CN102048737B - Pharmaceutical composition for treating tumor diseases - Google Patents
Pharmaceutical composition for treating tumor diseases Download PDFInfo
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- CN102048737B CN102048737B CN200910209164A CN200910209164A CN102048737B CN 102048737 B CN102048737 B CN 102048737B CN 200910209164 A CN200910209164 A CN 200910209164A CN 200910209164 A CN200910209164 A CN 200910209164A CN 102048737 B CN102048737 B CN 102048737B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Abstract
The invention discloses a pharmaceutical composition for treating tumor diseases, a preparation method of the pharmaceutical composition and application of the pharmaceutical composition in preparing the medicines for treating tumor diseases, wherein the pharmaceutical composition consists, in a fixed dosage, of N-[4-(1-cyan cyclopentyl)phenyl]-2-(4-picolyl) amidogen-3-pyridinecarboxamide or pharmaceutically acceptable salts thereof and angiostatin or pharmaceutically acceptable salts thereof, or N-[4-(1-cyan cyclopentyl)phenyl]-2-(4-picolyl) amidogen-3-pyridinecarboxamide or pharmaceutically acceptable salts thereof and gefitinib or pharmaceutically acceptable salts thereof.
Description
Technical field
The present invention relates to treat the pharmaceutical composition of tumor disease; Particularly contain N-[4-(1-cyanic acid cyclopenta) phenyl]-2-(4-picolyl) amino-3-ascorbyl palmitate or its pharmaceutically acceptable salt and Erlotinib or its pharmaceutically acceptable salt or contain the pharmaceutical composition of the fixed dosage combination of N-[4-(1-cyanic acid cyclopenta) phenyl]-2-(4-picolyl) amino-3-ascorbyl palmitate or its pharmaceutically acceptable salt and gefitinib or its pharmaceutically acceptable salt, prepare the method and the purposes of said pharmaceutical composition in the medicine of preparation treatment tumor disease of said pharmaceutical composition.
Background technology
Cancer is commonly encountered diseases, the frequently-occurring disease of serious harm human health.All the time, cancer chemotherapeutic drug commonly used clinically mainly is a cytotoxic drug, and this kind anti-cancer drugs has shortcomings such as poor selectivity, strong, the easy generation drug resistance of toxic and side effects.In recent years, along with the further understanding to the oncobiology characteristic, found several kinds of new antitumor target spots, wherein EGFR-TK has become the important target spot of present Development of New Generation antitumor drug.EGFR-TK is the key protein matter of cellular signal transduction path, and protein tyrosine kinase can be divided into receptor type and non-receptor type.The hydrophobic alpha helical region that receptor tyrosine kinase is all striden film by the combination territory, extracellular of containing ligand-binding site point, single, this three part of cell intracellular domain that contains protein tyrosine kinase activity are formed.When part combines the territory to combine with the extracellular after, growth factor signal to be imported in the cell from the extracellular, many physiological functions such as cell growth, angiogenesis and the apoptosis inhibition etc. of cell in this process control.In malignant tumor, this signal path and growth of tumor and transfer relationship are close.
Vascular endothelial growth factor receptor (VEGFR) EGFR-TK is exactly a kind of in the receptor tyrosine kinase; It is in people's tumor; Especially in glioma and the cancer; Giving expression to high level, in the new vessels of tumor generates, have important role, is the important target spot during the blocking-up tumor neogenetic blood vessels generates.VEGF (VEGF) is the factor of topmost promotion angiogenesis in the body.VEGF and the reaction that causes multiple angiogenesis after the vascular endothelial growth factor receptor that is positioned at endotheliocyte (VEGFR) combines, as cell proliferation, migration, vascular permeability increase, the endotheliocyte precursor shifts out from bone marrow.
The special VEGF-A of VEGF and Geng Duo exists with the form of three kinds of isomers (through changing and connecing) in the mankind, and their name decides according to the numeral of amino acid group: VEGF 121, VEGF 165 and VEGF 189.These three kinds of isomer bases have different functionalities with the combination and the diffusibility of heparin.Placenta growth factor (PIGF) only combines with VEGF-R 1/Fl t-1.
The expression of VEGF is to be caused by anoxia (Shweiki etc., Nature 1992,359,843) and cytokines, growth factor multiformity, interleukin-1 for example, interleukin-6, epidermal growth factor and abnormal growth factor α, abnormal growth factor β.
The vegf receptor membrane boundary is present in active endothelial cell surface, and has controlled intracellular tyrosine kinases area under one's jurisdiction, and this conduction for signal in the cell is very necessary.Reasonable argumentation VEGF dimer is to be polymerized by two acceptor molecules, and it has caused the connection of interior part autophosphorylation of recipient cell and SH2 repressible protein matter thereupon.The follow-up phosphorylation of phospholipase C, phosphatidylinositol 3-kinase and guanosine triphosphatase reactive protein (GAP) is proved to be.
170 kilodaltons (kDa) membrane bound protein that EGF-R ELISA (EGFR) is expressed for surface epithelial cell.EGFR belongs to the growth factor receptors family of protein tyrosine kinase.EGFR is the protein of growth oncogene erbBErbB or erbB1, and it is a member of the ERBB family of family's proto-oncogene (protooncogenes), it is believed that in the generation of the many cancers of the mankind and development to play a crucial role.Especially in breast carcinoma, bladder cancer, pulmonary carcinoma and glioblastoma, observed the enhanced expression of EGFR.Relevant transmembrane receptor, i.e. EGFR, HER-2/neu (erbB2), HER-3 (erbB3) and HER-4 (erbB4) on four kinds of structures of ERBB family coding of oncogene.Clinically, the ERBB oncogene amplification in the existing report tumor and/or the recurrence and the prognosis of patients difference correlation of receptor overexpression and disease, and with the relevant (L.Harris etc. of response of therapy; 1999; Int.J.Biol.Markers, 14:8-15 and J.Mendelsohn and J.Baselga, 2000; Oncogene, 19:6550-6565).
