Peptide rectal absorption

Many drugs can now be delivered rectally instead of by parenteral injection (intravenous route) or oral administration. Generally, the rectal delivery route is particularly suitable for pediatric and elderly patients who experience difficulty ingesting medication or who are unconscious. However, rectal bioavailabilities tend to be lower than the corresponding values of oral administration. The nature of the drug formulation has been shown to be an essential determinant of the rectal absorption profiles. The development of novel absorption enhancers with potential efficacy without mucosal irritation (low toxicity) is very important. The delivery of peptide and protein drugs by the rectal route is currently being explored and seems to be feasible. 

De Boer, A.G., E.J. Van Hoogdalem, and D.D. Breimer. 1992. (D) Routes of delivery Case studies, (4) rate-controlled rectal peptide drug absorption enhancement. Adv Drug Deliv Rev 8 237. 

In this chapter, we especially focus on the strategies for enhancement of rectal absorption of various drugs including peptides and proteins from rectal mucosa using pharmaceutically useful excipients, cyclodextrins (CyDs), and the other absorption enhancers. 

Many reports have indicated the findings that the effects of CyDs on the rectal delivery of drugs depend markedly on vehicle type (hydrophilic or oleaginous), physicochemical properties of the complexes, and an existence of tertiary excipients such as viscous polymers. The enhancing effects of CyDs on the rectal absorption of lipophilic drugs are generally based on the improvement of the release from vehicles and the dissolution rates in rectal fluids, whereas those of CyDs on the rectal delivery of poorly absorbable drugs such as antibiotics, peptides,... 

As mentioned above, the rectal route is very attractive for systemic delivery of peptide and protein drugs, but rectal administration of peptides often results in very low bioavailability due to not only poor membrane penetration characteristics (transport barrier) but also due to hydrolysis of peptides by digestive enzymes of the GI tract (enzymatic barrier). Of these two barriers, the latter is of greater importance for certain unstable small peptides, as these peptides, unless they have been degraded by various proteases, can be transported across the intestinal membrane. Therefore, the use of protease inhibitors is one of the most promising approaches to overcome the delivery problems of these peptides and proteins. Many compounds have been used as protease inhibitors for improving the stability of various peptides and proteins. These include aprotinin, trypsin inhibitors, bacitracin, puromycin, bestatin, and bile salts such as NaCC and are frequently used with absorption enhancers for improvement in rectal absorption. 

Nishihata, T., et al. 1984. The effects of salicylate on the rectal absorption of phenylalanine and some peptides, and the effects of these peptides on the rectal absorption of cefoxitin and cefmetazole. J Pharm Sci 73 1326. 

Yata, N., et al. 1985. Enhanced rectal absorption of sodium ampicillin by TV-acyl derivatives of collagen peptide in rabbits and rats. J Pharm Sci 74 1058. 

Luangtana-anan M, Opanasopit P, Ngawhirunpat T, Nunthanid J, Sriamornsak P, Limmat-vapirat S, Lim LY (2005) Effect of chitosan salts and molecular weight on a nanoparticulate carrier for therapeutic protein. Pharm Dev Technol 10(2) 189-196 Mackay M, Phillips J, Hastewell J (1997) Peptide drug delivery Colonic and rectal absorption. Adv Drug Del Rev 28(2) 253-273... 

Due to a combination of poor membrane permeability and metabolism at the site of absorption, rectal bioavailability of peptide and proteins is low. As in other mucosal bioavailability testing, insulin is the most studied polypeptide with respect to rectal absorption. 

M. Murakami, Enhanced absorption and lymphatic transport of macromolecules via the rectal route, in Delivery Systems for Peptide Drugs (S. S. Davis, L. Ilium, and E. Tomlinson, eds.), Plenum Press, New York, 1986, p. 177. 

