CN104586808A

CN104586808A - Anti-tumour medicine composition

Info

Publication number: CN104586808A
Application number: CN201410836104.6A
Authority: CN
Inventors: 王立强; 郑金琪; 黄丽华
Original assignee: BEIJING YUANYAN MEDICAL TECHNOLOGY Co Ltd
Current assignee: BEIJING YUANYAN MEDICAL TECHNOLOGY Co Ltd
Priority date: 2014-12-27
Filing date: 2014-12-27
Publication date: 2015-05-06
Anticipated expiration: 2034-12-27
Also published as: CN104586808B

Abstract

The invention relates to an anti-tumour medicine composition, and specifically relates to a medicine composition. The anti-tumour medicine composition comprises an active pharmaceutical compound, a diluent, a disintegrant, an adhesive and a lubricant. The compound is a compound shown in a formula I specified in the description or a pharmaceutically acceptable salt, a solvate, a polycrystalline type compound and the like. The invention further relates to coated tablets prepared by the medicine composition. The composition disclosed by the invention is excellent in pharmaceutical properties.

Description

Antineoplastic pharmaceutical compositions

Technical field

The present invention relates to new antineoplastic pharmaceutical compositions, it can be used for treating the disease that mediated by VEGFR, PDGFR, raf, p38 and/or flt-3 kinase signal of exception and disease symptoms.

Background technology

The activation of ras signal transduction pathway means that on cell proliferation, differentiation and conversion have the cascade reaction of the event of profound influence.Raf kinases as Ras downstream effect is that these signals are delivered to a nuclear key transmitter from cell surface receptor.Verified, suppress the effect activating ras that the cellular-restoring transformed can be caused for grow phenotype normally by using the coexpression of raf kinase whose deactivation antibody or dominant raf kinases or dominant MEK (the kinase whose substrate of raf) to suppress raf kinase signal pathway.Kolch etc. further demonstrate and have blocked film by antisense RNA to the suppression that raf expresses and to be correlated with the cell proliferation that oncogene causes.Similarly, in tube assay and experiment in vivo, confirmed that the kinase whose suppression of raf (by antisense oligonucleotide) is relevant to the growth inhibited of multiple human tumor types.

Maintain size and need functioning stroma more than the continued tumor growth of the tumor cell of 1-2mm3, this is the supporting structure comprising fibroblast, smooth muscle cell, endotheliocyte, extracellular matrix proteins and soluble factors.Tumor causes the formation of stroma by secreting the soluble growth factor such as such as PDGF and transforming growth factor β (TGF-β), described somatomedin is the complementary factor such as stimulation of host emiocytosis such as fibroblast growth factor (FGF), epidermal growth factor (EGF) and VEGF (VEGF) separately.These stimulating factors cause new angiogenesis, and this provides oxygen and nutrient substance to tumor and makes it grow and provide route for neoplasm metastasis.Believe that some Therapeutic Method for suppressing interstitial to be formed can be suppressed the growth of the epithelial tumor being derived from Various Tissues type.But, because the complexity of its character and multiple somatomedin participate in angiogenesis and tumor progression, effect that a kind of material for single signal approach may be only limited.Wish to provide Therapeutic Method to multiple key signaling pathways of tumor for causing angiogenesis in host stroma.These approach comprise PDGF (the effective stimulus factor that interstitial is formed), FGF (chemokine of fibroblast and endotheliocyte and mitogenesis element) and VEGF (angiopoietic effective regulatory factor).

PDGF is a kind of key regulator that interstitial is formed, and it secrete with paracrine form by kinds of tumors and promotes the growth of fibroblast, smooth muscle and endotheliocyte, thus promotes interstitial formation and angiogenesis.PDGF is identified as the v-sis oncogene products of simian sarcoma virus.This somatomedin is made up of 2 peptide chains being called as A chain or B chain, and peptide chain primary amino acid sequences has the homology of 60%.Peptide chain warp disulfide bond is connected to form the maturation protein of the 30kDa be made up of AA, BB or AB homology or heterodimer.In platelet, found high-caliber PDGF, and PDGF can by endotheliocyte and Expression of Vascular Smooth Muscle Cell.In addition, under the hypoxia condition found in the tumor tissues of such as vascularization deficiency, the generation of PDGF is raised.PDGF combines with high-affinity and pdgf receptor (PDGFR), and this receptor is the transmembrane tyrosine kinase receptor of the 124kDa of 1106 Amino acid profiles.PDGFR is homology or heterodimer peptide chain form, and peptide chain always has the homology of 30% on its aminoacid sequence, and between its kinase domain, have the homology of 64%.PDGFR is the member of the tyrosine kinase receptor family with kinase domain separately, and this family comprises VEGFR2 (KDR), VEGFR-3 (flt-4), c-Kit and flt-3.PDGFR mainly expresses fibroblast, smooth muscle cell and pericyte (pericyte) are upper, and expresses on a small quantity on the Schwann cell of neurocyte, messangial cell, Leydig cell and central nervous system.Once and receptors bind, PDGF causes Receptor dimerization and experiences the self-phosphorylation of tyrosine residue and mutual phosphorylation, and this can improve the kinase activity of receptor and promote that the downstream effect factor is by activating raising of SH2 protein binding domain.Comprise PI-3 kinases, the multi-signal molecule of Phospholipase C-γ, src and GAP (the GTP (guanosine triphosphate) acid ras GTPase activating protein ras-GTP for p21-ras) and the PDGFR of activation and form complex.By activating PI-3 kinases, PDGF activates Rho cellular pathways thus causes cell movement and migration, and causes by activating GAP the mitosis activated by p21-ras and MAPK signal pathway.

In adult, the Main Function of PDGF promotes and improves the speed of wound healing and keep the homoiostasis of blood vessel.In platelet, found the PDGF of high concentration, it is a kind of effective chemokine for fibroblast, smooth muscle cell, neutrophil cell and macrophage.Except its effect in wound healing, PDGF helps the homoiostasis keeping blood vessel.In new vessels growth course, PDGF raises pericyte required for blood vessel structure integrity and smooth muscle cell.PDGF is considered in tumor angiogenesis, play similar effect.As a part for its role in angiogenesis, PDGF controls the fluid pressure of interstice to the permeability of adjustment blood vessel interactional between connective tissue cell and extracellular matrix by it.Suppress the activity of PDGFR can reduce the pressure of interstice and promote cytotoxin to flow into tumor and improve the antitumor efficacy of these materials.

PDGF can directly stimulate the PDGFR on Interstitial cell or tumor cell by paracrine or autocrine or be amplified by the signal of receptor or promoted tumor growth through recombination activation receptor.The PDGF of process LAN can make the cell type of the melanoma cells of people and keratinocyte these two kinds not PDGF-B expression receptor can transform the direct effect that interstitial is formed and induction of vascular generates by PDGF.Tumor PDGF-B expression but the paracrine that not also been observed this mesenchyma stroma of tumors in the tumor such as the colon cancer of expressed receptor, pulmonary carcinoma, breast carcinoma and carcinoma of prostate stimulate wherein.The autocrine stimulation to growth of tumour cell has been reported, wherein major part tumor cells expression PDGF part by analysis and receptor in spongioblastoma, soft-tissue tumor, ovarian cancer, carcinoma of prostate, cancer of pancreas and pulmonary carcinoma.The receptor activation of non-ligand-dependent type finds less, but has been reported in chronic myelomonocytic leukemia (CMML), and wherein a chromosome translocation forms fusion rotein between class Ets transcription factor TEL and pdgf receptor.In addition, in gastrointestinal stromal tumor, had been found that the activated mutant activated with c-Kit in irrelevant PDGFR.Mesenchyma stroma of tumors can be disturbed to grow for PDGFR inhibitor and Tumor suppression grows and shifts and do not have excessive side effect.

VEGF (VEGF is also referred to as Vascular Permeability Factor VPF) is the another kind of main regulatory factors occurred with disease medium vessels new life and the blood vessel of the dependence of some angiogenesis at fetal development.VEGF represents due to selectivity RNA montage with the former isomer family of mitogenesis that homodimer form exists.VEGF isomer is high special for vascular endothelial cell.

Vegf expression is by cytokine profiles and the growth factor-induced such as anoxia and such as interleukin-11, interleukin 6, epidermal growth factor and transforming growth factor.Report at present, one or more in VEGF and VEGF family member and following three kinds of transmembranous receptor tyrosine kinases combine: vegf receptor 1 (also referred to as flt-1 (class fms tyrosine kinase 1)), VEGFR-2 (also referred to as containing Kinase insert Domain receptor (KDR), the mice analog of KDR is called tire liver kinases 1 (flk-1)) and VEGFR-3 (also referred to as flt-4).Verified, VEGFR-2 and flt-1 has different signal transduction character.Therefore, VEGFR-2 experiences the strong tyrosine phosphorylation of ligand-dependent in intact cell, and flt-1 shows weak response.Therefore, believe that being combined with VEGFR-2 is key request for the biological answer-reply of the FR VEGF mediation of induction.

