Post-marketed Re-evaluation On The Quality Of Poorly Water-soluble Drug

Post-marketed re-evaluation on the quality of drugs in China is still in its early stages. At present, post-marketing quality evaluation system needs to be developed. Many quality standards are too loose to fully reveal the gap of quality between the products. There is no Orange Book in our country. That is why many generic drugs which have the differences in quality or effects in the market, and they can not interchangeabilities in clinical. Many manufacturers produce carbamazepine (CBZ) tablets. However, the products were different in the quality and efficacy. Higher surfactant concentration used in USP 34 as the dissolution media, and higher speed used in Chinese Pharmacopoeia 2010 (ChP 2010). These methods may result in solubility overestimation and reduce the discriminative power between the products, or be out of human physiological situation. That is why a discriminatory dissolution test to evaluate the performance and consistency in quality of CBZ commercial preparations is very important. CBZ tablets were a good model drug for the study of the quality re-evaluation in post-marketed.The purpose of the present study was to improve the quality of CBZ immediate-release tablets. Multisoure of CBZ tablets (22 commercial products) were investigated to grasp the core of the quality and technical indicators to develop a simple, reliable and efficient evaluation of the experimental identification system. At the same time, the reasons of the differences between the CBZ tablets were deeply analyzed by the factors. The study will be contributed to develop our "Orange book" and the safety and clinical effect.Firstly,22 commercial CBZ tablets were investigated by the content, hardness, disintegration, friability, etc. And the tablets were in line with the provisions of ChP 2010, but between them were significantly difference. Solubility of CBZ in the different media, oil-water distribution coefficient and absorption coefficient of CBZ in the small intestine were investigated to understand the physicochemical and biopharmaceutical properties. As stated in ChP 2010, USP 34 and JP-Orange Book, differences in the dissolution among the products were compared. The dissolutions of all tablets were favored by the requirements of dissolution in ChP 2010, but the larger differences were found between curves. There was 2 or 7 tablets failure to meet the requirements of USP or JP, respectively.Effects of the main factors on the dissolution were evaluated in detail, such as hydrodynamics (basket or paddle), agitation and media. The results showed that paddle method was more suitable for CBZ tablets in the dissolution testing with the rotation of 75 rpm. The pH values (1.2-7.4) in the media were not significantly impact on the dissolution of the marketed CBZ tablets. Comparison of the studies of the medium containing the different surfactants, such as anionic, cationic or non-ionic surfactant showed that the optimum concentration of SLS had a good discriminatory. Moreover, the ionic strength and type were investigated. In summary, the dissolution test method (1) of CBZ tablets was optimized.The study was to evaluate the interchangeability of 18 commercially available carbamazepine (CBZ) tablets through comparing the bioavailability and pharmacokinetic properties in beagle dogs. The pharmacokinetic parameters of marketed CBZ tablets revealed significantly differences:tmax:0.75-6.33 h, Cmax: 1.23-4.74 μg·ml-1 and AUC0-t:4.51-14.41 μg·hml-1. The range of absolute bioavailability was 47.89% to 166.90%. The rate of absorption of CBZ marketed tablets showed marked differences in absorption behavior in vivo, suggesting that not all of them are bioequivalent with each other. In order to ensure the safety and effectiveness, CBZ products’ interchangeability should be treated carefully.The effect of dosing time on the bioavailability of CBZ IR tablets was investigated when administrated to beagle dogs who were fasting, with coadministration of food (Co-food), and 0.5 h before food and 2 h after food. Food intake significantly increased the rate and extent of tablets absorption. The Cmax (μg·ml-1,8.13/3.65) and tmax(h,1.90/0.90) were increased more than twofold and the AUC0-24 (μg·h·ml-1,20.09/8.19) was 2.5 times that of the values obtained under fasting conditions. The bioavailability of the tablets under fasting conditions was 91.2 %, but increased to 223.5%,182.8% and 148.4% in the Co-food,0.5 h before food and 2 h after food groups, respectively (p< 0.05). To obtain the optimum clinical effect and tolerability, it is recommended that CBZ IR tablets be taken with plain water and at least 2h after food.The in vitro - in vivo relationship of CBZ tablets was related by deconvolution and time scaling based approach for level A IVIVR Model. Then, the dissolution test was adjusted and verified to obtain the final dissolution method of CBZ IR tablets as follows, Medium:water containing 1% sodium lauryl sulfate (SLS),900 ml; Apparatus 2:75 rpm; Time:5 min and 60 min. Tolerances:not more than 60%(Q) of the labeled amount of CBZ is dissolved in 5 min and not less than 75% in 60 min.Reasons for the differences in the inherent quality of products were analyzed by several aspects, such as the solid phase characteristics of drug, the stability of excipients, the compatibilities of drug and excipients, formulations and preparations. Firstly, two anhydrate polymorphs of CBZ (CBZ Ⅰ and CBZ Ⅲ) and a dihydrate (DH) were prepared and confirmed by powder X-ray diffraction (XRD) and DSC analysis. Secondly, the polymorphs of CBZ commercial tablets were confirmed by the XRD and DSC analysis. The results showed that the different polymorphs were used in tablets, and CBZ Ⅲ, CBZ Ⅰ, both of them were found in 16 commercial tablets,1 tablet and 4 tablets, respectively. Pharmacokinetics of each form was investigated in rats following a single oral/intravenous administration of 10 and 80 mg·kg-1. The bioavailabilities of each form markedly decreased with the increasing of doses in rats. At the low dose, the bioavailability of CBZ Ⅲ, Ⅰ and DH was 82.99%,87.66% and 92.62%, respectively. At the high dose, the bioavailability of each form was 45.38%, 56% and 38.38%, respectively.The results of stability of drug indicated that CBZ Ⅰ was easier to moisture absorption than CBZ Ⅲ. The stability of 13 excipients which were commonly used in tablets were investigated, and showed that the stable materials were lactose, MCC, magnesium stearate, L-HPC and aerosil under the conditions of high temperature, high humidity and light conditions. The compatibilities of CBZ and 13 excipients were evaluated by the factors. The content of CBZ in the mixture decreased under the condition of humidity. There may be incompatibility between CBZ and stearic acid or lactose by the analysis of XRD and DSC. Starch had a trend in the moisture absorption and turned into yellow powder, so it was inappropriate as an ingredient for crystalline substances of CBZ.The preparation process should not be under the high-temperature when the SLS exists in the formulation. Lactose in the formulation significantly influenced on the solid phase characteristics of CBZ. MCC、L-HPC、PVP K30 and HPMC K4M in the formulations were not influence the stability of CBZ.The results of the preparation process showed that the press was in the range of 4-8 kg/cm2, which will not impact on the solid phase characteristics of CBZ. Drying temperature of 60 ℃ and drying time of 4 h will be suitable for wet granulation of CBZ tablets.In conclusion, the discriminatory dissolution test method of CBZ was developed and the reasons for the differences of the quality between the products were evaluated. The results will helpful to improve product quality of CBZ. The methods of this study will be suitable to reference for the re-evaluation of product quality of insoluble drugs.