CN108498477A - A kind of Pharmaceutical composition and preparation method thereof of 2- amino-metadiazine compounds - Google Patents

A kind of Pharmaceutical composition and preparation method thereof of 2- amino-metadiazine compounds Download PDF

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Publication number
CN108498477A
CN108498477A CN201710108703.XA CN201710108703A CN108498477A CN 108498477 A CN108498477 A CN 108498477A CN 201710108703 A CN201710108703 A CN 201710108703A CN 108498477 A CN108498477 A CN 108498477A
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China
Prior art keywords
pharmaceutical composition
filler
mannitol
compound
microcrystalline cellulose
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CN201710108703.XA
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Chinese (zh)
Inventor
陈庆财
丁健
丁克
金雪锋
耿美玉
谢华
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Shanghai Institute of Materia Medica of CAS
Guangzhou Institute of Biomedicine and Health of CAS
Jiangsu Aosaikang Pharmaceutical Co Ltd
Original Assignee
Shanghai Institute of Materia Medica of CAS
Guangzhou Institute of Biomedicine and Health of CAS
Jiangsu Aosaikang Pharmaceutical Co Ltd
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Application filed by Shanghai Institute of Materia Medica of CAS, Guangzhou Institute of Biomedicine and Health of CAS, Jiangsu Aosaikang Pharmaceutical Co Ltd filed Critical Shanghai Institute of Materia Medica of CAS
Priority to CN201710108703.XA priority Critical patent/CN108498477A/en
Priority to PCT/CN2018/077435 priority patent/WO2018153379A1/en
Priority to CN201880014402.3A priority patent/CN110446701B/en
Publication of CN108498477A publication Critical patent/CN108498477A/en
Pending legal-status Critical Current

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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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/495—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/495—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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present invention provides a kind of Pharmaceutical compositions of 2 amino-metadiazine compound.Specifically, the present invention provides one kind including the Pharmaceutical composition of N ((5 (2 base of (5 chlorine 4 ((2 base of naphthalene) amino)) pyrimidine) amino) 2 ((N methyl Ns dimethylaminoethyl) amino) 4 methoxyphenyls) acrylamide, and the method for preparing the Pharmaceutical composition.

Description

A kind of Pharmaceutical composition and preparation method thereof of 2- amino-metadiazine compounds
Technical field
The invention belongs to field of pharmaceutical preparations, specifically, the present invention relates to compound N-((5- ((chloro- the 4- ((naphthalenes-of 5- 2- yls) amino)) pyrimidine -2-base) amino) -2- ((N- methyl-N- dimethylaminoethyls) amino) -4- methoxyphenyls) propylene The Pharmaceutical composition of amide, and the method for preparing the Pharmaceutical composition.
Background technology
EGF-R ELISA (EGFR), a kind of receptor tyrosine protein kinase, regulated and controled the proliferation of cell, survival, Adhesion, migration and differentiation.EGFR overactivity or continuous activation in kinds of tumor cells, such as lung cancer, breast cancer, prostate Cancer etc..It is that leading method carrys out targeting therapy on tumor cell by clinical verification to block the activation of EGFR and Erb-B2.Two kinds of targets To the micromolecular inhibitor of EGFR, Gefitinib and Tarceva, obtained U.S. FDA it is quick approval it is non-for treating late period Small Cell Lung Cancer (NSCLC) patient, these patients have lost reaction to conventional chemotherapy.
Reactivity of the NSCLC patient of the EGFR Activating mutations positives to EGFR-TKI (EGFR- tyrosine kinase inhibitors) It is significantly higher than EGFR wild type NSCLC patients, Progression free survival (PFS) phase and total existence (OS) phase also significantly extend.But although In this way, the PFS of major part EGFR mutation positive patients is no more than 12~14 months, i.e., drug resistance is had occurred to TKI.Acquired resistance Mechanism and its clinical countermeasure become the another research hotspot in targeted therapy field.
