CN104546776B

CN104546776B - Rui Gefeini troche medical compositions and preparation method

Info

Publication number: CN104546776B
Application number: CN201510069115.0A
Authority: CN
Inventors: 李阅东; 唐建飞; 沈如杰; 何海珍; 马雯霞; 姚成娥; 张群; 赵福斌; 张婧
Original assignee: HANGZHOU ZHUYANGXIN PHARMACEUTICAL CO Ltd
Current assignee: HANGZHOU ZHUYANGXIN PHARMACEUTICAL CO Ltd
Priority date: 2015-02-10
Filing date: 2015-02-10
Publication date: 2017-08-22
Anticipated expiration: 2035-02-10
Also published as: CN104546776A

Abstract

The present invention relates to Rui Gefeini troche medical compositions and preparation method.Specifically, the present invention relates to a kind of pharmaceutical composition, including：Active pharmaceutical compounds, diluent, disintegrant, adhesive, lubricant；The active pharmaceutical compounds are the formamide of 4 [4 ({ [4 chlorine 3 (trifluoromethyl) phenyl] carbamyl } amino) 3 fluorophenoxies] N picolines 2 or its pharmaceutically acceptable salt, solvate, polymorphic；The pharmaceutical composition, it has 40~100 ° of contact angle, particularly with 40~90 ° of contact angle, particularly with 40~80 ° of contact angle, particularly with 40~70 ° of contact angle.Pharmaceutical composition of the present invention can be used for treatment by the disease and disease symptomses of the abnormal kinase signal of VEGFR, PDGFR, raf, p38, and/or flt 3 mediation.The invention further relates to the preparation method of the antineoplastic pharmaceutical compositions.Pharmaceutical composition of the present invention has excellent preparation performance.

Description

Rui Gefeini troche medical compositions and preparation method

Technical field

The present invention relates to a kind of new antineoplastic pharmaceutical compositions, more particularly to a kind of Rui Gefeini tablet medicines combination Thing, it can be used for treatment by the disease and disease of abnormal VEGFR, PDGFR, raf, p38, and/or flt-3 kinase signal mediation Symptom.The invention further relates to the preparation method of the antineoplastic pharmaceutical compositions.

Background technology

The activation of ras signal transduction pathways means the event of cell proliferation, differentiation and conversion with profound influence Cascade reaction.As Ras downstream effects son Raf kinases be these signals are delivered to nucleus from cell surface receptor one Individual key transmitter.It has been proved that by using the inactivation antibody or dominant raf kinases or dominant MEK of raf kinases The effect that the coexpression of (substrate of raf kinases) suppresses raf kinase signal pathways and suppresses to activate ras can cause the cell of conversion Revert to normal growth phenotype.Kolch etc. is further demonstrated has blocked film phase by antisense RNA to the raf suppression expressed Close cell propagation caused by oncogene.Similarly, the suppression of raf kinases is had confirmed in tube assay and experiment in vivo (by ASON) is related to the growth inhibition of a variety of human tumor types.

The continued tumor growth for maintaining size to exceed 1-2mm3 tumour cell needs functioning stroma, and this is to include into fibre Tie up the support structure of cell, smooth muscle cell, endothelial cell, extracellular matrix proteins and soluble factors.Tumour passes through secretion The soluble growth factor such as PDGF and transforming growth factor β (TGF-β) causes the formation of interstitial tissue, the growth factor Respective stimulation of host cell secretion such as fibroblast growth factor (FGF), EGF (EGF) and blood vessel endothelium life The complementary factors such as the long factor (VEGF).These stimulating factors cause new angiogenesis, and this provides oxygen and nutriment to tumour And it is grown and is provided route for metastases.Believing can be to from more for suppressing some treatment methods of interstitial formation The growth for planting the epithelial tumor of histological type is suppressed.However, due to the complexity and a variety of growth factors of its property Angiogenesis and tumor progression are participated in, a kind of material for single signal approach may only have limited effect.Wish It can be used to trigger multiple key signaling pathways of angiogenesis to provide treatment method in host stroma tumour.These approach bags Include PDGF (the effective stimulus factor of interstitial formation), (chemokine and rush of fibroblast and endothelial cell have silk to FGF Mitogen) and VEGF (effective regulatory factor of vascularization).

PDGF is a kind of key regulator of interstitial formation, and it is secreted and promoted into paracrine form by kinds of tumors The growth of fibrocyte, smooth muscle and endothelial cell, so as to promote interstitial formation and angiogenesis.PDGF is initially as ape and monkey Sarcoma viral v-sis oncogene products are identified.The growth factor is made up of 2 peptide chains for being referred to as A chains or B chains, Peptide chain primary amino acid sequences have 60% homology.Peptide chain warp disulfide bond is connected to form homologous or heterologous by AA, BB or AB The 30kDa of dimer composition maturation protein.High-caliber PDGF is found that in blood platelet, and PDGF can be by endothelial cell And Expression of Vascular Smooth Muscle Cell.In addition, under hypoxia condition found in the not enough tumor tissues of such as vascularization PDGF generation is raised.PDGF is combined with high-affinity and pdgf receptor (PDGFR), and this receptor is 1106 amino acid structures Into 124kDa transmembrane tyrosine kinase acceptor.PDGFR is homologous or heterodimer peptide chain form, and peptide chain is in its amino Generally there is 30% homology on acid sequence, and with 64% homology between its kinase domain.PDGFR is tool There is the member of the tyrosine kinase receptor family of separated kinase domain, the family includes VEGFR2 (KDR), VEGFR-3 (flt-4), c-Kit and flt-3.PDGFR is main in fibroblast, smooth muscle cell and pericyte (pericyte) upper table Reach, and expressed on a small quantity on the Schwann cells of nerve cell, messangial cell, Leydig cells and central nervous system.One Denier is combined with acceptor, and PDGF causes Receptor dimerization and undergoes the self-phosphorylation and mutual phosphorylation of tyrosine residue, this energy Improve the kinase activity of acceptor and promote the downstream effect factor by activating the recruitments of SH2 protein binding domains.Including PI-3 Multi-signal point including kinases, Phospholipase C-γ, src and GAP (for the p21-ras sour ras GTPase activating protein ras-GTP of GTP) Son and the PDGFR formation compounds of activation.By activating PI-3 kinases, PDGF activation Rho cellular pathways are so as to cause cell to be transported Dynamic and migration, and cause the mitosis activated by p21-ras and MAPK signal pathways by activating GAP.

In adult, PDGF main function is to promote and improve the speed of wound healing and keep the internal of blood vessel to put down Weighing apparatus.The PDGF of high concentration is found that in blood platelet, it is for fibroblast, smooth muscle cell, neutrophil cell and huge It is a kind of effective chemokine for phagocyte.In addition to its effect in wound healing, PDGF is assisted in keeping The homeostasis of blood vessel.In new vessels growth course, PDGF raises the pericyte peace required for blood vessel structure integrality Sliding myocyte.PDGF is considered as playing similar effect in tumor angiogenesis.As it played in angiogenesis A part for effect, PDGF adjusts blood vessel by the regulation of its interphase interaction to phoirocyte and extracellular matrix Permeability and the Fluid pressure for controlling tissue space.The pressure of tissue space can be reduced and promote thin by suppressing PDGFR activity Born of the same parents' toxin flows into tumour and improves the antitumor efficacies of these materials.

PDGF can directly be stimulated by paracrine or autocrine PDGFR on interstitial cell or tumour cell or by by The signal amplification of body promotes tumour growth through recombination activation acceptor.The PDGF of overexpression can make people melanoma cells and Keratinocyte both not PDGF-B expression acceptor cell type may by PDGF to interstitial formation and induction of vascular generate Direct effect and convert.Tumour PDGF-B expression but the not colon cancer of expressed receptor, lung cancer, breast cancer and prostate wherein Also the paracrine of this mesenchyma stroma of tumors is observed in the tumours such as cancer to stimulate.In spongioblastoma, soft-tissue tumor, ovary It has been reported that to the autocrine stimulation of growth of tumour cell, wherein most is through dividing in cancer, prostate cancer, cancer of pancreas and lung cancer The tumor cells expression PDGF parts and acceptor of analysis.The receptor activation of non-ligand-dependent type find it is less, but in chronic grain list It has been reported that wherein a chromosome translocations are between class Ets transcription factors TEL and pdgf receptor in monocytic leukaemia (CMML) Form fusion protein.In addition, having discovered that the activation in the PDGFR unrelated with c-Kit activation is dashed forward in gastrointestinal stromal tumor Become.PDGFR inhibitor can disturb mesenchyma stroma of tumors to develop and suppress growth and metastasis of tumours without excessive side effect.

VEGF (VEGF, also referred to as Vascular Permeability Factor VPF) be it is another in embryonic development and Newborn and angiogenesis the main regulatory factors of the disease medium vessels that some angiogenesis are relied on.VEGF is represented due to selectivity RNA montages and the former isomers family of mitogenesis existed in homodimer form.VEGF isomers is for blood vessel endothelium It is high special for cell.

Vegf expression is more by anoxic and interleukin-11, interleukin 6, EGF and TGF etc. Plant cell factor and growth factor-induced.At present it is reported that VEGF and VEGF family members and following three kinds of transmembrane receptor junket One or more combinations in histidine kinase：Vegf receptor 1 (also referred to as flt-1 (class fms EGFR-TKs 1)), VEGFR-2 (also referred to as acceptor containing Kinase insert Domain (KDR), KDR mouse analog be referred to as tire liver kinases 1 (flk-1)) and VEGFR- 3 (also referred to as flt-4).Have confirmed, VEGFR-2 and flt-1 have different signal transduction properties.Therefore, VEGFR-2 is complete The strong tyrosine phosphorylation of ligand-dependent is undergone in whole cell, and flt-1 shows weak response.It is therefore believed that complete for inducing For the biological answer-reply of the VEGF mediations of scope, it is key request to be combined with VEGFR-2.

VEGF plays central role in angiogenesis in vivo, and causes angiogenesis and Vascular permeability.It is not added with regulation Vegf expression trigger a variety of diseases, it is characterized in that abnormal angiogenesis and/or high osmosis effect.Believe some materials The regulation of the signal transduction cascade mediated to VEGF can provide effectively control to abnormal angiogenesis and/or high osmosis effect System.Anti-tumor cell in tumor hypoxia region is by stimulating VEGF productions to react, and this causes the endothelial cell of silence Activate to stimulate new vascularization.In addition, the VEGF in the tumor region without angiogenesis is produced and ras can be promoted to believe Number transduction pathway.In situ hybridization research shows, including lung cancer, thyroid cancer, breast cancer, gastroenteric tumor, kidney and tumor of bladder, VEGF mRNA notable up-regulation in various human tumors including oophoroma, cervical carcinoma and hemangioma and several intracranial tumors. Neutrality VEGFR-2 monoclonal antibodies are proved to be effective in neonate tumour blood vessel is blocked.