VEGF in vivo blood vessel plays central role in occurring, and causes angiogenesis and Vascular permeability.The vegf expression not adding adjustment causes various diseases, it is characterized in that abnormal angiogenesis and/or high osmosis effect.Believe that some material can provide effective control to abnormal angiogenesis and/or high osmosis effect to the adjustment of the signal transduction cascade that VEGF mediates.Anti-tumor cell in tumor hypoxia region is reacted by stimulating VEGF to produce, and this causes the activation of reticent endotheliocyte to stimulate new vascularization.In addition, the VEGF in the tumor region not having angiogenesis produces can promote ras signal transduction pathway.In situ hybridization research shows, the remarkable rise of VEGF mRNA in the various human tumors comprising pulmonary carcinoma, thyroid carcinoma, breast carcinoma, gastroenteric tumor, kidney and tumor of bladder, ovarian cancer, cervical cancer and hemangioma and several intracranial tumor.Neutrality VEGFR-2 monoclonal antibody is proved to be effective in blocking-up neonate tumour blood vessel.

The process LAN (such as under extreme oxygen deficiency condition) of VEGF can cause angiogenesis in eyeball, causes blood vessel excessive proliferation, finally causes blind.In the multiple retinopathy comprising diabetic retinopathy, ischemic retinal vein inaccessible and retinopathy of prematurity and age related macular degeneration, observed such cascade reaction.

In rheumatic arthritis (RA), the generation of angiogenesis factor can mediate vascular nebula interior to growth.In the synovial fluid of RA patient, there is high-caliber immunoreactivity VEGF, and in the synovial fluid of other form arthritis or degenerative joint disease patient VEGF low SI.Verified in anti-rat collagen induction type arthritis model, angiogenesis inhibitor AGM-170 hinders the neovascularization in joint.

Form to subepidermal blister the raising also showing vegf expression in relevant herpes diseases at psoriasis and such as bullous pemphigoid, erythema multiforme and dermatitis herpetiformis etc.

VEGF (VEGF, VEGF-C, VEGF-D) and receptor (VEGFR2, VEGFR3) thereof are not only tumor-blood-vessel growth and are the key regulators that lymphatic vessel generates.VEGF, VEGF-C and VEGF-D are main frequent with the horizontal expression fully improved during tumor growth in most of tumor.The stimulation of the oncogene of vegf expression by anoxia, cytokine, such as ras or the deactivation by tumor suppressor gene.

The biologic activity of VEGF is by being mediated with the combination of its receptor.The main lymphatic endothelial cells in normal adult tissue of VEGFR3 (also referred to as flt-4) is expressed.New lymphatic vessel is formed and needs VEGFR3 function, but the already present lymphatic vessel of maintenance is not then needed.VEGFR3 raises.Recently, the ligand VEGF-C of VEGFR3 and VEGF-D are confirmed as the regulatory factor that in mammal, lymphatic vessel generates.The lymphatic vessel generation that the lymphatic vessel that tumor is correlated with generates factor induction may promote that new vessel growth enters tumor, and this enters the passage of systemic circulation for tumor cell provides.Invade vasculolymphatic cell and can enter blood circulation by thoracic duct.Tumor expression study has allowed to express the clinical pathology factor (such as lymphatic metastasis, lymphatic vessel invade, Secondary cases shift and disease free survival phase) directly related with same primary tumo(u)r diffusivity to VEGF-C, VEGF-D and VEGFR3 and has directly compared.In many cases, these researchs describe the statistics dependency between lymphatic vessel generation factor expression and constitutional entity tumor transfer ability.

For VEGF in malignant cell produces, it seems that anoxia be a kind of important stimulating factor.Concerning anoxia, response produced for tumor cell and induces VEGF, needing the kinase whose activation of p38MAP.Except participating in except angiogenesis by regulating VEGF to secrete, p38MAP kinases promotes the migration of malignant cell intrusion and different tumor type by regulating collagenase activity and urokinase Plasminogen Activator to express.

The suppression of the former activated protein kinase of mitogenesis (MAPK) p38 is proved to be and in test tube and/or body, the T suppression cell factor can forms (such as TNF, IL-1, IL-6, IL-8) and protease generation (such as MMP-1, MMP-3).The former activated protein kinase p38 of mitogenesis participates in IL-1 and TNF signal pathway.

Tumor necrosis factor (TNF) has produced and/or has linked up to the various diseases comprising rheumatoid arthritis by clinical research.In addition, in multiple inflammatory and/or immunomodulating class disease, the TNF of excessive levels has been found.These diseases comprise acute rheumatic fever, bone resorption, postmenopausal osteoporosis, pyemia, septic shock, endotoxic shock, systemic inflammatory reaction disease, asthma etc.TNF is also relevant to infectious disease, and these diseases comprise the helicobacter pylori infections etc. in pulmonary tuberculosis, gastric ulcer process.

Numerous disease is considered to active by excessive or unwanted matrix destruction metalloproteases (MMP) or is mediated by the proportional imbalance of the tissue depressant (TMP) of MMP and metalloproteases.Retrograde cartilage defects after the coronary artery thrombosis that these diseases comprise osteoarthritis, rheumatic arthritis, septic arthritis, neoplasm metastasis, periodontal disease, cornea come off, albuminuria, atheromatous plaque break to be caused, aortic aneurysm, infertile, EBD, traumatic joint injury, the osteoporosis of MMP activity mediation, jawbone arthrosis and neural demyelinating disease.

Owing to suppressing p38 to cause the suppression that TNF is formed and MMP is formed, believe and suppress mitogenesis former activated protein kinase p38 can provide the means comprising the above-mentioned disease of osteoporosis and inflammation disease for the treatment of such as rheumatoid arthritis and COPD.

For VEGF in malignant cell produces, it seems that anoxia be a kind of important stimulating factor.Concerning anoxia, response produced for tumor cell and induces VEGF, needing the kinase whose activation of p38MAP.Except participating in except angiogenesis by regulating VEGF to secrete, p38MAP kinases promotes the migration of malignant cell intrusion and different tumor type by regulating collagenase activity and urokinase Plasminogen Activator to express.Therefore, also wish that suppressing p38 kinases to invade relevant signal cascade by interference to angiogenesis and malignant cell affects tumor growth.

The serine-threonine kinase inhibitor have some urea and/or tyrosine kinase inhibitor activity are described.Especially the treatment being used for cancer, angiogenesis disease, inflammatory diseases as the active component of pharmaceutical composition using some urea has been confirmed.

This area still expects there is effective antitumour medicine, and such as it can be used for situation mentioned above.

Summary of the invention

The object of the present invention is to provide a kind of antineoplastic pharmaceutical compositions with excellent pharmaceutical properties.The present invention have been surprisingly found that, after the compositions of contained I is processed, effectively can change its physical property and then advantageously can obtain the pharmaceutical composition particularly solid composite medicament such as tablet with excellent pharmaceutical property.The present invention is based on this find and be accomplished.Formula I of the present invention is the omega-carboxyaryl diphenyl urea with the fluoro-4-of the 2-be combined with carbamide (2-(N-methylcarbamoyl)-4-pyridyloxy) phenylene group; it is the kinase whose effective inhibitor of raf kinases, VEGFR kinases, p38 kinases and PDGFR, and described kinases is all for the osteoporosis treating and prevent to comprise cancer, inflammatory diseases, excess proliferative disease and the interested molecular target of angiogenesis disease.

For this reason, first aspect present invention provides a kind of pharmaceutical composition, comprising: active pharmaceutical compounds, diluent, disintegrating agent, binding agent, lubricant; Described compound is with compounds of Formula I or the acceptable salt of its pharmacy, solvate, polymorphic etc.:

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

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

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein said diluent includes but not limited to: calcium hydrogen phosphate, Kaolin, dextrin, lactose, mannitol, sucrose, microcrystalline Cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol and starch and derivant (such as corn starch, potato starch, amylum pregelatinisatum, modified starch, pregelatinized Starch etc.), erythritol, xylitol, fructose etc. and their combination.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the active pharmaceutical compounds wherein comprised counts 40 weight portions with formula I, and the amount of described diluent is 50 ~ 500 weight portions; The amount of such as described diluent is 50 ~ 400 weight portions; The amount of such as described diluent is 50 ~ 300 weight portions; The amount of such as described diluent is 50 ~ 200 weight portions.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein said disintegrating agent includes but not limited to: low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, crosslinked carboxymethyl fecula sodium, sodium starch glycolate, cross-linking sodium carboxymethyl cellulose etc. and their combination.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the active pharmaceutical compounds wherein comprised counts 40 weight portions with formula I, and the amount of described disintegrating agent is 50 ~ 500 weight portions; Such as 50 ~ 400 weight portions; Such as 50 ~ 300 weight portions; Such as 50 ~ 200 weight portions.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein said binding agent such as, such as but not limited to hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone (molecular weight is the PVP of 5000 ~ 50000, PVP K15, PVP K17, PVP K25, PVP K30 etc.), polyvinyl alcohol, arabic gum, alginic acid, sodium alginate, gelatin etc. and their combination.Preferredly comprise hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone or polyvinyl alcohol.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the active pharmaceutical compounds wherein comprised counts 40 weight portions with formula I, and the amount of described binding agent is 50 ~ 500 weight portions; Such as 50 ~ 400 weight portions; Such as 100 ~ 300 weight portions; Such as 100 ~ 200 weight portions.Binding agent can be added by dry method, and adopts typical compressing dry granulation to prepare tablet; Binding agent can be added by dry method, and adopts water or aquiferous ethanol to be that wetting agent carries out wet granulation to whole material and then prepares tablet; Binding agent can also use water or aquiferous ethanol wiring solution-forming as binder solution, then carries out wet granulation with this binder solution and then prepares tablet; Binding agent can also be dissolved in suitable solvent (such as ethanol and/or acetone) together with active medicine, more spray-dried for this solution technique is added in diluent and/or disintegrating agent.These different types of binding agent feed postition all well known to a person skilled in the art, and are that appearance is facile.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein said lubricant also can be described as fluidizer in this area, is usually referred to as lubricant.Lubricant includes but not limited to: magnesium stearate, stearic acid, calcium stearate, zinc stearate, liquid Paraffin, Polyethylene Glycol, silicon dioxide, silica sol, micropowder silica gel, Pulvis Talci, starch, hydrogenated vegetable oil etc. or its combination.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the active pharmaceutical compounds wherein comprised counts 40 weight portions with formula I, and the amount of described lubricant is 1 ~ 50 weight portion; The amount of such as described lubricant is 1 ~ 25 weight portion; The amount of such as described lubricant is 1 ~ 20 weight portion; The amount of such as described lubricant is 1 ~ 10 weight portion; The amount of such as described lubricant is 2 ~ 8 weight portions.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the acceptable salt of pharmacy of wherein said formula I comprises traditional nontoxic salt, such as, by salt that method well known in the art obtains from inorganic or organic acid.The such as sulfate of formula I, phosphate, fluoroform sulphonate, tosilate, 1-naphthalene sulfonic aicd salt, trifluoroacetate, malate, fumarate, benzoate, Salicylate, phenylacetate, acetate, adipate, alginate, Ascorbate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, citrate, camphorate, camsilate, cinnamate, cipionate, two gluconate, lauryl sulfate, isethionic acid, fumarate, glucose enanthate, glycerophosphate, Hemisulphate, enanthate, caproate, hydrochlorate, hydrobromate, hydriodate, 2-hydroxyethanesulfonic acid salt, itaconate, lactate, maleate, mandelate, methane sulfonates, 2-naphthalene sulfonate, nicotinate, nitrate, oxalates, embonate, pectate, persulfate, 3-phenpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, rhodanate, toluenesulfonic acid and undecylate are at interior acid-addition salts.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the solvate of wherein said formula I or its pharmaceutical salts can be its any acceptable solvate thereof.The such as hydrate of formula I, the such as monohydrate etc. of formula I.

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

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it has the contact angle of 40 ~ 100 °, particularly has the contact angle of 40 ~ 90 °, particularly has the contact angle of 40 ~ 80 °, particularly has the contact angle of 40 ~ 70 °.The present invention have been surprisingly found that, the troche medical composition with low contact angle has significantly more excellent pharmaceutical properties, and this is that the present invention contributes the substance of prior art.

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

(1) active medicine of recipe quantity and binding agent two kinds of solid materials are dissolved in suitable solvent (such as ethanol and/or acetone, such as by ethanol and acetone with the mixed solvent of weight ratio 1:2 ~ 6 proportions; Such as, weight ratio between the solid material added and solvent is 1:1 ~ 5, such as 1:2 ~ 5, such as 1:2 ~ 4) in, make containing drug solns; At the temperature of 60-70 DEG C, use fluidised bed granulator by this solution spray to diluent and all or part of disintegrating agent and in fluid bed except desolventizing, obtain preformed particles;

(2) step (1) gained granule is extruded by roller press and sieved obtain granule; Then mixed homogeneously by the disintegrating agent of compressed granule with lubricant and optional surplus, the end obtaining preparing plain sheet (i.e. the tablet of non-coated) mixes thing;

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

(4) by step (3) gained element sheet wrap film clothing, the pharmaceutical composition of the present invention in coated tablet form is obtained.

(1) active medicine of recipe quantity and binding agent two kinds of solid materials are dissolved in suitable solvent (such as ethanol and/or acetone, such as by ethanol and acetone with the mixed solvent of weight ratio 1:2 ~ 6 proportions; Such as, weight ratio between the solid material added and solvent is 1:1 ~ 5, such as 1:2 ~ 5, such as 1:2 ~ 4) in, make containing drug solns; At the temperature of 60-70 DEG C, use fluidised bed granulator by this solution spray to diluent and all or part of disintegrating agent and in fluid bed except desolventizing, obtain preformed particles; Then, this preformed particles is spread in hermetic container, at room temperature place 10 ~ 40 hours (such as 20 ~ 30 hours, such as about 24 hours), room atmosphere in described hermetic container 60 ~ 90% ethanol (such as 70 ~ 90% ethanol, such as 80 ~ 90% ethanol) saturated, fully contact to make the saturated atmosphere of this preformed particles and this, after this airtight disposal, use 50 ~ 60 DEG C of ventilating airs to be dried to moisture lower than 5% (such as lower than 4%, such as, lower than 3%) this preformed particles;

Further, second aspect present invention provides a kind of coated tablet, and it comprises pharmaceutical composition described in the arbitrary embodiment of first aspect present invention, and the clothing layer of its peripheral parcel.

The coated tablet of arbitrary embodiment according to a second aspect of the present invention, wherein said pharmaceutical composition is the form in tablet.

The coated tablet of arbitrary embodiment according to a second aspect of the present invention, wherein said clothing layer is film-coat.

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

The coated tablet of arbitrary embodiment according to a second aspect of the present invention, it is that method by comprising the following steps prepares:

(3) by step (2) gained mixed thing tabletting on tablet machine eventually, the pharmaceutical composition of the present invention of the plain sheet form in non-coated is obtained;

(4) by step (3) gained element sheet wrap film clothing, the pharmaceutical composition of the present invention in coated tablet form is obtained.I.e. coated tablet.

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

The coated tablet of arbitrary embodiment according to a second aspect of the present invention, the main filmogen of the coating material of wherein said clothing layer is selected from: ethyl cellulose, hydroxypropyl emthylcellulose and methacrylic acid-alkyl acrylate copolymer; Further, the main filmogen of coating material is hydroxypropyl emthylcellulose, such as, be its aqueous dispersion; Further, coating material is it is hydroxypropyl emthylcellulose aqueous dispersion; Further, coating material is selected from with

The coated tablet of arbitrary embodiment according to a second aspect of the present invention, the main filmogen of the coating material of wherein said clothing layer is polyvinyl alcohol.In one embodiment, they can prepare according to the conventional amount used of this area with water before to tablet coating temporarily, can also easily buy from market.Such as, can buy from the happy Kanggong department of card, such as Opadry film-coating premixing formula, such as powder pin again such as, can buy from Ai Leyi medical material company, such as, easily release beautiful series of products, such as, easily release beautiful a kind of typical coating material composition comprises: coloring agent (such as iron oxide red and/or iron oxide yellow or other), phospholipid (such as fabaceous lecithin), Polyethylene Glycol (such as PEG3350), polyvinyl alcohol, Pulvis Talci, titanium dioxide etc.Such as from the pink colour that the happy Kanggong department of card buys polyvinyl alcohol (accounting for 44% of mixture total weight amount) wherein containing partial hydrolysis, PEG3350 (accounting for 12.4% of mixture total weight amount), fabaceous lecithin, ferrum oxide (iron oxide red and iron oxide yellow), Pulvis Talci, titanium dioxide.

Third aspect present invention provides the method for the pharmaceutical composition of the arbitrary embodiment of preparation first aspect present invention, and it comprises the following steps:

Fourth aspect present invention provides the method for the coated tablet of the arbitrary embodiment of preparation second aspect present invention, and it comprises the following steps:

Fifth aspect present invention provides a kind of tablet, its have as arbitrary in description embodiment 1-25 as described in plain slice prescription.

Arbitrary technical characteristic that arbitrary embodiment of either side of the present invention or this either side has is suitable for arbitrary embodiment of other arbitrary embodiment or other either side equally, as long as they can not be conflicting, certainly at where applicable each other, necessary words can be done suitably to modify to individual features.Be further described with feature to various aspects of the present invention below.

As used herein, term " compacting " is defined through the compact sample that powder is converted to designated shape by compression (such as by roller press), such as powder is pressed in advance the tablet of bulk by suitable machinery, the tablet of this bulk can be used for the granule of tabletting when follow-up pulverizing is suitable for manufacturing tablet with preparation.

As used herein, term " pulverizing " is defined through screening and reduces granular size.