EGF or TGF-α combine activation signal transduction path and cause cell proliferation with EGFR's.The dimerization of EGFR molecule, conformation change and internalization play signal in the transfer cell, cause cell cycle regulation.Influence growth factor receptor function and regulate or cause hereditism's change of receptor and/or part overexpression, cause cell proliferation.In addition; Confirmed EGFR in the enhancing of cell differentiation, cell mobility, protein secreting, neovascularization, cancerous cell to the (M.-J.Oh etc. that work aspect invasion, transfer and the drug resistance of chemotherapeutant and lonizing radiation; 2000, Clin.Cancer Res., 6:4760-4763).
Developed some tyrosine kinase inhibitors at present successively, wherein the micromolecular inhibitor of VEGFR comprise the Novartis (Novartis) that attracts people's attention most in recent years/Schering Corp's research and development the treatment colorectal cancer VEGFR inhibitor Vatalanib (PTK787) and listing in 2006 Pfizer treatment gastrointestinal mesenchymal neoplasm and late period renal cell carcinoma many target spots inhibitor Sunitinib Malate (SU11248).Wherein the EGFR tyrosine kinase inhibitor comprises antineoplastic target medicine Erlotinib (Erlotinib, the Tarceva by the common exploitation of OSI pharmacy, Genentech and Luo Shi three companies
TM, Te Luokai, erlotinib) and by gefitinib (Gefitinib, the Iressa of AstraZeneca exploitation and listing
TM, Iressa).Erlotinib stops signal transduction path in the cell of this receptor mediation through the tyrosine kinase activity that suppresses EGFR-1, stop growth of tumour cell thus and finally present antitumor action.Gefitinib is through epidermal growth factor recipient tyrosine kinase (EGFR-TK) the catalysis region Mg-ATP binding site on competition cell surface; Blocking EGFR generation signal conducts to the interior EGFR of inhibition of cell and combines receptor generation phosphorylation in back with part; Suppress to form various homologies or heterodimer with other acceptor molecules; Thereby cause downstream a series of signal path such as activatory downward modulations such as P13K/AKT and RAS/RAF/MAPK kinase pathway; Thereby hinder growth of tumor, transfer and angiogenesis, but and the apoptosis of inducing tumor cell.
[4-(1-cyanic acid cyclopenta) phenyl]-amino-the 3-ascorbyl palmitate is a compd A to 2-(4-picolyl) to have the N-of following structural formula; It is a kind of VEGFR inhibitor, being disclosed in for information about in the one Chinese patent application numbers 02138671.4 and 200810146951.1 of this chemical compound and various salt thereof.
Compd A
Summary of the invention
The inventor finds that through a large amount of experiments it is active that the coupling of compd A or its pharmaceutically acceptable salt and EGFR tyrosine kinase inhibitor compounds has very strong synergistic antitumor, realized the enhancing of anti-tumor activity.Better effects if when compd A or its pharmaceutically acceptable salt and Erlotinib or its pharmaceutically acceptable salt or compd A or its pharmaceutically acceptable salt and gefitinib or its pharmaceutically acceptable salt coupling particularly.Therefore, technical purpose of the present invention provides a kind of antitumous effect better medicament compositions.
Therefore; First aspect of the present invention provides a kind of pharmaceutical composition of treating tumor disease; Said pharmaceutical composition contains Erlotinib or its pharmaceutically acceptable salt and compd A or its pharmaceutically acceptable salt of treating effective dose; Or said pharmaceutical composition contains gefitinib or its pharmaceutically acceptable salt and compd A or its pharmaceutically acceptable salt of treating effective dose; Wherein the weight ratio of Erlotinib or its pharmaceutically acceptable salt and compd A or its pharmaceutically acceptable salt is 1: 1-1: 20, and the weight ratio of gefitinib or its pharmaceutically acceptable salt and compd A or its pharmaceutically acceptable salt is 1: 1-1: 20, wherein compd A is N-[4-(1-cyanic acid cyclopenta) phenyl]-2-(4-picolyl) amino-3-ascorbyl palmitate;, structural formula is following:
Compd A
Especially; People's consumption per day of said compd A or its pharmaceutically acceptable salt is 100-1000mg; People's consumption per day of said Erlotinib or its pharmaceutically acceptable salt is 37.5-450mg; People's consumption per day of said gefitinib or its pharmaceutically acceptable salt is 62.5-750mg; Said pharmaceutical composition is tablet, hard capsule, soft capsule, oral solution, slow releasing agent, drop pill, electuary, granule or slow-release micro-pill; Said pharmaceutical composition be with once-a-day, the Pharmaceutical composition of twice on the one or three administrations on the one, said pharmaceutically acceptable salt is selected from phosphate, hydrochlorate, sulfate, nitrate, hydrobromate, mesylate, maleate, tartrate, benzoate, lactate or malate.
Second aspect of the present invention relates to aforesaid preparation of drug combination method, and wherein said method is wet granulation method and dry granulation method.
The third aspect of the invention relates to the purposes of aforesaid pharmaceutical composition in the medicine of preparation treatment people tumor disease.Especially, described tumor is pulmonary carcinoma, bladder cancer, cancer of pancreas, carcinoma of prostate, hepatocarcinoma, breast carcinoma, renal carcinoma, gastric cancer, esophageal carcinoma, thyroid carcinoma, ovarian cancer, carcinoma of gallbladder, skin carcinoma, epidermoid carcinoma or colon cancer.