N- ((5- ((the chloro- 4- of 5- ((naphthalene -2- bases) amino)) pyrimidine -2-base) amino) -2- ((N- methyl-N- dimethylaminos Ethyl) amino) -4- methoxyphenyls) acrylamide, chemical constitution is shown in formula I.Compound shown in Formulas I is selective depression The EGFR inhibitor of EGFR T790M mutation, can overcome the drug resistance of the inductions such as existing drug Gefitinib, Tarceva, to open country Raw type EGFR inhibitory activity is weak.However, this field, which still lacks, adapts to N- ((5- ((the chloro- 4- of 5- ((naphthalene -2- bases) amino)) pyrimidines - 2- yls) amino) -2- ((N- methyl-N- dimethylaminoethyls) amino) -4- methoxyphenyls) and acrylamide administration medicinal group Close object.
Invention content
The object of the present invention is to provide a kind of adaptation N- ((5- ((the chloro- 4- of 5- ((naphthalene -2- bases) amino)) pyrimidine -2-base) ammonia Base) -2- ((N- methyl-N- dimethylaminoethyls) amino) -4- methoxyphenyls) acrylamide administration Pharmaceutical composition.
The first aspect of the present invention provides a kind of Pharmaceutical composition containing compound shown in Formulas I,
The Pharmaceutical composition is prepared via direct powder compression, and the Pharmaceutical composition includes compound of formula I, filling Agent, glidant, lubricant, disintegrant.
In another preferred example, the filler is selected from the group：Starch, sucrose, dextrin, lactose, pregelatinized starch, crystallite Cellulose, calcium sulfate, calcium monohydrogen phosphate, sorbierite, mannitol, or combinations thereof；And/or
The glidant is talcum powder or colloidal silicon dioxide；It is preferred that colloidal silicon dioxide；And/or
The lubricant is selected from the group：Magnesium stearate, calcium stearate, zinc stearate, odium stearate, stearic acid, stearic richness Horse acid sodium, polyethylene glycol, lauryl sodium sulfate, or combinations thereof；It is preferred that sodium stearyl fumarate；And/or
The disintegrant is selected from the group：Dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl It is one or more in sodium cellulosate, crospovidone；It is preferred that low-substituted hydroxypropyl cellulose and/or cross-linked carboxymethyl cellulose Sodium；More preferably low-substituted hydroxypropyl cellulose or croscarmellose sodium.
In another preferred example, in the Pharmaceutical composition, the grain size of the compound of formula I is 10-150 μm, Preferably 30-100 μm.
In another preferred example, the filler is mannitol and microcrystalline cellulose；Preferably, in the filler, The weight ratio of mannitol and microcrystalline cellulose is (1.5~9)：1, it is therefore preferable to (1.8~8)：1, more preferably (3~7.6)： 1。
In another preferred example, the weight ratio of the filler and compound of formula I is 3~7)：1, it is therefore preferable to (4~6)： 1, more preferably (4.5~5.5)：1；And/or
The weight ratio of the glidant and compound of formula I is (0.04~0.2)：1, it is therefore preferable to (0.06~0.2)：1, more Preferably (0.08~0.15)：1；
The weight ratio of the lubricant and compound of formula I is (0.08~0.44)：1, it is therefore preferable to (0.09~0.33)：1, More preferably (0.1~0.22)：1；
The weight ratio of the disintegrant and compound of formula I is (0.15~0.8)：1, it is therefore preferable to (0.18~0.7)：1, more Preferably (0.2~0.65)：1.
In another preferred example, the Pharmaceutical composition includes：
In another preferred example, the Pharmaceutical composition includes：
And the filler includes mannitol and microcrystalline cellulose, and the weight of the mannitol and microcrystalline cellulose Than for (1.8~8)：1；
And the disintegrant is selected from the group：Low-substituted hydroxypropyl cellulose or croscarmellose sodium.