As used herein, drift term " compression " being defined through tablet machine is applied enough power and is compressed into tablet on powder, that is " tabletting " operation in tablet process industry.

Contact angle described herein refers to the contact angle with water.Particularly, contact angle refers to and drips in the water droplets on solid preparation compositions surface such as tablet and the angle of compositions surface contact.Those skilled in the art know the method and apparatus having many mensuration contact angles, and in the present invention, an exemplary assay method is as follows: at syringe needle, (such as model is SNSO52/026; HAMILTON company produces, stainless steel, internal diameter 0.26mm, external diameter 0.52mm; Or also can with the syringe needle with similar specification) needle point form 1 μ l pure water (MILLI-Q; MILLIPORE company) drop, then by contact angle determination device (such as OCA-15 type, Data physics company; Or there is other brand of similar functions or the contact angle determination device of model) measure water droplet be added to tablet surface 60 milliseconds after contact angle.When tablet surface has curvature, after straight line will being corrected to when resolving, measure contact angle again; Normally measure under room temperature.In the present invention, if not otherwise indicated, contact angle of the present invention is measured by following methods: at room temperature, at syringe needle (SNSO52/026; HAMILTON company produce, stainless steel, internal diameter 0.26mm, external diameter 0.52mm) needle point form 1 μ l pure water (MILLI-Q; MILLIPORE company) drop, then by contact angle determination device (OCA-15 type, Data physics company) measure water droplet be added to tablet surface 60 milliseconds after contact angle.Owing to measuring the contact angle obtained with above-mentioned conditions of similarity, at varying environment (such as different experiments room), distinct device (such as using the contact angle determination device that other company produces), these results do not have obvious difference, therefore when defining the contact angle of compositions of the present invention, without the need to being construed as limiting the concrete mensuration process of contact angle and condition determination.

For the solid composite medicament of the present invention not being tablet form, such as capsule, granule, powder etc., can by the powder contained in preparation, granule, semi-solid material etc. be pressed into figure of tablet, measure again, such as capsule, by taking out capsule 's content, get wherein about 200mg be pressed into diameter 8mm, thickness 3.5mm the smooth and smooth tablet in surface to measure contact angle.Even if for the tablet that effectively can not reflect its real property, the such as tablet of film coating, enteric coating or sugar-coat, also can by the clothing layer in tablet surface be scraped off, and then tablet is ground, refer again to the mode of above-mentioned capsule, tablet is ground gained powder and again measure again after tabletted.For the present composition, it is when preparing non-tabletted, measures after can getting the appropriate tabletted of powder; It can directly measure when being prepared into the plain sheet of non-coating; Its coated make coated tablet time, the clothing layer in tablet surface can be scraped off, and then tablet is ground, then to measure after gained powder again tabletted.

According to pharmaceutical composition of the present invention particularly tablet, its label (for uncoated tablets, refers to whole; For coated tablet, refer to the slice, thin piece inner core striking off clothing layer completely and obtain) grind after measure loss on drying (95 DEG C are dried to constant weight) lower than 5%, particularly lower than 4%, particularly lower than 3%.

The present invention have been surprisingly found that, the tablet label that the present composition is prepared into, there is beat all advantage, and these labels can select all multiple coating materials, such as can film coating, the material of such as this film-coat can be that main component (wherein can add appropriate polyvinyl alcohol, such as commercial prod with hydroxypropyl emthylcellulose series), certainly, for the object of the invention, also can use other coating material, such as, be the coating material of main component with ethyl cellulose.Therefore, in order to the object of the invention, can not be construed as limiting the coating material of the present composition.

the purposes of the present composition

The invention provides the pharmaceutical composition that can regulate and relate to kinase whose one or more signal transduction pathway of raf, VEGFR, PDGFR, p38 and/or flt-3.Raf is the important signaling molecule of regulation and control of many important cell processes participating in comprising Growth of Cells, cell survival and intrusion.It is Ras/raf/MEK/ERK approach member.This approach is present in most of tumor cell.VEGFR, PDGFR and flt-3 are the acceptor molecules of cross-film, can trigger Ras/raf/MEK/ERK Cell signal transduction pathway when it is subject to suitable ligand stimulation, cause intracellular level to join reaction.These acceptor molecules all have tyrosine kinase activity.

VEGFR receptor stimulates by VEGF (VEGF), and is the important control point in endothelial cell development and function point analysis.PDGF beta receptor regulates cell proliferation and survival in the various kinds of cell type comprising mesenchymal cell.Flt-3 is the receptor of FL part.Its similar in c-kit, and regulates the growth of multipotency hematopoietic cell, thus affects the growth of T cell, B cell and dendritic cell.

Any gene or the isomer that comprise raf, VEGFR, PDGFR, p38 and/or flt-3 of wild type and saltant type can regulate according to the present invention.Raf or raf-l kinases is serine/threonine kinase family, and it comprises at least 3 family members (a-raf, b-raf and c-raf or raf-1).C-raf and b-raf is the preferred target spot of pharmaceutical composition of the present invention.In the kinds of tumors comprising melanoma, authenticated the activated mutant (such as V599E mutant) of b-raf, and pharmaceutical composition as described herein may be used for suppressing it active.

Term " adjustment " refers to the functional activity changing described approach (or its component) compared with normal activity when not existing with described pharmaceutical composition.This effect comprises the adjustment in any quantity or degree, and this comprises raising, activation, enhancing, increase, promotion, stimulation, reduction, obstruction, suppression, minimizing, reduction, antagonism etc.

Pharmaceutical composition of the present invention also can regulate following one or more process, and these processes include but not limited to that such as Growth of Cells (comprising such as differentiation, cell survival and/or propagation), growth of tumour cell (comprising such as differentiation, cell survival and/or propagation), tumor regression, endothelial cell growth (comprising such as differentiation, cell survival and/or propagation), angiogenesis (angiogenic growth), lymphatic vessel generate (lymphatic growth) and/or hemopoietic function (growth of such as T cell and B cell, dendritic cell growth etc.).

Although do not wish the constraint being subject to any mechanism of action or mechanism, have been found that pharmaceutical composition of the present invention has the ability regulating kinase activity.But method of the present invention is not limited to any concrete mechanism or how described pharmaceutical composition realizes its therapeutical effect.Term " kinase activity " refers to the catalytic activity on the amino acid residue (such as serine, threonine or tyrosine) wherein transferred to from adenosine triphosphate (ATP) by a γ phosphate radical protein substrate.Pharmaceutical composition can regulate kinase activity, such as, compete kinase whose ATP-binding site by direct and ATP and suppressing its activity, affecting its activity (such as by destroying the three dimensional structure with biologic activity) etc. by producing conformation change in the structure of enzyme.

Use common detection methods can carry out conventional determining to kinase activity.Kinase assays generally includes kinases, substrate, buffer and detection system component.Typical kinase assay comprises protein kinase and peptide substrate and the ATP as P-ATP and reacts with the end-product producing phosphorylation (phosphorylated protein such as when using peptide substrate).Any suitable method can be used to detect end product.When using radioactivity ATP, use affinity membrane or gel electrophoresis radiolabeled phosphorylated protein can be separated with unreacted γ-32P-ATP, and use autoradiography develop on gel or use scintillation counter to detect subsequently.Also Non-radioactive methods can be used.The antibody (such as antiphosphotyrosine antibody) identifying phosphorylated substrate can be used.Such as, can there is ATP and kinase buffer liquid with substrate and hatch under the condition of substrate described in the acidify of described kinases available phosphorus in kinases.Can separate reacted mixture (such as passing through electrophoresis), and subsequently can the phosphorylation (such as by using the immunoblotting of antiphosphotyrosine antibody) of detection substrate.Described antibody can with detectable label labelling (enzyme of such as such as HRP, Avidin or biotin, chemical illuminating reagent etc.).Other method can adopt the separation of ELISA, affinity membrane, fluorescence polarization method, luminescence method etc.

Another kind of method outside radioactive form is time-resolved fluorescence resonant energy transfer (TR-FRET).Described method conveniently kinase reaction, wherein substrate (such as biotinylated poly-(GluTyr)) is by protein phosphatase phosphorylation under ATP existent condition.End product can detect with the phospho-specif iotac antibodies of europium chelating (anti-phosphotyrosine or phosphoserine/threonine) and the streptavidin-APC be combined with biotinylated substrate subsequently.Above-mentioned two components in conjunction with time spatially close, and produce the fluorescence reading of homogeneous form to the energy delivery of receptor (SA-APC) from phospho-specif iotac antibodies.

Pharmaceutical composition of the present invention may be used for treating and/or preventing any disease or disease that the one or more cellular signal transduction pathways that relate to raf, VEGFR, PDGFR, p38 and/or flt-3 mediate.Term " treatment " uses according to its conventional meaning, such as, process for the symptom of resisting, alleviating, reducing, removing, improving disease or dysfunction etc. object patient or look after.Described pharmaceutical composition also can for preventing and/or treating the disease that mediated by described signaling molecule and/or disease is described.Term " mediation " represents that such as described signaling molecule is a part for approach abnormal or not normal in described disease and/or disease.

