Nasal Absorption of Insulin in Dogs

Harai, Shota; Ikenaga, Toyotake; Matsuzawa, Tai

doi:10.2337/diab.27.3.296

Cited by 108 publications

(37 citation statements)

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“…Although there is abundant physical-chemical information concerning the micellar properties of bile salt molecules as well as their interactions with membrane and exogenous lipids (18,19), little is known about the mechanisms by which these molecules might enhance transmucosal absorption of drugs (17). As shown by us and others, bile salts promote the nasal absorption of insulin in man (20,21) as well as in laboratory animals (6,22). Nevertheless, previous studies in rats, employing a range of bile salt species, failed to define any useful structure-function relationships (23).…”

mentioning

confidence: 99%

“…However, efficacy of absorption is typically low and variable (1)(2)(3)(4)(5), and therapeutically important peptides of larger molecular size, such as insulin, are not absorbed to any appreciable degree (6). Within the gastrointestinal tract, bile salts promote the transmembrane movement of endogenous and exogenous lipids (7) and the transmembrane and/or paracellular movement of several small endogenous and exogenous polar molecules-e.g., water (7), inorganic electrolytes (7), polyethylene glycols (8), and oxalate (9).…”

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confidence: 99%

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Nasal absorption of insulin: enhancement by hydrophobic bile salts.

Gordon¹,

Moses²,

Silver³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

235

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We demonstrate that therapeutically useful amounts of insulin are absorbed by the nasal mucosa of human beings when administered as a nasal spray with the common bile salts. By employing a series of bile salts with subtle differences in the number, position, and orientation of their nuclear hydroxyl functions and alterations in side chain conjugation, we show that adjuvant potency for nasal insulin absorption correlates positively with increasing hydrophobicity of the bile salts' steroid nucleus. As inferred from studies employing various concentrations of unconjugated deoxycholate and a constant dose of insulin, insulin absorption begins at the aqueous critical micellar concentration of the bile salt and becomes maximal when micelle formation is well established. These and other data are consistent with the complementary hypotheses that bile salts act as absorption adjuvants by (i) producing high juxtamembrane concentrations of insulin monomers via solubilization in mixed bile salt micelles and (ii) forming reverse micelles within nasal membranes, through which insulin monomers can diffuse through polar channels from the nares into the blood stream.Certain small peptides can be absorbed through the nasal mucosa as a "snuff" or directly from aqueous solution (1-5). However, efficacy of absorption is typically low and variable (1-5), and therapeutically important peptides of larger molecular size, such as insulin, are not absorbed to any appreciable degree (6). Within the gastrointestinal tract, bile salts promote the transmembrane movement of endogenous and exogenous lipids (7) and the transmembrane and/or paracellular movement of several small endogenous and exogenous polar molecules-e.g., water (7), inorganic electrolytes (7), polyethylene glycols (8), and oxalate (9). Because of these functions, as well as their detergent-like properties on biomembranes (10), bile salts are potential adjuvants for transmucosal delivery of drugs and have been widely explored for this purpose (11-17). Although there is abundant physical-chemical information concerning the micellar properties of bile salt molecules as well as their interactions with membrane and exogenous lipids (18,19), little is known about the mechanisms by which these molecules might enhance transmucosal absorption of drugs (17). As shown by us and others, bile salts promote the nasal absorption of insulin in man (20, 21) as well as in laboratory animals (6, 22). Nevertheless, previous studies in rats, employing a range of bile salt species, failed to define any useful structure-function relationships (23). We now report structure-function studies on a series of naturally occurring bile salts by testing their ability to enhance insulin absorption across the human nasal mucosa when administered intranasally as an insulin/bile salt spray. Dramatic differences in insulin absorption were observed between closely related bile salt species; the pattern was shown to be determined by the hydrophilic-hydrophobic balance (24) of the hydroxyl-substituted steroi...

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mentioning

confidence: 99%

mentioning

confidence: 99%

Nasal absorption of insulin: enhancement by hydrophobic bile salts.

