Absorption of insulin

S Hirai, T Yashiki, H Mima. (1981). Mechanisms for the enhancement of the nasal absorption of insulin by surfactants. Int J Pharm 9 173-184. 

JP Longenecker, AC Moses, JS Flier, RD Silver, MC Carey, EJ Dubovi. (1987). Effects of sodium taurodihydrofusidate on nasal absorption of insulin in sheep. J Pharm Sci 76 351-355. 

Oh CK, Ritschel WA (1990) Biopharmaceutic aspects of buccal absorption of insulin. Methods Find Exp Clin Pharmacol 12 205-212... 

Zhang J, Niu S, McJames S, Stanley T (1991a) Buccal absorption of insulin in an in vivo dog model—evidence of mucosal storage. Pharm Res 8 S—155... 

Seki T, Kanbayashi H, Nagao T, Chono S, Tomita M, Hayashi M, Tabata Y, Morimoto K (2005) Effect of aminated gelatin on the nasal absorption of insulin in rats. Biol Pharm Bull 28 510-514. 

Wise S, Chien J, Yeo K, Richardson C (2006) Smoking enhances absorption of insulin but reduces glucodynamic effects in individuals using the Lilly-Dura inhaled insulin system. Diabet Med 23 510-515. 

M. Hashizume, T. Douen, M. Murakami, A. Yamamoto, K. Takada, S. Muranishi, Improvement of Large Intestinal Absorption of Insulin by Chemical Modification with Palmitic Acid in Rats , J. Pharm. Pharmacol. 1992, 44, 555-559. 

Takeuchi, H., Yamamoto, H., Niwa, T., Hino, T., and Kawashima, Y., Enteral absorption of insulin in rats from mucoadhesive chitosan-coated liposomes, Pharm. Res., 13 896-901 (1996). 

The difficulty with HLB as an index of physicochemical properties is that it is not a unique value, as the data of Zaslavsky et al. (1) on the haemolytic activity of three alkyl mercaptan polyoxyethylene derivatives clearly show in Table 1. Nevertheless data on promotion of the absorption of drugs by series of nonionic surfactants, when plotted as a function of HLB do show patterns of behaviour which can assist in pin-pointing the necessary lipophilicity required for optimal biological activity. It is evident however, that structural specificity plays a part in interactions of nonionic surfactants with biomembranes as shown in Table 1. It is reasonable to assume that membranes with different lipophilicities will"require" surfactants of different HLB to achieve penetration and fluidization one of the difficulties in discerning this optimal value of HLB resides in the problems of analysis of data in the literature. For example, Hirai et al. (8 ) examined the effect of a large series of alkyl polyoxyethylene ethers (C4,C0, Cj2 and C 2 series) on the absorption of insulin through the nasal mucosa of rats. Some results are shown in Table II. 

Relationship between HLB values of nonionic surfactant ethers and esters and the nasal absorption of insulin (lOU/kg) in rata measured as a percentage reduction (D) in glucose levels from 0-4h. Surfactant applied at a concentration of 1 . 9 ethers, 0 esters. Data... 

The enzymatic degradation of insulin was also shown to occur in the cytosol of alveolar cells, the pH optimum of the proteases being 7.4 [38]. To what extent intracellular proteases play a significant role in limiting the absorption of insulin is not clear, since the size of insulin likely allows paracellular transport over the alveolar epithelium. However, for proteins of higher molecular weight, that require transcellular transport, these proteases might certainly limit bioavailability. 

Liposomes were formed from 1,2-dipalmitoylphosphatidylcholine (DPPC) and cholesterol (Choi) and the effect of liposomal entrapment on pulmonary absorption of insulin was related to oligomerization of insulin (Liu et al. 1993). Instillation of both dimeric and hexameric insulin produced equivalent duration of hypoglycemic response. However, the initial response from the hexameric form was slightly slower than that from dimeric insulin, probably due to lower permeability across alveolar epithelium of the hexameric form caused by larger molecular size. The intratracheal administration of liposomal insulin enhanced pulmonary absorption and resulted in an absolute bioavailability of 30.3%. Nevertheless, a similar extent of absorption and hypoglycemic effects was obtained from a physical mixture of insulin and blank liposomes and from liposomal insulin. This suggests a specific interaction of the phospholipid with the surfactant layer or even with the alveolar membrane. 

A composition based on diketopiperazine derivatives (3,6-bis (N-fumaryl-N-(n-butyl) amino-2, 5-diketopiperazine) has been investigated as a pulmonary drug delivery system, termed Technospheres (Pharmaceutical Discovery Corp., Elmsford, NY) (Pohl et al. 2000 Steiner et al. 2002). The diketopiperazine derivatives self-assemble into microparticles at low pH with a mean diameter of approximately 2 pm. During self-assembly, diketopiperazine derivatives microencapsulate peptides present in the solution. Insulin incorporated in diketopiperazine derivatives (TI) was administered to five healthy humans by the use of a capsule-based inhaler with a passive powder deagglomeration mechanism. Relative and absolute bioavailability of TI in the first 3 hours (0-180 min) were 26 12% and 15 5%, and for 6 hours (0-360 min) 16 8% and 16 6%, respectively (Steiner et al. 2002). The time to peak action for glucose infusion rates was shorter with both IV (14 6 min) injection and inhalation (39 36 min), as compared to SC administration (163 25 min). This rapid absorption of insulin would be beneficial for diabetic patients who need to rapidly affect their glucose levels. 