Treatable disease and disease comprise any above and disease mentioned below and:

Comprise the raf relevant disease of such as cell generation disorders, cancer, tumor etc.;

Comprise the VEGFR-2 relevant disease of such as cancer, tumor growth, inflammation disease, rheumatic arthritis, retinopathy, psoriasis, glomerule nephropathy, asthma, chronic bronchitis, arteriosclerosis, transplant rejection, the disease relating to angiogenesis etc.;

Draw together such as cancer, keratopathy, cornea redness, corneal transplantation, lymph gland hypertrophy, the disease relating to lymphatic vessel generation etc. VEGFR-3 relevant disease;

Comprise the PDGFR-ss related diseases of disease or the disease being such as characterised in that the formation of cell proliferation, cellular matrix, cell movement and/or extracellular matrix are formed.Concrete example comprises such as tumor, malignant tumor, cancer, cancer metastasis, chronic lymphocytic leukemia, inflammation, nephropathy, diabetic nephropathy, mesangium hyperplastic glomerular nephropathy, fibrotic conditions, arteriosclerosis, heart lobe restenosis, hypertension related arteriosclerosis, venous bypass graft arteriosclerosis, scleroderma, interstitial lung disease, synovial fluid disease, arthritis, leukemia, lymphoma etc.;

Comprise such as immune correlated disease, blood cell disease, relate to the Flt-3 relevant disease of disease, cancer, anemia, HIV, acquired immunodeficiency disease etc. that hematopoietic cell (such as T cell, B cell, dendritic cell) is grown;

Comprise the p38 relevant disease of inflammation disease, immunoregulatory disorder and other produce to abnormal cytokine (particularly TNF α) or the MMP activity of exception is relevant other diseases.These diseases include but not limited to rheumatic arthritis, chronic obstructive pulmonary disease (COPD), osteoporosis, Crohn disease and psoriasis.

In addition, pharmaceutical composition of the present invention may be used for treating such as following disease and disease: glomerular sclerosis, interstitial nephritis, interstitial pulmonary fibrosis, arteriosclerosis, wound scar and scleroderma.

Pharmaceutical composition of the present invention also has therapeutic activity widely in order to treatment or the progress of preventing various disease, these diseases such as inflammatory disorders, coronary restenosis, tumor-associated vessels generates, arteriosclerosis, autoimmune disease, inflammation, some relevant nephropathy is bred to glomerule or mesangial cell, and the oculopathy relevant to retinal vessel proliferation, psoriasis, liver cirrhosis, diabetes, arteriosclerosis, restenosis, vascular graft restenosis, in-stent restenosis, angiogenesis, oculopathy, lung fiber is sick, bronchiolitis obliterans, glomerule nephropathy, rheumatic arthritis.

The present invention is also for one or more people following and/or other mammiferous diseases provide treatment, prevention, regulate etc.: the retinopathy comprising diabetic retinopathy, ischemic retinal vein obturation, retinopathy of prematurity and age related macular degeneration, rheumatic arthritis, psoriasis, or form relevant bullous disease to subcutaneous blister and (comprise bullous pemphigoid, erythema multiforme or dermatitis herpetiformis), rheumatic fever, bone resorption, postmenopausal osteoporosis, pyemia, Gram-negative pyemia, septic shock, endotoxin shock, Toxin shock syndrom, Systemic inflammatory syndrome, inflammatory bowel (Crohn disease and ulcerative colitis), Herxheimer reaction, asthma, adult respiratory distress waits group, Acute Lung fibrotic disease, pulmonary sarcoidosis, anaphylaxis respiratory disease, silicosis, coal miner pneumoconiosis, alveolar damage, liver failure, hepatopathy in acute inflammation, serious symptom alcoholic hepatitis, malaria (Plasmodium falciparum malaria and brain malaria), non-insulin-dependent diabetes mellitus (NEDDM), congestive heart failure, damage after heart disease, arteriosclerosis, Alzheimer, acute encephalitis, brain injury, multiple sclerosis (demyelination in multiple sclerosis and few dendritic cell disappearance), terminal cancer, malignant lymphoma, pancreatitis, in infection, wound healing weakens, inflammation and cancer, myelodysplastic syndrome, systemic lupus erythematosus (sle), biliary cirrhosis, bowel necrosis, toxicity after radiational injury/give monoclonal antibody, host-transplant reaction (ischemia reperfusion injury and kidney, liver, heart and skin allograft rejection), lung allograft rejection (bronchitis obliterans), total hip displacement complication, and be selected from pulmonary tuberculosis, helicobacter pylori infections in gastric ulcer, the summer Graves disease that Ku Shi Trypanosoma cruzi infection causes, the shiga-like toxin effect that coli-infection causes, the enterotoxin A effect that staphy lococcus infection causes, the infectious disease of meningococcal infection, and lyme disease spirochete, leptospira, the huge virus of cell, influenza virus, the infection that theiler's encephalomyelitis virus and human immunodeficiency virus (HIV) cause, papilloma, bud shape glioma, Kaposi's sarcoma, melanoma, pulmonary carcinoma, ovarian cancer, carcinoma of prostate, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, bladder cancer, breast carcinoma, colorectal carcinoma, thyroid carcinoma, cancer of pancreas, gastric cancer, hepatocarcinoma, leukemia, lymphoma, Hodgkin, Hugh Burkitt is sick, arthritis, rheumatic arthritis, diabetic retinopathy, angiogenesis, restenosis, in-stent restenosis, vascular graft restenosis, pulmonary fibrosis, liver cirrhosis, arteriosclerosis, glomerule nephropathy, diabetic nephropathy, transplant rejection, psoriasis, diabetes, wound healing, inflammation, and neurodegenerative disease, excessive immune is sick, hemangioma, angiogenesis of cardiac muscle, crown and brain collateral is formed, ischemia, keratopathy, iridopathy, neovascular glaucoma, premature labor maculopathy retinopathy, wound healing, Helicobacter pylori ulcers relevant disease, fracture, endometriosis, diabetic symptom, cat scratch fever, thyroid is loose, asthma or burnt degree edema, wound, chronic lung disease, apoplexy, polyp, cyst, synovitis, chronic and allergic inflammation, ovary height stimulates syndrome, pulmonary and brain edema, keloid, cystic fibrosis, sclerosis, carpal tunnel syndrome, adult respiratory distress syndrome, ascites, oculopathy, cardiovascular diseases, Ke-Fu (POEMS) syndrome, Crohn disease, glomerule nephropathy, osteoarthritis, multiple sclerosis, transplant rejection, Lyme arthritis, pyemia, Feng's angiomatosis retinae et cerebelli syndrome, pemphigoid, Paget, multicystic kidney disease, sarcoidosis, thyroiditis, hyperviscosity syndrome, Osier-Weber-Rendir is sick, chmnic. obstructive's pneumonopathy, radiation, anoxia, preeclampsia, menorrhagia, endometriosis, herpes simplex infection, ischemic retinopathies, corneal vessels generates, herpes zoster, human immunodeficiency virus, parapoxvirus, protozoacide, toxoplasmosis and relevant the oozing out and edema of tumor.

Pharmaceutical composition of the present invention can have more than one described activity and therefore can for many bars transduction pathway.Therefore, these pharmaceutical compositions can realize usually can only when using different pharmaceutical combination of compositions just obtainable treatment and preventive effect.Such as, be particularly useful by use single medicine compositions to suppress new conduit to be formed cell proliferation exception that (being such as connected with VEGFR-2 with VEGFR-3 function) (such as blood vessel and/or lymphatic vessel) and cell proliferation (being such as connected with raf with PDGFR β function) promote by new vascularization at Therapeutic cancer and other.Therefore, the invention particularly relates to the pharmaceutical composition at least with cell proliferation and angiogenesis inhibitor (i.e. inhibiting angiogenesis) activity.The disease can benefiting from vessel growth and cell inhibitory effect to any according to the present invention or disease are treated.Due to its field of activity can be defined more accurately, single medicine compositions is used also to be favourable.

Pharmaceutical composition of the present invention can be treated any tumor, and these tumors include but not limited in raf, ras and/or flt-3 and have the tumor of one or more sudden change in any upstream of signal pathway of participating in or downstream member.As discussed previously, tumor can be carried out treating with pharmaceutical composition of the present invention and not consider the mechanism corresponding to it.Can treat the tumor of any organ, this includes but not limited to such as colon cancer, cancer of pancreas, breast carcinoma, carcinoma of prostate, osteocarcinoma, hepatocarcinoma, renal carcinoma, pulmonary carcinoma, carcinoma of testis, skin carcinoma, gastric cancer, colorectal carcinoma, renal cell carcinoma, hepatocarcinoma, melanoma etc.

The example of breast carcinoma includes but not limited to IDC, ILC, ductal carcinoma in situ and LCIS.