In other words, the present invention relates to be used for medical science administration compd A or its pharmaceutically acceptable salt and the compositions of Erlotinib or its pharmaceutically acceptable salt or compd A or its pharmaceutically acceptable salt and gefitinib or its pharmaceutically acceptable salt and the dosage form of fixed dosage combination thereof.Said dosage form is to be suitable for oral dosage form, for example can be powder or solid form, and comprise tablet, capsule, pouch or the like.Concrete solid dosage forms relates to and contains compd A or its pharmaceutically acceptable salt and Erlotinib or its pharmaceutically acceptable salt or contain compd A or the tablet of the fixed dosage combination of its pharmaceutically acceptable salt and gefitinib or its pharmaceutically acceptable salt.
The present invention also provides the method for pharmaceutical composition that is equipped with the fixed dosage combination of compd A or its salt and Erlotinib or its salt or compd A or its salt and gefitinib or its salt through dry granulation method or wet granulation legal system.
Another aspect of the present invention provides the purposes of pharmaceutical composition of the present invention in the medicine of preparation treatment tumor disease, and this purposes comprises the pharmaceutical composition of the present invention of the main body treatment effective dose that needs said treatment.Described tumor comprises following tumor without limitation: pulmonary carcinoma (comprising minicell and nonsmall-cell lung cancer and adenocarcinoma of lung), bladder cancer (comprising fast and the transitivity bladder cancer), cancer of pancreas (comprising exocrine cancer of pancreas), carcinoma of prostate, hepatocarcinoma, breast carcinoma, renal carcinoma, gastric cancer, esophageal carcinoma, thyroid carcinoma, ovarian cancer, carcinoma of gallbladder, epidermoid carcinoma, skin carcinoma (comprising squamous cell carcinoma, malignant melanoma) or colon cancer (comprising colorectal carcinoma).
In a specific embodiments of the present invention, pharmaceutical composition comprises: (1) compd A or its pharmaceutically acceptable salt are first kind of active pharmaceutical ingredient; (2) Erlotinib or gefitinib or its salt are second kind of active pharmaceutical ingredient; (3) lubricant or fluidizer.In the specific embodiments of the present invention aspect this; Pharmaceutical composition can also contain one or more excipient, and said excipient is selected from one or more binding agents (bonding agent), one or more diluent, one or more surfactants or one or more disintegrating agents of wetting agent or one or more antioxidants.
The salt of pharmaceutically acceptable compd A, Erlotinib or gefitinib includes but not limited to, phosphate, hydrochlorate, sulfate, nitrate, hydrobromate, mesylate, maleate, tartrate, benzoate, lactate or malate.
It is 100 milligrams～1000 milligrams that the day for human beings of integrating with compd A or its salt in the pharmaceutical composition of the present invention is used dosage range.It is 100,250,500,750 or 1000 milligrams of compd As or its salt that the discrete day for human beings is used dosage.
It is 37.5 milligrams～450 milligrams that the day for human beings of integrating with Erlotinib or its salt in the fixed dosage of the present invention combination is used dosage; It is 37.5,75,150,300 and 450 milligrams that the discrete day for human beings is used dosage; It is 62.5 milligrams～750 milligrams that the day for human beings of gefitinib or its salt is used dosage, and it is 62.5,125,250,500 and 750 milligrams that the discrete day for human beings is used dosage.The daily dose form of these of Erlotinib or gefitinib or its salt is shown in the daily dosage that the approval of China and/or the U.S. is used for commercially available treatment tumor.
In fixed dosage combination of the present invention, compd A or its salt and Erlotinib or its salt or compd A or its salt and gefitinib or its salt day for human beings are following with the specific embodiments of dosage:
Compd A or its salt (mg) 100,250,500,750,1000
Erlotinib or its salt (mg) 37.5,75,150,300,450
Gefitinib or its salt (mg) 62.5,125,250,500,750.
Pharmaceutical composition of the present invention can be compd A or the Erlotinib of its salt and any treatment effective dose or the compositions of its salt or compd A or its salt and gefitinib or its salt of any treatment effective dose, for example: 100+37.5,100+150,100+450; 250+37.5,250+150,250+450,500+150; 500+300,750+150 or 250+62.5,250+250,250+500; 500+125,500+250,750+250 or the like.
Pharmaceutical composition of the present invention prepares through wet granulation method or dry granulation method.In one embodiment, pharmaceutical composition prepares through the wet granulation method.In carrying out wet granulation, can use high shear granulation or fluid bed granulation.In one embodiment, using fluid bed granulation to have makes tablet have the more advantage of high radial strength.
Can the pharmaceutical composition that obtain through dry granulation method or wet granulation method be compressed into tablet, encapsulate or be metered in the pouch.
Pharmaceutical composition contains one or more lubricants or fluidizer.The instance of lubricant comprises magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, castor oil hydrogenated or its mixture.Preferred lubricant is magnesium stearate or sodium stearyl fumarate or its mixture.The instance of fluidizer comprises silica sol, calcium phosphate, magnesium silicate and Talcum.
Optional one or more binding agents that contains of pharmaceutical composition of the present invention.The embodiment of binding agent comprises hydroxypropyl cellulose (HPC), hydroxypropyl emthylcellulose (HMPC), hydroxyethyl-cellulose, starch 1500, polyvinylpyrrolidone (polyvinyl pyrrolidone) and copolymerization alkene pyrrone.Preferred adhesive is a polyvinylpyrrolidone.
Pharmaceutical composition of the present invention can also be chosen wantonly and contain one or more diluent.The instance of diluent comprises mannitol, sorbitol, biphosphate calcium dihydrate, microcrystalline Cellulose and efflorescence cellulose.Preferable absorbent is a microcrystalline Cellulose.Microcrystalline Cellulose can be obtained from several suppliers, comprises Avicel PH 101, Avicel PH 102, Avicel PH 103, Avicel PH 105 and Avicel PH 200 that FMC Corporation makes.