VEGF overexpression (such as under the conditions of extreme oxygen deficiency) can cause angiogenesis in eyeball, cause blood vessel excessive Hyperplasia, ultimately results in blindness.Including diabetic retinopathy, ischemic retinal vein occlusion and premature retinal Such cascade reaction is observed in a variety of retinopathies including disease and age related macular degeneration.

In rheumatic arthritis (RA), angiogenesis factor produce can with mediate vascular screen to growth.RA suffers from There is high-caliber immunoreactivity VEGF in the synovia of person, and in other forms arthritis or degenerative joint disease patient VEGF low SIs in synovia.Had confirmed in anti-rat collagen induction type arthritis model, angiogenesis inhibitors AGM-170 Hinder the neovascularization in joint.

Formed in psoriasis and bullous pemphigoid, erythema multiforme and dermatitis herpetiformis etc. and subepidermal blister Also the raising of vegf expression is shown in related herpes diseases.

VEGF (VEGF, VEGF-C, VEGF-D) and its acceptor (VEGFR2, VEGFR3) are not only tumour Angiogenesis and be lymphatic vessel generation key regulator.VEGF, VEGF-C and VEGF-D are main in most of tumour Horizontal expression during tumour growth simultaneously often fully to improve.Vegf expression is caused by anoxic, cell factor, such as ras Oncogene or the stimulation for the inactivation for passing through tumor suppressor gene.

VEGF biological activity by and the combination of its acceptor mediated.VEGFR3 (also referred to as flt-4) mainly exists Expressed on lymphatic endothelial cells in normal adult tissue.Being formed for new lymphatic vessel needs VEGFR3 functions, but for Already present lymphatic vessel is maintained then need not.VEGFR3 is also up-regulation on the vascular endothelial cell of tumour.Recently, VEGFR3 Ligand VEGF-C and VEGF-D be confirmed as the regulatory factor of lymphatic vessel generation in mammal.The related lymphatic vessel life of tumour The lymphatic vessel generation induced into the factor may promote new vessel growth to enter tumour, and this is provided for tumour cell enters system The passage of circulation.Blood circulation may be entered by ductus thoracicus by invading vasculolymphatic cell.Tumour expression study has allowed for pair VEGF-C, VEGF-D and VEGFR3 express the clinicopathologia factor directly related with same primary tumo(u)r diffusivity and (for example drenched Fawn on transfer, lymphatic vessel intrusion, Secondary cases transfer and DFS phase) directly compared.In many cases, these are studied Illustrate the correlation statistically between lymphatic vessel generation factor expression and primary entity tumor transfer ability.

For VEGF in malignant cell is produced, anoxic appears to be a kind of important stimulating factor.For tumour cell , it is necessary to the activation of p38MAP kinases for VEGF being induced to anoxic generation response.Except being participated in by adjusting VEGF secretions Beyond angiogenesis, p38MAP kinases is promoted by adjusting collagenase activity and the expression of urokinase Plasminogen Activator Malignant cell invades the migration with different tumor types.

Mitogenesis original activated protein kinase (MAPK) p38 suppression is demonstrated to suppress thin in test tube and/or in vivo Intracellular cytokine formation (such as TNF, IL-1, IL-6, IL-8) and protease produce (such as MMP-1, MMP-3).Mitogenesis is former Activated protein kinase p38 participates in IL-1 and TNF signal pathways.

Clinical research produces TNF (TNF) and/or to many including rheumatoid arthritis Disease is planted to link up.In addition, being found that the TNF of excessive levels in a variety of inflammatories and/or immunological regulation class disease.These Disease includes acute rheumatic fever, bone information, postmenopausal osteoporosis, pyaemia, septic shock, endotoxic shock, systemic Inflammatory reaction disease, asthma etc..TNF is also related to infectious diseases, and these diseases include the pylorus during pulmonary tuberculosis, gastric ulcer Pylori (Hp) infection etc..

Many diseases be considered as by excessive or unwanted matrix destruction metalloproteinases (MMP) activity or by What the proportional imbalance of the tissue depressant (TMP) of MMP and metalloproteinases was mediated.These diseases include osteoarthritis, rheumatism Property arthritis, septic arthritis, metastases, periodontosis, cornea come off, the rupture of albuminuria, atherosclerotic plaque After caused coronary artery thrombosis, aortic aneurysm, infertile, malnutrition bullous epidermis, traumatic joint injury The demyelinating disease of osteoporosis, jawbone arthropathy and nervous system that degenerative cartilage missing, MMP activity are mediated.

Cause the suppression of TNF formation and MMP formation due to suppressing p38, it is believed that suppress the former activator protein of mitogenesis and swash Enzyme p38 can provide the above-mentioned disease including osteoporosis and inflammation disease for the treatment of such as rheumatoid arthritis and COPD The means of disease.

For VEGF in malignant cell is produced, anoxic appears to be a kind of important stimulating factor.For tumour cell , it is necessary to the activation of p38MAP kinases for VEGF being induced to anoxic generation response.Except being participated in by adjusting VEGF secretions Beyond angiogenesis, p38MAP kinases is promoted by adjusting collagenase activity and the expression of urokinase Plasminogen Activator Malignant cell invades the migration with different tumor types.As a result, it may also be desirable to which suppressing p38 kinases passes through interference and angiogenesis and evil Property the related signal cascade influence tumour growth of cell intrusion.

Serine-threonine kinase inhibitor and/or the tyrosine kinase inhibitor activity having to some ureas are It is described.Especially having confirmed that is used to some ureas as the active component of pharmaceutical composition give birth to cancer, blood vessel Into the treatment of disease, inflammatory disease.

Formula (I) compound 4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamyl } amino) -3- fluorophenoxies] - N- picoline -2- formamides, i.e. 4- [4- ({ [4-chloro-3- (trifluoromethyl) phenyl] carbamoyl } Amino) -3-fluorophenoxy]-N-methylpyridine-2-carboxamide is disclosed in WO2005009961：

The monohydrate of formula (I) compound is that Rui Gefeini (Regorafenib) is listed with trade name Stivarga, is used for Treat excess proliferative disease, such as cancer, tumour, lymthoma, sarcoma and leukaemia.Rui Gefeini molecular formula is C₂₁H₁₅ClF₄N₄O₃·H₂O, molecular weight is 500.83.

The Rui Gefeini of monohydrate form is referred in WO2008043446.In addition, the salt of formula (I) compound, such as Its hydrochloride, mesylate and phenylbenzimidazole sulfonic acid salt refers in WO2005009961, and can be by using corresponding acid treatment Formula (I) compound is formed.Formula (I) compound is described for treating excess proliferative disease, such as cancer, tumour, pouring Bar knurl, sarcoma and leukaemia.

This area still expects there is effective antitumour medicine, and for example it can be used for situation described above.And it is such The beneficial preparation method of antineoplastic pharmaceutical compositions.

The content of the invention

It is an object of the invention to provide a kind of antineoplastic pharmaceutical compositions with excellent pharmaceutical properties.The present invention goes out people Expect ground to find, make after the composition comprising compound of formula I handled, can effectively change its physical property and then can have The particularly solid composite medicament of the pharmaceutical composition with excellent pharmaceutical property such as tablet is obtained sharply.The present invention is based on this It was found that and being accomplished.The present invention compound of formula I be with combined with urea the fluoro- 4- of 2- (2- (N- methylcarbamoyls)- 4- pyridines epoxide) phenylene group omega-carboxyaryl diphenyl urea, it be raf kinases, VEGFR kinases, p38 kinases and Effective inhibitor of PDGFR kinases, the kinases is all to treating and preventing osteoporosis, inflammatory disease including cancer Molecular target interested for disease, excess proliferative disease and angiogenesis disease.

Therefore, first aspect present invention provides a kind of pharmaceutical composition, including：Active pharmaceutical compounds, dilution Agent, disintegrant, adhesive, lubricant；The compound be with compounds of Formula I or its pharmaceutically acceptable salt, solvate, Polymorphic etc.：

Formula I is 4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamyl } amino) -3- fluorobenzene Epoxide]-N- picoline -2- formamides.

The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is solid composite medicament.

The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is the solid drugs group in tablet form Compound.

The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the diluent includes but do not limited In：Calcium monohydrogen phosphate, kaolin, dextrin, lactose, mannitol, sucrose, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, Sorbierite and starch and its derivative (such as cornstarch, potato starch, amylum pregelatinisatum, modified starch, pregelatinized starch Deng), erythritol, xylitol, fructose etc. and combinations thereof.

The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the active pharmaceutical compounds included with Compound of formula I is calculated as 40 parts by weight, and the amount of the diluent is 50~500 parts by weight；The amount of such as described diluent be 50~ 400 parts by weight；The amount of such as described diluent is 50~300 parts by weight；The amount of such as described diluent is 50~200 weight Part.

The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the disintegrant includes but do not limited In：Low-substituted hydroxypropyl cellulose, PVPP, crosslinked carboxymethyl fecula sodium, sodium starch glycolate, cross-linked carboxymethyl are fine Plain sodium of dimension etc. and combinations thereof.

The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the active pharmaceutical compounds included with Compound of formula I is calculated as 40 parts by weight, and the amount of the disintegrant is 50~500 parts by weight；Such as 50~400 parts by weight；Such as 50 ~300 parts by weight；Such as 50~200 parts by weight.

The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein described adhesive for example but are not limited In：(molecular weight is 5000~50000 PVP, for example for hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone PVP K15, PVP K17, PVP K25, PVP K30 etc.), polyvinyl alcohol, Arabic gum, alginic acid, sodium alginate, gelatin etc. And combinations thereof.More preferably include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone or poly- second Enol.

The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the active pharmaceutical compounds included with Compound of formula I is calculated as 40 parts by weight, and the amount of described adhesive is 50~500 parts by weight；Such as 50~400 parts by weight；Such as 100 ~300 parts by weight；Such as 100~200 parts by weight.Adhesive can be added by dry method, and use typical dry granulation pressure Piece method prepares tablet；Adhesive can be added by dry method, and use water or hydrous ethanol to be carried out for wetting agent to whole material Then wet granulation prepares tablet again；Adhesive can also use water or hydrous ethanol wiring solution-forming as binder solution, connect And wet granulation is carried out with the binder solution and then tablet is prepared again；Adhesive can also be dissolved in suitable together with active medicine In suitable solvent (such as ethyl acetate and/or ethanol), then the spray-dried technique of the solution is added to diluent and/or collapsed Solve in agent.These different types of adhesive feed postitions are all that well known to a person skilled in the art and be easily able to.