The example of respiratory cancer includes but not limited to minicell and nonsmall-cell lung cancer and bronchial adenoma and pleuropulinonary blastoma.

The example of the brain cancer includes but not limited to brain stem and hypophtalmic glioma, cerebellum and cerebral astrocytoma, medulloblastoma, ependymoma and neural outer embryoma and strobile adenoma.

Genital orgnas,male's tumor includes but not limited to carcinoma of prostate and carcinoma of testis.Tumors of female reproductive organ includes but not limited to carcinoma of endometrium, cervical cancer, ovarian cancer, cancer of vagina and carcinoma vulvae and sarcoma of uterus.

Digestive tract tumor includes but not limited to anus cancer, colon cancer, colorectal carcinoma, esophageal carcinoma, carcinoma of gallbladder, gastric cancer, rectal cancer, carcinoma of small intestine and salivary-gland carcinoma.

Urethral system tumor includes but not limited to bladder cancer, carcinoma of penis, renal carcinoma, carcinoma of renal pelvis, carcinoma of ureter and carcinoma of urethra.

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

The example of hepatocarcinoma includes but not limited to hepatocarcinoma (having or do not have the hepatocarcinoma of fibrolamellar form), cholangiocellular carcinoma and mixed type hepatocyte cholangiocellular carcinoma.

Skin carcinoma includes but not limited to squamous cytoma, Kaposi sarcoma, malignant melanoma, Merkel cell skin cancer and non-melanoma skin carcinoma.

Head and neck cancer includes but not limited to laryngeal carcinoma, hypopharyngeal cancer, nasopharyngeal carcinoma and/or oropharynx cancer and lip and oral cancer.

Lymphoma includes but not limited to AIDS associated lymphoma, non-Hodgkin lymphoma, cutaneous T cell lymphoma, Hodgkin and central nervous system lymphoma.

Sarcoma includes but not limited to soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma and rhabdomyosarcoma.

Leukemia includes but not limited to acute myeloid leukemia, Acute Lymphoblastic Leukemia, chronic lymphocytic leukemia, chronic lymphocytic leukemia and hairy cell leukemia.

Except inhibition tumor cell propagation, pharmaceutical composition of the present invention also can cause tumor regression, the reduction of the reduction of such as tumor size or tumor distribution in vivo.

Detailed description of the invention

The following examples provided only for task of explanation instead of for, should not be interpreted as limiting the present invention by any way yet.Those skilled in the art will recognize that can make routine to following examples when not surmounting the spirit or scope of the present invention changes and amendment.Below prepare in the example of compositions, if not otherwise indicated, with the preparation of the amount of 50,000 unit formulations such as (sheet) that feed intake, the active pharmaceutical compounds that per unit formulation example comprises as (sheet) counts 40mg with the formula I of free alkali form.Below prepare in the example of compositions, if not otherwise indicated, various material all carries out before use pulverizing and can by 100 mesh sieve.When preparing coated tablet from plain sheet, the plain sheet only getting about 4/5 carries out coating, and all the other plain sheets are used for other test and use.

Hereinafter, the active component used is the various forms of formula I is well known in the art, the formula I of such as free alkali form and the monohydrate (CN102947271A of formula I, CN201180019150.1), the isetionate (1:1) of formula I and esilate (the 1:1) (CN103923001A of formula I, CN201410181182.7) etc., when they are as active component in following test, can buy from market, also can prepare according to these literature methods.

embodiment 1: the pharmaceutical composition preparing tablet form

element tablet recipe (every sheet):

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

Polyvinylpyrrolidone (k25): 160mg,

Cross-linking sodium carboxymethyl cellulose (inside adding partial disintegration agent): 100mg,

Microcrystalline Cellulose: 100mg;

Cross-linking sodium carboxymethyl cellulose (Extra Section disintegrating agent): 54mg,

Silica sol (anhydrous level, i.e. colloidal silicon dioxide are also called colloidal anhydrous silica usually): 2.4mg,

Magnesium stearate: 3.6mg.

method for making:

(1) active medicine of recipe quantity and polyvinylpyrrolidone two kinds of solid materials are dissolved in etoh solvent-acetone mixture (ethanol: acetone=1:4 by (a), solid material and weight of solvent are than being 1:3) in, make containing drug solns; B () is at the temperature of 60-70 DEG C, use fluid bed vacuum granulator by this solution spray in the powder bed of diluent and Nei Jia partial disintegration agent mixed-powder, except desolventizing in fluid bed, obtain preformed particles (after measured, its moisture is lower than 3%); C () then, this preformed particles is spread in hermetic container, at room temperature place 24 hours, room atmosphere in described hermetic container is saturated with 85% ethanol, to make the saturated atmosphere of this preformed particles and this fully contact, after this airtight disposal, 50 ~ 60 DEG C of ventilating airs are used to be dried to moisture lower than 3% (note: the level substantially reaching step (b) end-product) this preformed particles;

(2) step (1) gained granule extruded with 3.15mm and 1.0mm hole pattern respectively by roller press and sieve; Then it mixed homogeneously with lubricant, Extra Section disintegrating agent, the end obtaining preparing plain sheet (i.e. the tablet of non-coated) mixes thing;

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

(4) by step (3) gained element sheet with the pink colour of every sheet 12mg clothing material (it makes even suspension with 48mg water before coating) carries out coating in seed-coating machine, and exit flow temperature controls, at 35 DEG C, to obtain the coated tablet of surface uniform.

embodiment 2: the pharmaceutical composition preparing tablet form

element tablet recipe (every sheet):

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

Polyvinylpyrrolidone (k30): 100mg,

Cross-linking sodium carboxymethyl cellulose (inside adding partial disintegration agent): 150mg,

Microcrystalline Cellulose: 50mg;

Cross-linking sodium carboxymethyl cellulose (Extra Section disintegrating agent): 50mg,

Silica sol: 2mg,

Magnesium stearate: 3mg.

method for making:

(1) active medicine of recipe quantity and polyvinylpyrrolidone two kinds of solid materials are dissolved in etoh solvent-acetone mixture (ethanol: acetone=1:2 by (a), solid material and weight of solvent are than being 1:2) in, make containing drug solns; B () is at the temperature of 60-70 DEG C, use fluid bed vacuum granulator by this solution spray in the powder bed of diluent and Nei Jia partial disintegration agent mixed-powder, except desolventizing in fluid bed, obtain preformed particles (after measured, its moisture is lower than 3%); C () then, this preformed particles is spread in hermetic container, at room temperature place 20 hours, room atmosphere in described hermetic container is saturated with 90% ethanol, to make the saturated atmosphere of this preformed particles and this fully contact, after this airtight disposal, 50 ~ 60 DEG C of ventilating airs are used to be dried to moisture lower than 3% (note: the level substantially reaching step (b) end-product) this preformed particles;

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

embodiment 3: the pharmaceutical composition preparing tablet form

element tablet recipe (every sheet):

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

Polyvinylpyrrolidone (k15): 200mg,

Cross-linking sodium carboxymethyl cellulose (inside adding partial disintegration agent): 40mg,

Microcrystalline Cellulose: 200mg;

Cross-linking sodium carboxymethyl cellulose (Extra Section disintegrating agent): 10mg,

Silica sol: 2mg,

Magnesium stearate: 3mg.

method for making:

(1) active medicine of recipe quantity and polyvinylpyrrolidone two kinds of solid materials are dissolved in etoh solvent-acetone mixture (ethanol: acetone=1:6 by (a), solid material and weight of solvent are than being 1:4) in, make containing drug solns; B () is at the temperature of 60-70 DEG C, use fluid bed vacuum granulator by this solution spray in the powder bed of diluent and Nei Jia partial disintegration agent mixed-powder, except desolventizing in fluid bed, obtain preformed particles (after measured, its moisture is lower than 3%); C () then, this preformed particles is spread in hermetic container, at room temperature place 30 hours, room atmosphere in described hermetic container is saturated with 80% ethanol, to make the saturated atmosphere of this preformed particles and this fully contact, after this airtight disposal, 50 ~ 60 DEG C of ventilating airs are used to be dried to moisture lower than 3% (note: the level substantially reaching step (b) end-product) this preformed particles;

(4) by step (3) gained element sheet with the pink colour of every sheet 10mg clothing material (it makes even suspension with 40mg water before coating) carries out coating in seed-coating machine, and exit flow temperature controls, at 35 DEG C, to obtain the coated tablet of surface uniform.

embodiment 4: the pharmaceutical composition preparing tablet form

The formula of reference example 1 and method for making, different only: anhydride formula I monohydrate wherein being replaced with formula I, coating material to use hydroxypropyl methylcellulose based plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 5: the pharmaceutical composition preparing tablet form

The formula of reference example 1 and method for making, different only: disintegrating agent is wherein replaced with crosslinked carboxymethyl fecula sodium.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 6: the pharmaceutical composition preparing tablet form

The formula of reference example 1 and method for making, different only: disintegrating agent is wherein replaced with sodium starch glycolate.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 7: the pharmaceutical composition preparing tablet form

