| The basic requirement of pharmaceutical preparation is safety, utility and stability, and stability is an important factor to ensure that the preparation is safe. And the solubility of drug will directly influence the dissolution rate and bioavailability of drugs in vivo, thus influences the clinical curative effect of concentration dependent drugs seriously. Therefore, people have pay more and more attention to increase the stability and solubility of drugs, and this has become an important topic in pharmaceutical research. Studies on inclusion compound become more and more widely, it has been realized the influence of inclusion compound on drugs, such as to improve the solubility and stability of drugs, to influence the absorption, distribution, and time of utility of drug in vivo, etc. Recently, it was found that CD can accommodate different kinds of non-aqueous drugs in the cavity, forming host-guest inclusion complexes, therefore, the stability and dissolubility of non-aqueous drugs will be improved remarkably, of whichβ-CD is widely used. However, its anomalous low aqueous solubility, renal toxicity and hemoylsis serious forbid its wider utilization. So, on account of solubility, easier to form inclusion compound, and safety of drugs, it becomes necessary to modify or reconstructβ-CD. In this work, a kind of water-solubleβ-CD derivative (represented SPE-β-CD) has been synthesized. The superior nature of SPE7-β-CD has been researched by the study of inclusion compound between Fluconazole and four kinds of CD. The content and result of this study as follows:①Withβ-CD and 1, 3-propane sultone as the main reagents, three different degrees of substitution of SPE-β-CD were synthesized. The specific substitution position of hydroxyl inβ-CD was selected and the DS of product was controlled by choosing a suitable reaction conditions. The solution was then filtered with an ultra filtration cell or glucan gel filtration chromatography to wash out the small molecular inorganic salts and to concentrate the solution. Then the retentate solution was freeze-dried, and to give white powers. IR, 1H-NMR, 13C-NMR, EIS-MS and elemental analysis were used in the characterization, it indicates that bulky substituents prefer to react with the primary hydroxyl groups on C-6, also the DS of product has been better controlled.②Method of continue change of molar concentration has been used to ensure the ratio of CD and Fluconazole. Four inclusion compounds of Flu-β-CD, Flu-M-β-CD Flu-HP-β-CD, and Flu-SPE7-β-CD were prepared by using ultrasonic method. Inclusion rate, dosage of drug in inclusion compounds, yield and dissolution rate have been researched, and inclusion rate and dissolution rate were regarded as the main factor to value the compounds, and the four inclusion compounds have been valued. It showed that the inclusion result was as follows: SPE7-β-CD>M-β-CD>HP-β-CD>β-CD. In the present work, modification ofβ-CD has been realized by lead-in negative group of -CH2-CH2-CH2-SO3-, and inclusion compounds of slightly soluble drug Fluconazole was successfully prepared with chemical modified CD.③The phase-solubilization data of Fluconazole toβ-CD,M-β-CD,HP-β-CD and SPE7-β-CD were determined under the temperature of 25℃, 37℃and 45℃. The result indicated that the solubilization of Flu inβ-CD,M-β-CD,HP-β-CD and SPE7-β-CD was improved notably, of which SPE7-β-CD was the best, and a liquid formulation of Fluconazole could be prepared by forming inclusion complexes. The inclusion mechanism between CD and Fluconazole was determined by the apparent stability constant and it is showed as follows: SPE7-β-CD>HP-β-CD>M-β-CD>β-CD. In addition, the apparent stability constant at 37℃is higher than that at 25℃and 45℃, indicating that the reaction would be easier at this temperature.
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