Study On The Interaction Of γ-cyclodextrin And Its Derivatives With Commonly Used Clinical Drugs

y-Cyclodextrin (y-CD), consist of eight a(1â†'4)-linked d-glucopyranose subunits, are shaped like a truncated cone, characterized by a hydrophilic outer surface and an internal relatively hydrophobic cavity, offer cavities to encapsulate within their guest molecules of suitable size as host molecules. Bridion is artificial modified derivative, based on y-CD as the matrix, and also is new muscle relaxant antagonist, the formation of inclusion complexes with rocuronium and vecuronium in a 1:1 stoichiometric ratio, but there are still limits. Aom0498-16(HS-7), is improved on the basis of Bridion, it also can form inclusion complexes with amino steroidal muscle relaxants. In the present paper, y-CD, Bridion and HS-7 were chosen as the subject to be researched from the following aspects:1. Four analysis method of study on the interaction between γ-CD and its two derivatives with two muscle relaxantsAt first, determination method of inclusion of γ-CD, Bridion and HS-7 with rocuronium and vecuronium was developed using isothermal titration calorimetry, fitting the binding constant, thermodynamic constant and binding sites of y-CD with rocuronium, Bridion and HS-7 with rocuronium and vecuronium. ITC fitting results showed that HS-7, Bridion combined with rocuronium and vecuronium in a 1:1 molar ratio, and y-CD combined with rocuronium in a 2:1 molar ratio. The binding constant of HS-7 with rocuronium was 3.44(±2.18)×107 L/mol,HS-7 with vecuronium was 5.80(×1.83)×106 L/mol, Bridion with rocuronium was 1.04(±0.34)×107 L/mol, Bridion with vecuronium was 2.53(±1.07)×106 L/mol, y-CD with rocuronium was 2.84(±3.41)×104L/mol. Then, determination method of inclusion of γ-CDwith rocuronium and vecuronium was developed using ultraviolet-visible spectrophotometry, determination of the binding constant and the inclusion ratio. The results of UV-vis method showed that y-CD combined with rocuronium and vecuronium in a 2:1 molar ratio, the binding constant of y-CD with rocuronium was 6.93×104L/mol, γ-CD with vecuronium was 5.17×104L/mol. Afterwards, characterization of the inclusion compound of y-CD, Bridion and HS-7 with rocuronium and vecuronium by nuclear magnetic resonance spectroscopy, to evaluate the inclusion ability of three cyclodextrins by chemical shift changes. The NMR spectra indicated that rocuronium and vecuronium was included in cavities of y-CD, Bridion and HS-7, the inclusion ability of Bridion and HS-7 was far more than y-CD, but the inclusion ability of Bridion and of HS-7 could not be judged simply by NMR spectra. At last, characterization of the inclusion compound of y-CD and HS-7 with rocuronium and vecuronium by infrared spectroscopy, the results suggested that two cyclodextrins included rocuronium and vecuronium indeed.2. Three analysis method of study on the interaction between y-CD and its two derivatives with endocrine drugsFirst, I picked out 13 commonly used clinical hormone drugs, most of them have similar structure to muscle relaxant rocuronium, and determination of the binding constant and the inclusion ratio of y-CD with all drugs and HS-7 with part of drugs by UV-vis method. The results showed that the binding constant of y-CD with estradiol was 4.85×103L/mol, with progesterone was 1.60x 104L/mol, with ethinylestradiol was 1.28×104L/mol, with ethisterone was 6.34×103L/mol, with norethindrone was 7.12×103L/mol, with fluocinolone acetonide was 1.78×103L/mol,with corticosterone was 4.79×103L/mol, with cortisone acetate was 2.30×103L/mol, with Prednisone was 3.82×103L/mol,with dexamethasone was 1.76×103L/mol, with clomifene citrate was 1.79×104L/mol, with tamoxifen citrate was 1.63×104L/mol, with testosterone was 1.75×104L/mol. The binding constant of HS-7 with estradiol was 1.13×104L/mol, with ethinylestradiol was 1.45×10 L/mol, with clomifene citrate was 1.86×104L/mol, with tamoxifen citrate was 2.39x104L/mol, with testosterone was 3.26×104L/mol, with corticosterone was 9.25×103L/mol. Secondly, characterization of the inclusion compound of three cyclodextrins with endogenous hormone estradiol, progesterone and testosterone by 1HNMR and IR method, the results proved that three cyclodextrins included endogenous hormone indeed, the ability of inclusion with endogenous hormone of Bridion was a bit more than HS-7, and of two derivatives were far more than y-CD.3. Two analysis method of study on the interaction between y-CD and its two derivatives with central nervous system drugsFirst of all, I choosed 16 commonly used clinical central nervous system drugs, and determination of the binding constant and the inclusion ratio of γ-CD with all drugs and HS-7 with part of drugs by UV-vis method. The results suggested that the binding constant of y-CD with Propofol was 4.33×102L/mol, with Flumazenil was 1.80×103L/mol, with Phenylephrine Hydrochloride was 5.18×102L/mol, with aspirin was 2.37×102L/mol, with Paracetamol was 2.49x102L/mol, with Phenacetin was 1.33×103L/mol, with Perphenazine was 1.06×103L/mol, with librium was 1.09×103L/mol, with Zopiclone was 1.59×103L/mol, with Olanzapine was 1.89×103L/mol, with fluoxetine hydrochloride was 4.92×103L/mol, with Cozapine was 8.88×102L/mol, with mirtazapine was 1.01×103L/mol, with Etomidate was 3.82×103L/mol, with Rotundine was 4.60×102L/mol, with Carbamazepine was 4.23×103L/mol. The binding constant of HS-7 with Propofol was 8.86×102L/mol, with Phenylephrine Hydrochloride was 1.19×103L/mol, with Perphenazine was 1.26×103L/mol, with Librium was 2.72×103L/mol, with Rotundine was 3.33×103L/mol, with Zopiclone was 1.64×103L/mol, with Olanzapine was 2.10×103L/mol, with Carbamazepine was 1.61×104L/mol, with Cozapine was 7.43×102L/mol, with mirtazapine was 9.81×103L/mol. Then characterization of the inclusion compound of three cyclodextrins with fluoxetine hydrochloride, Carbamazepine, mirtazapine and Cozapine by 1HNMR method, the results revealed that three cyclodextrins included four drugs indeed.