The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the lubricant also may be used in this area Referred to as glidant, is generally referred to as lubricant.Lubricant includes but is not limited to：Magnesium stearate, stearic acid, calcium stearate, Zinc stearate, liquid paraffin, polyethylene glycol, silica, cataloid, superfine silica gel powder, talcum powder, starch, hydrogenation are planted Thing oil etc. or its combination.

The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the active pharmaceutical compounds included with Compound of formula I is calculated as 40 parts by weight, and the amount of the lubricant is 1~50 parts by weight；The amount of such as described lubricant is 1~25 weight Measure part；The amount of such as described lubricant is 1~20 parts by weight；The amount of such as described lubricant is 1~10 parts by weight；For example it is described The amount of lubricant is 2~8 parts by weight.

The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the pharmacy of the compound of formula I can The salt of receiving includes traditional nontoxic salt, the salt for example obtained by methods known in the art from inorganic or organic acid.Example Such as sulfate, phosphate, fluoroform sulphonate, tosilate, 1-naphthalene sulfonic aicd salt, trifluoroacetate, the apple of compound of formula I Tartaric acid salt, fumarate, benzoate, salicylate, phenylacetate, acetate, adipate, alginates, ascorbate, Aspartate, benzoate, benzene sulfonate, disulfate, butyrate, citrate, camphor hydrochlorate, camphorsulfonic acid Salt, cinnamate, cipionate, double gluconates, lauryl sulfate, isethionic acid, fumarate, glucose heptan Hydrochlorate, glycerophosphate, Hemisulphate, enanthate, caproate, hydrochloride, hydrobromate, hydriodate, 2- hydroxyl ethane sulphurs Hydrochlorate, itaconate, lactate, maleate, mandelate, methane sulfonates, 2- naphthalene sulfonates, nicotinate, nitrate, grass Hydrochlorate, embonate, pectate, persulfate, 3- phenpropionates, picrate, pivalate, propionate, amber Acid-addition salts including amber hydrochlorate, sulfonate, tartrate, rhodanate, toluenesulfonic acid and undecylate.

The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the compound of formula I or its is medicinal The solvate of salt can be its any acceptable solvate thereof.The one of the hydrate of such as compound of formula I, such as compound of formula I Hydrate etc..

The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the compound of formula I or its is medicinal The polymorphic of salt, can be any crystal formation disclosed in prior art, such as I crystal of known compound of formula I, etc..

The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it has 40~100 ° of contact angle, special It is not with 40~90 ° of contact angle, particularly with 40~80 ° of contact angle, particularly with 40~70 ° of contact angle. It has been found, unexpectedly, the troche medical composition with low contact angle has significantly more excellent pharmaceutical properties, this It is that the present invention is contributed the substance of prior art.

The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is placed in temperature 45 C, relative humidity 75% time sealing preserve 5 months, determine it in the case of without the above-mentioned high-temperature treatment dissolution percentage of 60 minutes is determined in addition Its 60 minutes dissolution percentage in the case of through above-mentioned high-temperature treatment, be calculated as follows its after high-temperature treatment dissolution rate become Change percentage：

Dissolution rate percent change=(60 minutes dissolution percentage of high-temperature treatment sample is except ÷ is without high-temperature treatment sample 60 Minute dissolution percentage) × 100%

The pharmaceutical composition or the dissolution rate percent change (%) of tablet are in the range of 98.4~101.7%.

The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is the method by comprising the following steps Prepare：

(1) two kinds of solid materials of the active medicine of recipe quantity and adhesive are dissolved in suitable solvent (such as acetic acid second Ester and/or ethanol, such as by ethyl acetate and ethanol with weight ratio 1：The mixed solvent of 2~6 proportions；Such as addition is consolidated Weight ratio between body material and solvent is 1：1~5, such as 1：2~5, such as 1：2~4) in, be made containing drug solns；In 60- At a temperature of 70 DEG C, the solution is sprayed in diluent and all or part of disintegrant using fluidised bed granulator and in stream Change in bed and remove solvent, obtain preformed particles；

(2) particle obtained by step (1) is extruded and sieved by roller press and obtain particle；Then by compressed particle with Lubricant and the disintegrant of optional surplus are well mixed, and the end for obtaining preparing plain piece (i.e. the tablet of non-coated) mixes thing；

(3) by mixed thing tabletting on tablet press machine eventually obtained by step (2), the medicine of the present invention of the plain piece form in non-coated is obtained Compositions；Optionally

(4) by plain piece wrap film clothing obtained by step (3), obtain in the pharmaceutical composition of the present invention for being coated sheet form.

(1) two kinds of solid materials of the active medicine of recipe quantity and adhesive are dissolved in suitable solvent (such as acetic acid second Ester and/or ethanol, such as by ethyl acetate and ethanol with weight ratio 1：The mixed solvent of 2~6 proportions；Such as addition is consolidated Weight ratio between body material and solvent is 1：1~5, such as 1：2~5, such as 1：2~4) in, be made containing drug solns；In 60- At a temperature of 70 DEG C, the solution is sprayed in diluent and all or part of disintegrant using fluidised bed granulator and in stream Change in bed and remove solvent, obtain preformed particles；Then, the preformed particles are spread in closed container, 10 is placed at room temperature Room atmosphere in~40 hours (such as 20~30 hours, e.g., from about 24 hours), the closed container is with 60~90% ethanol (such as 70~90% ethanol, such as 80~90% ethanol) saturation, so that the preformed particles are fully contacted with the saturation atmosphere, warp The preformed particles are less than 5% (such as less than 4%, example using 50~60 DEG C of ventilating air dryings to moisture after this closed disposal Such as less than 3%)；

Further, second aspect of the present invention provides a kind of coated tablet, and it includes any reality of first aspect present invention Apply scheme described pharmaceutical composition, and the clothing layer that its periphery is wrapped up.

The coated tablet of any embodiment according to a second aspect of the present invention, wherein described pharmaceutical composition is in tablet Form.

The coated tablet of any embodiment according to a second aspect of the present invention, wherein described clothing layer is film-coating.

The coated tablet of any embodiment according to a second aspect of the present invention, it is peelled off after clothing layer, and label material has 40 ~100 ° of contact angle, particularly with 40~90 ° of contact angle, particularly with 40~80 ° of contact angle, particularly has 40~70 ° of contact angle.

The coated tablet of any embodiment according to a second aspect of the present invention, it is the method system by comprising the following steps It is standby to obtain：

(3) by mixed thing tabletting on tablet press machine eventually obtained by step (2), the medicine of the present invention of the plain piece form in non-coated is obtained Compositions；

(4) by plain piece wrap film clothing obtained by step (3), obtain in the pharmaceutical composition of the present invention for being coated sheet form.I.e. Coated tablet.

The coated tablet of any embodiment according to a second aspect of the present invention, wherein described clothing layer accounts for total weight of tablet 1~5%, such as 1~4%, such as 2~3%.

The coated tablet of any embodiment according to a second aspect of the present invention, wherein the coating material of clothing layer is main Filmogen is selected from：Ethyl cellulose, hydroxypropyl methyl cellulose and methacrylic acid-alkyl acrylate copolymer；Enter one Step ground, the main filmogen of coating material is hydroxypropyl methyl cellulose, is, for example, its aqueous dispersion；Further, wrap Clothing material isIt is hydroxypropyl methyl cellulose aqueous dispersion；Further, coating material is selected from With

The coated tablet of any embodiment according to a second aspect of the present invention, wherein the coating material of clothing layer is main Filmogen is polyvinyl alcohol.In one embodiment, they can use water according to the conventional amount used of this area to tablet Prepared, easily can also be bought from market temporarily before being coated.For example, can be bought from the happy Kanggong department of card, such as Europe bar GenerationFilm-coating premixing is formulated, such as powder pinIn another example, can be from Ai Leyi medical materials company Buy, for example, easily release beautifulSeries of products, for example, easily release beautifulA kind of typical coating material composition includes： Colouring agent (such as iron oxide red and/or iron oxide yellow are other), phosphatide (such as Fabaceous Lecithin), polyethylene glycol (such as poly- second two Alcohol 3350), polyvinyl alcohol, talcum powder, titanium dioxide etc..The pink colour for example bought from the happy Kanggong department of card Polyvinyl alcohol (account for total weight of the mixture 44%), PEG3350 wherein containing partial hydrolysis (account for total weight of the mixture 12.4%), Fabaceous Lecithin, iron oxide (iron oxide red and iron oxide yellow), talcum powder, titanium dioxide.

The coated tablet of any embodiment according to a second aspect of the present invention, it is placed in temperature 45 C, relative humidity 75% Lower sealing preserve 5 months, determine it in the case of without the above-mentioned high-temperature treatment dissolution percentage of 60 minutes, determine in addition its Through the dissolution percentage of 60 minutes in the case of above-mentioned high-temperature treatment, it was calculated as follows in the dissolution rate change hundred after high-temperature treatment Fraction：

The dissolution rate percent change (%) of the coated tablet is in the range of 97.2~99.2%.

The method that third aspect present invention provides the pharmaceutical composition for preparing first aspect present invention any embodiment, It comprises the following steps：

The method of any embodiment according to a third aspect of the present invention, it comprises the following steps：

The method that fourth aspect present invention provides the coated tablet for preparing second aspect of the present invention any embodiment, its Comprise the following steps：

Fifth aspect present invention provides a kind of tablet, and there is the plain piece as described in specification embodiment 1-25 is any to match somebody with somebody for it Side.

The tablet of any embodiment according to a fifth aspect of the present invention, it is placed in close under temperature 45 C, relative humidity 75% Envelope is preserved 5 months, determine it in the case of without the above-mentioned high-temperature treatment dissolution percentage of 60 minutes, and it is determined in addition through upper State the dissolution percentage of 60 minutes in the case of high-temperature treatment, be calculated as follows its after high-temperature treatment dissolution rate change percentage Number：

The dissolution rate percent change (%) of the tablet is in the range of 98.4~101.7%.

Any technical characteristic that any embodiment of either side or the either side of the present invention has is equally applicable Any embodiment of other any embodiments or other either sides, as long as they will not be conflicting, certainly mutual Between where applicable, if necessary can individual features be made with appropriate modification.Make to various aspects of the present invention with feature into one below The description of step.

As used herein, term " compacting " is defined as being converted into powder (such as by roller press) by compression specifying Powder, for example, be pressed into the tablet of bulk, the sheet of this bulk by the compact sample of shape in advance by suitable machinery Thing can be used for the follow-up particle for crushing tabletting when suitably manufacturing tablet to prepare.

