| The overall conditions and prevalence trend of 28 types of cancers from more than 180 countries are described and analyzed comprehensively in Report on Global Cancers 2014 which predicts that cancer cases worldwide will grow rapidly,specifically showing that the cancer cases progressively increase from 14 million people in 2012 to 19 million people in 2025, and will reach 24 million people in 2035. Thereinto, 3.07 million patients with cancers newly increase in China and cause deaths of about 2.20 million people which account for 21.9% and 26.8% of global total respectively. In the 4 types of malignant tumors in liver, esophagus, stomach and lung, cases increasing newly and death toll in China both rank first in the world. The number has been very approached to the number of people who died from acute cardiovascular diseases, as well as driven the rapid increasing of markets of antitumor drug around the world.Capecitabine is the first marketed oral antitumor drug of fluorine pyrimidine carbamates which transforms into 5-FU in vivo to inhibit cell division and interfere synthesis of RNA and protein, and applies to the further treatment in advanced primary or metastatic breast cancer which is treated ineffectively using paclitaxel and chemotherapy regimens including anthracycline antibiotics, and the treatment in advanced primary or metastatic colorectal cancer, colon cancer and stomach cancer.Capecitabine was developed and marketed by America Roche Group in 1998 at the earliest with trade name of Xeloda, and approved to market in China on Oct. 2000 with the strength of 0.5g and 0.15g. Dosage form of capecitabine applied in clinic is oral tablets which enter into intestinal tract to have effect directly, and have higher drug concentration in blood than that in tumor tissues, it has high selectivity, cell targeting,high bioavailability, excellent broad-spectrum anti-cancer property, less toxic and side effects,good tolerance,convenient oral administration and flexible dose adjustment,complying with the administration mode of patients thus to drive the growth of market.Global sales of xeloda reached more than 10 billions of dollars in 2014 which was the"heavy bomb" drug.In recent years, according to current situations of pharmaceutical industry in China,our country has issued many policies to encourage technological transformation of large variety of generic drugs,especially the industrialization of "heavy bomb" drugs which have been marketed; To meet the clinical requirements, and make domestic products achieve international quality standard thus to substitute for imported goods and reduce the burdens of patient family and national medical costs, study on industrialization technological transformation of capecitabine and its tablets is conducted.According to the requirements on consistency evaluation of newest drug technology and product quality in China, the requirements on consistency of product impurities and release behaviors in vivo and vitro are more and more strict, and concept of "impurity profile" is put forward, for the impurity with content more than 0.1%, its structure identification and toxicity evaluation are performed, therefore, consistency of impurity control and product quality becomes the key factor to restrict the industrialization of product. To realize industrialization, two problems below need to be solved: 1. Raw material: Product purity, impurity spectrum analysis, impurity control; 2. Preparation:Product stability, consistency of release behaviors in vivo and vitro.In existing synthetic technique, all raw materials of capecitabine have smaller industrialized production scales, environmental pollution, high costs, low purity and more amount of impurities (It contains 9 impurities with known structures and impurities with unknown structures and total content of impurities is 1.5% according to the FDA standard). The product structure of the ester bond and sugar part is not stable,easy decomposition with water or alkali,and relatively stable in weak acid,this has the glycosyl,It is more binding into pieceshigh Under the condition of high water content and long-term storage,To product stability is poor dissolution, the product quality decline under Long-term storage.Capecitabine preparation has bigger strength (0.5g), main ingredient has high percentage in formulation, raw materials have high viscosity,preparations degrade easily under the conditions of high temperature and humidity with impurities increasing, therefore, the requirements on conditions of materials,manufacturing process and production environment are strict in large-scale industrialized production of preparations. To solve above-mentioned problems and make the output quality of large-scale industrialized production up to the quality of preparation product specified in international standard, firstly, the synthetic processes of raw materials need to be optimized to prepare active ingredients with high purity; Secondly, preparation process shall be optimized to manufacture the products with stable and reliable quality. Quality of preparation products shall meet international standards by consistency quality evaluation in vivo and vitro.The idea and method of QbD (Quality by design) was used in this subject, and industrialized manufacturing process of capecitabine was confirmed, thus to produce capecitabine active ingredient with high purity and high quality; Formulation and industrialized manufacturing process of capecitabine tablets were confirmed thus to prepare capecitabine tablets with good stability; Analysis method for IVIVC was established, and stability, uniformity and consistency of quality of capecitabine tablets were evaluated by experiment in vivo and vitro; A set of quality management requirements which met the international GMP standard was established to make the quality of products