Rectal absorption improvement

Miyake, M., et al. 2004. Development of suppository formulation safely improving rectal absorption of rebamipide, a poorly absorpbable drug, by utilizing sodium laurate and taurine. J Control Rel 99 63. 

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. 

Sekine, M., et al. 1985. Improvement of bioavailability of poorly absorbed drugs. V. Effect of surfactants on the promoting effect of medium chain glyceride for the rectal absorption of (3-lactam antibiotics in rats and dogs. J Pharmacobiodyn 8 653. 

Ogiso, T., et al. 1993. Rectal absorption of acyclovir in rats and improvement of absorption by triglyceride base. Biol Pharm Bull 16 315. 

Takeichi, Y., et al. 1990. Combinative improving effect of increased solubility and the use of absorption enhancers on the rectal absorption of uracil in beagle dogs. Chem Pharm Bull 38 2547. 

Takeichi Y, Kimura T. Improvement of aqueous solubility and rectal absorption of 6-mercaptopurine by addition of sodium benzoate. Biol Pharm Bull 1994 17(10) 1391-1394. 

Absorption enhancement Hexetil hydrochloride/a-CD (improvement of oral bioavailability) ketoconazole/p-CD (improvement of oral bioavailability) ethyl 4-biphenylyl acetate /2-HP-P-CD (improvement of rectal absorption) estradiol/DM-P-CD (enhancement of nasal absorption) nifedipine/2-HP-6-CD (improvement of the oral bioavailability). 

Rectal administration with nonionic surfactants also demonstrated an increased absorption. It has been proven in vivo that triglycerides, polysorbates, and fatty acids improve rectal absorption of antibiotic agents [55]. 

Many studies have been published on the use of various enhancers for the rectal absorption. They increase the absorption of an active substance by enhancing the membrane permeation, rather than increasing the solubility. Published examples of absorption enhancers are capric acid and sodium caprate, lauric acid and sodium laurate, sodium salicylate and sodium cholate. These enhancers however give an unpredictable and strongly variable improvement of the biological availability [5b]. Nevertheless they sometimes lead to a licensed medicine sodium caprate is already in use in a suppository product available in Japan [7]. 

This section discusses the active substance (particle size and solubility), the bases and the excipients to obtain optimal release and absorption. Obviously these three components are closely interrelated. The active substance must be used in a chemical form, ionised or not, and with a particle size that are optimal for release and rectal absorption. In addition a base has to be chosen that optimises release, see also Fig. 11.1. Excipients can be added to improve dissolution and absorption or for technological reasons. However, excipients aimed at technological improvement may also influence the release of active substance. Whatever choice is made for active substance, base and excipients, their impact on the preparation process, the stability of the product and the shelf life must also be considered. 

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. 

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

The effect of various absorption enhancers on insulin transport across the rectal membrane of albino rabbits was examined by an in vitro Us sing chamber method [18]. Insulin was unable to cross the rectal mucosa without absorption enhancers, but its transport was improved in their presence. Among these enhancers, Na glyco-cholate (NaGC) was more effective than Na taurocholate (NaTC), but less effective than Na deoxycholate (NaDC) and poly-... 

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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