In another preferred example, the Pharmaceutical composition is composed of the following components：
And the filler includes mannitol and microcrystalline cellulose, and the weight of the mannitol and microcrystalline cellulose Than for (1.8~8)：1；
And the disintegrant is selected from the group：Low-substituted hydroxypropyl cellulose or croscarmellose sodium.
In another preferred example, the Pharmaceutical composition is prepared by direct compression method.
The second aspect of the present invention provides a kind of method preparing Pharmaceutical composition described in first aspect present invention, institute Stating preparation method includes：
(1) first glidant, first part's filler, disintegrant are mixed, sieving；
(2) compound shown in Formulas I and second part filler are added, lubricant is added after mixing, continues to mix Uniformly, intermediate powder is obtained；
(3) content detection for carrying out intermediate powder calculates piece weight according to intermediate product assay result, carries out tabletting.
In another preferred example, compound shown in the Formulas I is powder type.
In another preferred example, the compound of formula I powder is obtained by mechanical crushing compound of formula I bulk pharmaceutical chemicals.
In another preferred example, the filler is mannitol and microcrystalline cellulose, and the first part fills Agent is microcrystalline cellulose, and second part filler is mannitol.
In another preferred example, the Pharmaceutical composition is preparing the drug for treating cancer in patients, preferably Ground, the cancer are the non-small cell lung cancer (NSCLC) of EGFR T790M mutation.
The third aspect of the present invention, provides a kind of medicinal tablets, and the medicinal tablets include such as first party of the present invention Pharmaceutical composition described in face.
In another preferred example, the medicinal tablets include：Label, the label are described in first aspect present invention Pharmaceutical composition, and the coating that is coated on outside the label.
In another preferred example, the weight ratio of the coating and label is 2-5：100, preferably 3-4:100.
In another preferred example, the medicinal tablets are used to prepare the drug for treating cancer in patients, preferably Ground, the cancer are the non-small cell lung cancer (NSCLC) of EGFR T790M mutation.
The fourth aspect of the present invention, provides a kind of medicine box, and the medicine box includes：
Pharmaceutical composition as described in the first aspect of the invention；With
For with the Pharmaceutical composition associated with second therapeutic agent.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment) It can be combined with each other between each technical characteristic of body description, to constitute new or preferably technical solution.As space is limited, exist This no longer tires out one by one states.
Description of the drawings
Fig. 1 is stripping curve of the three batches of labels of the preparation of embodiment 1 in pH1.2 dissolution mediums；
Fig. 2 is stripping curve of the three batches of labels of the preparation of embodiment 1 in pH4.5 dissolution mediums；
Fig. 3 is stripping curve of the three batches of labels of the preparation of embodiment 1 in FASSIF dissolution mediums；
Fig. 4 is stripping curve of the three batches of 10mg specifications tablets of the preparation of embodiment 8 in pH3.8 dissolution mediums；
Fig. 5 is stripping curve of the three batches of 80mg specifications tablets of the preparation of embodiment 8 in pH3.8 dissolution mediums.
Specific implementation mode
The present inventor's in-depth study by long-term, provides a kind of suitable N- ((5- ((chloro- 4- of 5- ((naphthalene -2- bases) Amino)) pyrimidine -2-base) amino) -2- ((N- methyl-N- dimethylaminoethyls) amino) -4- methoxyphenyls) acrylamide gives The Pharmaceutical composition of medicine.The Pharmaceutical composition has excellent dissolution rate and chemical stability.Based on above-mentioned discovery, invention People completes the present invention.
Term
As used herein, in use, term " about " means that the value can be from enumerating in mentioning the numerical value specifically enumerated Value changes not more than 1%.For example, as used herein, statement " about 100 " include 99 and 101 and between whole values (for example, 99.1,99.2,99.3,99.4 etc.).
As used herein, term " containing " or " including (including) " can be open, semi-enclosed and enclosed.It changes Yan Zhi, the term also include " substantially by ... constitute " or " by ... constitute ".
