Hydrophilic CyDs

Monographs on the native CyDs can be found in several pharmacopoeias. For example, a- and y -CyDs are listed in the US, European, and Japanese Pharmacopoeias. On the other hand, a monograph for hydroxypropylated fi-CyD, HP-yS-CyD (Encapsin , 6), has recently appeared in the European Pharmacopoeia [24]. Hydrophilic CyDs such as methylated -CyDs [1, 5, 25), hydroxypropylated jS-CyDs [26-28], and branched y8-CyDs [29, 30] have received special attention (see Chapter 

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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,... 

The haemolytic activities of natural CyDs are reported to be in the order p- > a- > y-CyD. These differences are ascribed to the differential solubilization of membrane components by each CyD. When the CyD cavity is modified by chemical derivatization, its effects on cell membranes can be changed dramatically from those of parent CyDS. When the muscle tissue damage due to the injection of hydrophilic CyDs was compared with that of mannitol and nonionic surfactants, following a single injection (100 mg ml" ) of the compounds into M. vastus lateralis of rabbits (Fig. 38.2), a-CyD and DM-P-CyD showed a relatively high irritation reaction, the degree of... 

Hemolysis data are known to provide a simple and reliable measure for the estimation of CyD-induced membrane damage or cytotoxicity [10, 14). Figure 14.2 shows the hemolysis curves of hydrophilic CyDs on rabbit erythrocytes. The hemolytic effects of methylated CyDs are much higher than those of other CyDs [32, 33). In a series of CyD derivatives, there is a positive correlation between the hemolytic activity and their capacity to solubilize the lipophilic components of the cell membranes (cholesterol and phospholipids). Since the methylated CyDs remove cholesterol significantly from human intestinal epithelial cell monolayers [34], this will... 

Fig. 14.2. Hemolysis curves of the effects of hydrophilic -CyDs on rabbit erythrocytes in 0.1-M phosphate buffer solution (pH 7.4) at 37 °C.

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). 

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