Development Of Imatinib Mesylate Tablet

Background and ObjectiveImatinib mesylate tablet is a micromolecular targeted inhibitor for the treatment of philadelphia chromosome-positive chronic myelogenous leukemia (Ph+CML) in chronic stage, acceleration period or blast crisis phase and unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST) in adult patients. The drug was firstly marketed by Novartis as Gleevec in the USA in 2001. Imatinib mesylate initiated a new era of tumor molecular targeting treatment as the first targeted therapeutic drug, currently, the drug have been approved in more than 90 countries. The US,EU and other countries also have approved imatinib mesylate tablets as a treatment drug for gastrointestinal stromal tumor, the drug was imported to China as Gleevec in 2005.The objective of this study was to investigate formulation and preparation technology of imatinib mesylate tablet according to the current drug registration regulations. Experimental research, pilot scale research and large-scale production research were performed to determine reasonable formulation, preparation technology and critical process parameters, so as to develop imatinib mesylate tablet with the same quality as the original drug and realize industrial production of imatinib mesylate tablet.MethodExperimental research:analysis and study of literatures, physicochemical properties of imatinib mesylate were researched, so as to determine main types of auxiliary materials, after then compatibility test of auxiliary materials were carried out to select suitable auxiliary materials. Gleevec was detected and analyzed, dissolution curves under four medium conditions were obtained as the basic reference data, formulation screening experiments were performed for getting suitable auxiliary material ratio and technology, dissolution curves of experimental products were matched with that of Gleevec, so as to make sure that quality of the product met the requirements of the specification.Pilot scale research:pilot scale researches were performed on the basis of experimental process formulation, process parameters for milling, mixing, granulation, final blending, tabletting and coating were determined, equipments and sites for pilot scale production were also determined, comprehensive quality comparison studies between pilot scale product and Gleevec were carried out, in addition,10 days’forced degradation test was performed, all quality indexes of pilot scale product of imatinib mesylate tablet should be in accordance with that of Gleevec.Large-scale production research:large-scale production research was performed on the basis of pilot scale research, production process validation was performed for determination of formulation, preparation technology, process parameters, equipments and sites of large-scale production batches, comprehensive quality comparison studies between large scale product of imatinib mesylate tablet and Gleevec were performed, all quality indexes of large scale product should be in accordance with that of Gleevec. Accelerated stability test and long-term stability test were performed for three production batches of products, feasibility of formulation and technology was validated, determine the period of validity of product.; ResultsFormulation, preparation technology, process parameters, equipments and sites were determined, and all quality indexes of production batches were in accordance with that of Gleevec.Formulation:Every 70000 tablets contain:imatinib mesylate 8.37kg, microcrystalline cellulose (I) 1.75kg, hydroxypropyl methylcellulose 0.175kg, microcrystalline cellulose (II) 0.7kg, polyvinylpolypyrrolidone 1.96k g, silicon dioxide 0.088kg, magnesium stearate 0.098kg, purified water 910kg, coating contains film coating premixed agent (29F62341), purified water 2.6kg.Preparation technology and process parameters:imatinib mesylate is milled and screened with a universal pulverizer equipped with a 100 mesh sieve. Prescribed amount of screened imatinib mesylate, microcrystalline cellulose, hydroxypropyl methyl cellulose, polyvinylpolypyrrolidone, silicon dioxide and magnesium stearate are respectively weighed, standby. The above prepared imatinib mesylate, microcrystalline cellulose (Ⅰ), hydroxypropyl methylcellulose are added into a wet mixing granulator, mix for 10min, stirring speed and shear speed for mixing are all set as ’low speed’. Then purified water is added into the mixing granulator with stirring for preparation of soft material, additive amount of purified water is 910ml, stirring speed is set as ’low speed’, the shear switch is opened after addition of purified water, the shear speed is set as ’high speed’, shear time period is 2-5min.After discharge, the material obtained is transferred into an oscillating granulator equipped with a 20 mesh sieve for granulation. The wet particles obtained are put into a 60℃ hot air circulating oven for drying until water content is less than 2.5%, the dried particles are taken out of the oven and transferred into a oscillating granulator equipped with a 24 mesh sieve for breaking, the screened particles polyvinylpolypyrrolidone, microcrystalline cellulose (Ⅱ) and silicon dioxide are added into a multi-direction movement mixer for mixing. Rotate speed is set as 9rpm, mixing time is 20min, after that magnesium stearate is added, continue to mix for 15min, discharge. The final blended powder is sampled for testing content of imatinib mesylate, theoretical weight of a tablet is calculated. Tabletting of the final blended powder is performed with a rotary tablet machine. Round biconcave punches (φ9mm) is used to control average tablet weight within the scope of theoretical weight ±3%, hardness 50-70N. Coating is performed with a BG-80D coating machine, intlet air temperature was 55-60℃, outlet air temperature was 40-50℃, rotate speed is 6-8rpm, the weight of the tablet is increased by 2-4% after coating. Aluminum plastic packing machine is used for blister packaging, one plate contains 10 tablets. Blister plates are packaged in compound membrane bags. ConclusionUse alpha crystal in this product, avoid the patent protection with beta crystal.This study overcame the difficulties caused by high drug loading during the preparation process.Granulation process without the use of ethanol,avoid the formation of genotoxic impurities.Adopt the method of LC-MS on the genotoxic impurities of impurities A control, limit to 3 ppm.This study reflected the concept of’quality by design’.Successful development of imatinib mesylate can raise price competition with expensive imported drugs and provide super and cheap anticancer drug for native patients, the development of this drug can not only treat patients, it can also promote national economic development, the drug has significant social benefit and economic benefit.