阅读说明：本技术 包含 1,3,5-三嗪衍生物或其盐的固体药物组合物 (Solid pharmaceutical composition comprising 1,3, 5-triazine derivative or salt thereof ) 是由 孙源源 周山 刘雷 董平 高静 李来存 陈智林 许易 王尚 于 2019-09-03 设计创作，主要内容包括：包含1,3,5-三嗪衍生物或其可药用盐的固体药物组合物及其制备方法,具体而言涉及包含4-(叔丁氧氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺或其可药用盐的固体药物组合物及其制备方法。所述固体药物组合物具有良好的稳定性、较快的溶出速度和较高的生物利用度,适合临床生产和使用。(A solid pharmaceutical composition containing 1,3, 5-triazine derivative or medicinal salt thereof and a preparation method thereof, in particular to a solid pharmaceutical composition containing 4- (tert-butoxy amino) -6- (6- (trifluoromethyl) pyridine-2-yl) -N- (2- (trifluoromethyl) pyridine-4-yl) -1, 3, 5-triazine-2-amine or medicinal salt thereof and a preparation method thereof. The solid pharmaceutical composition has good stability, faster dissolution speed and higher bioavailability, and is suitable for clinical production and use.)

A solid pharmaceutical composition comprising a compound of formula i or a pharmaceutically acceptable salt thereof as an active ingredient and at least one pharmaceutically acceptable excipient;

the solid pharmaceutical composition according to claim 1, wherein the compound of formula i or a pharmaceutically acceptable salt thereof is contained in an amount of 10 to 100 mg; or the compound of the formula I or the pharmaceutically acceptable salt thereof accounts for 0.5-50 wt%, preferably 0.5-30 wt%, more preferably 1-25 wt% of the total mass of the solid pharmaceutical composition.

The solid pharmaceutical composition of claim 1 or 2, wherein the excipient comprises a diluent, a binder, a disintegrant, and/or a lubricant.

The solid pharmaceutical composition of claim 1 or 2, wherein the pharmaceutically acceptable salt of the compound of formula I is selected from the group consisting of the monohydrochloride salt of the compound of formula I, the dihydrochloride salt of the compound of formula I, the trihydrochloride salt of the compound of formula I, the monomethanesulfonate salt of the compound of formula I, the dimesylate salt of the compound of formula I, the trimethanesulfonate salt of the compound of formula I, the p-toluenesulfonate salt of the compound of formula I, the di-p-toluenesulfonate salt of the compound of formula I, and the tri-p-toluenesulfonate salt of the compound of; preferably the mono-mesylate salt of the compound of formula I, the bis-mesylate salt of the compound of formula I or the tris-mesylate salt of the compound of formula I; even more preferred are the monomethanesulfonates of the compounds of formula I.

The solid pharmaceutical composition according to claim 3, wherein the diluent is selected from the group consisting of starch, pregelatinized starch, sucrose, lactose, fructose, maltose, trehalose, pullulan, polydextrose, dextrin, maltodextrin, microcrystalline cellulose, cellulose acetate, ethylcellulose, mannitol, sorbitol, erythritol, isomalt, lactitol, maltitol, polyethylene glycol, xylitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate, sodium chloride, or a mixture of any two or more thereof; wherein preferably, the diluent accounts for 10-90 wt% of the solid pharmaceutical composition.

A solid pharmaceutical composition according to claim 3 wherein the binder is selected from povidone, starch slurry, dextrin, powdered sugar, sugar syrup, cellulose derivatives (such as hydroxypropylmethyl cellulose, methyl cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose), sodium alginate, polyethylene glycol, magnesium aluminium silicate, N-vinyl pyrrolidone, acacia or a mixture of any two or more thereof; wherein preferably, the binder accounts for 1-10 wt% of the solid pharmaceutical composition.