Fujii, S., Yokoyama, T., Ikegaya, K., Sato, F., and Yokoo, N. (1985). Promoting effect of the new chymotrypsin inhibitor Fk-448 on the intestinal absorption of insulin in rats and dogs. J. Pharm. Pharmacol., 37, 545-549. 

Femandez-Urrusuno et al. (1999) investigated the potential of chitosan (MW <50,000-130,000 DD 70-87%) nanoparticles as a system for improving the systemic absorption of insulin following nasal instillation. Nanoparticles prepared by ionotropic gelation with tripolyphosphate... 

Fernandez-Urrusuno, R., Calvo, P., Remunan-Lopez, C., Vila-Jato, J. L., and Alonso, M. J. (1999). Enhancement of nasal absorption of insulin using chitosan nanoparticles. Pharm. Res. 16,1576-1581. 

The effects of insulin are modified by various factors. The speed and extent of absorption of insulin depends, for example, on the site of injection (1), the depth of the subcutaneous injection, skin temperature (2), the presence of lipodystrophy, and variation in the extent of inactivation of injected insulin. The disposal of insulin depends on many factors. Exercise and hard work lower the blood glucose and thereby increase the effect of insulin. Infections and obesity reduce its effect. The timing of food intake and the composition of meals are also related to the action of insulin. A thin layer of fat, as sometimes occurs in the upper arm or in the thighs of thin men, can result in intramuscular injection, leading to faster absorption of long-acting insulins. This can reduce the absorption time by half (3). The major factors that affect the fate of injected insulin (and thereby also its risks) are listed in Table 1 (4). 

It may be that the more rapid diffusion and absorption of insulin lispro in diabetics who achieve tight metabolic control and have hypoglycemia unawareness destabilizes glycemic control. 

The absorption of insulin glargine was delayed compared with protamine zinc insulin in a study using radioactive tracers (11). 

Touitou, E., and M. Donbrow. 1983. Promoted rectal absorption of insulin Formulative parameters involved in the absorption from hydrophilic bases. Int J Pharm 15 13. 

Mesiha, M.S., M.B. Sidhom, and B. Fasipe. 2005. Oral and subcutaneous absorption of insulin poly(isobutylcyanoacrylate) nanoparticles. Int J Pharm 288 289. 

Shao, Z., et al. 1994. Cyclodextrins as mucosal absorption promoters of insulin. II. Effects of beta-cyclodextrin derivatives on alpha-chymotryptic degradation and enteral absorption of insulin in rats. Pharm Res 11 1174. 

Touitou, E., M. Donbrow, and E. Azaz. 1978. New hydrophilic vehicle enabling rectal and vaginal absorption of insulin, heparin, phenol red and gentamicin. J Pharm Pharmacol 30 662. 

Shichiri, M., et al. 1978. Increased intestinal absorption of insulin An insulin suppository. J Pharm Pharmacol 30 806. 

Guzman, A., and R. Garcia. 1990. Effects of fatty ethers and stearic acid on the gastrointestinal absorption of insulin. P R Health Sci J 9 155. 

Eaimtrakarn, S., et al. 2002. Absorption enhancing effect of Labrasol on the intestinal absorption of insulin in rats. J Drug Target 10 255. 

Contrary to the above-mentioned inhibitors, FK-448 (4-(4-isopropylpiperadinocarbonyl) phenyl 1,2,3,4,-tetrahydro-l-naphthoate methanesulfonate) is a low toxic as well as a potent and specific inhibitor of chymotrypsin. The effectiveness of this substance as an intestinal absorption enhancer has already been demonstrated in rats as well as in dogs. Coadministra-tion of FK-448 led to an enhanced absorption of insulin, which was monitored by a decrease in blood glucose level. The inhibition of chymotrypsin was found to be mainly responsible for the enhanced bioavailability [3]. Camostat mesilate (A,A -dimethyl carbamoylmcthyl-/)-(//-guanidino-benzoyloxy)phenylacetate methanesulfonate) [5] and Na-glycocholate [5,27] are further representatives of this class, exhibiting low toxicity. 

Watanabe, Y., et al. 1992. Absorption enhancement of polypeptide drugs by cyclodextrins. I. Enhanced rectal absorption of insulin from hollow-type suppositories containing insulin and cyclodextrins in rabbits. Chem Pharm Bull 40 3042. 

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