Rectal drug absorption enhancement

This chapter focuses on rectal drug administration, which represents one of the most common routes of transmucosal drug delivery, and some aspects of rectal drug absorption, including enhancement strategies. 

Takahashi, H., et al. 1997. The enhancing mechanism of capric acid (CIO) from a suppository on rectal drug absorption through a paracellular pathway. Biol Pharm Bull 20 446. 

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. 

CYCLODEXTRINS AS MULTIFUNCTIONAL ENHANCERS FOR RECTAL DRUG ABSORPTION... 

Sodium salicylate and 5-methoxysalicylate increased the absorption of insulin. Sodium glycocholate was more effective than sodium taurocholate but less effective than sodium-deoxycholate and PE-9-laurylether in enhancing rectal insulin absorption in rabbits. The role of disodium EDTA in the enhancement of rectal drug absorption, along with the damaging effects on the rectal mucosa, has been described for several drugs. ... 

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... 

New Types of Absorption Enhancing Systems Used in Rectal Drug Administration... 

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. 

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. 

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. 

CyDs are known to be able to solubilize lipophilic drugs as well as lipophilic absorption enhancers, leading to the improvement of the enhancer s efficiency. There are some reports on the use of CyDs as a candidate for a coenhancer. For example, Yanagi et al. [35] reported that CyDs may promote the potency of absorption enhancers in rectum of rabbits. Inclusion complex of decanoic acid (CIO), an absorption enhancer, with a-CyD was prepared as an additive of cefmetazole sodium suppository and rectally administered to rabbits. Plasma concentration and area under the curve (AUC) of cefmetazole sodium after rectal administration of a suppository containing ClO-a-CyD complex to rabbits increased more significantly than those with no additive. 

The most efficient rectal absorption enhancers, which have been studied, include surfactants, bile acids, sodium salicylate (NaSA), medium-chain glycerides (MCG), NaCIO, enamine derivatives, EDTA, and others [45 17]. Transport from the rectal epithelium primarily involves two routes, i.e., the paracellular route and the transcellular route. The paracellular transport mechanism implies that drugs diffuse through a space between epithelial cells. On the other hand, an uptake mechanism which depends on lipophilicity involves a typical transcellular transport route, and active transport for amino acids, carrier-mediated transport for (3-lactam antibiotics and dipeptides, and endocytosis are also involved in the transcellular transport system, but these transporters are unlikely to express in rectum (Figure 8.7). Table 8.3 summarizes the typical absorption enhancers in rectal routes. 

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. 

Combinations of various absorption enhancers are known to increase drug absorption in rectal routes as follows a-CyD and CIO [35], NaSA and EDTA [157], NaGC and EDTA [68],... 

Matsumoto, Y., et al. 1989. Rectal absorption enhancement of gentamicin in rabbits from hollow type suppositories by sodium salicylate or sodium caprylate. Drug Des Deliv 4 247. 

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

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 presence of medium chain fatty acids and glycerides in food products has stimulated interest in their potential utility as absorption enhancers. Some fatty acids and glycerides have been shown to increase drug absorption under a variety of conditions, almost always in animals and in most cases after rectal dosing. However, some studies have yielded positive results after oral dosing. Oral insulin bioavailability was increased to 9-13% relative to IM administration by a mixture of sodium dodecanoate and cetyl alcohol. Aftiraxone absorption was enhanced by glyceryl-1-monooctanoate after oral, duodenal, and rectal administration to animals. 

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