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Enteral Absorption of Water-In-Oil-In-Water Insulin Emulsions in Rabbits

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Enteral Absorption of Water-In-Oil-In-Water Insulin Emulsions in Rabbits Diabetologia 10, 317--321 (1974) by Springer-Verlag 1974 Enteral Absorption of Water-in-Oil-in-Water Insulin Emulsions in Rabbits M. Shichiri, Y. Shimizu, u Yoshida, R. Kawamori, M. Fukuchi, Y. Shigeta and H. Abe First Department of Medicine, Osaka University Medical School, Osaka, Japan Received: January 3, 1974, and in revised form: April 4, 1974 Summary. Water-in-oil-in-water (W/O/W) insulin the administration of aqueous insulin. Insulin, when emulsions with a concentration of 100 U/ml of insulin administered to the stomach, did not cause hypoglycemia were prepared, and the possible absorption of insulin in at doses up to 150 U/kg. W~e~ W/O/W insulin emulsions emulsion form was examined. The following results were were administered orally, on the other hand, definite obtained: W/O/W insulin emulsions were quite resistant responses were observed in 3 out of 7 rabbits with 100 to proteolytie enzymes in vitro. In the presence of U/kg and in 4 out of 7 rabbits with 150 U/kg. }'or devel- pancreatic lipase, however, W/O/W insulin emulsion oping an effective method for oral administration of gradually lost its activity by the action of proteoly~ic insulin, the present results indicate a possible means of enzymes. When administered to the jejunum at doses protecting insulin molecule from proteolytie destruction, over 10 U/kg, a significant and consistent increase in and of facilitating intestinal absorption of insulin. plasma insulin was observed, followed by a fall in blood glucose. The infusion of W/O/W insulin emulsions into Key words: Water-in-oil-in-water emulsions, insulin, the jejunum was three to four times more effective than enteraI absorption, hypoglycemia, plasma insulin, rabbit. As judged by plasma insulin and hypoglycemic and immunologically in rabbits. The effectiveness of responses, we have demonstrated that insulin can be oral administration of such emulsions was also ex- absorbed from the intestine of mammals in a physiolo- amined. gically active form [1--3]. In these experiments, the hypoglyeemie effect is most marked in the rabbits with Thiry-Vella loop, into which no pancreatic secre- Materials and Methods tion entered, but the fraction absorbed is relatively small [1]. The relatively small absorption of insulin is, Preparation of water-in-oil-in-water (W/O/W) in- therefore, attributable either to inactivation of the sulin emulsions : major portion by intestinal proteolytic enzymes or in- A method for preparing W/O/W insulin emulsions herent physical obstacle to diffusion imposed by the [6] was modified as follows. Insulin solution (26.4 U/ protein character of insulin. rag, bovine crystalline insulin, Sigma Chem. Co.), To facilitate enteral absorption of insulin, represent- 1000 U/ml, was made in 0.003 M ZnCI~ at pH 2.2. The ative attempts have been directed to main objectives; oil phase was 0.03 M palmitic acid in octyl-deeyl tri- 1. inhibition of proteolytic enzymes, 2. increase in glyceride (Nisshin Seiyu Co., Japan). The oil phase permeability of the intestinal wall. We have attempted (12 ml) was placed in a beaker, sonification was begun to prepare insulin derivatives or substitutes which are and the insulin solution (8 ml) was Mlowed to drain not affected by digestive enzymes [4, 5]. It is interest- from a pipette into the beaker. Sonifieation was con- ing to note the possible use of water-in-oil-in-water tinued for about 20 see with a sonifier (model USV- emulsions as a means of facilitating gastrointestinal 3000 V, 22 KtIz). This resulted in a water-in-oil (W/O) absorption of normally non-absorbed water soluble bio- insulin emulsions. Twenty milliliter of the resulting polymers. Engel et al. [6] reported that intraduodenal W/O emulsions was added to a second aqueous phase injection of such an emulsion containing insulin re- (60 ml) containing 1% sodium lauryl sulfate (Nikko suited in a significant hypoglycemie activity in rats. Chem. Co., Japan). Sonification was carried out for In their experiments, however, the enteral absorption 20 see. The resulting emulsions (W/O/W insulin of water-in-oil-in-water insulin emulsions was measured emulsions) was adjusted to pit 6.5 with dilute NaOH only indirectly by measuring the hypoglycemie re- and stored at 4~ for up to one month. The W/O/W sponse. A more direct approach can be made by insulin emulsions thus prepared contained insulin at a measuring plasma insulin concentrations. concentration of 100 U/ml emulsions. In a preliminary To obtain additional information on the enterM experiment, no demonstrable loss of insulin activity absorption of insulin, we have prepared water-in-oil- was observed after sonification of insulin solution. In- in-water insulin emulsions with a concentration of sulin free emulsions were prepared as a control. 