As used herein, term " ... specification label " or " ... specification tablet " have following meaning：Each label or Containing compound shown in a certain number of Formulas I in each tablet；Such as 10mg specification labels represent and contain about 10mg in each label Formulas I shown in compound.
N- ((5- ((the chloro- 4- of 5- ((naphthalene -2- bases) amino)) pyrimidine -2-base) amino) -2- ((N- methyl-N- dimethylaminos Ethyl) amino) -4- methoxyphenyls) acrylamide Pharmaceutical composition
The purpose of the present invention is to provide compound N-((5- ((the chloro- 4- of 5- ((naphthalene -2- bases) amino)) pyrimidine -2-base) ammonia Base) -2- ((N- methyl-N- dimethylaminoethyls) amino) -4- methoxyphenyls) the suitable industrialized production of acrylamide, symbol Close the Pharmaceutical composition of Clinical practice demand.
The present inventor's compound shown in Research-type I suitable for industrialized production, meet the medicine of Clinical practice demand During with composition, multiple technical barriers are encountered.For example, the poor fluidity of compound shown in (1) Formulas I, affects medicinal The uniformity of dosage units of composition, batch between dissolution rate consistency etc.；(2) compound shown in Formulas I is easily aoxidized, and needs technique quickly simple Just, shorten preparation time as possible；(3) Patients with Non-small-cell Lung, especially patients with terminal, the obstacle of respiratory system to swallow tired Difficulty needs drug that can be administered by modes such as nasal feedings.
Those skilled in the art can be divided into tabletting method two major classes, that is, pelletize it is known that according to the process route of tabletting difference Pressed disc method and direct compression method.It is further that granulating tabletting process can be divided into wet granule compression tablet method, dry granulation tabletting again Direct compression method is divided into direct powder compression, two group of half dry type granulation method by two group of method.
Direct powder compression (direct compression method) is without pelletization, directly drug The method for carrying out tabletting with the mixture of auxiliary material.Direct compression method is with powder flowbility is poor, uniformity of dosage units is poor, tablet weight variation Big disadvantage；Therefore the mobility of bulk pharmaceutical chemicals is required relatively high.The poor fluidity of raw materials of compound medicine shown in Formulas I, and send out A person of good sense's research shows that poor fluidity is unrelated with the crystal structure of bulk pharmaceutical chemicals.To those skilled in the art, powder is direct Pressed disc method be unsuitable for manufacturing compound shown in Formulas I suitable for industrialized production, meet the Pharmaceutical composition of Clinical practice demand.
However inventor to four group tabletting methods carry out largely attempt after, surprisingly find by the invention it is possible to The defect for overcoming poor fluidity, using direct powder compression, the Formulas I institute for the tablet form that acquisition content is uniform, piece is stablized again Show the Pharmaceutical composition of compound.More amazing to be, piece dosage form is made in the direct powder compression provided through the invention Formula Pharmaceutical composition disintegration time is short, and dissolution rate is fast.
Therefore, first aspect present invention provides a kind of suitable industrialized production, meets shown in the Formulas I of Clinical practice demand The Pharmaceutical composition form of compound；The Pharmaceutical composition of compound shown in Formulas I is preferably tablet form.The Pharmaceutical composition passes through It is prepared by direct powder compression, including compound, filler, glidant, lubricant and disintegrant shown in Formulas I.
Compound shown in the Formulas I exists as the active constituent in Pharmaceutical composition, and content usually can be according to administration The needs of mode are flexibly arranged.
The Pharmaceutical composition of the present invention can select a kind of, two kinds, three or more fillers.Filler can also claim For diluent, main function is the weight and/or volume for increasing Pharmaceutical composition；The agent of active constituent can be reduced simultaneously It measures deviation, improve compressibility.Acceptable filler includes but not limited to starch, sucrose, dextrin, lactose, pregelatinized starch, micro- It is one or more in crystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, sorbierite, mannitol.
In the present invention, the weight ratio of filler and compound of formula I is (3~7)：1, preferably (4~6)：1, more preferably It is (4.5~5.5)：1.
