| Objective:Bipolar disorder, also known as manic depression or schizophrenia, is a common disease, whose morbidity is 1%～8%, and the major manifestations are repeated attacks of mania and depression. Bipolar disorder is a relatively high handicapped and complicated disease which is easy to relapse and difficult to cure.Therefore, national mental health workers have been paying more attention to this disease for a long time. Quetiapine fumarate as one of the main medicine drugs for the treatment of bipolar disorder, is the second generation antipsychotic drugs. At present, there is only quetiapine fumarate tablets for clinical use, which needs to take several times one day, so the patient’s compliance is poorer. We studied the quetiapine fumarate extended-release tablet, which could have the same effect and reduce the frequency to take medicine. It can not only get a smooth and effective blood drug concentration also reduces the side-effects, bringing convenience to the patients.Methods:To begin with, I carried out the preformulation experiment, and measured the equilibrium solubility of quetiapine fumarate in different pH buffer solution. At the time, the method of determination of release curve in vitro was established and verified.Secondly, I made true the type of this product was a HPMC tablet which was prepared by wet granulation tabletting process. Single factor experiment was carried out, including viscosity and dosage of HPMC, the dosage of lactose and sodium citrate, and tablet hardness, taking release rate in vitro and the similarity factor compared with market control sample as index. Then, by using orthogonal experimental design, I determined the best prescription and prepared three batches’ samples to verify the repeatability of process. At the same time, I established the main test method of quetiapine fumarate extended-release tablet, verified the methods of assay and related substances, and inspected the stability of the three batches’ samples at the same time. Finally, I established a method for the determination of the quetiapine fumarate in plasma, and carried out studies of pharmacokinetic and IVIVC, taking quetiapine fumarate tablets as control sample and beagles as test objects.Results:The result of equilibrium solubility of quetiapine fumarate in different pH buffer solution showed that QF meet the requirements of the release test. Release test was carried out in two media[pH4.0 (0-4 hours) and pH6.6 (5-24 hours)], using the roting basket method at the speed of 200 r/min. Release test samples were determined by UV-Spectrophotometer at the wavelength of 289nm.Results of single factor experiment of quetiapine fumarate showed that releasing rate of the drug reduced along with the increase of HPMC viscosity and dosage, and increased as the dosage of lactose and sodium citrate increasing. Factor of film hardness had no obvious effect to releasing rate.Taken the dosage of HPMC-K15M(A), HPMC-K4M(B), sodium citrate(C) and lactose amount(D) as factors, I designed three levels orthogonal experiment whose results showed that primary and secondary order of the four factors was C,D, B, A, and the best prescription contained 10% of HPMC K4M,8% of HPMC K15M,15% of lactose,10%of sodium citrate. The quality of the three groups of samples were good.Assay and related substances can be determinated by high performance liquid chromatography (HPLC) method which was suitable for the quality control of the samples, and the results of methodology validation showed that both methods had good specificity, accuracy and sensitivity. The result of the stability test showed that the stability of the three batches’samples was good.The determination of drug concentration in Beagle blood was carried out, using high performance liquid chromatography, which has good specificity, accuracy and sensitivity. The pharmacokinetic parameter of IR tablets and XR tablets showed that the Cmax were 362.51ng/ml and 725.80ng/ml, that the Tmax were 2.5h and 1.5h, that the ti/2 were 4.88 h and 2.52 h, and that the AUC0-τ were2291.83 μg·h/L and 2468.70 μg·gh/L. Bioavailability of the XR tablets versus IR tablets was 92.8%. Release in vitro of quetiapine fumarate XR tablets complied with the Higuchi model and it is non-fick diffusion, that is, it is the result under the joint action of matrix erosion and diffusion. I drew a linear equations curve using the data of Fa (%) and Ft (%), and then obtained the R2=0.9650, indicating that the correlation between in vivo and in vitro was in good condition.Conclusion:The prescription and preparation process of the quetiapine fumarate XR tablet were stably and reliably were determined. The methods of the release, assay and related substances were established and were confirmed scientific and effective, and they are suitable for the quality control. Quetiapine fumarate XR tablet had good bioavailability, obviously extended-release effect and was good in vitro-in vivo correlation, so it has good development prospect. |
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