Penetration enhancers are low molecular weight compounds that can increase the absorption of poorly absorbed hydrophilic drugs such as peptides and proteins from the nasal, buccal, oral, rectal, and vaginal routes of administration [186], Chelators, bile salts, surfactants, and fatty acids are some examples of penetration enhancers that have been widely tested [186], The precise mechanisms by which these enhancers increase drug penetration are largely unknown. Bile salts, for instance, have been shown to increase the transport of lipophilic cholesterol [187] as well as the pore size of the epithelium [188], indicating enhancement in both transcellular and paracellular transport. Bile salts are known to break down mucus [189], form micelles [190], extract membrane proteins [191], and chelate ions [192], While breakdown of mucus, formation of micelles, and lipid extraction may have contributed predominantly to the bile salt-induced enhancement of transcellular transport, chelation of ions possibly accounts for their effect on the paracellular pathway. In addition to their lack of specificity in enhancing mem-... 

Similarly, the 4-methoxy-2-naphthylamides of Leu, Ala, Arg, and Glu (6.1, R=side chain of amino acid, R =MeO) were used to assess the type and activity of aminopeptidase in homogenates of conjunctival, nasal, buccal, duodenal, ileal, rectal, and vaginal tissues from rabbits. This systematic comparison afforded a better understanding of the role of the aminopeptidase barrier in peptide absorption from oral vs. non-oral routes [18]. In a comparable manner, the y-glutamyltranspeptidase and dipeptidase activities were investigated in mammary tissue with the 4-nitroanilides of Leu, Met, Lys, Glu, and Asp (6.2, R=side chain of amino acid) [19]. 

To achieve a reasonable degree of absorption, peptide and protein pharmaceuticals may need permeation enhancers to promote passage across mucosal cells. Another concern is that studies of insulin and enkephalin in animals suggest that protease activity may be high, especially in the rectal cavity [5,6]. On the other hand, the density of lymphatic vessels and drainage therein at these sites may be advantageous compared with other routes of administration. 

In the past two decades, many studies have tested adjuvants that act by either permeabilizing the rectal mucosa or inhibiting drug degradation. Oral and rectal routes of drug administration are unsuitable for adequate absorption of various compounds with a peptide or protein structure and of several hydrophilic antibiotics. The use of absorption enhancers, e.g., salicylates, enamines, surfactants, and straight-chain fatty acids, has gained wide interest... 

Yamamoto, A., and S. Muranishi. 1997. Rectal drug delivery systems—Improvement of rectal peptide absorption by absorption enhancers, protease inhibitors and chemical modification. 

Muranishi, S., Yamamoto, A. and Okada, H. (1993) Rectal and vaginal absorption of peptides and proteins. In Biological Barriers to Protein Delivery. (Audus K.L. and Raub T.J., eds). Plenum Press, New York, pp. 199-227. Zhou, X.H. (1994) Overcoming enzymatic and absorption barrier to non-parenterally administered protein and peptide drug. J. Contr. Rel 29 239-252. 

Polyacrylic acid aqueous gel enhances the absorption of calcitonin after nasal as well as rectal administration. When [Asul,7]-eel calcitonin (lOU/kg) was administered nasally in polyacrylic acid gel at a concentration of 0.1% w/v, a prominent hypocalcemic effect was seen in the first 30min. Nasal administration of [Asul,7]-eel calcitonin in saline had no hypocalcemic effect at the same dose when given by the nasal route. In addition to this, the effect of [Asul,7]-eel calcitonin in the dose range of 1-10 U/kg has also been studied. The resulting data showed that a rapid reduction in plasma calcium concentrations can be achieved at doses of 5 and 10 U/kg however, at doses of 1 U/kg only a small reduction in the plasma calcium concentration was observed, suggesting that polyacrylic acid gel can be used for the intranasal administration of peptides such as calcitonin. The possible side effects, however, were not known at the time the study was performed [76-78],... 

Bagger MA, Nielsen HW, Bechgaard E. Nasal bioavailability of peptide T in rabbits absorption enhancement by sodium glycocholate and glycofurol. Eur ] Pharm Sci 2001 14(1) 69-74. Dale O, Sheffels P, Khorasch ED. Bioavailabilities of rectal and oral methadone in healthy subjects. Br ] Clin Pharmacol 2004 58(2) 156-162. 

NaGC). The use of protease inhibitors to improve absorption of peptides and proteins is summarized in Table 5.2. As shown in the table, protease inhibitors were utilized not only for the oral route but also for other routes such as nasal, buccal, and rectal. 

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