, it is preferable to use mannitol and microcrystalline cellulose are as filler in the present invention.Wherein, mannitol and microcrystalline cellulose Weight ratio be (1.5~9)：1；Preferably, weight ratio is (1.8~8)：1；It is highly preferred that weight ratio be (3~ 7.6)：1.
, it is preferable to use being suitable for the material of direct tablet compressing in the present invention.
The average grain diameter of suitable mannitol is 50~200 μm, preferably 100~200 μm, can be commercially available, such as Pearlitol 100sd and the Pearlitol 200sd of Roquette companies.Present invention preferably uses Pearlitol 100sd, Its good fluidity can meet tabletting and the requirement of uniformity of dosage units.
The average grain diameter of suitable microcrystalline cellulose is 20~200 μm, preferably close with the grain size of mannitol, can be with quotient Purchase obtain, as the Avicel PH-102 of FMC Corp., Avicel HFE-102, Avicel PH-301, Avicel PH-302, Avicel PH-200.Present invention preferably uses Avicel PH-302, good fluidity, compressibility is better than mannitol, grain size and Heap density is close with PEARLITOL 100SD earlitol 100sd, can be to avoid the layering in tableting processes.
" glidant " used in the present invention refers to being added before tabletting, to reduce the auxiliary material of frictional force between particle, is added Powder fluidity can be improved by entering glidant, reach and stream is helped to act on.The Pharmaceutical composition of the present invention can select it is a kind of, two kinds, Three or more glidants.Glidant includes but not limited to talcum powder or colloidal silicon dioxide.In the present invention, glidant and formula The weight ratio of Compound I is (0.04~0.2)：1, preferably (0.06~0.2)：1, more preferably (0.08~0.15)： 1。
" lubricant " used in the present invention refers to being added before tabletting, to reduce between particle or tablet and punch die The auxiliary material of frictional force, lubricant, which is added, can reduce the friction with punch die, increase the sliding of particle, make that filling is good, tablet Density Distribution it is uniform, also ensure release tablet integrality.The Pharmaceutical composition of the present invention can select it is a kind of, two kinds, Three or more lubricants.Lubricant includes but not limited to magnesium stearate, calcium stearate, zinc stearate, odium stearate, tristearin Acid, sodium stearyl fumarate, polyethylene glycol, lauryl sodium sulfate.The preferred sodium stearyl fumarate of lubricant of the present invention.The present invention In, the weight ratio of lubricant and compound of formula I is (0.08~0.44)：1, preferably (0.09~0.33)：1, more preferably For (0.1~0.22)：1.
The Pharmaceutical composition of the present invention can select a kind of, two kinds, three or more disintegrants.Disintegrant is to promote piece Agent is fragmented into rapidly the auxiliary material of fine particle in gastro-intestinal Fluid.Medicinal disintegrating agent includes but not limited to dried starch, carboxymethyl starch Sodium, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone.Present invention preferably uses low-substituted hydroxypropyls Base cellulose and/or croscarmellose sodium are as disintegrant；More preferably use low-substituted hydroxypropyl cellulose or friendship Join sodium carboxymethylcellulose.In the present invention, the weight ratio of disintegrant and compound of formula I is (0.15~0.8)：1, preferably (0.18~0.7)：1, more preferably (0.2~0.65)：1.
The dissolution rate of the Size Distribution tablet of bulk pharmaceutical chemicals.In order to ensure the dissolution of compound shown in active medicine Formulas I Degree, in the present invention, it is preferred to, control the grain size D of compound shown in Formulas I90It is 30~120 μm；It is highly preferred that control grain size D90It is 30~85 μm.Manner known in the art can be used to control shown in the starting materials of formulae I as one of ingredient in tablets in the present invention Compound particle size, it is preferable that handle compound shown in Formulas I by sieving mode；It is highly preferred that chemical combination shown in Formulas I The processing mode of object is 80~200 mesh of sieving.