The formula of reference example 1 and method for making, different only: all change disintegrating agent wherein into interior addition, also all add in step (1) (b) by the disintegrating agent in step (2).Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 8: the pharmaceutical composition preparing tablet form

The formula of reference example 2 and method for making, different only: benzene sulfonate active component wherein being changed into formula I; Magnesium stearate is wherein replaced with stearic acid, and silica sol replaces with Pulvis Talci, and the two is with being be respectively 1.5mg and 0.5mg.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 9: the pharmaceutical composition preparing tablet form

The formula of reference example 3 and method for making, different only: hydrochlorate active component wherein being changed into formula I, changes magnesium stearate wherein and silica sol consumption into 5mg and 3mg respectively.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 10: the pharmaceutical composition preparing tablet form

With reference to the formula of embodiment 1.Method for making: according to the technique preparing tablet of formulation art routine, by active component, polyvinylpyrrolidone, in add partial disintegration agent and microcrystalline Cellulose mix homogeneously, be that wetting agent carries out wet granulation with 50% ethanol, be dried to moisture and reach less than 3%; Then by step (1) (c) process of dry for gained granule according to embodiment 1 method for making; Then successively according to step (2), (3), (4) process of embodiment 1 method for making.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 11: the pharmaceutical composition preparing tablet form

With reference to the formula of embodiment 1 and method for making, different only: do not carry out step (1) (c), but directly step (1) (b) gained granule directly carried out step (2) process.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 12: the pharmaceutical composition preparing tablet form

With reference to the formula of embodiment 2 and method for making, different only: do not carry out step (1) (c), but directly step (1) (b) gained granule directly carried out step (2) process.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 13: the pharmaceutical composition preparing tablet form

With reference to the formula of embodiment 3 and method for making, different only: do not carry out step (1) (c), but directly step (1) (b) gained granule directly carried out step (2) process.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 14: the pharmaceutical composition preparing tablet form

With reference to the formula of embodiment 4 and method for making, different only: do not carry out step (1) (c), but directly step (1) (b) gained granule directly carried out step (2) process.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 15: the pharmaceutical composition preparing tablet form

With reference to the formula of embodiment 5 and method for making, different only: do not carry out step (1) (c), but directly step (1) (b) gained granule directly carried out step (2) process.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 16: the pharmaceutical composition preparing tablet form

With reference to the formula of embodiment 6 and method for making, different only: do not carry out step (1) (c), but directly step (1) (b) gained granule directly carried out step (2) process.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 17: the pharmaceutical composition preparing tablet form

With reference to the formula of embodiment 7 and method for making, different only: do not carry out step (1) (c), but directly step (1) (b) gained granule directly carried out step (2) process.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 18: the pharmaceutical composition preparing tablet form

With reference to the formula of embodiment 8 and method for making, different only: do not carry out step (1) (c), but directly step (1) (b) gained granule directly carried out step (2) process.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 19: the pharmaceutical composition preparing tablet form

With reference to the formula of embodiment 9 and method for making, different only: do not carry out step (1) (c), but directly step (1) (b) gained granule directly carried out step (2) process.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 20: the pharmaceutical composition preparing tablet form

With reference to the formula of embodiment 10 and method for making, different only: do not carry out step (1) (c), but directly carry out step (2) process.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 21: the pharmaceutical composition preparing tablet form

With reference to the formula of embodiment 1 and method for making, different only: diluent wherein used is replaced with corn starch.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 22: the pharmaceutical composition preparing tablet form

With reference to the formula of embodiment 1 and method for making, different only: diluent wherein used is replaced with lactose.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 23: the pharmaceutical composition preparing tablet form

With reference to the formula of embodiment 1 and method for making, different only: disintegrating agent wherein used is replaced with polyvinylpolypyrrolidone.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 24: the pharmaceutical composition preparing tablet form

With reference to the formula of embodiment 1 and method for making, different only: disintegrating agent wherein used is replaced with low-substituted hydroxypropyl cellulose.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

embodiment 25: the pharmaceutical composition preparing tablet form

With reference to the formula of embodiment 1 and method for making, different only: binding agent wherein used is replaced with hydroxypropyl emthylcellulose.Plain sheet and coated tablet is prepared respectively in step (3) and step (4).

experimental example 1: measure contact angle

Syringe needle: model is SNSO52/026; HAMILTON company produces, stainless steel, internal diameter 0.26mm, external diameter 0.52mm;

Pure water: MILLI-Q (MILLIPORE company product) pure water processed;

Contact angle determination device: CA-15 type, Data physics company produces;

Assay method: form 1 μ l pure water drop at needle point, measures the contact angle behind its 60 milliseconds, surface dripping to tabletted.

Sample pretreating: the granule materials before tabletting is first pressed into plane tablet and measures; Compressing tablet directly measures, but corrects the curvature of tablet surface when calculating; For coated sheet, clothing layer is struck off completely, then is ground into fine powder, and then be pressed into plane tablet and measure again.

Result:

The sample of each embodiment above, for each batch sample, it is granule, plain sheet, coated tablet before tabletting, the contact angle substantially identical (for every batch to be tested, its granule and coated tablet differ with the contact angle of plain sheet and be all no more than 2 °) that three kinds of samples record; The such as sample of embodiment 1, granule, the plain sheet be pressed into, coated tablet, the contact angle that three samples record is respectively 57.2 °, 56.8 °, 56.3 °;

The each Lot sample of embodiment 1 ~ 10, the contact angle of its plain sheet is all within the scope of 42 ~ 67 °;

The each Lot sample of embodiment 11 ~ 25, the contact angle of its plain sheet is all within the scope of 78 ~ 106 °;

The each Lot sample of embodiment 11 ~ 20 is only different from step (1) (c) with each Lot sample of embodiment 1 ~ 10 respectively in method for making, and formula is identical, for the tablet that the different method for making of same formula obtains, perform embodiment 11 ~ 20 sample of each sample of embodiment 1 ~ 10 relative to its corresponding formula of step (1) (c), contact angle reduces more than 36 ° respectively, the plain sheet contact angle of such as embodiment 3 56.8 °, and the plain sheet contact angle of the embodiment 13 of same recipe 95.2 °.

experimental example 2: coated tablet Performance

By the coated tablet (tablet surface is normal, and clothing layer is flawless) of foregoing embodiments, at least 300, each sample, is placed in temperature 60 C, relative humidity is placed 30 days for 75% time, observes tablet surface clothing layer after disposing 30 days thus and whether occurs slight crack.Calculate every Lot sample slight crack rate (i.e. the percent of slight crack appearance is occur the percent of the sheet number of slight crack divided by test total tablet number gained used).Result shows, and these contact angles of embodiment 1 ~ 10 are lower than the sample of 70 °, and slight crack rate is between 2 ~ 6%; And embodiment 11 ~ 25 these there is the tablet sample of high contact angle, slight crack rate is all between 17 ~ 25%.Such as the slight crack rate of embodiment 2 and embodiment 12 coated tablet is respectively 2.8% and 20.4%.

experimental example 3: coated tablet stripping property is investigated

(1) dissolution determination method: Chinese Pharmacopoeia version in 2010 two annex XC second methods (paddle method), with 0.2% sodium dodecyl sulfate solution for dissolution medium, rotating speed is 75 turns per minute, sampled through 60 minutes time, filter, measure stripping quantity according to following HPLC chromatographic condition HPLC method, calculate the stripping quantity of every sheet.

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

(3) the plain sheet prepared by foregoing embodiments 1-10 and embodiment 11-25, be placed in temperature 45 C, relative humidity 75% lower seal preserves 5 months, measure each sample in without the above-mentioned high-temperature treatment situation stripping percent of 60 minutes, measure each sample in addition at the stripping percent of 60 minutes in above-mentioned high-temperature treatment situation, calculate dissolution percent change (%, high-temperature treatment sample 60 minutes stripping percent is multiplied by 100% again divided by without high-temperature treatment sample 60 minutes stripping percent) after high-temperature treatment.Surprisingly, the embodiment 1-10 sample that contact angle is less than 70 °, their dissolution percent change (%) is all in 97 ~ 102% scopes, show that these samples are not showing obvious dissolution situation of change after high-temperature process, namely these samples have splendid stripping stability.Regrettably, the embodiment 11-25 sample that contact angle is greater than 78 °, their dissolution percent change (%), all in 71 ~ 86% scopes, shows complete unsafty stripping stability.The dissolution percent change (%) of such as embodiment 2 and embodiment 12 is respectively 98.2% and 78.6%.It should be noted that, herein, parameter stripping stability is the dynamic parameter of reflection Dissolution of Tablet change, the difference namely during a period of time, reflection be the stability of tablet, it distinguishes the dissolution of usual the considered static state of people at ordinary times.