As used herein, term " crushing " is defined as reducing granular size by sieving.

As used herein, by term " compression " be defined as by the drift of tablet press machine on powder using enough power by its Compress " tabletting " operation in piece agent, that is, tablet process industry.

Contact angle described herein refers to the contact angle with water.Specifically, contact angle refers to be added dropwise in solid pharmaceutical preparations such as tablets The angle that the water droplet on composition surface is contacted with composition surface.Those skilled in the art know the side for having many measure contact angles Method and device, in the present invention, an exemplary assay method are as follows：In syringe needle (such as model SNSO52/026； HAMILTON companies produce, stainless steel, internal diameter 0.26mm, external diameter 0.52mm；Or also can use the syringe needle with similar specification) 1 μ l pure water (MILLI-Q of needle point formation；MILLIPORE companies) drop, then by contact angle determination device (such as OCA-15 types, Data physics companies；Or other brands or the contact angle determination device of model with similar functions) determine water droplet add Contact angle after to 60 milliseconds of tablet surface.When tablet surface has curvature, contact is determined again after being corrected to straight line in parsing Angle；Typically determine at room temperature.In the present invention, if not otherwise indicated, contact angle of the present invention is determined by following methods 's：At room temperature, in syringe needle (SNSO52/026；HAMILTON companies produce, stainless steel, internal diameter 0.26mm, external diameter 0.52mm) Needle point formation 1 μ l pure water (MILLI-Q；MILLIPORE companies) drop, then by contact angle determination device (OCA-15 types, Data physics companies) determine water droplet be added to the contact angle after 60 milliseconds of tablet surface.Due to being determined with above-mentioned conditions of similarity Obtained contact angle, in varying environment (such as different experiments room), distinct device (such as contact angle produced using other companies Determine device), these results do not have obvious difference, therefore when defining the contact angle of composition of the present invention, without Specific continuous mode and condition determination to contact angle are construed as limiting.

Solid composite medicament of the present invention for not being tablet form, can be with such as capsule, granule, powder By the way that the powder contained in preparation, particle, semi-solid material etc. are pressed into figure of tablet, then it is measured, such as glue Wafer, can by taking out capsule 's content, take wherein about 200mg be pressed into diameter 8mm, thickness 3.5mm surface is flat and light Sliding tablet determines contact angle.Even for can not effectively reflect the tablet of its real property, such as film coating, enteric coating Or the tablet of sugar-coat, then tablet can also be ground again, above-mentioned glue is referred again to by the way that the clothing layer in tablet surface is scraped off The mode of wafer, by tablet grind gained powder it is again tabletted after determine again.For the present composition, it is being prepared not When tabletted, can take powder it is appropriate it is tabletted after be measured；It, can be direct when being prepared into uncoated plain piece It is measured；Its it is coated coating tablet is made when, can by tablet surface clothing layer scrape off, then tablet is ground again, Again by gained powder again tabletted rear measure.

According to pharmaceutical composition of the present invention particularly tablet, its label (for uncoated tablets, refers to whole piece；For Coated tablet, refers to strike off the slice, thin piece inner core that clothing layer is obtained completely) grind after determine loss on drying (95 DEG C of dryings to constant weight) Less than 5%, especially less than 4%, especially less than 3%.

It has been found, unexpectedly, the tablet label that the present composition is prepared into, have the advantages that it is unexpected, And these labels can select all a variety of coating materials, for example can with film coating, the material of such as film-coating can be with Hydroxypropyl methyl cellulose (can wherein add appropriate polyvinyl alcohol, such as commercial prod for main component Series), certainly, for the purposes, other coating materials also can be used, such as using ethyl cellulose as the bag of main component Clothing material.Therefore, for the object of the invention, the coating material of the present composition can not be construed as limiting.

The purposes of the present composition

The invention provides can adjust be related to raf, VEGFR, PDGFR, p38 and/or flt-3 kinases one or more letter The pharmaceutical composition of number transduction pathway.Raf is to participate in many important thin including cell growth, cell survival and intrusion The important signaling molecule of the regulation and control of born of the same parents' process.It is Ras/raf/MEK/ERK approach members.This approach is present in major part In tumour cell.VEGFR, PDGFR and flt-3 are the acceptor molecules of cross-film, when it can be triggered by appropriate ligand stimulation Ras/raf/MEK/ERK Cell signal transduction pathways, cause intracellular cascade reaction.These acceptor molecules all have tyrosine-kinase enzyme activity Property.

VEGFR acceptors are stimulated by VEGF (VEGF), and are endothelial cell development and function point analysis Important control point.PDGF beta receptors are including adjusting cell propagation and surviving in the various kinds of cell type including mesenchymal cell. Flt-3 is the acceptor of FL parts.Its structure is similar to c-kit, and adjusts the growth of multipotency hematopoietic cell, thus influence T cell, The development of B cell and dendritic cells.

Any gene or isomery of raf, VEGFR, PDGFR, p38 and/or flt-3 including wild type and saltant type Body can be adjusted according to the present invention.Raf or raf-l kinases is serine/threonine kinase family, and it includes at least three Family member (a-raf, b-raf and c-raf or raf-1).C-raf and b-raf are the preferred of pharmaceutical composition of the present invention Target spot.In the activated mutant (such as V599E mutant) including authenticated b-raf in the kinds of tumors including melanoma, and Pharmaceutical composition as described herein can be used for suppressing its activity.

Term " regulation " changed compared with referring to normal activity when described pharmaceutical composition is not present the approach (or Its component) functional activity.This effect includes the regulation in any quantity or degree, and this includes improving, activates, strengthens, increasing Plus, promote, stimulate, reduction, hinder, suppress, reducing, reducing, antagonism etc..

Pharmaceutical composition of the present invention can also adjust following one or more processes, and these processes include but is not limited to Such as cell growth (including for example break up, cell survival and/or propagation), growth of tumour cell (including for example break up, cell is deposited It is living and/or breed), tumor regression, endothelial cell growth (including for example break up, cell survival and/or propagation), angiogenesis (angiogenic growth), lymphatic vessel generation (lymphatic growth) and/or hematopoiesis function (such as T cell and B cell development, dendritic cells Development etc.).

While not wishing to be fettered by any mechanism of action or mechanism, it has been found that pharmaceutical composition tool of the present invention There is the ability of regulation kinase activity.However, method of the present invention is not limited to any specific mechanism or the drug regimen How thing realizes its therapeutic action.Term " kinase activity " refers to wherein turn a γ phosphate radical from atriphos (ATP) The catalytic activity moved on in protein substrate amino acid residue (such as serine, threonine or tyrosine).Medicine group Compound can adjust kinase activity, for example by directly suppress with the ATP ATP-binding sites for competing kinases its activity, by Conformation change is produced in the structure of enzyme influences its activity (such as by destroying the three-dimensional structure with biological activity) etc..

Using common detection methods conventional determining can be carried out to kinase activity.Kinase assays generally include kinases, Substrate, buffer solution and detecting system component.Typical kinase assay includes protein kinase with peptide substrate and such as P-ATP ATP reacts to produce the end-product (such as phosphorylated protein when using peptide substrate) of phosphorylation.It is any appropriate to use Method final product is detected., can be by radioactivity mark using affinity membrane or gel electrophoresis when using radioactivity ATP The phosphorylated protein of note is separated with unreacted γ -32P-ATP, and is then developed or used on gel using autoradiograph Scintillation counter is detected.Non-radioactive methods can also be used.Antibody (such as anti-phosphoric acid of identification phosphorylated substrate can be used Phosphotyrosine antibody).For example, kinases can have ATP and kinase buffer liquid and kinases available phosphorus acidifying institute with substrate State incubation under conditions of substrate.Reactant mixture (such as by electrophoresis) can be separated, and then can be with the phosphoric acid of detection substrate Change (such as by using the Western blot of antiphosphotyrosine antibody).The antibody can use detectable mark substance markers (such as such as HRP enzyme, Avidin or biotin, chemical illuminating reagent etc.).Other methods can use ELISA, parent With UF membrane, fluorescence polarization method, luminescence method etc..

Another method outside radioactive form is time-resolved fluorescence resonant energy transfer (TR-FRET).The side Method is reacted according to standard kinase, and wherein substrate (such as biotinylated poly- (GluTyr)) is deposited by protein phosphatase in ATP Phosphorylation under the conditions.Phospho-specif iotac antibodies (anti-phosphotyrosine or phosphoric acid that final product can then be chelated with europium Serine/threonine) and the streptavidin-APC that is combined with biotinylated substrate detected.Above-mentioned two component is when combining It is spatially near, and the fluorescence for producing homogeneous form to the energy transmission of acceptor (SA-APC) from phospho-specif iotac antibodies is read Number.

Pharmaceutical composition of the present invention can be used for treating and/or prevent to be related to raf, VEGFR, PDGFR, p38 and/or Any disease or illness that flt-3 one or more cellular signal transduction pathways are mediated.Term " treatment " is according to its routine Meaning is used, for example, patient is entered for the symptom of resistance, mitigation, reduction, releasing, improvement disease or dysfunction etc. purpose Row processing is looked after.Described pharmaceutical composition can also be for preventing and/or treat the disease mediated by the signaling molecule And/or illness is described.Term " mediation " represent for example described signaling molecule be it is abnormal in the disease and/or illness or A part for not normal approach.

Treatable disease and illness include any disease mentioned above and below and：

Raf relevant diseases including such as cell generation disorders, cancer, tumour etc.；

Including such as cancer, tumour growth, inflammation disease, rheumatic arthritis, retinopathy, psoriasis, glomerulonephritis Disease, asthma, chronic bronchitis, arteriosclerosis, graft rejection, the illness etc. for being related to angiogenesis VEGFR-2 it is related Disease；

Include such as cancer, disease of cornea, cornea redness, corneal transplantation, lymph gland hyperplasia, the illness for being related to lymphatic vessel generation Etc. VEGFR-3 relevant diseases；

Including being for example characterised by cell propagation, cellular matrix formation, cell movement and/or the disease of extracellular matrix formation The PDGFR- ss related diseases of disease or illness.Specific example includes such as tumour, malignant tumour, cancer, cancer metastasis, chronic Myelomatosis, inflammation, nephrosis, diabetic nephropathy, mesangium hyperplastic glomerular nephrosis, fibrotic conditions, artery are hard Change disease, heart valve ISR, hypertension related arteriosclerosis, venous bypass graft artery sclerosis, chorionitis, interstitial lung disease, cunning Liquid disease, arthritis, leukaemia, lymthoma etc.；

Including such as immune correlated disease, blood cell disease, being related to hematopoietic cell, (for example T cell, B cell, dendron shape are thin Born of the same parents) illness of development, cancer, anaemia, HIV, the Flt-3 relevant diseases of acquired immunodeficiency disease etc.；

Including inflammation disease, immunoregulatory disorder and other and abnormal cell factor (particularly TNF α) generation or different The p38 relevant diseases of the related other diseases of normal MMP activity.These diseases include but is not limited to rheumatic arthritis, chronic Obstructive lung disease (COPD), osteoporosis, Crohn disease and psoriasis.