Above-mentioned Pharmaceutical composition is prepared via direct powder compression, and the direct powder compression includes：(1) it will first help Flow agent, first part's filler, disintegrant mixing, sieving；(2) compound shown in Formulas I and second part filling are sequentially added Lubricant is added in agent after mixing, continues to be uniformly mixed, obtains intermediate powder；(3) the content inspection of intermediate powder is carried out It surveys, piece weight is calculated according to intermediate product assay result after qualification, carry out tabletting.According to the present invention, described in step (2) Two partially filled agents can may be the same or different with first part's filler described in step (1).First part's filler refers to A part for filler, the partially filled agent are added in step (1)；Second part filler refers to the remainder in filler Point, which is added in step (2).When filler is the combination of microcrystalline cellulose and mannitol, it is preferable that First part's filler is microcrystalline cellulose, and second part filler is mannitol；Preferred microcrystalline cellulose with it is sweet It is direct tablet compressing type to reveal alcohol.
Second aspect, the present invention provide the preparation method of above-mentioned Pharmaceutical composition.The preparation method includes：(1) first will Glidant, first part's filler, disintegrant mixing, sieving；(2) compound and second part shown in Formulas I is sequentially added to fill out Agent is filled, lubricant is added after mixing, continues to be uniformly mixed, obtains intermediate powder；(3) the content inspection of intermediate powder is carried out It surveys, piece weight is calculated according to intermediate product assay result after qualification, carry out tabletting.
Preferably, an embodiment according to the present invention, the glidant are colloidal silicon dioxide；More preferably and Formulas I The shown comparable colloidal silicon dioxide of compound particle diameter distribution.
According to the present invention, the second part filler described in step (2) can be filled out with the first part described in step (1) Agent is filled to may be the same or different.
Preferably, an embodiment according to the present invention, first part's filler are microcrystalline cellulose；More preferably Ground, microcrystalline cellulose are direct tablet compressing type.
Preferably, an embodiment according to the present invention, the disintegrant are croscarmellose sodium.
According to the present invention, in step (1) described " first mixing glidant, first part's filler, disintegrant, sieving " Sifting step is sieved using 30-80 mesh screens；It is preferable to use 40-60 mesh screens.
Preferably, an embodiment according to the present invention controls compound grain size D shown in Formulas I by sieving90For 30~ 120μm。
Preferably, an embodiment according to the present invention, the second part filler are mannitol；It is highly preferred that Mannitol is direct tablet compressing type.
Preferably, step (2) is described " sequentially adds compound shown in Formulas I and second part filler, after mixing The mixing carried out in addition lubricant ", incorporation time are 5-25 minutes, and mixing velocity is 10-25 revs/min；It is highly preferred that Incorporation time is 10-20 minutes, and mixing velocity is 15-20 revs/min.
Preferably, an embodiment according to the present invention, the lubricant are sodium stearyl fumarate.
Preferably, the mixing carried out in " continuing to be uniformly mixed, obtain intermediate powder " described in step (3), incorporation time It it is 5-15 minutes, mixing velocity is 10-25 revs/min；It is highly preferred that incorporation time is 5-10 minutes, mixing velocity 15-20 Rev/min.
According to the present invention, step suitably adjusts tableting pressure in (3), keeps the tablet friability of compacting and disintegration qualified, Ensure that product does not occur sliver problem in transportational process.
Medicinal tablets and its preparation
The present invention also provides a kind of medicinal tablets, the medicinal tablets include Pharmaceutical composition as described above.It is preferred that Ground, in the present invention, the weight based on tablet, the absolute content of compound shown in Formulas I in tablets is 1-2000mg/ pieces；More Preferably, absolute content is 10-500mg/ pieces, for example, the absolute content of compound shown in Formulas I in tablets can be 10mg/ pieces, 20mg/ pieces, 40mg/ pieces, 80mg/ pieces, 100mg/ pieces, 160mg/ pieces, 240mg/ pieces.