The solid pharmaceutical composition of claim 3, wherein the disintegrant is selected from the group consisting of dry starch, sodium starch glycolate, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, methyl cellulose, croscarmellose sodium, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, crospovidone, alginic acid, calcium alginate, sodium alginate, chitosan, colloidal silicon dioxide, glycine, guar gum, magnesium aluminum silicate, or povidone; wherein preferably, the disintegrant accounts for 1-10 wt% of the solid pharmaceutical composition.

The solid pharmaceutical composition of claim 3, wherein the lubricant is selected from stearic acid, calcium stearate, sodium stearate, zinc stearate, magnesium stearate, glyceryl monostearate, glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, palmitoyl stearoyl glyceride, leucine, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate or talc; wherein preferably, the lubricant accounts for 0.5-5 wt% of the solid pharmaceutical composition.

The solid pharmaceutical composition of any one of claims 3-8, wherein the solid pharmaceutical composition may further comprise a solubilizing agent; wherein the solubilizer is selected from hypromellose, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyhydroxy pentadecastearate, sodium dodecyl sulfate, magnesium dodecyl sulfate, sorbitan ester, caprylic glyceride, triolein, polyoxylglyceride, povidone, pyrrolidone, poloxamer, phospholipid or vitamin E polyethylene glycol succinate; wherein preferably, the solubilizer accounts for 0.5-5 wt% of the solid pharmaceutical composition.

The solid pharmaceutical composition of any one of claims 3-9, wherein the solid pharmaceutical composition may comprise: a mixture containing a compound of formula I or a pharmaceutically acceptable salt thereof, and a fluidization aid; preferably, the pharmaceutically acceptable salt of the compound of formula I is selected from the group consisting of the monomethanesulfonate salt of the compound of formula I, the dimethanesulfonate salt of the compound of formula I, and the trimethanesulfonate salt of the compound of formula I.

The solid pharmaceutical composition of claim 10 further comprising an additional excipient.

A solid pharmaceutical composition according to claim 10 or 11 wherein the mixture comprising a compound of formula I or a pharmaceutically acceptable salt thereof further comprises a binder, diluent and/or solubilizer; preferably, the diluent in the mixture containing the compound of formula I or the pharmaceutically acceptable salt thereof accounts for 10-50 wt%, preferably 15-50 wt%, more preferably 17-35 wt% of the total amount of the diluent in the solid pharmaceutical composition.

The solid pharmaceutical composition of claim 12 wherein the mixture comprising the compound of formula I or a pharmaceutically acceptable salt thereof comprises a binder and a diluent; wherein the binder is preferably selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose or povidone; the diluent is preferably selected from microcrystalline cellulose, lactose, starch, mannitol, xylitol, a mixture of microcrystalline cellulose and lactose, a mixture of microcrystalline cellulose and starch, a mixture of microcrystalline cellulose and mannitol, or a mixture of microcrystalline cellulose and xylitol.

A solid pharmaceutical composition according to claim 12 wherein the mixture comprising a compound of formula I or a pharmaceutically acceptable salt thereof comprises a binder and a solubilizer; wherein the binder is preferably selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose or povidone; wherein, the solubilizer is preferably selected from sodium dodecyl sulfate or magnesium dodecyl sulfate.

A solid pharmaceutical composition according to claim 12 wherein the mixture comprising a compound of formula I or a pharmaceutically acceptable salt thereof comprises a binder, a diluent and a solubilizer; wherein the binder is preferably selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose or povidone; the diluent is selected from microcrystalline cellulose, lactose, starch, mannitol, xylitol, a mixture of microcrystalline cellulose and lactose, a mixture of microcrystalline cellulose and starch, a mixture of microcrystalline cellulose and mannitol or a mixture of microcrystalline cellulose and xylitol; wherein, the solubilizer is preferably selected from sodium dodecyl sulfate or magnesium dodecyl sulfate.