In addition, pharmaceutical composition of the present invention can be used for treating for example following illness and disease：Glomerulosclerosis, Interstitial nephritis, interstitial pulmonary fibrosis, arteriosclerosis, wound scar and chorionitis.

Pharmaceutical composition of the present invention also has progress of the extensive therapeutic activity to treat or prevent various diseases, These diseases such as inflammatory disorders, coronary restenosis, tumor-associated vessels generation, arteriosclerosis, autoimmunity disease, inflammation Disease, some nephrosis related to glomerulus or mesangial cell propagation and the illness in eye related with retinal vessel proliferation, silver Consider disease, hepatic sclerosis, diabetes, arteriosclerosis, ISR, vascular graft restenosis, in-stent restenosis, angiogenesis, eye to be worth doing Disease, lung fiber disease, bronchiolitis obliterans, glomerulus nephrosis, rheumatic arthritis.

The present invention also provides treatment, prevention, regulation for the illness of one or more of people and/or other mammals Etc.：Include the view of diabetic retinopathy, ischemic retinal vein occlusion, retinopathy of prematurity and age related macular degeneration Film disease；Rheumatic arthritis, psoriasis form related bullous disease (including bullous pemphigoid, multiform to subcutaneous bubble Erythema or dermatitis herpetiformis), rheumatic fever, bone information, PMO, pyaemia, Gram-negative pyaemia, purulence blood Property shock, endotoxin shock, Toxin shock syndrom, Systemic inflammatory syndrome, inflammatory bowel disease (Crohn disease and ulcer Property colitis), Herxheimer reaction, asthma, adult respiratory distress wait group, Acute Lung fibrotic disease, sarcoidosis of lung, mistake Quick property respiratory disease, silicosis, coal miner pneumoconiosis, alveolar damage, hepatic failure, the hepatopathy in acute inflammation, severe Alcoholic Hepatitis, malaria (Plasmodium falciparum malaria and brain malaria), Non-Insulin Dependent Diabetes Mellitus (NEDDM), congestive cardiac decline Exhaust, damage, arteriosclerosis, Alzheimer disease, acute encephalitis, brain damage, multiple sclerosis (multiple sclerosis after heart disease In demyelinate and few BMDC missing), advanced cancer, malignant lymphoma, pancreatitis, wound healing reduction in infection, Inflammation and cancer, myelodysplastic syndrome, systemic loupus erythematosus, biliary cirrhosis, bowel necrosis, radiational injury/give Toxicity after monoclonal antibody, (ischemia reperfusion injury and kidney, liver, heart and skin are same for host-transplant reaction Kind of allograft rejection), lung allograft rejection (bronchitis obliterans), total hip displacement complication and Summer Graves disease, coli-infection caused by helicobacter pylori infections, Ku Shi Trypanosoma cruzi infections in pulmonary tuberculosis, gastric ulcer Enterotoxin A effect caused by the effect of caused shiga-like toxin, staphy lococcus infection, the infectious diseases of meningococcal infection, with And the huge virus of lyme disease spirochete, Leptospira, cell, influenza virus, theiler's encephalomyelitis virus and human immune deficiency Infection caused by viral (HIV), papilloma, bud shape glioma, Kaposi's sarcoma, melanoma, lung cancer, oophoroma, Prostate cancer, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, carcinoma of urinary bladder, breast cancer, colorectal cancer, thyroid cancer, pancreas Cancer, stomach cancer, hepatocellular carcinoma, leukaemia, lymthoma, Hodgkin's disease, Hugh Burkitt disease, arthritis, rheumatic arthritis, diabetes are regarded Nethike embrane disease, angiogenesis, ISR, in-stent restenosis, vascular graft restenosis, pulmonary fibrosis, hepatic sclerosis, artery sclerosis Disease, glomerulus nephrosis, diabetic nephropathy, graft rejection, psoriasis, diabetes, wound healing, inflammation and neurodegenerative disease, Excessive immune disease, hemangioma, myocardial angiogenesis, coronal and the formation of brain collateral, ischemic, keratonosus, iridopathy, new green blood Pipe glaucoma, premature labor ARM retinopathy, wound healing, Helicobacter pylori ulcers relevant disease, fracture, endometrium Dystopy, diabetic symptom, cat scratch fever, thyroid gland hypertrophy, asthma or burnt degree edema, wound, chronic lung disease, apoplexy, polyp, capsule Swollen, synovitis, chronic and allergic inflammation, ovary height stimulates syndrome, lung and brain edema, cheloid, cystic fibrosis, hard Change, carpal tunnel syndrome, adult respiratory distress syndrome, ascites, illness in eye, cardiovascular disease, Ke-richness (POEMS) syndrome, Crow grace Disease, glomerulus nephrosis, osteoarthritis, multiple sclerosis, graft rejection, Lyme arthritis, pyaemia, Feng Xi-woods Er Shi are comprehensive Simulator sickness, pemphigoid, Paget disease, polycystic kidney disease, sarcoidosis, thyroiditis, hyperviscosity syndrome, Osier-Weber- Rendir diseases, chmnic. obstructive's tuberculosis, radiation, anoxic, pre-eclampsia, menorrhalgia, mullerianosis, herpe simplex sense Dye, ischemic retinopathies, corneal vessels generation, herpes zoster, human immunodeficiency virus, parapoxvirus, protozoan, arch Parasitosis and tumour are related to ooze out and oedema.

Pharmaceutical composition of the present invention can have more than one the activity and therefore can be directed to a plurality of letter Number transduction pathway.Therefore, these pharmaceutical compositions can realize be typically only capable to using different pharmaceutical combination of compositions when could The treatment and prevention effect of acquisition.For example, suppressing new conduit formation (such as with VEGFR-2 by using single medicine composition Be connected with VEGFR-3 functions) (such as blood vessel and/or lymphatic vessel) and cell propagation (be for example connected with raf and PDGFR β functions ) be particularly useful in treating cancer and other cell proliferative disorders promoted by new vascularization.Therefore, it is of the invention More particularly at least there is the pharmaceutical composition of suppressing cell reproduction and anti-angiogenesis (suppressing angiogenesis) activity.According to The present invention can be treated to any disease or illness for benefiting from vessel growth and cell inhibitory effect.Due to can be more smart Its field of activity really is defined, is also advantageous using single medicine composition.

Pharmaceutical composition of the present invention can be treated to any tumour, and these tumours include but is not limited in raf, ras And/or there is the swollen of one or more mutation in flt-3 and its in any upstream of signal pathway participated in or downstream member Knurl.As it was earlier mentioned, tumour can be treated without considering the mechanism corresponding to it with pharmaceutical composition of the present invention.Can Treated with the tumour to any organ, this includes but is not limited to such as colon cancer, cancer of pancreas, breast cancer, prostate cancer, bone Cancer, liver cancer, kidney, lung cancer, carcinoma of testis, cutaneum carcinoma, stomach cancer, colorectal cancer, clear-cell carcinoma, hepatocellular carcinoma, melanoma etc..

The example of breast cancer includes but is not limited to invasive ductal carcinoma, ILC, DCIS and leaflet in situ Cancer.

The example of respiratory cancer includes but is not limited to cellule and non-small cell lung cancer and bronchial adenoma and pleura lung Blastoma.

The example of the cancer of the brain includes but is not limited to brain stem and hypophtalmic glioma, cerebellum and cerebral astrocytoma, into nerve Solencyte knurl, ependymoma and the outer embryoma of nerve and pine nut adenoma.

Genital orgnas,male's tumour includes but is not limited to prostate cancer and carcinoma of testis.Tumors of female reproductive organ is included but not It is limited to carcinoma of endometrium, cervical carcinoma, oophoroma, carcinoma of vagina and carcinoma of vulva and sarcoma of uterus.

Tumor in digestive tract includes but is not limited to cancer of anus, colon cancer, colorectal cancer, cancer of the esophagus, gallbladder cancer, stomach cancer, straight Intestinal cancer, carcinoma of small intestine and salivary-gland carcinoma.

Urethral system tumour includes but is not limited to carcinoma of urinary bladder, carcinoma of penis, kidney, carcinoma of renal pelvis, carcinoma of ureter and carcinoma of urethra.

Cancer eye includes but is not limited to intraocular melanoma and retinoblastoma.

The example of liver cancer includes but is not limited to hepatocellular carcinoma (with or without the hepatocellular carcinoma of fibrolamellar form), courage Solencyte cancer and mixed type liver cell cholangiocellular carcinoma.

Cutaneum carcinoma include but is not limited to squamous cytoma, Kaposi sarcoma, chromoma, Merkel cell skin cancer with And non-melanoma cutaneum carcinoma.

Head and neck cancer includes but is not limited to laryngocarcinoma, hypopharyngeal cancer, nasopharyngeal carcinoma and/or oropharyngeal cancer and lip and carcinoma of mouth.

Lymthoma includes but is not limited to AIDS associated lymphomas, NHL, skin T cell lymphoma, Huo Qi Golden disease and central nervous system lymphoma.

Sarcoma includes but is not limited to soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma and horizontal stroke Line muscle tumor.

It is white that leukaemia includes but is not limited to acute myeloid leukemia, Acute Lymphoblastic Leukemia, chronic lymphocytic Blood disease, chronic myelogenous leukemia and hairy cell leukemia.

Except suppressing tumor cell proliferation, pharmaceutical composition of the present invention can also cause tumor regression, and such as tumour is big The reduction of small reduction or tumour distribution in vivo.

Embodiment

The following examples provided are only used for task of explanation rather than are used for, and are also not necessarily to be construed as limiting in any way The system present invention.Those skilled in the art will recognize that in the case of not past the spirit or scope of the present invention can to Lower embodiment makes conventional change and modifications.In the example for preparing composition below, if not otherwise indicated, with 50,000 units that feed intake Prepared by the amount of preparation such as (piece), the per unit preparation active pharmaceutical compounds that for example (piece) is included are with the Formulas I of free alkali form Compound is calculated as 40mg.In the example for preparing composition below, if not otherwise indicated, various materials are crushed using preceding And 100 mesh sieve can be passed through.When preparing coating tablet from plain piece, about 4/5 plain piece is only taken to be coated, remaining plain piece is used Used in other experiments.