(4) the plain sheet prepared by foregoing embodiments 1-10 and embodiment 11-25, be placed in temperature 45 C, relative humidity 75% lower seal preserves 5 months, measure each sample in without the above-mentioned high-temperature treatment situation stripping percent of 60 minutes, measure each sample in addition at the stripping percent of 60 minutes in above-mentioned high-temperature treatment situation, calculate dissolution percent change (%, high-temperature treatment sample 60 minutes stripping percent is multiplied by 100% again divided by without high-temperature treatment sample 60 minutes stripping percent) after high-temperature treatment.Surprisingly, the embodiment 1-10 sample that contact angle is less than 70 °, their dissolution percent change (%) is all in 97 ~ 101% scopes, show that these samples are not showing obvious dissolution situation of change after high-temperature process, namely these samples have splendid stripping stability.Regrettably, the embodiment 11-25 sample that contact angle is greater than 78 °, their dissolution percent change (%), all in 73 ~ 87% scopes, shows complete unsafty stripping stability.The dissolution percent change (%) of such as embodiment 3 and embodiment 13 is respectively 99.3% and 80.3%.

experimental example 4: chemical stability

This experimental example investigates the situation of change of impurity 4-(4-amino-3-the fluorophenoxy)-N-picoline-2-Methanamide in various tablet.

HPLC algoscopy:

Tablet is ground into fine powder, gets the tablet powder being equivalent to 50mg formula I and be placed in 25ml measuring bottle, add acetone in proper, at 10 DEG C of place ultrasonic Treatment 20min, standardize solution, centrifuging and taking supernatant, as test solution, 10 DEG C of preservations;

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

Mobile phase: be made up of the mixture of kaliumphosphate buffer pH 2.4 (A) and acetonitrile/ethanol (6/4) (B), carry out gradient elution;

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

The UV determined wavelength 232nm of impurity 4-(4-amino-3-fluorophenoxy)-N-picoline-2-Methanamide, use external standard 3-point (0.04 μ g/ml, the impurity reference substance solution of 0.1 μ g/ml, 1 μ g/ml tri-kinds of concentration) correct straight line quantitatively.Impurity 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide In analogy peak occurred about 4 minutes time.

Sample investigation method: plain sheet prepared by foregoing embodiments 1-10 and embodiment 11-25 and coated tablet, is placed in temperature 45 C, relative humidity 75% lower seal preserves 5 months; Measure each sample without the content (C0) of impurity 4-(4-amino-3-the fluorophenoxy)-N-picoline-2-Methanamide in above-mentioned high-temperature treatment situation relative to formula I, then measure the content (C1) of impurity 4-(4-amino-3-the fluorophenoxy)-N-picoline-2-Methanamide of each sample in the above-mentioned high-temperature treatment situation of experience relative to formula I; Below examination calculates the impurity of each sample after this high-temperature treatment of experience increases percent: impurity increases percent=[(C1-C0) ÷ C0] × 100%

Result shows, the impurity of plain sheet prepared by embodiment 1-10 and embodiment 11-20 increases percent all in 17 ~ 29% scopes, the impurity of coated tablet prepared by embodiment 1-9 and embodiment 11-25 increases percent all in 19 ~ 27% scopes, plain sheet and coated tablet result suitable (all differ and be no more than 4 percentage points) of each sample; And embodiment 1-10 and corresponding embodiment 11-20 these only step (1) (c) with the tablet of different disposal options, each prescription impurity each other increases percent result quite (all difference is no more than 5 percentage points), and this shows that product of the present invention has excellent chemical stability.

By present pre-ferred embodiments, spirit of the present invention is elaborated above.It will be appreciated by those skilled in the art that every above embodiment is done according to the technology of the present invention essence any amendment, equivalent variations and modification, all drop in protection scope of the present invention.

Claims

1. a pharmaceutical composition, comprising: active pharmaceutical compounds, diluent, disintegrating agent, binding agent, lubricant; Described compound is with compounds of Formula I or the acceptable salt of its pharmacy, solvate, polymorphic etc.:

2. pharmaceutical composition according to claim 1, is characterized in that:

It is solid composite medicament;

It is the solid composite medicament in tablet form;

Described diluent includes but not limited to: calcium hydrogen phosphate, Kaolin, dextrin, lactose, mannitol, sucrose, microcrystalline Cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol and starch and derivant (such as corn starch, potato starch, amylum pregelatinisatum, modified starch, pregelatinized Starch etc.), erythritol, xylitol, fructose etc. and their combination;

Described disintegrating agent includes but not limited to: low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, crosslinked carboxymethyl fecula sodium, sodium starch glycolate, cross-linking sodium carboxymethyl cellulose etc. and their combination;

Described binding agent such as, such as but not limited to hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone (molecular weight is the PVP of 5000 ~ 50000, PVP K15, PVP K17, PVP K25, PVP K30 etc.), polyvinyl alcohol, arabic gum, alginic acid, sodium alginate, gelatin etc. and their combination; And/or

Described lubricant includes but not limited to: magnesium stearate, stearic acid, calcium stearate, zinc stearate, liquid Paraffin, Polyethylene Glycol, silicon dioxide, silica sol, micropowder silica gel, Pulvis Talci, starch, hydrogenated vegetable oil etc. or its combination.

3., according to the pharmaceutical composition of any one of claim 1-2, the active pharmaceutical compounds wherein comprised counts 40 weight portions with formula I:

The amount of described diluent is 50 ~ 500 weight portions; The amount of such as described diluent is 50 ~ 400 weight portions; The amount of such as described diluent is 50 ~ 300 weight portions; The amount of such as described diluent is 50 ~ 200 weight portions;

The amount of described disintegrating agent is 50 ~ 500 weight portions; Such as 50 ~ 400 weight portions; Such as 50 ~ 300 weight portions; Such as 50 ~ 200 weight portions;

The amount of described binding agent is 50 ~ 500 weight portions; Such as 50 ~ 400 weight portions; Such as 100 ~ 300 weight portions; Such as 100 ~ 200 weight portions; And/or

The amount of described lubricant is 1 ~ 50 weight portion; The amount of such as described lubricant is 1 ~ 25 weight portion; The amount of such as described lubricant is 1 ~ 20 weight portion; The amount of such as described lubricant is 1 ~ 10 weight portion; The amount of such as described lubricant is 2 ~ 8 weight portions.

4., according to the pharmaceutical composition of any one of claim 1-3, the acceptable salt of pharmacy of described formula I is selected from the sulfate of formula I, phosphate, fluoroform sulphonate, tosilate, 1-naphthalene sulfonic aicd salt, trifluoroacetate, malate, fumarate, benzoate, Salicylate, phenylacetate, acetate, adipate, alginate, Ascorbate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, citrate, camphorate, camsilate, cinnamate, cipionate, two gluconate, lauryl sulfate, isethionic acid, fumarate, glucose enanthate, glycerophosphate, Hemisulphate, enanthate, caproate, hydrochlorate, hydrobromate, hydriodate, 2-hydroxyethanesulfonic acid salt, itaconate, lactate, maleate, mandelate, methane sulfonates, 2-naphthalene sulfonate, nicotinate, nitrate, oxalates, embonate, pectate, persulfate, 3-phenpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, rhodanate, toluenesulfonic acid and undecylate.

5., according to the pharmaceutical composition of any one of claim 1-4, the solvate of described formula I or its pharmaceutical salts can be its any acceptable solvate thereof, the such as hydrate of formula I, the such as monohydrate etc. of formula I.

6. according to the pharmaceutical composition of any one of claim 1-5, it has the contact angle of 40 ~ 100 °, particularly has the contact angle of 40 ~ 90 °, particularly has the contact angle of 40 ~ 80 °, particularly has the contact angle of 40 ~ 70 °.

7. according to the pharmaceutical composition of any one of claim 1-6, it is tablet, and its label (for uncoated tablets, refers to whole; For coated tablet, refer to the slice, thin piece inner core striking off clothing layer completely and obtain) grind after measure loss on drying (95 DEG C are dried to constant weight) lower than 5%, particularly lower than 4%, particularly lower than 3%.

8. a coated tablet, it comprises the pharmaceutical composition of any one of claim 1-7, and the clothing layer of its peripheral parcel; Further, described clothing layer is film-coat.

9. coated tablet according to claim 7, is characterized in that:

After it peels off clothing layer, label material has the contact angle of 40 ~ 100 °, particularly has the contact angle of 40 ~ 90 °, particularly has the contact angle of 40 ~ 80 °, particularly has the contact angle of 40 ~ 70 °;

Described clothing layer accounts for 1 ~ 5% of tablet total weight amount, and such as 1 ~ 4%, such as 2 ~ 3%;

The main filmogen of the coating material of described clothing layer is selected from: ethyl cellulose, hydroxypropyl emthylcellulose and methacrylic acid-alkyl acrylate copolymer, polyvinyl alcohol; And/or

Coating material composition comprises: coloring agent (such as iron oxide red and/or iron oxide yellow or other), phospholipid (such as fabaceous lecithin), Polyethylene Glycol (such as PEG3350), polyvinyl alcohol, Pulvis Talci, titanium dioxide etc.

10. a tablet, its have as arbitrary in description embodiment 1-25 as described in plain slice prescription.