Study On The Preparation Of Cyclosporine A Solid Dispersion Tablet And Its Pharmacokinetics In Beagle Dogs

Cyclosporine A (cyclosporine A, CsA) as an immunosuppressant is a cyclic peptide formed by 11 amino acids, which is widely used for liver, kidney, lung, bone marrow, pancreas and other organ or tissue transplant recipients patients, to prevent and treatment of rejection. Due to its great molecular weight, strong lipophilicity , low water-solubility and low oral bioavailability, the effects and applications of CsA have been seriously affected. In this study, solid dispersion technology was used to improve the dissolution performance of the insoluble drugs cyclosporin A (CsA), and thus to increase its bioavailability. Additionally, the marketable fast-release formulations, solid tablet, was prepared, which increased the dissolution rate of drug and the absorption rate of the gastrointestinal tract and as a result improved the bioavailability.CsA-F68(1:3) solid dispersion and CsA-F68-PEG(1:2:1), CsA-F68-PVP(1:2:1), CsA-F68-PVP-PEG(1:1:1:1) joint carrier-solid dispersion significantly increased the dissolution of CsA. X-ray diffraction suggested that cyclosporin A solid dispersion existed of the amorphous, and had connection with the change of the parameter, such as the spacing of crystal lattice, the grain size and orientation of the crystal lattice etc. Fourier transform infrared could confirmed that there was no interaction between the carriers and CsA in the process of forming SD. SEM visualizedly confirmed new form of the solid dispersion, different from that of crude drug and that of the physical mixture. At the same time the stability of four solid dispersions was inspected. The dissolution percentage of the solid dispersion with CsA-F68-PVP (1:2:1) changed from 98.12% to 86.16% after six months, solid dispersion with CsA-F68-PVP-PEG (1:1:1:1) from 87.27 percent to 76.57 percent after six months. However, both the solid dispersions with CsA-F68 (1:3) and CsA-F68-PEG (1:2:1) had good stability. They still had a complete dissolution after six months. It can be explained with X-ray tests for the dissolution of the last two prescriptions. However, this stability change of the solid dispersion can not be reflected by the infrared spectra. In the two prescription that had good stability, compared with solid dispersion with CsA-F68 (1:3), solid dispersions with CsA-F68-PEG (1:2:1) had clear advantages for lowing viscosity, increasing formability and improving recovery, Therefore CsA-F68-PEG (1:2:1) was chosen as the formulation of solid dispersion for the next step experiment.The disintegration time of the solid dispersion, the dissolution percentage of the CsA and the flowability of tabletting materials were selected as the main objectives of the study. A prescription screening was carried out. At the beginning, single factors were inspected, such as the disintegrating agents, filler, the lubricants and their dosage. Then a further four factors and three levels orthogonal experimental design was adopted for the optimization of the dosage of filler, disintegrating agents, lubricants. The ultimate prescription was determined: CsA solid dispersion 25%, MCC 66% PVPP 8%, silica powder 0.5%, Magnesium Stearate 0.5% (400 mg/tablet). The preparation and process was inspected after determining prescription. Besides three batches sample was produced in advance in order to study quality standards, quality inspection and stability test. Additionally, the critical relative humidity of the tabletting materials (76.43%) had been determined. Thus the relative humidity of environment should be controlled below 76.43% for tabletting, and there are some requirements for the humidity of the preservation environment.On quality evaluation of Cyclosporin A solid dispersion tablets, the HPLC method which determinates the concentration of cyclosporine A was established. The results of stability determination tests showed that solid dispersion tablets was more stable at 40℃high temperature, but the concentration of CsA in solid dispersion tablets reduced significantly in illumination condition and in 75% humidity conditions, which proved that the illumination and humidity showed impact to quality, and thus suggested that solid dispersion tablets should be packed in sealed dark condition.With two-crossover design, the pharmacokinetics and bioavailability of CsA solid dispersion tablets in beagle dogs were studied comparing with Neoral?. The HPLC method which determined cyclosporine A concentration in dog blood was established. By a series of study of precision and accuracy, the method was tested and proved to be suitable for the pharmacokinetics study of cyclosporine A. The result of t he pharmacokinetics trial indicated that pharmacokinetics of CsA solid dispersion tablets and Neoral(?) in vivo single dosage tests fit the two-compartment in beagle dogs. The AUC_0→24 of CsA solid dispersion tablets and the referrence microemulse were(4074.973±574.376)ng·h/mL,(4463.306±861.289)ng·h/mL.The peak concentration Cmax was (780.975±49.527)ng/ml, (1066.28±80.906)ng/ml; Tmax(2.25±0.5)h,(1.75±0.289)h. The relative bioavailability of CsA solid dispersion tablets was 91.30%.This study proved that self-made CsA solid dispersion tablets could significantly improve the dissolution rate in vitro and there were no significant difference beween CsA solid dispersion tablets and the referrence microemulse. In the pharmacokinetics tests, the relative bioavailability of CsA solid dispersion tablets was 91.30%. This experiment can reduce manufacturing costs and improve the patient's compliance, besides, have a good therapy effect and preparation stability. It holds the promise of becoming a new preparation for clinical in the future.