Hereinafter, using to active component for compound of formula I various forms be it is known in the art that for example dissociate The compound of formula I of alkali form and monohydrate (CN102947271A, CN201180019150.1), the Formulas I chemical combination of compound of formula I The isetionate (1 of thing:1) with the esilate (1 of compound of formula I:1) (CN103923001A, CN201410181182.7) etc., When they are as active component in tests below, it can buy, can also be prepared according to these literature methods from market.

Embodiment 1：Prepare the pharmaceutical composition of tablet form

Plain piece prescription (every)：

The monohydrate of compound of formula I：40mg (in terms of anhydride),

Polyvinylpyrrolidone (k25)：160mg,

Ac-Di-Sol (interior plus partial disintegration agent)：100mg,

Microcrystalline cellulose：100mg；

Ac-Di-Sol (Extra Section disintegrant)：54mg,

Cataloid (anhydrous level, i.e. colloidal silicon dioxide, also known as generally colloidal anhydrous silica)：2.4mg,

Magnesium stearate：3.6mg.

Preparation method：

(1) two kinds of solid materials of the active medicine of recipe quantity and polyvinylpyrrolidone are dissolved in solvent acetic acid second by (a) Ester-alcohol mixeding liquid (ethyl acetate：Ethanol=1：4, solid material is 1 with weight of solvent ratio:3) in, it is made containing drug solns； (b) at a temperature of 60-70 DEG C, the solution is sprayed to diluent and Nei Jia partial disintegration agent using fluid bed vacuum granulator In the powder bed of mixed-powder, solvent is removed in fluid bed, obtaining preformed particles, (after measured, its moisture is less than 3%)；(c) connect , the preformed particles are spread in closed container, place 24 hours at room temperature, the room atmosphere in the closed container is used 85% ethanol saturation, so that the preformed particles are fully contacted with the saturation atmosphere, makes the preformed particles after this closed disposal With 50~60 DEG C of ventilating air dryings to moisture less than 3% (note：Substantially achieve the level of step (b) end-product)；

(2) particle obtained by step (1) is extruded and sieved with 3.15mm and 1.0mm hole patterns respectively by roller press；Then It is well mixed with lubricant, Extra Section disintegrant, the end for obtaining preparing plain piece (i.e. the tablet of non-coated) mixes thing；

(3) by mixed thing tabletting on tablet press machine eventually obtained by step (2), the pharmaceutical composition of the present invention in plain piece form is obtained (ellipse slice being made with suitable punch die, be about 16mm, wide about 7mm)；

(4) by plain piece obtained by step (3) with the every pink colour with 12mg(it is before coating for clothing material Uniform suspension is made with 48mg water) it is coated in seed-coating machine, exit flow temperature control obtains surface uniform at 35 DEG C Coating tablet.

Embodiment 2：Prepare the pharmaceutical composition of tablet form

Plain piece prescription (every)：

The monohydrate of compound of formula I：40mg (in terms of anhydride),

Polyvinylpyrrolidone (k30)：100mg,

Ac-Di-Sol (interior plus partial disintegration agent)：150mg,

Microcrystalline cellulose：50mg；

Ac-Di-Sol (Extra Section disintegrant)：50mg,

Cataloid：2mg,

Magnesium stearate：3mg.

Preparation method：

(1) two kinds of solid materials of the active medicine of recipe quantity and polyvinylpyrrolidone are dissolved in solvent acetic acid second by (a) Ester-alcohol mixeding liquid (ethyl acetate：Ethanol=1：2, solid material is 1 with weight of solvent ratio:2) in, it is made containing drug solns； (b) at a temperature of 60-70 DEG C, the solution is sprayed to diluent and Nei Jia partial disintegration agent using fluid bed vacuum granulator In the powder bed of mixed-powder, solvent is removed in fluid bed, obtaining preformed particles, (after measured, its moisture is less than 3%)；(c) connect , the preformed particles are spread in closed container, place 20 hours at room temperature, the room atmosphere in the closed container is used 90% ethanol saturation, so that the preformed particles are fully contacted with the saturation atmosphere, makes the preformed particles after this closed disposal With 50~60 DEG C of ventilating air dryings to moisture less than 3% (note：Substantially achieve the level of step (b) end-product)；

(3) by mixed thing tabletting on tablet press machine eventually obtained by step (2), the pharmaceutical composition of the present invention in plain piece form is obtained (ellipse slice is made with suitable punch die)；

Embodiment 3：Prepare the pharmaceutical composition of tablet form

Plain piece prescription (every)：

The monohydrate of compound of formula I：40mg (in terms of anhydride),

Polyvinylpyrrolidone (k15)：200mg,

Ac-Di-Sol (interior plus partial disintegration agent)：40mg,

Microcrystalline cellulose：200mg；

Ac-Di-Sol (Extra Section disintegrant)：10mg,

Cataloid：2mg,

Magnesium stearate：3mg.

Preparation method：

(1) two kinds of solid materials of the active medicine of recipe quantity and polyvinylpyrrolidone are dissolved in solvent acetic acid second by (a) Ester-alcohol mixeding liquid (ethyl acetate：Ethanol=1：6, solid material is 1 with weight of solvent ratio:4) in, it is made containing drug solns； (b) at a temperature of 60-70 DEG C, the solution is sprayed to diluent and Nei Jia partial disintegration agent using fluid bed vacuum granulator In the powder bed of mixed-powder, solvent is removed in fluid bed, obtaining preformed particles, (after measured, its moisture is less than 3%)；(c) connect , the preformed particles are spread in closed container, place 30 hours at room temperature, the room atmosphere in the closed container is used 80% ethanol saturation, so that the preformed particles are fully contacted with the saturation atmosphere, makes the preformed particles after this closed disposal With 50~60 DEG C of ventilating air dryings to moisture less than 3% (note：Substantially achieve the level of step (b) end-product)；

(4) by plain piece obtained by step (3) with the every pink colour with 10mg(it is before coating for clothing material Uniform suspension is made with 40mg water) it is coated in seed-coating machine, exit flow temperature control obtains surface uniform at 35 DEG C Coating tablet.

Embodiment 4：Prepare the pharmaceutical composition of tablet form

The formula and preparation method of reference implementation example 1, different is only：Compound of formula I monohydrate therein is replaced with into Formulas I The anhydride of compound, coating material uses hydroxypropyl methyl cellulose baseRespectively in step (3) and Step prepares plain piece and coating tablet in (4).

Embodiment 5：Prepare the pharmaceutical composition of tablet form

The formula and preparation method of reference implementation example 1, different is only：Disintegrant therein is replaced with into crosslinked carboxymethyl fecula Sodium.Respectively plain piece and coating tablet are prepared in step (3) and step (4).

Embodiment 6：Prepare the pharmaceutical composition of tablet form

The formula and preparation method of reference implementation example 1, different is only：Disintegrant therein is replaced with into starch hydroxyacetic acid Sodium.Respectively plain piece and coating tablet are prepared in step (3) and step (4).

Embodiment 7：Prepare the pharmaceutical composition of tablet form

The formula and preparation method of reference implementation example 1, different is only：Disintegrant therein is all changed to interior addition, that is, Disintegrant in step (2) is all added in step (1) (b).Respectively plain piece is prepared in step (3) and step (4) And coating tablet.

Embodiment 8：Prepare the pharmaceutical composition of tablet form

The formula and preparation method of reference implementation example 2, different is only：Active component therein is changed to the benzene of compound of formula I Sulfonate；Magnesium stearate therein is replaced with into stearic acid, cataloid replaces with talcum powder, the two is with being to be respectively 1.5mg and 0.5mg.Respectively plain piece and coating tablet are prepared in step (3) and step (4).

Embodiment 9：Prepare the pharmaceutical composition of tablet form

The formula and preparation method of reference implementation example 3, different is only：Active component therein is changed to the salt of compound of formula I Hydrochlorate, 5mg and 3mg are changed to by magnesium stearate therein and cataloid consumption respectively.Respectively in step (3) and step (4) plain piece and coating tablet are prepared in.

Embodiment 10：Prepare the pharmaceutical composition of tablet form

With reference to the formula of embodiment 1.Preparation method：According to the conventional technique for preparing tablet of formulation art, by active component, poly- second Alkene pyrrolidone, interior plus partial disintegration agent and microcrystalline cellulose are well mixed, are that wetting agent carries out wet granulation with 50% ethanol, Dry to moisture up to less than 3%；Then the step of gained dry particl being shone into 1 preparation method of embodiment (1) (c) is handled；Then according to The step of secondary 1 preparation method of photograph embodiment (2), (3), (4) processing.Respectively plain piece and bag are prepared in step (3) and step (4) Garment piece.

Embodiment 11：Prepare the pharmaceutical composition of tablet form

With reference to the formula and preparation method of embodiment 1, different is only：Without step (1) (c), but directly by step (1) (b) gained particle directly carries out step (2) processing.Respectively plain piece and coating tablet are prepared in step (3) and step (4).

Embodiment 12：Prepare the pharmaceutical composition of tablet form

With reference to the formula and preparation method of embodiment 2, different is only：Without step (1) (c), but directly by step (1) (b) gained particle directly carries out step (2) processing.Respectively plain piece and coating tablet are prepared in step (3) and step (4).

Embodiment 13：Prepare the pharmaceutical composition of tablet form

With reference to the formula and preparation method of embodiment 3, different is only：Without step (1) (c), but directly by step (1) (b) gained particle directly carries out step (2) processing.Respectively plain piece and coating tablet are prepared in step (3) and step (4).

Embodiment 14：Prepare the pharmaceutical composition of tablet form

With reference to the formula and preparation method of embodiment 4, different is only：Without step (1) (c), but directly by step (1) (b) gained particle directly carries out step (2) processing.Respectively plain piece and coating tablet are prepared in step (3) and step (4).

Embodiment 15：Prepare the pharmaceutical composition of tablet form

With reference to the formula and preparation method of embodiment 5, different is only：Without step (1) (c), but directly by step (1) (b) gained particle directly carries out step (2) processing.Respectively plain piece and coating tablet are prepared in step (3) and step (4).

Embodiment 16：Prepare the pharmaceutical composition of tablet form

With reference to the formula and preparation method of embodiment 6, different is only：Without step (1) (c), but directly by step (1) (b) gained particle directly carries out step (2) processing.Respectively plain piece and coating tablet are prepared in step (3) and step (4).

Embodiment 17：Prepare the pharmaceutical composition of tablet form

With reference to the formula and preparation method of embodiment 7, different is only：Without step (1) (c), but directly by step (1) (b) gained particle directly carries out step (2) processing.Respectively plain piece and coating tablet are prepared in step (3) and step (4).