The solid pharmaceutical composition of claim 10, wherein the fluidization aid comprises a diluent and a disintegrant; wherein preferably the diluent is selected from microcrystalline cellulose, lactose, starch, mannitol, xylitol, a mixture of microcrystalline cellulose and lactose, a mixture of microcrystalline cellulose and starch, a mixture of microcrystalline cellulose and mannitol or a mixture of microcrystalline cellulose and xylitol; wherein preferably, the disintegrant is selected from croscarmellose sodium, sodium carboxymethyl starch, crospovidone, or low substituted hydroxypropyl cellulose.

The solid pharmaceutical composition of claim 11 wherein the additional excipient comprises a lubricant; wherein preferably, the lubricant is selected from magnesium stearate, glyceryl behenate, sodium lauryl sulfate or sodium stearyl fumarate.

The solid pharmaceutical composition of any one of claims 1-17, wherein the solid pharmaceutical composition is obtained by fluid bed granulation.

A process for the preparation of a solid pharmaceutical composition according to any one of claims 1 to 18, characterized in that the process of preparation is fluid bed granulation comprising: (1) preparing a suspension containing a compound of formula I or a pharmaceutically acceptable salt thereof; (2) preparing a fluidization auxiliary material; (3) placing the fluidization auxiliary material in a fluidized bed, and spraying suspension containing the compound shown in the formula I or the pharmaceutically acceptable salt thereof into the fluidized bed for granulation; and (4) straightening the granules; and optionally (5) mixing the additional auxiliary materials with the whole grain materials.

The preparation method according to claim 19, wherein, in step (1), the solvent in the suspension is selected from methanol, ethanol, isopropanol, acetone or water, or any combination thereof; preferably, the mass ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the solvent in the suspension is 1: 5 to 20.

The preparation method according to claim 19, wherein, in step (1), the suspension further comprises a binder, a diluent and/or a solubilizer; wherein preferably the binder is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose or povidone; wherein preferably the diluent is selected from microcrystalline cellulose, lactose, starch, mannitol, xylitol, a mixture of microcrystalline cellulose and lactose, a mixture of microcrystalline cellulose and starch, a mixture of microcrystalline cellulose and mannitol or a mixture of microcrystalline cellulose and xylitol; wherein preferably, the solubilizer is selected from sodium dodecyl sulfate or magnesium dodecyl sulfate.

The method of claim 21, wherein the diluent in the suspension comprises 10 to 50 wt%, preferably 15 to 50 wt%, more preferably 17 to 35 wt% of the total amount of diluent in the solid pharmaceutical composition.

A process according to claim 21 or 22, wherein in step (1) the compound of formula I or a pharmaceutically acceptable salt thereof is first mixed with a binder, diluent and/or solubiliser to give a mixture comprising the compound of formula I or a pharmaceutically acceptable salt thereof, and the mixture is then mixed with the solvent to give the suspension comprising the compound of formula I or a pharmaceutically acceptable salt thereof.

The production method according to any one of claims 19 to 23, wherein, in step (2), the fluidization auxiliary material contains a diluent and a disintegrant; wherein preferably the diluent is selected from microcrystalline cellulose, lactose, starch, mannitol, xylitol, a mixture of microcrystalline cellulose and lactose, a mixture of microcrystalline cellulose and starch, a mixture of microcrystalline cellulose and mannitol or a mixture of microcrystalline cellulose and xylitol; wherein preferably, the disintegrant is selected from croscarmellose sodium, sodium carboxymethyl starch, crospovidone, or low substituted hydroxypropyl cellulose.

The production method according to any one of claims 19 to 24, wherein, in step (5), the additional excipient comprises a lubricant; wherein preferably, the lubricant is selected from magnesium stearate, glyceryl behenate, sodium lauryl sulfate or sodium stearyl fumarate.

The solid pharmaceutical composition of any one of claims 1-18 for use in treating a cancer induced by an IDH2 mutation, wherein the cancer induced by an IDH2 mutation comprises: glioblastoma (glioma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), Acute Myelogenous Leukemia (AML), sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinoma, or angioimmunoblastic non-hodgkin's lymphoma (NHL).