Pharmaceutical composition of the present invention can also be chosen wantonly and contain disintegrating agent.Disintegrating agent can be a kind of in several modified starches, modified cellulose polymer or the polycarboxylic acids, such as crosslinked Carboxymethyl cellulose sodium, PRIMOGEL, polacrilin potassium and calcium carboxymethylcellulose (CMCCalcium).In one embodiment, disintegrating agent is a croscarmellose sodium.Croscarmellose sodium NF type A obtains with trade name " Ac-di-sol " on market.
Pharmaceutical composition of the present invention can also be chosen wantonly and contain one or more surfactants or wetting agent.Surfactant can be anion, cation or neutral surface active agent.Anion surfactant comprise sodium lauryl sulfate, dodecyl sodium sulfate, oleyl sodium sulfate and with stearate and the blended sodium laurate of Talcum.Cationic surfactant comprises benzalkonium chloride and alkyl trimethyl ammonium bromide.The neutral surface active agent comprises glycerol list olein, polyoxyethylene sorbitan fatty acid ester, polyvinyl alcohol and anhydro sorbitol fat.The embodiment of wetting agent comprises poloxamer, polyoxyethylene alkyl ether, castor oil derivatives and polyoxyethylene 8 stearate fat.
Can choose wantonly antioxidant is joined in the preparation, thereby give its chemical stability.Antioxidant is selected from the extract of alpha-tocopherol, Gamma-Tocopherol, Delta-Tocopherol, tocopherol enrichment natural origin, L-ascorbic acid and its sodium or calcium salt, anti-bad blood acyl cetylate, propyl gallate, gallate monooctyl ester, gallate dodecyl ester, Yoshinox BHT (BHT) and butylated hydroxyanisol (BHA).In one embodiment, antioxidant is BHT or BHA.
The preferred dosage form of drug composition of the present invention is the tablet through the compression method preparation.Said tablet can contain titanium dioxide and/or other coloring agent, such as ferrum oxide, dyestuff and Se Dian with filming such as the mixture of hydroxypropyl cellulose and hydroxypropyl emthylcellulose in this mixture; The mixture of polyvinyl alcohol (PVA) and Polyethylene Glycol (PEG) contains titanium dioxide and/or other coloring agent, such as ferrum oxide, dyestuff and Se Dian; Perhaps any other suitable instant-free applies agent.Coating provides taste masked and other stability to final tablet.Commercially available
for the preparation mixture of powders that film and provide for Colorcon.
At last, if desired, can add sweeting agent and/or fumet.
Pharmaceutical tablet composition of the present invention can also contain one or more and other be selected from the preparation composition in the known excipient of multiple field of pharmaceutical preparations.According to performance,, can separately or unite and select kind composition arbitrarily based on they known application in the preparation tablet composition to the expectation of drug regimen.Said composition includes but not limited to diluent, compression aid, fluidizer, disintegrating agent, lubricant, spice, fumet, sweeting agent and/or antiseptic.
Term " tablet " in this use refers to comprise all shapes and big or small compression pharmaceutical dosage formulation, no matter whether applies.The material that can be used to apply comprises hyprolose, hydroxypropyl emthylcellulose, titanium dioxide, Talcum, sweeting agent, coloring agent and fumet.
The main body that the present invention also provides the administered through oral administration to need said treatment is treated the method for the fixed dosage composition of medicine combination treatment tumor a kind of of the present invention of effective dose.In one embodiment, it is human needing the main body of said treatment.In another embodiment, pharmaceutical composition is the form of tablet, also can be Capsule form.
Contain pharmaceutical composition (QD), every day twice (BID) or three (TID) administrations every day once a day of fixed dosage combination.
The specific embodiment
Following examples have further described and have explained embodiment within the scope of the present invention.Embodiment only is a purpose for the purpose of illustration and providing, and is not intended it is regarded as limitation of the present invention, and possibly there is the multiple variant that does not deviate from spirit and scope of the invention in it.
The preparation of embodiment 1, compd A mesylate
In the 5L reaction bulb, drop into compd A 170g (0.428mol), Loprazolam 42.5g (0.442mol); 95% isopropanol water solution 2.55L is heated with stirring to complete dissolving under nitrogen protection and lucifuge condition, get light yellow transparent solution; Filtered while hot, cooling crystallization to room temperature after-filtration, isopropyl alcohol is washed; Vacuum drying gets white needle-like crystals 180.2g (0.365mol), yield 85.4%.
In the 5L reaction bulb, drop into compd A 180.2g, 95% isopropanol water solution 2.52L is heated with stirring to complete dissolving under nitrogen protection and the lucifuge condition; Filtered while hot, the filtrating cooling crystallization filters to room temperature, and isopropyl alcohol is washed; Vacuum drying gets white needle-like crystals 161.5g, yield 89.6%.Melting range: 193.5～195 ℃.
Embodiment 2, compd A maleate and hydrochloric acid Erlotinib compound tablet
Write out a prescription every and contain:
Compd A maleate 750mg (in compd A)
Hydrochloric acid Erlotinib 150mg
Microcrystalline Cellulose 120mg
2% starch slurry is an amount of
Magnesium stearate 5mg
Method for preparing: with the compd A maleate, the hydrochloric acid Erlotinib, the microcrystalline Cellulose mixing is with 2% starch slurry wet granulation.Drying adds magnesium stearate, the mixing tabletting.
Embodiment 3, compd A mesylate and hydrochloric acid Erlotinib compound tablet
Write out a prescription every and contain:
Compd A mesylate 400mg (in compd A)
Hydrochloric acid Erlotinib 150mg
Microcrystalline Cellulose 120mg
2% starch slurry is an amount of
Magnesium stearate 5mg
Method for preparing: with the compd A mesylate, the hydrochloric acid Erlotinib, the microcrystalline Cellulose mixing is with 2% starch slurry wet granulation.Drying adds magnesium stearate, the mixing tabletting.