Embodiment 18：Prepare the pharmaceutical composition of tablet form

With reference to the formula and preparation method of embodiment 8, different is only：Without step (1) (c), but directly by step (1) (b) gained particle directly carries out step (2) processing.Respectively plain piece and coating tablet are prepared in step (3) and step (4).

Embodiment 19：Prepare the pharmaceutical composition of tablet form

With reference to the formula and preparation method of embodiment 9, different is only：Without step (1) (c), but directly by step (1) (b) gained particle directly carries out step (2) processing.Respectively plain piece and coating tablet are prepared in step (3) and step (4).

Embodiment 20：Prepare the pharmaceutical composition of tablet form

With reference to the formula and preparation method of embodiment 10, different is only：Without step (1) (c), but directly carry out step (2) handle.Respectively plain piece and coating tablet are prepared in step (3) and step (4).

Embodiment 21：Prepare the pharmaceutical composition of tablet form

With reference to the formula and preparation method of embodiment 1, different is only：Diluent wherein used is replaced with into cornstarch. Respectively plain piece and coating tablet are prepared in step (3) and step (4).

Embodiment 22：Prepare the pharmaceutical composition of tablet form

With reference to the formula and preparation method of embodiment 1, different is only：Diluent wherein used is replaced with into lactose.Respectively Plain piece and coating tablet are prepared in step (3) and step (4).

Embodiment 23：Prepare the pharmaceutical composition of tablet form

With reference to the formula and preparation method of embodiment 1, different is only：Disintegrant wherein used is replaced with into the poly- dimension of crosslinking Ketone.Respectively plain piece and coating tablet are prepared in step (3) and step (4).

Embodiment 24：Prepare the pharmaceutical composition of tablet form

With reference to the formula and preparation method of embodiment 1, different is only：Disintegrant wherein used is replaced with into low-substituted hydroxypropyl Base cellulose.Respectively plain piece and coating tablet are prepared in step (3) and step (4).

Embodiment 25：Prepare the pharmaceutical composition of tablet form

With reference to the formula and preparation method of embodiment 1, different is only：Adhesive wherein used is replaced with into hydroxypropyl methyl Cellulose.Respectively plain piece and coating tablet are prepared in step (3) and step (4).

Experimental example 1：Determine contact angle

Syringe needle：Model SNSO52/026；HAMILTON companies produce, stainless steel, internal diameter 0.26mm, external diameter 0.52mm；

Pure water：MILLI-Q (production of MILLIPORE companies) pure water processed；

Contact angle determination device：CA-15 types, the production of Data physics companies；

Assay method：In needle point 1 μ l pure water drops of formation, its contact dripped to behind 60 milliseconds of tabletted surface is determined Angle.

Sample pretreating：Granule materials before tabletting are first compressed into plane tablet and determined again；Compressing medicine Piece is directly determined, but the curvature when calculating to tablet surface is corrected；For coated piece, clothing layer is struck off completely, Fine powder is ground into again, it is then re-compacted to be determined again into plane tablet.

As a result：

The sample of various embodiments above, for each batch of sample, its particle, plain piece, coated tablet before tabletting, three kinds of examinations Contact angle that sample is measured is essentially identical, and (for every batch to be tested, its particle and coating tablet are differed with the contact angle of plain piece and not surpassed Cross 2 °)；Such as sample of embodiment 1, particle, the plain piece being pressed into, coated tablet, the contact angle that three samples are measured point Wei not be 57.2 °, 56.8 °, 56.3 °；

Each Lot sample of embodiment 1~10, the contact angle of its plain piece is in the range of 42~67 °；

Each Lot sample of embodiment 11~25, the contact angle of its plain piece is in the range of 78~106 °；

Each Lot sample of embodiment 11~20 is only different from step (1) with each Lot sample of embodiment 1~10 in preparation method respectively (c), and identical, to be obtained for the different preparation methods of same formula tablet is formulated, the embodiment 1~10 for performing step (1) (c) is respectively tried Sample is relative to the sample of embodiment 11~20 that it is accordingly formulated, and contact angle reduces more than 36 °, such as plain piece of embodiment 3 respectively 56.8 ° of contact angle, and 95.2 ° of the 13 plain piece contact angle of embodiment of same recipe.

Experimental example 2：Coating tablet Performance

By the coated tablet (tablet surface is normal, and clothing layer is flawless) of foregoing embodiments, at least 300, each sample is put In temperature 60 C, 75% time placement of relative humidity 30 days, whether tablet surface clothing layer there is slight crack after thus observation disposes 30 days. Calculating every Lot sample slight crack rate, (percentage that i.e. slight crack occurs is to occur obtained by the piece number divided by experiment total tablet number used of slight crack Percentage).As a result show, these contact angles of embodiment 1~10 are less than 70 ° of sample, and slight crack rate is between 2~6%；And it is real Applying example 11~25, these have the tablet sample of high contact angle, and slight crack rate is between 17~25%.Such as embodiment 2 and implementation The slight crack rate of the coating tablet of example 12 is respectively 2.8% and 20.4%.

Experimental example 3：Coating tablet stripping property is investigated

(1) dissolution determination method：Chinese Pharmacopoeia two methods of annex XC second (paddle method) of version in 2010, with 0.2% 12 Sodium alkyl sulfate solution is dissolution medium, and rotating speed is 75 turns per minute, is sampled during through 60 minutes, is filtered, according to following HPLC chromatogram Condition determines stripping quantity with HPLC methods, calculates the stripping quantity of every.

(2) HPLC chromatogram condition：Chromatographic column：Symmetry C18 posts (150x4.6mm, 3.5 μm of granularities, Waters, Eschborn, Germany), column temperature：40 DEG C, mobile phase：2.4 kaliumphosphate buffers of pH-acetonitrile-ethanol (2：1：1, volume Than), flow velocity：1ml/min, detector：UV Detection wavelength 265nm, system suitability：Number of theoretical plate is calculated by compound of formula I peak 3000 should be not less than.Reference substance solution is configured to the concentration of the μ g/ml containing compound of formula I 50 with mobile phase.

(3) plain piece for preparing example 1 above -10 and embodiment 11-25, is placed in temperature 45 C, relative humidity 75% Lower sealing preserve 5 months, determine each sample in the case of without the above-mentioned high-temperature treatment dissolution percentage of 60 minutes is determined in addition Each sample dissolution percentage of 60 minutes in the case of through above-mentioned high-temperature treatment, calculates the dissolution rate after high-temperature treatment and changes percentage Number (%, 60 minutes dissolution percentages of high-temperature treatment sample divided by without 60 minutes dissolution percentage of high-temperature treatment sample multiplied by with 100%).It was unexpectedly determined that contact angle is less than 70 ° of embodiment 1-10 samples, their dissolution rate percent change (%) In the range of 98.4~101.7%, show that these samples are not showing obvious dissolution rate situation of change after high-temperature process, I.e. these samples have splendid dissolution stability.Regrettably, contact angle is more than 78 ° of embodiment 11-25 samples, it Dissolution rate percent change (%) in the range of 71~86%, display unsatisfactory dissolution stability completely. The dissolution rate percent change (%) of such as embodiment 2 and embodiment 12 is respectively 98.4% and 78.6%.It should be noted that Herein, parameter dissolution stability is the dynamic parameter for reflecting Dissolution of Tablet change, i.e., the difference during a period of time, reflection Be tablet stability, it distinguishes static dissolution rate that usually people are generally considered.

(4) coating tablet for preparing example 1 above -10 and embodiment 11-25, is placed in temperature 45 C, relative humidity 75% time sealing preserve 5 months, determine each sample in the case of without the above-mentioned high-temperature treatment dissolution percentage of 60 minutes, in addition Each sample is determined in the case of through the above-mentioned high-temperature treatment dissolution percentage of 60 minutes, calculates the dissolution rate after high-temperature treatment and changes Percentage (%, 60 minutes dissolution percentages of high-temperature treatment sample divided by without 60 minutes dissolution percentage of high-temperature treatment sample again It is multiplied by 100%).It was unexpectedly determined that contact angle is less than 70 ° of embodiment 1-10 samples, their dissolution rate percent change (%) shows that these samples are not showing obvious dissolution rate change feelings after high-temperature process in the range of 97.2~99.2% Condition, i.e. these samples have splendid dissolution stability.Regrettably, contact angle is more than 78 ° of embodiment 11-25 examinations Sample, their dissolution rate percent change (%) is in the range of 73~87%, and the complete unsatisfactory dissolution of display is steady It is qualitative.The dissolution rate percent change (%) of such as embodiment 3 and embodiment 13 is respectively 99.2% and 80.3%.

Experimental example 4：Chemical stability

This experimental example investigates impurity 4- (4- amino -3- fluorophenoxies)-N- picoline -2- formamides in various tablets Situation of change.

HPLC determination methods：

Tablet is ground into fine powder, the tablet powder taken equivalent to 50mg compound of formula I is placed in 25ml measuring bottles, plus acetone is suitable Amount, uses ultrasonication 20min at 10 DEG C, and constant volume, centrifuging and taking supernatant is used as test solution, 10 DEG C of preservations；

Chromatographic condition：In Agilent 1100HPLC systems, Symmetry C18 posts (150x4.6mm-3.5 μm of granularity, Waters, Eschborn, Germany), 20 DEG C of column temperature, flow velocity 1ml/min, the μ l of sample size 10；

Mobile phase：It is made up of kaliumphosphate buffer pH 2.4 (A) and acetonitrile/ethanol (6/4) (B) mixture, carries out ladder Degree elution；

Gradient elution program：0 minute：A62%/B38%；5 minutes：A44%/B56%；5.01 minute：A15%/ B85%；9 minutes：A15%/B85%；9.01 minute：A62%/B38%；12 minutes：A62%/B38%；

The UV Detection wavelength 232nm of impurity 4- (4- amino -3- fluorophenoxies)-N- picoline -2- formamides, using outer Mark 3- points (0.04 μ g/ml, 0.1 μ g/ml, the impurity reference substance solution of 1 tri- kinds of μ g/ml concentration) correct straight line to quantify.Impurity 4- (4- amino -3- fluorophenoxies) pyridine -2- carboxylic acid methyl amide In analogies peak occurred at about 4 minutes.

