PolyEthylene GlycolAlkyl Dextran Ether DexPEGiCn for Drug Delivery
Amphiphilic poly(ethylene glycol)-alkyl dextran ethers are emerging as vehicles in the oral delivery of poorly water soluble drugs [251, 268, 269]. They form polymer micelles of low critical association concentrations (CAC) and small micelle sizes in aqueous solution. Particulate delivery systems lead to an enhancement of the absorption efficiency and bioavailability of highly lipophilic drugs orally applied, and provide the drug with some level of pro
tection against degradation within the GI tract, prolonged drug transition time, and improved drug absorption [270].
Low molecular weight surfactant micelles are widely used as drug carrier systems due to their good pharmacological characteristics [271,272]. They are formed above a critical micelle concentration (CMC) and rapidly break apart upon dilution. In contrast to the low molecular weight surfactant micelles, the association of amphiphilic polymers like DexPEO10Cn in water takes place at concentrations (CAC), which are lower by several orders of magnitude than typical surfactant CMC values. The polymeric micelles consist of a hydrophobic core (cetyl or stearyl groups) and the hydrophilic shell (dextran backbone) exposed to the aqueous environment [273,274]. The hydrophobic cetyl and stearyl groups are attached via short PEG linker to dextran (Fig. 36).
The poly(ethylene glycol)-cetyl and stearyl dextrans are synthesised as follows: the terminal hydroxyl groups of cetyl or stearyl poly(ethylene glycol) are tosylated using p-toluenesulfonyl chloride and either pyridine or a mixture of Et3NH+Cl- and Me3NH+Cl-. The tosylated poly(ethylene glycols) are converted with dextran to give the corresponding DexPEG10Cn [251,252]. The degree of PEG10Cn substitution can be calculated using 1H NMR spectra. The size of the polymeric micelles ranges from 10 to 100 nm.
CAC values of the copolymers are estimated by fluorescence spectroscopy using pyrene as probe. The excitation spectra of the hydrophobic fluorescence probe, preferentially arranged into the hydrophobic core of the micelle, undergoes a small shift to longer wavelengths (from A = 333 nm in a hydrophilic environment to A = 336 nm in a hydrophobic environment) [275-277]. An increase in the length of the hydrophobic residue at a given length of the hy-drophilic polymer chain causes a decrease in the CAC value and an increase in micelle stability [252,278]. Cyclosporin A (CsA), a highly effective immunosuppressive agent, was incorporated into DexPEG10Cn micelles by a dialysis method. An aqueous DexPEG10Cn solution was treated with a solution of CsA in ethanol, followed by extensive dialysis against water. The solubility of the lipophilic drug CsA in aqueous solutions of DexPEG10Cn through encapsulation in the hydrophobic core of the micelles can be increased with increasing DS and decreasing molecular weight of the dextran [252]. The cytotoxicity of DexPEG10Cn micelles towards a Caco-2 cell line, deriving from human colon denocarcinoma, is significantly lower than that of unlinked PEG10Cn. DexPEG10Cn micelles exhibit high stability in gastric and intestinal
- Fig. 36 Synthesis of poly(ethylene glycol)-cetyl and -stearyl dextran ether
fluids and their size is optimal for effective drug delivery. The permeability of CsA encapsulated in DexPEG10Cn micelles across Caco-2 cells is significantly increased compared to free CsA. The application of CsA encapsulated in vitamin B12-modified DexPEO10Cn micelles also enhances the permeability through Caco-2 cell monolayers [279]. The characteristic of the biopolymeric micelle systems indicates that this approach can provide practical opportunities in the oral delivery of hydrophobic drugs.
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