Embodiment 4: different proportion Erlotinib and compd A pharmaceutical composition compare the curative effect of people's nonsmall-cell lung cancer A549 Nude Mice
Nude mouse subcutaneous vaccination people nonsmall-cell lung cancer A549 cell treats that tumor growth is to 100-300mm
3After, nude mouse is divided into 10 groups at random, 6 every group.Dosage regimen: at d0-4, d7-11, pressed hydrochloric acid Erlotinib, hydrochloric acid Erlotinib in d14-18 days: the compd A mesylate was respectively 1: 1,1: 2.5; 1: 5,1: 7.5,1: 10,1: 15; 1: 20, compd A mesylate, dosage were 40mg/kg/ days, oral administration.Survey the tumor volume weekly 2-3 time, claim that Mus is heavy, record data.Gross tumor volume (V) computing formula is: V=1/2 * a * b
2(wherein a, b represent length and width respectively), the result sees table 1:
Table 1: oral (p.o) different proportion Erlotinib and compd A pharmaceutical composition are to the curative effect of people's nonsmall-cell lung cancer A549 Nude Mice
D0: administration time for the first time; Dn: after the administration 21 days for the first time; TV: gross tumor volume; RTV: relative tumour volume;
*P＜0.01VS contrast.
Embodiment 5: different proportion Erlotinib and compd A pharmaceutical composition compare the curative effect of human colon carcinoma HT-29 Nude Mice
Nude mouse subcutaneous vaccination human colon carcinoma HT-29 cell treats that tumor growth is to 100-300mm
3After, nude mouse is divided into 10 groups at random, 6 every group.Dosage regimen: at d0-4, d7-11, pressed hydrochloric acid Erlotinib, hydrochloric acid Erlotinib in d14-18 days: the compd A mesylate was respectively 1: 1,1: 2.5; 1: 5,1: 7.5,1: 10,1: 15; 1: 20, compd A mesylate, dosage were 40mg/kg/ days, oral administration.Survey the tumor volume weekly 2-3 time, claim that Mus is heavy, record data.Gross tumor volume (V) computing formula is: V=1/2 * a * b
2(wherein a, b represent length and width respectively), the result sees table 2:
Table 2: oral (p.o) different proportion Erlotinib and compd A pharmaceutical composition are to the curative effect of human colon carcinoma HT-29 Nude Mice
D0: administration time for the first time; Dn: after the administration 21 days for the first time; TV: gross tumor volume; RTV: relative tumour volume;
*P＜0.01VS contrast.
Embodiment 6: different proportion Erlotinib and compd A pharmaceutical composition compare the curative effect of people's pulmonary carcinoma NCI-H460 Nude Mice
Nude mouse subcutaneous vaccination people pulmonary carcinoma NCI-H460 cell treats that tumor growth is to 100-300mm
3After, nude mouse is divided into 10 groups at random, 6 every group.Dosage regimen: at d0-4, d7-11, pressed hydrochloric acid Erlotinib, hydrochloric acid Erlotinib in d14-18 days: the compd A mesylate was respectively 1: 1,1: 2.5; 1: 5,1: 7.5,1: 10,1: 15; 1: 20, compd A mesylate, dosage were 30mg/kg/ days, oral administration.Survey the tumor volume weekly 2-3 time, claim that Mus is heavy, record data.Gross tumor volume (V) computing formula is: V=1/2 * a * b
2(wherein a, b represent length and width respectively), the result sees table 3:
Table 3: oral (p.o) different proportion Erlotinib and compd A pharmaceutical composition are to the curative effect of people's pulmonary carcinoma NCI-H460 Nude Mice
D0: administration time for the first time; Dn: after the administration 21 days for the first time; TV: gross tumor volume; RTV: relative tumour volume;
*P＜0.01VS contrast.
Embodiment 7: different proportion Erlotinib and compd A pharmaceutical composition compare the curative effect of people's epidermoid carcinoma A431 Nude Mice
Nude mouse subcutaneous vaccination people epidermoid carcinoma A431 cell treats that tumor growth is to 100-300mm
3After, nude mouse is divided into 10 groups at random, 6 every group.Dosage regimen: at d0-4, d7-11, pressed hydrochloric acid Erlotinib, hydrochloric acid Erlotinib in d14-18 days: the compd A hydrochlorate was respectively 1: 1,1: 2.5; 1: 5,1: 7.5,1: 10,1: 15; 1: 20, compd A hydrochlorate, dosage were 40mg/kg/ days, oral administration.Survey the tumor volume weekly 2-3 time, claim that Mus is heavy, record data.Gross tumor volume (V) computing formula is: V=1/2 * a * b
2(wherein a, b represent length and width respectively), the result sees table 4:
Table 4: oral (p.o) different proportion Erlotinib and compd A pharmaceutical composition are to the curative effect of people's epidermoid carcinoma A431 Nude Mice
D0: administration time for the first time; Dn: after the administration 21 days for the first time; TV: gross tumor volume; RTV: relative tumour volume;
*P＜0.01VS contrast.
