Absorption hydrophilic CyDs

It is generally recognized that the gastrointestinal (GI) absorption of CyDs in intact form is limited because of their bulky and hydrophilic nature. Only an insignificant amount of intact 3-CyD was absorbed from the GI tract in rats. ... 

In the case of the rectal route, when oleaginous suppositories containing 3-CyD derivatives were administered to the rat rectum, large amounts of intact (3-CyDs were excreted into the urine up to 24 h after administration. The relatively high absorption observed for (3-CyDs was ascribed to a change in the permeability of the rectal mucosa and/or an interaction between the surface-active 3-CyDs and glycerides, which are principle components of the suppository bases. Similarly, the hydrophilic CyDs... 

Intemasal delivery of peptide and protein drugs is severely restricted by pre-systemic elimination due to enz5miatic degradation or mucociliary clearance and by the limited extent of mucosal membrane permeability. a-CyD has been shown to remove some fatty acids from nasal mucosa and to enhance the nasal absorption of leuprolide acetate in rats and dogs. The utility of chemically modified CyDs as absorption enhancers for peptide drugs in rats has been demonstrated. For example, DM-P-CyD was shown to be a potent enhancer of insulin absorption in rats, and a minimal effective concentration of DM-(3-CyD for absorption enhancement exerted only a mild effect on the in vitro ciliary movement.The scope of interaction of insulin with CyDs is limited, because CyDs can only partially include the hydrophobic amino acid residues in peptides with small stability constants. Under in vivo conditions, these complexes will readily dissociate into separate components, and hence the displacement by membrane lipids may further destabilize the complexes. The direct interaction of peptides with CyDs is therefore of minor importance in the enhancement of nasal absorption. Of the hydrophilic CyDs tested, DM- 3-CyD had the most prominent inhibitory effect on the enzymatic degradation of both BLA and insulin in rat nasal tissue homogenates. Because of the limited interaction between peptides and CyDs,... 

Recently, Loftsson et al. proposed that CyDs can enhance absorption of Class II as vell as Class IV drugs, whereas CyD can modify oral absorption and/or reduce local irritation by drugs of Classes I and III [52], In fact, we have recently reported that hydrophilic CyDs can enhance the oral bioavailabUity of itraconazol [53] and tacrolimus [33], typical Class II drugs. Additionally j8-CyD is capable of shortening the onset time of action of piroxicam and to reduce the risk of directgastric irritation [54]. Furthermore, DM-a-CyD and 2 also enhance the bioavailability of cyclosporine A, a Class IV drug [55] (see below. Section 14.4.1). 

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,... 

However, some negative effects of the combination of CyDs and polysaccharide on the rectal drug delivery were reported. Lin et al. [38] demonstrated that the mixture of (3-CyD and hydroxypropylmethylcellulose (HPMC) markedly reduced the in vivo bioavailability of acetaminophen from both aqueous solution and hydrogels. Not only the lower partition coefficient but also the higher hydrophilic property of the (3-CyD complex and the higher viscosity of HPMC hydrogel matrix might be responsible for the decrease in the in vitro permeation rate and depression of in vivo rectal absorption of acetaminophen. 

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