manufactured reach international level. It has maked significant breakthrough in synthetic process and stability of tablets.1. Manufacturing process improvement and quality control of capecitabine based on the idea of QbDObjective: To confirm the synthetic process route and industrialized manufacturing process of capecitabine and establish quality control method and limit of capecitabine active ingredient. Method: During the research and development of synthetic process route of capecitabine active ingredient, the idea of QbD was used to design synthetic routes and manufacturing process, and firstly, quality target product profile (QTPP) was defined to confirm its critical quality attributes (CQAs); For operations of all units, risk evaluation was conducted, then design of experiment (DOE) method was used to study high-risk variables recognized to confirm critical quality attributes (CQAs) and critical process parameters (CQAs). Reaction conditions and environmental protection conditions of synthetic process route of active ingredients and feasibility of refining and purification of products were considered comprehensively, and enlarged pilot production with scale of 30 Kg/batch and type-selection of industrialized manufacturing equipment which met GMP conditions and process design were conducted. Content of impurities (Content of impurities met international standards) and product yield (80-90%) were made as evaluation indexes. Process route was applicable to industrialized production. Results:5-deoxidation-1,2,3-three-O-acetyl-?-D-ribofuranose and silicon etherified 5-fluorocytosine were made as starting materials to prepare capecitabine by condensation,esterification and acetylysis reactions, in which, trimethylsilyl trifluoromethanesulfonate(TMSOTF) was used to replace heavy metal reagent tin chloride as condensation agent of glycosylation in condensation reaction, and preferred reacting weight was 1:1.0?1.5;Preferred reaction temperature was room temperature 20?25?,reaction conditions were mild, using saturated sodium bicarbonate solution to quench the reaction after completion of reaction by TLC monitoring (React for about 15h) could reduce the occurrence of side reactions, oily primary product obtained was recrystallized once by isopropyl alcohol, the white intermediate I could be obtained with purity of more than 99% by HPLC analysis and yield of 85%?90%. In esterification reaction,intermediate was used to react with N4 position of pentyl chloroformate by esterification, and preferred reacting weight was 1:1.3?1.5; Inorganic base K2CO3 was used to replace organic base pyridine as acid-binding agent, and preferred reacting weight was 1:1.0?1.3; Dimethylamino pyridine was used as catalyst to accelerate reaction I,and preferred reacting weight was 1:0.1?0.2;0.1mol/L diluted hydrochloric acid was used to wash after completion of reaction by TLC monitoring (React for about 45min) under the ice-bath (0-1?) conditions, mixed solvent of ethyl acetate and n-hexane was used to refine once, then white intermediate II could be obtained with purity of more than 99% by HPLT analysis and yield of 90%?92%. In acetylysis reaction, intermediate II stripped acetyl in the existing system of potassium hydroxide//15?-hydroxyl jervine (5:1), preferred reacting weight was (1:2), reaction temperature was 5?15?,reaction time was 1h,dichloromethane was used to extract,saturated sodium bicarbonate aqueous solution was used to wash, and capecitabine was obtained after recrystallization by ethyl acetate with purity of 99.8% by HPLC analysis and yield of 95%?97%. During the research and development of process route, analysis method was introduced to conduct strict quality control to reaction intermediates and starting materials in all steps. Conclusions: Synthetic process route and industrialized manufacturing process of capecitabine is confirmed,a set of quality management requirements which meet international GMP standard is established, and test methods for impurities of starting materials and intermediate are established thus to realize process control and ensure the quality of products. Quality control method and limit of capecitabine active ingredient are established. Purity of capecitabine active ingredient prepared reaches 99.8% and overall yield reaches 69.6%.It has low contentsof impurities,Failed to check out the other impurities except USP39 known impurities A, B, C?the impurity content is far less than in the USP impurity content and quantity of the product quality standard(9 impurities with known structures in USP3 9).2. Manufacturing process improvement and quality control of capecitabine tablets based on the idea of QbDObjective: To confirm formulation and industrialized manufacturing process of capecitabine tablets and establish quality control method and limit of capecitabine tablets.Method: The idea of QbD was used for research and development of formulation and manufacturing process to ensure quality, safety and effectiveness of products. Referring to formulation ingredients of reference preparation and combined with actual situations of production of pharmaceutical excipients in China,as well as aiming at the characteristics of less stability of active ingredient, formulation optimization was performed to tablets.Commercialized manufacturing process (Ensure the process was controlled) and control strategy of production were formulated. Enlarged pilot production with the scale of 100 thousands tablets/batch and type-selection of industrialized manufacturing equipment which met GMP conditions and process design were performed. The process route was applicable to industrialized production. According to higher content of raw materials in formulation, big viscosity and poor mobility of raw materials and considering cost of production, traditional wet granulation was used to conduct