Embodiment 8: different proportion Erlotinib and compd A pharmaceutical composition compare the curative effect of the pernicious melanin A375 of people Nude Mice
The pernicious melanin A375 of nude mouse subcutaneous vaccination people cell treats that tumor growth is to 100-300mm
3After, nude mouse is divided into 10 groups at random, 6 every group.Dosage regimen: at d0-4, d7-11, pressed hydrochloric acid Erlotinib, hydrochloric acid Erlotinib in d14-18 days: the compd A hydrochlorate was respectively 1: 1,1: 2.5; 1: 5,1: 7.5,1: 10,1: 15; 1: 20, compd A first hydrochlorate, dosage were 30mg/kg/ days, oral administration.Survey the tumor volume weekly 2-3 time, claim that Mus is heavy, record data.Gross tumor volume (V) computing formula is: V=1/2 * a * b
2(wherein a, b represent length and width respectively), the result sees table 5:
Table 5: oral (p.o) different proportion Erlotinib and compd A pharmaceutical composition are to the curative effect of the pernicious melanin A375 of people Nude Mice
D0: administration time for the first time; Dn: after the administration 21 days for the first time; TV: gross tumor volume; RTV: relative tumour volume;
*P＜0.01VS contrast.(numeral 890 in the table suspects it is 8.90)
Embodiment 9: different proportion Erlotinib and compd A pharmaceutical composition compare the curative effect of people's hepatocarcinoma Bel-7402 Nude Mice
Nude mouse subcutaneous vaccination people hepatocarcinoma Bel-7402 cell treats that tumor growth is to 100-300mm
3After, nude mouse is divided into 10 groups at random, 6 every group.Dosage regimen: at d0-4, d7-11, pressed hydrochloric acid Erlotinib, hydrochloric acid Erlotinib in d14-18 days: the compd A maleate was respectively 1: 1,1: 2.5; 1: 5,1: 7.5,1: 10,1: 15; 1: 20, compd A maleate, dosage were 40mg/kg/ days, oral administration.Survey the tumor volume weekly 2-3 time, claim that Mus is heavy, record data.Gross tumor volume (V) computing formula is: V=1/2 * a * b
2(wherein a, b represent length and width respectively), the result sees table 6:
Table 6: oral (p.o) different proportion Erlotinib and compd A pharmaceutical composition are to the curative effect of people's hepatocarcinoma Bel-7402 Nude Mice
D0: administration time dn for the first time: after the administration for the first time 21 days; TV: gross tumor volume; RTV: relative tumour volume;
*P＜0.01VS contrast.
Embodiment 10: different proportion Erlotinib and compd A pharmaceutical composition compare the curative effect of people's renal carcinoma Caki-1 Nude Mice
Nude mouse subcutaneous vaccination people renal carcinoma Caki-1 cell treats that tumor growth is to 100-300mm
3After, nude mouse is divided into 10 groups at random, 6 every group.Dosage regimen: at d0-4, d7-11, pressed hydrochloric acid Erlotinib, hydrochloric acid Erlotinib in d14-18 days: the compd A maleate was respectively 1: 1,1: 2.5; 1: 5,1: 7.5,1: 10,1: 15; 1: 20, compd A maleate, dosage were 20mg/kg/ days, oral administration.Survey the tumor volume weekly 2-3 time, claim that Mus is heavy, record data.Gross tumor volume (V) computing formula is: V=1/2 * a * b
2(wherein a, b represent length and width respectively), the result sees table 7:
Table 7: oral (p.o) different proportion Erlotinib and compd A pharmaceutical composition are to the curative effect of people's renal carcinoma Caki-1 Nude Mice
D0: administration time for the first time; Dn: after the administration 21 days for the first time; TV: gross tumor volume; RTV: relative tumour volume;
*P＜0.01VS contrast.
Embodiment 11, compd A maleate and gefitinib compound tablet
Write out a prescription every and contain:
Compd A maleate 750mg (in compd A)
Gefitinib 250mg
Microcrystalline Cellulose 120mg
2% starch slurry is an amount of
Magnesium stearate 5mg
Method for preparing: with the compd A maleate, gefitinib, the microcrystalline Cellulose mixing is with 2% starch slurry wet granulation.Drying adds magnesium stearate, the mixing tabletting.
Embodiment 12, compd A mesylate and gefitinib compound tablet
Write out a prescription every and contain:
Compd A mesylate 400mg (in compd A)
Gefitinib 125mg
Microcrystalline Cellulose 120mg
2% starch slurry is an amount of
Magnesium stearate 5mg
Method for preparing: with the compd A mesylate, gefitinib, the microcrystalline Cellulose mixing is with 2% starch slurry wet granulation.Drying adds magnesium stearate, the mixing tabletting.
Similarly; Through regulating compd A or its salt in the compound recipe; The consumption of Erlotinib or its salt; The compound recipe for preparing two kinds of active component that contain different proportion, for example the ratio of Erlotinib or its salt and compd A or its salt is 1: 1～1: 20, for example 1: 1,1: 2.5,1: 5,1: 7.5,1: 10,1: 15,1: 20 or the like.
Perhaps; Through regulating compd A or its salt in the compound recipe; The consumption of gefitinib or its salt; The compound recipe for preparing two kinds of active component that contain different proportion, for example the ratio of gefitinib or its salt and compd A or its salt is 1: 1～1: 20, for example 1: 1,1: 3,1: 6,1: 9,1: 12,1: 15,1: 20 or the like.
Embodiment 13: different proportion gefitinib and compd A pharmaceutical composition compare the curative effect of people's nonsmall-cell lung cancer A549 Nude Mice
Nude mouse subcutaneous vaccination people nonsmall-cell lung cancer A549 cell treats that tumor growth is to 100-300mm
3After, nude mouse is divided into 10 groups at random, 6 every group.Dosage regimen: at d0-4, d7-11, pressed gefitinib, gefitinib in d14-18 days: the compd A mesylate was respectively 1: 1, and 1: 3,1: 6,1: 9,1: 12,1: 15,1: 20, compd A mesylate, dosage were 40mg/kg/ days, oral administration.Survey the tumor volume weekly 2-3 time, claim that Mus is heavy, record data.Gross tumor volume (V) computing formula is: V=1/2 * a * b
2(wherein a, b represent length and width respectively), the result sees table 8:
Table 8: oral (p.o) different proportion gefitinib and compd A pharmaceutical composition are to the curative effect of people's nonsmall-cell lung cancer A549 Nude Mice
D0: administration time for the first time; Dn: after the administration 21 days for the first time; TV: gross tumor volume; RTV: relative tumour volume;
*P＜0.01VS contrast.
