increase of the insulin dose was accompanied by an increase in AUC and maximum reduction in plasma glucose level Cmax. A combination of NaDC (100 mg) and NaC (50 mg) produced an AUC of 252 ± 13 mg% h and an RH of 49% ± 2.6%, which were higher than produced by either of its individual components (NaC 50 mg or NaDC 100 mg) when used alone or when compared with an equivalent amount of NaDC (150 mg). When the effect of sodium taurocholate (NaTC) and sodium taurodeoxycholate (NaTDC) was studied, it was found that an insulin suppository containing 100 mg of either NaTC or NaTDC produced an RH equivalent to that produced previously with a mixture of NaDC (100 mg) and NaC (50 mg). On the other hand, NaC (50 mg) did not improve the hypoglycemic effect of NaTC any further. In conclusion, a relative hypoglycemia of about 50% can be reached using insulin suppositories containing Witepsol W35 as a base and NaDC plus NaC (100 mg plus 50 mg, respectively), NaTDC (100 mg), or NaTC (100 mg) as rectal absorption enhancers of insulin. A desirable hypoglycemia, expressed as Cmax, and/or AUC can be reached by adjusting the insulin dose in the formulation according to the degree of hyperglycemia.

経皮経粘膜吸収とＤＤＳ インスリン製剤への経皮・経粘膜応用

In order to control diabetic patients, basal and postprandial insulin supplementation must be needed. To facilitate rapid delivery or stabilize delivery of subcutaneous insulin, biotechnology realizes ultra-rapid delivered insulin and slowly delivered insulin. Ultra-rapid insulin well controlled postprandial hyperglycemia of diabetics by injection immediately before meal-intake. Slowly-delivered insulin may stabilize insulin delivery from subcutaneous depot of insulin and reduce the frequency of hypoglycemia. Various types of transmucosal delivery of insulin are established, such as insulin suppository, intranasal insulin, inhaled insulin, etc. Insulin suppository can be absorbed rapidly as intramuscular injection of insulin and control daily glycemic excursion by applying insulin suppository after every meal. As inhaled insulin, crystalline powder is inhaled for 3 minutes and insulin is appeared immediately in plasma. Insulin action lasts for more than 5 hours after inhalation. Thus, these approaches may improve “quality of life” of diabetic patients.

Relative Hypoglycemia of Rectal Insulin Suppositories Containing Deoxycholic Acid, Sodium Taurocholate, Polycarbophil, and Their Combinations in Diabetic Rabbits

In this study, insulin suppositories containing 50 U insulin incorporated with 50 mg of deoxycholic acid, sodium taurocholate, or both were placed in the rectum of alloxan-induced hyperglycemic rabbits. A large decrease in plasma glucose concentrations was observed, and the relative hypoglycemias were calculated to be 38.0%, 34.9%, and 44.4%, respectively, compared with insulin subcutaneous (s.c.) injection (40 U). Insulin suppositories containing 50 mg polycarbophil alone or mixed with 50 mg deoxycholic acid produced relative hypoglycemia of 43.1% and 42.2%, respectively. The most pronounced effect was observed with the addition of polycarbophil to the suppository formulation containing a combination of deoxycholic acid and sodium taurocholate, which produced a 56% relative hypoglycemia compared with subcutaneous injection. These suppository formulations could be very promising alternatives to the current insulin injections, being roughly half as efficacious as subcutaneous injection.

Effectiveness of Rectal Insulin Suppositories Containing Sodium Cholate in Normal and Insulin Dependent Diabetic Subjects

The effectiveness of 100-U porcine insulin suppository containing 5% sodium cholate was examined in 3 normal volunteers (controls) and 15 diabetics. The hypoglycaemic response, in controls, started at 15 min, peaked at 30 min and returned to the initial level after 45 min, while in diabetics, started at 15 min, peaked at 120 min and persisted for the duration of the study (150 min). The maximum percent reduction in plasma glucose was found to be significantly greater in controls than in diabetics, while the AUC for percent glucose reduction was greater in diabetics than in controls. This was accompanied by a significant rise in serum insulin in controls than in diabetics. The serum insulin peaked at 15 min and remained above the initial value for 45 and 120 min, post administration, in controls and diabetics, respectively. Thus, rectal insulin could be considered as alternative to existing therapies.

Insulin suppositories can inhibit postprandial hyperglycaemia

Insulin suppositories can inhibit postprandial hyperglycaemia

An effective formulation for an insulin suppository; examination in normal dogs

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.

Trials of rectal insulin suppositories in healthy humans

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.

Adjuvant Effects of Glyceryl Esters of Acetoacetic Acid on Rectal Absorption of Insulin and Inulin in Rabbits

□ The promoting effect of glyceryl esters of acetoacetic acid on the rectal absorption of insulin and inulin was studied. A decrease in the serum glucose level was observed in rabbits following the administration of an insulin suppository containing glyceryl-1,3-diacetoacetate (adjuvant II) or l,2-isopropylideneglycerine-3-acetoacetate (adjuvant IV). The promoting effects of adjuvants II and IV on the rectal absorption of insulin and inulin were suppressed by the addition of calcium and magnesium to the suppository. This indicates that adjuvant interaction with the calcium and magnesium ion located in the rectal membrane is involved in the enhanced absorption of insulin and inulin. Adjuvant release from the suppository formulation in addition to adjuvant lipid solubility were found to be other important factors for enhanced absorption of insulin and inulin.

The effectiveness of rectal administration of insulin suppository on normal and diabetic subjects.

The effectiveness of insulin administration by rectal suppository was examined in normal and non-insulin-dependent nonobese diabetic subjects. A 100-U insulin suppository (mean 1.8 U/kg) given to the diabetic subjects caused four times as great a fall in plasma glucose compared with the normal subjects given the same dose (mean 1.6 U/kg). The insulin response after suppository administration demonstrated a significantly positive correlation (r = 0.83, P less than 0.01) with the plasma glucose level before administration. Diabetic subjects given a 100-U insulin suppository (mean 1.7 U/kg) 15 min after meals three times daily showed a significant (P less than 0.05) improvement in postprandial hyperglycemia accompanied by a restoration of the normal circadian profile of plasma IRI and a reduction of urinary glucose from 26 +/- 5.9 to 2.0 +/- 1.0 g/day. No untoward reactions were observed. These data strongly imply a unique characteristic of the insulin suppository in spite of low bioavailability.

Effect of Insulin Suppository on Daily Profiles of Plasma Glucose and Insulin Concentrations in Diabetic Patients

Effect of Insulin Suppository on Daily Profiles of Plasma Glucose and Insulin Concentrations in Diabetic Patients

Daily. Administration of Insulin Suppositories to Alloxan Diabetic Dogs

Daily. Administration of Insulin Suppositories to Alloxan Diabetic Dogs