tableting, according to stability of raw materials and considering the raw materials were easy to hydrolyze,anhydrous wet granulation process was used, for bonding agent, medicinal ethyl alcohol was used to control the water in tablets thus to control the production of degradation impurities, and process parameters were screened to improve stability of products and ensure uniformity of release behavior. Granularity of raw materials in formulation, and amount and category of bonding agent, thinning agent, disintegrating agent and lubricating agent were screened, and consistency of quality evaluation indexes, including mobility of particles,angle of repose, disintegration time, compressibility,content uniformity, impurity, dissolution behavior, with original product, were used to evaluate and control. Results: For preparation, medicinal ethyl alcohol was selected as bonding agent,wet granulation process was used,lactose anhydrous and microcrystalline cellulose were selected as main thinning agents, orthogonal design method was used to optimize formulation, the formulation selected finally reduced the quantity of three degradation products greatly which ensured the stability of product better, and it found that dissolution curve was similar to that of reference preparation Xeloda by dissolution test in vitro with f2 reaching more than 70% which provided a good basic guarantee for bioequivalence in vivo. The formula was as below: Capecitabine 0.5g, lactose 54mg, microcrystalline cellulose 28mg, croscarmellose sodium 20mg, 2% hydroxypropyl methylcellulose ethanol solution 20ml, silicon dioxide 6mg, magnesium stearate 3mg and opadry coating power 3%. Conclusions: Industrialized manufacturing process of capecitabine tablets is confirmed thus to improve stability of products and reduce production of degradation impurities; Test method of intermediate is established thus to realize process control and ensure quality of products; Quality control method and limit of capecitabine tablets are established; A set of quality management requirements which meet GMP standard is established; Impurity content of final product is less than that of reference preparation,release behavior in vitro is in accordance with that of reference preparation (f2 factor>70),and product quality meets the requirements of international quality standards.3. Study on stability of capecitabine tabletsObjective: To study stability conditions of capecitabine tablets, confirm feasibility of product process and establish storage conditions and period of validity of product after marketing. Method: According to the relevant provisions specified in Guidelines for Stability Test of Active Ingredients and Pharmaceutical Preparations, study on stability of stress test, accelerated test and long-term test was conduct, and the study items included appearance, dissolution, related substances and content. Results: Appearance, dissolution,related substances and content had no obvious changes after the product was placed for 10 days under the conditions of illumination, high humidity and temperature, known from the study of product by an accelerated test for 6 months and a long-term test for 18 months, all study items had no obvious changes compared with that on month 0, and all indexes met the requirements of quality standard of this product. Conclusions: It shows that this product is relatively stable under illumination, high RH 92.5% and high temperature 60°C. It shows that this product has better stability under this packing conditions. Long-term test is conducted continuously to confirm the final period of validity and storage conditions of this product. Period of validity is 24 months tentatively,and storage condition is airtight storage.4. Study on in vitro/in vivo correlation of capecitabineObjective: To study the pharmacokinetic parameters of capecitabine tablets(Self-prepared preparations) and capecitabine tablets (Xeloda(?)) (Reference preparation)in bodies of Beagle canines, calculate the relative bioavailability and correlation between release in vitro and absorption in vivo of capecitabine tablets and provide basis for process optimization. Method: Select 12 healthy Beagle canines, give one tablet of self-prepared preparation and reference preparation (strength 0.5g) respectively, and take blood from vein within 0-6h after administration. Use high-performance liquid chromatography (HPLC) to determine the concentration of capecitabine in plasma,calculate its main pharmacokinetic parameters according to compartment model, and use Wanger-Nelson method to evaluate the IVIVC of capecitabine. Method: Half-life periods(t1/2) of self-prepared preparation and reference preparation were (1.06±0.52) and(1.08±0.54) h respectively, time to peak (tmax) were (1.0±0.52) and (1.0±0.41) h respectively,peak concentrations (Cmax) were (4.01 ±0.11) and (3.89±0.09) ?g·L-1 respectively, areas under the curve of concentration-time (AUC0-t) were (9.04±1.36) and(9.12±1·.26) ?g·L-1·h respectively,and AUC0-? were (9.89±1.35) and (9.96±2.01)?g·L-1·h respectively. Confidence limit of AUC0-6h was in the equivalent range between 0.80 and 1.25. The relation between absorption fraction fa in vivo and release rate ft in vitro was Y = 1.242X-39.27 (r = 0.966, p<0.01). Conclusions: Using HPLC method to determine the concentration of capecitabine has no impurity interference as well as has good repeatability and high accuracy. Absorption of this product in bodies of canines is equivalent to that of reference preparation, and bioequivalent; IVIVC is good, in vivo absorption regulation of drug can be judged and predicted according to in vitro he dissolution results of capecitabine, indicating that in vitro dissolution test can be applied to the screening and optimization of formulation of capecitabine tablets. |
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