Embodiment 14: different proportion gefitinib and compd A pharmaceutical composition compare the curative effect of human colon carcinoma HT-29 Nude Mice
Nude mouse subcutaneous vaccination human colon carcinoma HT-29 cell treats that tumor growth is to 100-300mm
3After, nude mouse is divided into 10 groups at random, 6 every group.Dosage regimen: at d0-4, d7-11, pressed gefitinib, gefitinib in d14-18 days: the compd A mesylate was respectively 1: 1, and 1: 3,1: 6,1: 9,1: 12,1: 15,1: 20, compd A mesylate, dosage were 40mg/kg/ days, oral administration.Survey the tumor volume weekly 2-3 time, claim that Mus is heavy, record data.Gross tumor volume (V) computing formula is: V=1/2 * a * b
2(wherein a, b represent length and width respectively), the result sees table 9:
Table 9: oral (p.o) different proportion gefitinib and compd A pharmaceutical composition are to the curative effect of human colon carcinoma HT-29 Nude Mice
D0: administration time for the first time; Dn: after the administration 21 days for the first time; TV: gross tumor volume; RTV: relative tumour volume;
*P＜0.01VS contrast.
Embodiment 15: different proportion gefitinib and compd A pharmaceutical composition compare the curative effect of people's pulmonary carcinoma NCI-H460 Nude Mice
Nude mouse subcutaneous vaccination people pulmonary carcinoma NCI-H460 cell treats that tumor growth is to 100-300mm
3After, nude mouse is divided into 10 groups at random, 6 every group.Dosage regimen: at d0-4, d7-11, pressed gefitinib, gefitinib in d14-18 days: the compd A mesylate was respectively 1: 1, and 1: 3,1: 6,1: 9,1: 12,1: 15,1: 20, compd A mesylate, dosage were 20mg/kg/ days, oral administration.Survey the tumor volume weekly 2-3 time, claim that Mus is heavy, record data.Gross tumor volume (V) computing formula is: V=1/2 * a * b
2(wherein a, b represent length and width respectively), the result sees table 10:
Table 10: oral (p.o) different proportion gefitinib and compd A pharmaceutical composition are to the curative effect of people's pulmonary carcinoma NCI-H460 Nude Mice
D0: administration time for the first time; Dn: after the administration 21 days for the first time; TV: gross tumor volume; RTV: relative tumour volume;
*P＜0.01VS contrast.
Embodiment 16: different proportion gefitinib and compd A pharmaceutical composition compare the curative effect of people's epidermoid carcinoma A431 Nude Mice
Nude mouse subcutaneous vaccination people epidermoid carcinoma A431 cell treats that tumor growth is to 100-300mm
3After, nude mouse is divided into 10 groups at random, 6 every group.Dosage regimen: at d0-4, d7-11, pressed gefitinib, gefitinib in d14-18 days: the compd A hydrochlorate was respectively 1: 1, and 1: 3,1: 6,1: 9,1: 12,1: 15,1: 20, compd A hydrochlorate, dosage were 40mg/kg/ days, oral administration.Survey the tumor volume weekly 2-3 time, claim that Mus is heavy, record data.Gross tumor volume (V) computing formula is: V=1/2 * a * b
2(wherein a, b represent length and width respectively), the result sees table 11:
Table 11: oral (p.o) different proportion gefitinib and compd A pharmaceutical composition are to the curative effect of people's epidermoid carcinoma A431 Nude Mice
D0: administration time for the first time; Dn: after the administration 21 days for the first time; TV: gross tumor volume; RTV: relative tumour volume;
*P＜0.01VS contrast.
Embodiment 17: different proportion gefitinib and compd A pharmaceutical composition compare the curative effect of the pernicious melanin A375 of people Nude Mice
The pernicious melanin A375 of nude mouse subcutaneous vaccination people cell treats that tumor growth is to 100-300mm
3After, nude mouse is divided into 10 groups at random, 6 every group.Dosage regimen: at d0-4, d7-11, pressed gefitinib, gefitinib in d14-18 days: the compd A hydrochlorate was respectively 1: 1, and 1: 3,1: 6,1: 9,1: 12,1: 15,1: 20, compd A hydrochlorate, dosage were 20mg/kg/ days, oral administration.Survey the tumor volume weekly 2-3 time, claim that Mus is heavy, record data.Gross tumor volume (V) computing formula is: V=1/2 * a * b
2(wherein a, b represent length and width respectively), the result sees table 12:
Table 12: oral (p.o) different proportion gefitinib and compd A pharmaceutical composition are to the curative effect of the pernicious melanin A375 of people Nude Mice
D0: administration time for the first time; Dn: after the administration 21 days for the first time; TV: gross tumor volume; RTV: relative tumour volume;
*P＜0.01VS contrast.
Embodiment 18: different proportion gefitinib and compd A pharmaceutical composition compare the curative effect of people's hepatocarcinoma Bel-7402 Nude Mice
Nude mouse subcutaneous vaccination people hepatocarcinoma Bel-7402 cell treats that tumor growth is to 100-300mm
3After, nude mouse is divided into 10 groups at random, 6 every group.Dosage regimen: at d0-4, d7-11, pressed gefitinib, gefitinib in d14-18 days: the compd A maleate was respectively 1: 1, and 1: 3,1: 6,1: 9,1: 12,1: 15,1: 20, compd A maleate, dosage were 30mg/kg/ days, oral administration.Survey the tumor volume weekly 2-3 time, claim that Mus is heavy, record data.Gross tumor volume (V) computing formula is: V=1/2 * a * b
2(wherein a, b represent length and width respectively), the result sees table 13:
Table 13: oral (p.o) different proportion gefitinib and compd A pharmaceutical composition are to the curative effect of people's hepatocarcinoma Bel-7402 Nude Mice
D0: administration time for the first time; Dn: after the administration 21 days for the first time; TV: gross tumor volume; RTV: relative tumour volume;
*P＜0.01VS contrast.
