The Inclusion Characteristic Of Hydroxypropy1-β-cyclodextrin And Its Effects On Drug Pharmacokinetics In Vivo

Cyclodextrins are cyclic oligosaccharides, known for their ability to form inclusion complexes with many lipophilic drugs, thereby changing the physicopharmaceutical properties of these drugs. Complexation may increase aqueous solubility and bioavailability, improve stability, and affect the drug's effects. p-Cyclodextrin, which is the most practically used in the pharmaceutical industry, unfortunately has low water solubility, and is difficult to make liquid formulation. Thus, attempts to improve cyclodextrins by chemical derivatization have been made and among these derivatives 2-hydroxypropyl- -cyclodextrin (HPCD) was suggested as one of the most applicable one for its safety. In this paper, conditions for condensation of p-cyclodextrin with propylene oxide were found which give preparations of hydroxypropyl-p-cyclodextrin with a narrow and symmetrical distribution of the degree of substitution. Furthermore, methods for purification of hydroxypropyl-p-cyclodextrin from the contaminating oligopropylene glycols were developed. Ion-exchange method was used to separate the sodium chloride. Ice-salt condenser was used to control the reaction temperature. The degree of substitution was detected using a chemical method. Good reproducibility of the degree of substitution for different batches of HPCD was observed. 1H-NMR ,13C-NMR and MS spectra showed average degree of substitution very similar to the imported one. The stability constants of 9 drugs for forming complexes with HPCD were calculated according to phase solubility diagrams. These drugs include ibuprofen, indomethacin, nimodipine, nitrendipine, digoxin, meloxicam, piroxicam, cinnarizine and nicardipine. Nateglinide, a novel highly physiologic, mealtime glucose regulator recently approved for the treatment of type 2 diabetes mellitus, was used as a model drug for the preparation of HPCD-drug inclusion. The formation of solid nateglinide inclusion complexes has been evaluated by using kneading and freeze-drying methods. X-ray diffraction, and differential scanning calorimetry indicated that inclusion complexes can be obtained by freeze drying. According to the phase solubility results, drug solubility in different media at various pH was improved by inclusion with HPCD.The dissolution rate of nateglinide for freeze drying includion was 100% in 0.1 mol/L HC1, whereas the dissolution of nateglinide itself was less than 20%. When nateglinide-HPCD complex was orally administered to rabbits, the absorption rate and extent was enhanced significantly comparing to the nateglinide itself.The everted sac method was used to test the permeability of inclusion complexes of the HPCD and digoxin through rat intestinal membrane. It has been shown that with the increase of the concentration of HPCD, the fraction of digoxin penetrated through the rat membrane decreased as a result. The result indicated that cyclodextrin inclusion decrease the absorption rate of the drug, however, a quick equilibrium was existed between the free drug and drug in inclusion, so the absorption was only partially inhibited. The pharmacokinetic properties of digoxin after oral administration of its HPCD inclusion complex to rabbits and human volunteers were investigated in comparison with those of commercially available tablets. The aqueous solubility of digoxin was enhanced by HPCD for about 2000 times at HPCD concentration of 50% (w/v). But in human bioavailability study no significant difference was observed in the extent of absorption (AUCo-t) and Cmax between the two formulations. Time to reach peak was significantly earlier for solution than tablets (p<0.01). The pharmacokinetic results from the rabbit study were similar to that of human studies and no significant difference was observed for AUC, Cmax and Tmax. As the bioavailability of both tablets and solution is equivalent it is recommended that HPCD based oral digoxin solution could also be an alternative formulation.The pharmacokinetic interaction for HPCD to digoxin after HPCD and digoxin intravenous administration to rab...