Insulin rectal delivery

Ritschel WA, Ritschel GB, Ritschel BEC, et al. Rectal delivery system for insulin. Methods Find Exp Clin Pharmacol 1988 10 645-656. 

The rectal cavity has the potential of convenient access and easy administration of suppositories or gels, although patient acceptance of rectal delivery is low in some cultures. It has a limited surface area (de Boer et al, 1992) and relatively high proteolytic activity (Lee et al, 1987), but with respect to administration of insulin the rectal route offers the particular physiological advantage of potential delivery, via the upper rectal veins, into the portal system. This would mimic the natural secretion of insulin and result in reduced peripheral hyperinsulinemia. However, nearly two-thirds of the insulin absorbed firom the rectum reaches the general circulation via the lymphatic pathway (Caldwell et al, 1982). 

Nidtihata, T., Liversidge, G., and Higuchi, T., 1983a, Effect ofaprotiiun on the rectal delivery of insulin,/. Pharm. Pharmacol. 35 616-617. 

Introduction Oral Delivery of Proteins and Peptides Buccal Delivery Vaginal Delivery of Insulin Transdermal Delivery Rectal Delivery of Protein Drugs... 

Aungst BJ, Rogers NJ (1988a) Site dependence of absorption-promoting actions of laureth-9, Na salicylate, Na2EDTA, and aprotinin on rectal, nasal, and buccal insulin delivery. Pharm Res 5 305-308... 

In 1978, two papers, one from Israel and one from Japan, published in the same issue of the Journal of Pharmacy and Pharmacology reported successful rectal insulin absorption by use of polyoxyethylene (POE) ether nonionic surfactants [59,60], These reports led to further investigations on the use of surfactants for enhancing the absorption of macromolecules. Later in this chapter we will discuss the work done on the enteral delivery of large molecules with nonionic and anionic promoters, which have been the most investigated ones to date. 

Furthermore, the permeation-enhancing effects of NO donors seem to be strongly dose-dependent. Utoguchi et al. (1998) reported that the absorptionenhancing effect of S-nitroso-A-acetyl-penicillamine for rectal insulin absorption was dose-dependent over the range of 0.25-4.0 mg in rats. Similarly, Salzman et al. (1995) demonstrated that incubation with sodium nitroprusside resulted in a concentration-dependent increase in the transepithelial transport of fluorescein sulphonic acid in Caco-2 cells. To our knowledge the potential of NO donors for oral macromolecular delivery, however, has so far not been tested in a valid animal model. 

With the advent of new biotechnological techniques endogenous compounds like insulin, buserelin or octreotide have become available at affordable prices. All of these substances still have to undergo needle application. Until today the development of alternative delivery systems for the nasal, buccal, peroral, rectal and pulmonary routes for the administration of those class III drugs according to the biopharmaceutics classification system (BCS) (Amidon et al. 1995) could not keep pace with this development of endogenous compounds or is not economic enough for the health care payers (e.g. insulin application via the pulmonary route). 

Bile salts were also used for the enhancement of drug absorption, but several studies indicated severe damage due to their use in rectal drug delivery. Sodium tauro-24, 25-dihydrofusidate (STDHF) had a positive effect on the availability of cefoxitin, vasopres-sine, and insulin in rats. ... 

The fact that rectal administration in humans only partially avoids delivery of the drug to the portal system has been suggested as an advantage of rectal administration of insulin over parenteral administration.Delivery of insulin to the portal blood system is suggested to be more physiological than delivery to the peripheral cells from subcutaneous injections. 

Teng, C.L.D. Groves, M.J. The effect of compactional pressure on urease activity. Pharm. Res. 1988, 5, 776-780. Alur, H.H. Paher, S.I. Mitra, A.K. Johnston, T.P. Transmucosal sustained delivery of chlorpheniramine maleate in rabbits using a novel, natural mucoadhesive gum as an excipient in buccal tablets. Int. J. Pharm. 1999,188, 1-10. Kondo, S. Sugimoto, I. Moment analysis of intravenous, intraduodenal, buccal, rectal, and percutaneous nifedipine in rats. J. Pharmacobio. Dyn. 1987, 10, 462 69. Yamamoto, A. Hayakawa, E. Lee, V.H. Insulin and proinsulin proteolysis in mucosal homogenates of the albino rabbit implications in peptide delivery from nonoral routes. Life Sci. 1990, 26, 2465-2474. 

Hormones, proteins, and small peptides are not suitable for oral administration without complex modifications in the formulation. A variety of approaches for insulin delivery, as a model drug, have been attempted to improve on its bioavailability. Advances have been realized in the delivery of insulin through oral, nasal, rectal, dermatologic, and ocular routes. Proteins can also be delivered transdermally, using a lipid-based, biphasic delivery system in therapeutic quantity. 

The ocular, buccal, rectal, and vaginal routes of administration all have inherent limitations and serious drawbacks for delivery of insulin and therefore are highly unlikely to be of any use for chronic insulin therapy. 

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