Embodiment 19: different proportion gefitinib and compd A pharmaceutical composition compare the curative effect of people's renal carcinoma Caki-1 Nude Mice
Nude mouse subcutaneous vaccination people renal carcinoma Caki-1 cell treats that tumor growth is to 100-300mm
3After, nude mouse is divided into 10 groups at random, 6 every group.Dosage regimen: at d0-4, d7-11, pressed gefitinib, gefitinib in d14-18 days: the compd A maleate was respectively 1: 1, and 1: 3,1: 6,1: 9,1: 12,1: 15,1: 20, compd A maleate, dosage were 40mg/kg/ days, oral administration.Survey the tumor volume weekly 2-3 time, claim that Mus is heavy, record data.Gross tumor volume (V) computing formula is: V=1/2 * a * b
2(wherein a, b represent length and width respectively), the result sees table 14:
Table 14: oral (p.o) different proportion gefitinib and compd A pharmaceutical composition are to the curative effect of people's renal carcinoma Caki-1 Nude Mice
D0: administration time for the first time; Dn: after the administration 21 days for the first time; TV: gross tumor volume; RTV: relative tumour volume;
*P＜0.01VS contrast.
Claims (8)
1. pharmaceutical composition of treating tumor disease; It is characterized in that said pharmaceutical composition contains Erlotinib or its pharmaceutically acceptable salt and compd A or its pharmaceutically acceptable salt of treating effective dose; Wherein the weight ratio of Erlotinib or its pharmaceutically acceptable salt and compd A or its pharmaceutically acceptable salt is 1: 1-1: 20; Wherein compd A is N-[4-(1-cyanic acid cyclopenta) phenyl]-2-(4-picolyl) amino-3-ascorbyl palmitate, and structural formula is following:
Compd A.
2. pharmaceutical composition according to claim 1, the people's consumption per day that it is characterized in that said compd A or its pharmaceutically acceptable salt is 100-1000mg.
3. pharmaceutical composition according to claim 1, the people's consumption per day that it is characterized in that said Erlotinib or its pharmaceutically acceptable salt is 37.5-450mg.
4. according to each described pharmaceutical composition of claim 1-3, the dosage form that it is characterized in that said pharmaceutical composition is tablet, hard capsule, soft capsule, oral solution, drop pill, electuary, granule or slow-release micro-pill.
5. according to each described pharmaceutical composition of claim 1-3, it is characterized in that said pharmaceutical composition be with once-a-day, the Pharmaceutical composition of twice on the one or three administrations on the one.
6. according to each described pharmaceutical composition of claim 1-3, it is characterized in that said pharmaceutically acceptable salt is selected from phosphate, hydrochlorate, sulfate, nitrate, hydrobromate, mesylate, maleate, tartrate, benzoate, lactate or malate.
7. like each described preparation of drug combination method of claim 1-4, wherein said method is wet granulation method and dry granulation method.
8. according to the purposes of each described pharmaceutical composition of claim 1-6 in the medicine of preparation treatment people tumor disease, wherein said tumor is pulmonary carcinoma, hepatocarcinoma, renal carcinoma, epidermoid carcinoma or colon cancer.
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| CN103172576B (en) * | 2011-12-21 | 2015-08-05 | 沈阳药科大学 | The malate acid addition salt of Gefitinib and Synthesis and applications thereof |
| CN103110597B (en) * | 2013-02-02 | 2018-04-13 | 浙江华海药业股份有限公司 | Erlotinib Hydrochloride piece and preparation method thereof |
| CN104086484B (en) * | 2014-07-08 | 2016-05-25 | 上海宣创生物科技有限公司 | Mesylate solvate crystal of nicotinamide derivative and its preparation method and application |
| CN104288114B (en) * | 2014-10-27 | 2018-02-16 | 成都新恒创药业有限公司 | A kind of erlotinib Hydrochloride pharmaceutical composition without surfactant |
| CN105622499A (en) * | 2014-10-28 | 2016-06-01 | 华东理工常熟研究院有限公司 | New crystal of apatinib sulfate |
| CN105622498A (en) * | 2014-10-28 | 2016-06-01 | 华东理工常熟研究院有限公司 | New crystal of apatinib sulfate |
| CN105541708A (en) * | 2014-10-28 | 2016-05-04 | 华东理工常熟研究院有限公司 | New crystal form of apatinib sulfate |
| CN109381436A (en) * | 2017-08-14 | 2019-02-26 | 江苏恒瑞医药股份有限公司 | A Pa is for Buddhist nun's pharmaceutical composition and preparation method thereof |
| WO2020177678A1 (en) * | 2019-03-04 | 2020-09-10 | 江苏恒瑞医药股份有限公司 | Use of multi-target tyrosine kinase inhibitor in combination with egfr inhibitor in preparing drug for treating tumor |
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| CN1861047A (en) * | 2006-03-06 | 2006-11-15 | 济南帅华医药科技有限公司 | Slow-releasing injection contg. vasoinhibitor and potentiator type anticarcinogen |
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| CN1861047A (en) * | 2006-03-06 | 2006-11-15 | 济南帅华医药科技有限公司 | Slow-releasing injection contg. vasoinhibitor and potentiator type anticarcinogen |
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