Sample investigates method：Plain piece and coated tablet prepared by example 1 above -10 and embodiment 11-25, are placed in temperature 45 DEG C, the sealing preserve 5 months of relative humidity 75% time；Determine impurity 4- of each sample in the case of without above-mentioned high-temperature treatment (4- amino -3- fluorophenoxies)-N- picoline -2- formamides then determine each sample relative to the content (C0) of compound of formula I Impurity 4- (4- amino -3- fluorophenoxies)-N- picoline -2- formamides in the case of above-mentioned high-temperature treatment is undergone relative to The content (C1) of compound of formula I；Examination, which calculates impurity of each sample after this high-temperature treatment is undergone, below increases percentage：Impurity Increase percentage=[(C1-C0) ÷ C0] × 100%

As a result show, the impurity increase percentage of plain piece prepared by embodiment 1-10 and embodiment 11-20 17~ In the range of 29%, the impurity of coating tablet prepared by embodiment 1-9 and embodiment 11-25 increases percentage in 19~27% scopes Interior, the plain piece of each sample is suitable with coating tablet result (difference is no more than 4 percentage points)；And embodiment 1-10 and correspondingly Embodiment 11-20 these only steps (1) (c) with the tablet of different disposal options, the impurity increase of each prescription each other Percentage result quite (difference is no more than 5 percentage points), this shows that product of the present invention has excellent chemical stability.

The spirit of the present invention is elaborated above by present pre-ferred embodiments.Those skilled in the art manage Solution, every any modification, equivalent variations and modification substantially made according to the technology of the present invention to above example, all falls within this hair In bright protection domain.

Claims

1. a kind of pharmaceutical composition in tablet form, its plain piece, which is constituted, is：

Active pharmaceutical compounds, its with the parts by weight of free base 40,

The parts by weight of diluents microcrystalline cellulose 50 ~ 200,

The parts by weight of disintegrant 50 ~ 200, it is selected from：Crosslinked carboxymethyl fecula sodium, sodium starch glycolate, cross-linked carboxymethyl fiber Plain sodium,

The parts by weight of adhesive 100 ~ 200, it is the polyvinylpyrrolidone that molecular weight is 5000 ~ 50000,

The parts by weight of lubricant 2 ~ 8, it is selected from：Magnesium stearate, stearic acid, cataloid, talcum powder and combinations thereof；

The active pharmaceutical compounds are 4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamyl } amino) -3- fluorobenzene oxygen Base]-N- picoline -2- formamides or its pharmaceutically acceptable salt, monohydrate；The pharmaceutical composition has 40 ~ 70 ° and connect Feeler；

This in the pharmaceutical composition of tablet form is prepared by the method comprised the following steps：

(1) two kinds of solid materials of the active medicine of recipe quantity and adhesive are dissolved in by ethyl acetate and ethanol with weight ratio 1： The in the mixed solvent of 2 ~ 6 proportions, wherein the weight ratio between the solid material and mixed solvent that add is 1：1 ~ 5, it is made Containing drug solns；At a temperature of 60-70 °C, the solution is sprayed to diluent and all or part of using fluidised bed granulator Solvent is removed in disintegrant and in fluid bed, preformed particles are obtained；Then, the preformed particles are spread in closed container, Place 10 ~ 40 hours at room temperature, the room atmosphere in the closed container is with 60 ~ 90% ethanol saturations, so that the preformed particles Fully contacted with the saturation atmosphere, the preformed particles are used into 50 ~ 60 °C of ventilating air dryings to moisture after this closed disposal Less than 5%；

(2) particle obtained by step (1) is extruded and sieved by roller press and obtain particle；Then by compressed particle and lubrication The disintegrant of agent and optional surplus is well mixed, and the end for obtaining preparing plain piece mixes thing；

(3) by mixed thing tabletting on tablet press machine eventually obtained by step (2), the pharmaceutical composition of the plain piece form in non-coated is obtained； Optionally

(4) by plain piece wrap film clothing obtained by step (3), obtain in the pharmaceutical composition for being coated sheet form.

2. in pharmaceutical composition according to claim 1, wherein step (1), the weight between the solid material and solvent of addition Than for 1：2~4.

3. pharmaceutical composition according to claim 1, described adhesive is selected from PVP K15, PVP K17, PVP K25, PVP K30。

4. pharmaceutical composition according to claim 1, described 4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamyl } ammonia Base) -3- fluorophenoxies]-N- picoline -2- formamides pharmaceutically acceptable salt be selected from its sulfate, phosphate, fluoroform Sulfonate, tosilate, 1-naphthalene sulfonic aicd salt, trifluoroacetate, malate, fumarate, benzoate, salicylic acid Salt, phenylacetate, acetate, adipate, alginates, ascorbate, aspartate, benzoate, benzene sulfonic acid Salt, disulfate, butyrate, citrate, camphor hydrochlorate, camsilate, cinnamate, cipionate, double glucose Hydrochlorate, lauryl sulfate, isethionic acid, fumarate, glucose enanthate, glycerophosphate, Hemisulphate, enanthic acid Salt, caproate, hydrochloride, hydrobromate, hydriodate, 2- hydroxyethanesulfonic acids salt, itaconate, lactate, maleate, Mandelate, methane sulfonates, 2- naphthalene sulfonates, nicotinate, nitrate, oxalates, embonate, pectate, over cure Hydrochlorate, 3- phenpropionates, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanic acid Salt, toluenesulfonic acid and undecylate.

5. pharmaceutical composition according to claim 1, it is placed in temperature 45 C, the sealing preserve 5 months of relative humidity 75% time, surveys Its fixed 60 minutes dissolution percentage in the case of without above-mentioned high-temperature treatment, determines it through above-mentioned high-temperature treatment situation in addition The dissolution percentage of lower 60 minutes, is calculated as follows it in the dissolution rate percent change after high-temperature treatment：

Dissolution rate percent change=(60 minutes dissolution percentage of high-temperature treatment sample is except ÷ was without high-temperature treatment sample 60 minutes Dissolution percentage) × 100%

This is in the dissolution rate percent change (%) of the pharmaceutical composition of tablet form in the range of 98.4 ~ 101.7%.

6. pharmaceutical composition according to claim 1, its label or plain piece determine loss on drying after grinding is less than 5%.

7. pharmaceutical composition according to claim 1, it is Film coated tablets, and it is peelled off after clothing layer, and label material has 40 ~ 70 ° Contact angle.

8. pharmaceutical composition according to claim 7, described clothing layer accounts for the 1 ~ 5% of total weight of tablet.

9. pharmaceutical composition according to claim 7, the main filmogen of the coating material of the clothing layer is selected from：Ethyl cellulose Element, hydroxypropyl methyl cellulose and methacrylic acid-alkyl acrylate copolymer, polyvinyl alcohol.

10. pharmaceutical composition according to claim 7, coating material composition includes：Colouring agent, phosphatide, polyethylene glycol, polyethylene Alcohol, talcum powder, titanium dioxide.

11. according to any one of claim 1-10 pharmaceutical composition, it has described in following formula 1 to 9 any one of formula Plain piece is formulated：

Formula 1：4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamyl } amino) -3- fluorophenoxies]-N- methyl pyrroles The monohydrate of pyridine -2- formamides：The 40mg in terms of anhydride, polyvinylpyrrolidone k25：160mg, interior plus partial disintegration agent Ac-Di-Sol：100mg, microcrystalline cellulose：100mg, Extra Section disintegrant Ac-Di-Sol： 54mg, cataloid：2.4mg, magnesium stearate：3.6mg；

Formula 2：4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamyl } amino) -3- fluorophenoxies]-N- methyl pyrroles The monohydrate of pyridine -2- formamides：The 40mg in terms of anhydride, polyvinylpyrrolidone k30：100mg, interior plus partial disintegration agent is handed over Join sodium carboxymethylcellulose：150mg, microcrystalline cellulose：50mg, Extra Section disintegrant Ac-Di-Sol：50mg, Cataloid：2mg, magnesium stearate：3mg；

Formula 3：4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamyl } amino) -3- fluorophenoxies]-N- methyl pyrroles The monohydrate of pyridine -2- formamides：The 40mg in terms of anhydride, PVP k15：200mg, cross-linked carboxymethyl cellulose Add partial disintegration agent in sodium：40mg, microcrystalline cellulose：200mg, Ac-Di-Sol Extra Section disintegrant：10mg, Cataloid：2mg, magnesium stearate：3mg；

Formula 4：4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamyl } amino) -3- fluorophenoxies]-N- methyl pyrroles The anhydride of pyridine -2- formamides：The 40mg in terms of anhydride, polyvinylpyrrolidone k25：160mg, interior plus partial disintegration agent is handed over Join sodium carboxymethylcellulose：100mg, microcrystalline cellulose：100mg, Extra Section disintegrant Ac-Di-Sol： 54mg, cataloid：2.4mg, magnesium stearate：3.6mg；

Formula 5：4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamyl } amino) -3- fluorophenoxies]-N- methyl pyrroles The monohydrate of pyridine -2- formamides：The 40mg in terms of anhydride, polyvinylpyrrolidone k25：160mg, interior plus partial disintegration agent Crosslinked carboxymethyl fecula sodium：100mg, microcrystalline cellulose：100mg, Extra Section disintegrant crosslinked carboxymethyl fecula sodium：54mg, Cataloid：2.4mg, magnesium stearate：3.6mg；

Formula 6：4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamyl } amino) -3- fluorophenoxies]-N- methyl pyrroles The monohydrate of pyridine -2- formamides：The 40mg in terms of anhydride, polyvinylpyrrolidone k25：160mg, interior plus partial disintegration agent Sodium starch glycolate：100mg, microcrystalline cellulose：100mg, Extra Section disintegrant sodium starch glycolate：54mg, colloid Silica：2.4mg, magnesium stearate：3.6mg；

Formula 7：4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamyl } amino) -3- fluorophenoxies]-N- methyl pyrroles The monohydrate of pyridine -2- formamides：The 40mg in terms of anhydride, polyvinylpyrrolidone k25：160mg, interior plus partial disintegration agent Ac-Di-Sol：154mg, microcrystalline cellulose：100mg, cataloid：2.4mg, magnesium stearate：3.6mg；

Formula 8：4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamyl } amino) -3- fluorophenoxies]-N- methyl pyrroles The benzene sulfonate of pyridine -2- formamides：The 40mg in terms of anhydride, polyvinylpyrrolidone k30：100mg, interior plus partial disintegration agent is handed over Join sodium carboxymethylcellulose：150mg, microcrystalline cellulose：50mg, Extra Section disintegrant Ac-Di-Sol：50mg, Talcum powder：0.5mg, stearic acid：1.5mg；

Formula 9：4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamyl } amino) -3- fluorophenoxies]-N- methyl pyrroles The hydrochloride of pyridine -2- formamides：The 40mg in terms of anhydride, PVP k15：200mg, Ac-Di-Sol Interior plus partial disintegration agent：40mg, microcrystalline cellulose：200mg, Ac-Di-Sol Extra Section disintegrant：10mg, glue Body silica：3mg, magnesium stearate：5mg.