Gordon¹,

Moses²,

Silver³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

235

View full text Add to dashboard Cite

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“…22,23 Insulin is more stable at acidic pH, and the monomeric form absorbs rapidly in the alveolar region of the lungs. 24,25 Lowering the pH also causes paracellular permeability, possibly by displacing Ca 2+ from the tight junction. Hence, acidic pH was observed to favor higher penetration of insulin through the alveolar membrane and the pH of subsequent formulations (F5-F34) was 3.5.…”

Section: Resultsmentioning

confidence: 99%

Influence of absorption promoters on pulmonary insulin bioactivity

Kumar

Misra

2003

AAPS PharmSciTech

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KEYWORDS: insulin, combination of absorption promoters, blood glucose reduction, relative pulmonary bioactivity, pharmacodynamicsThe purpose of this research was to enhance the bioactivity of insulin by the pulmonary route using a combination of absorption promoters. Aliquots (100 µL) containing 1.0 IU/kg to 7.0 IU/kg doses of porcine insulin solutions with different classes of absorption promoters and combinations of these at 3 concentration levels were instilled intratracheally to the anesthetized rats. Blood concentrations of glucose were measured at specific time points. Out of 3 concentration levels of each of the absorption promoters used, the formulations having the least concentration with the maximum percentage of blood glucose reduction were selected for combining absorption promoters, and their pharmacodynamic parameters related to insulin absorption were determined. The pharmacodynamics of porcine insulin following subcutaneous administration of increasing doses were also determined. The relative pulmonary bioactivity of insulin in phosphate buffer pH 7.4 and citrate buffer pH 3.5 was 11.36% ± 1.27% and 43.20% ± 2.48%, respectively, compared to subcutaneous administration. Relative pulmonary bioactivity of 155.60% ± 5.19% was obtained when oleic acid sodium salt, sodium tauroglycocholate, bestatin, and chymostatin were coadministered in citrate buffer pH 3.5 solution. However, only 61.91% ± 3.21, 67.09% ± 3.23%, 67.24% ± 2.11%, and 69.84% ± 3.02% were obtained, respectively, upon incorporation of these absorption promoters individually. Absorption promoters in combination have significant potential for increasing the pulmonary bioactivity of insulin. These studies support the argument that pulmonary administration of insulin is a viable alternative to subcutaneous administration for diabetic patients.

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“…In the case of insulin absorption, inhibition of proteolysis and modification of the aggregation state of insulin were involved in the mechanism of enhanced absorption. 3,16) Therefore, the effect of aminated gelatins on insulin absorption was compared with that on CF absorption. Figure 7 shows the relationship between the AUC CF after nasal administration of CF and the D% after administration of insulin with various gelatins.…”

Section: Discussionmentioning

confidence: 99%

Effect of Aminated Gelatin on the Nasal Absorption of Insulin in Rats

Seki

Kanbayashi

Nagao

et al. 2005

Biological & Pharmaceutical Bulletin

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Absorption enhancers, which increase the permeability of drugs through epithelial membranes without damaging them, are especially useful for intranasal administration of peptide drugs. In this study, aminated gelatins, candidate enhancers, having different numbers of amino groups were prepared from gelatin (H-gelatin, isoelectric point‫,0.9؍‬ MW 100 kDa) and a partial gelatin hydrolysate (L-gelatin, isoelectric point‫,0.8؍‬ MW 5 kDa), and the enhancing effects on the nasal absorption of insulin, used as a model peptide drug, and 5(6)-carboxyfluorescein (CF), a paracellular marker, were examined in rats. The enhancing effect on insulin and CF depends on the MW and number of amino groups. A high correlation between the enhancing effects on insulin and CF was observed and this suggests that an increase in the paracellular permeability is the mechanism governing the nasal absorption-enhancement of aminated gelatins, at least as far as insulin and CF are concerned. The enhancing mechanism might be shared with other cationic polymers having absorption-enhancing effects.

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Nasal Absorption of Insulin in Dogs

Cited by 108 publications

References 0 publications

Nasal absorption of insulin: enhancement by hydrophobic bile salts.

Nasal absorption of insulin: enhancement by hydrophobic bile salts.

Influence of absorption promoters on pulmonary insulin bioactivity

Effect of Aminated Gelatin on the Nasal Absorption of Insulin in Rats

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