100 U/ml of insulin and analyzed the efficiency of Extraction of insulin from W/O/W insulin emul- intestinal administration of such emulsions biologically sions: Di~betologia, Vol. 10 22 318 IV[. Shichiri et al. : Enteral Absorpt, ion of Insulin Emulsions To extract insulin from W/O/W insulin emulsions, an equivalent dose of crystalline bovine insulin was a method described by Grodsky and Forsham [7] was given. modified as follows. A mixture of 0.5 ml of W/O/W in- Blood samples were obtained from a marginal ear sulin emulsions and 9.5 ml of acidic alcohol (15 ml of vein at 0, 30, 60, 90, 120, 150 and 180 min, and the 12 N hydrochloric acid diinted to one liter with 75~/o blood glucose was determined by the method of ethanol) was agitated for overnight at 4 ~C and centri- Somogyi-Nelson [8]. Immunoreactive insulin was fuged for 20 rain at 10000 rpm. After centrifugation measured by the method of Randle and Hales [9]. In- the precipitate was extracted again. The two snper- sulin immunoassay kit was purchased from the Radio- natants were combined and adjusted to pH 8.5 to 9.0 chemical Center, Amersham, England. with concentrated ammonium hydroxide. The super- natant thus obtained was poured into 15 volumes of cold acetone, and the mixture was chilled overnight at Results 4 ~C. After centrifugation the precipitate was dried in vacuum until the time of insulin assay. During the Properties of W/O/W Insulin Emulsions extraction from W/O/W insulin emulsions incubated The diameters of the W/O droplets in water were in with proteoly~ic enzymes, a very small amount of the range of 0.6 to 2.0 ~m. The degree of hydrolysis of insoluble proteins was precipitated when acidic alcohol W/O/W insulin emulsions by some proteolytic enzymes was adjusted to pH 8.5. After 30 rain at 4 ~C, insoluble was studies in vitro. W/O/W insulin emulsions were proteins were removed by centrifugation. In the present quite resistant to the action of pepsin, ~-chymotrypsin experiments, no demonstrable interference with the and trypsin. In the presence of pancreatic lipase, how- insulin assay was observed in the extract from insulin ever, W/O/W insulin emulsions gradually lost their free emulsions incubated with proteolytic enzymes. activity by the action of proteolytic enzymes, so that The extraction of W/O/W insulin emulsions with about 33~/o of insulin activity was retained after 3 h acidic alcohol resulted in approximately 80 to 86% incubation in vitro. recovery of insulin. Administration of W/O/W Insulin Emulsions to the Hydrolysis of W/O/W insulin emulsions with pro- Jejunum teolytic enzymes : The hypoglycemic effects of W/O/W insulin emul- Pepsin (two times crystallized, 3200 U/rag, Sigma sions given to the jejunum at doses of 10, 20, 40 and Chem. Co.), ~-chymotrypsin (three times crystallized, i00 U/kg are shown in Table 1. In rabbits with saline 3200 U/rag, Sigma Chem. Co.), trypsin (lyophilized, or W/O/W emulsions serving as control, the blood glu- 200 U/mg, Worthington Biochem. Corp.) and pan- cose levels increased gradually, but these changes were creatic lipase (crude from hog pancreas, 90 U/rag, not statistically significant. When insulin with doses Sigma Chem. Co.) were used in this experiment. W/O/ over 40 U/kg was infused into the jejunum via an W insulin emulsions containing 10 mg of insulin were indwelling catheter, there was a significant decrease in incubated for 3 h at 37~ with pepsin (weight ratio of blood glucose. With W/O/W insulin emulsions, on the substrate to enzyme, 200:1) in 0.2 M citrate buffer, other hand, a significant and consistent decrease in pH 2.2, and with e-chymotrypsin (10:1), trypsin (10: 1) blood glucose was found with doses over 10 U/kg. As and lipase (400: i) in 0.2 5{ borate buffer, pH 8.0. Since compared to the results with insulin, a greater fall in pancreatic lipase preparation contained a small amount blood glucose and a longer duration of hypoglycemia of trypsin, trasylol (Bayer Pharmaceutical Co.) was were observed with W/O/W insulin emulsions. added in the digestion mixtures at a concentration of The intrajejunal administration of insulin at doses 2000 KIE/ml to inhibit tryptic activity. Aliquots of the over 40 U/kg increased the levels of insulin in plasma. incubation mixture were withdrawn at 0, 60, 120 and On the other hand, a significant increase in plasma in- 180 rain, and extracted for the assay of insulin. sulin was observed when 10 U/kg of W]O/W insulin Enteral administration of W/O/W insulin emul- emulsions were infused. The magnitude of the increase sions : varied with the dose given. With a dose of 100 U/kg of Nale white rabbits, weighing from 2.0 to 2.5 kg, W/O/W insulin emulsions, the plasma insulin increased were fasted overnight and divided at random into two to a peak of 236 ~U/ml.
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