In one embodiment of the invention, a kind of medicinal tablets, including label are provided, which includes institute as above The Pharmaceutical composition stated, the label also have coating.
According to the difference of coating material, the tablet of coating can be broadly divided into sugar coated tablet, Film coated tablets, Enteric coated tablets.This In invention, the coating is the known suitable coating that will not have negative effect to the dissolution rate of final preparation, preferably film packet Clothing.Label can be made to have by film coating and seal coating, to reach protection patient, clinical staff and blocking label and sky The contact of gas and water point, reduces the chance of drugs from degradation.
Suitable membranes coating material includes film forming agent, such as film forming polymer.Preferably, thin film coating material further includes another Outer component, for example, plasticizer, colorant, dispersion aids and opacifier.The thin of film coating can be improved using plasticizer Film flexibility and durability and adhesion characteristics.Preferred film forming polymer is selected from film-forming vinyl polymer (such as polyethylene Alcohol), the ester of film-forming acrylic polymer (such as EUDRAGIT L100), water-soluble cellulose ether It is one or more in (such as hydroxypropyl methylcellulose phthalate) etc..Suitable plasticizer include such as glycerine, Monoglyceride, citrate, propylene glycol, polyethylene glycol, triglyceride or the phthalic acid ester of acetylation.Suitable shading Agent and colorant include such as titanium dioxide, di-iron trioxide.Suitable dispersion aids includes such as talcum.
Coating weight gain can be the 0.5% to 10% of Pharmaceutical composition, preferably 1% to 6% by weight, more preferably 2.5% to 5%.Suitable thin film coating material can be concentrate, and packet is prepared with water or organic solvent before being sprayed into label Clothing liquid.Such concentrate includes purchased from Opadry (Opadry) the series coating for blocking happy Kanggong department (Colorcon).
The purposes of Pharmaceutical composition
Finally, the present invention also provides above-mentioned Pharmaceutical compositions or tablet to prepare the medicine for treating cancer in patients Purposes in object.Preferably, the cancer is lung cancer, it is highly preferred that the cancer is non-small cell lung cancer, particularly preferably, The cancer is the acellular lung cancer of EGFR Positive mutants.In one embodiment of the invention, the cancer is EGFR The non-small cell lung cancer (NSCLC) of T790M mutation.
It is that compound shown in the Formulas I by safe and effective amount is applied to patient in need for the treatment of (such as when using Pharmaceutical composition People), wherein dosage is the effective dosage pharmaceutically thought when application, for the people of 60kg weight, chemical combination shown in Formulas I The day dosage of object is usually 1~2000mg, preferably 20~500mg.Certainly, specific dosage is also contemplated that administration route, disease The factors such as people's health status, within the scope of these are all skilled practitioners technical ability.The Pharmaceutical composition or tablet of the present invention is general Be administered by oral way, the patient having any problem swallowed for solid, can by the way that first tablet water is disintegrated into suspension, It takes orally or is administered through nasal feeding again, to solve the problems, such as administration.
Pharmaceutical composition or tablet of the present invention can be administered alone, or combine with other treatment drug (such as antidiabetic drug) to Medicine.
The Pharmaceutical composition or tablet of the present invention can be combined to the known other medicines for treating or improving similar symptom. When administering drug combinations, originally the administering mode of drug and dosage remain unchanged, and subsequently or simultaneously take the pharmaceutical compositions of the present invention Object or tablet.Drug combination be also included within overlapping period take the present invention Pharmaceutical composition or tablet with it is other a kind of or Several known drugs.When the Pharmaceutical composition of the present invention or tablet carry out drug combination with other one or more of drugs, this Dosage when Pharmaceutical composition/tablet of invention or the dosage of known drug may be than their independent medications is relatively low.
It can carry out the drug of drug combination with the Pharmaceutical composition or tablet of the present invention or active constituent includes but not office It is limited to：Estrogenic agents, androgen receptor modifier, retinoid-like receptor modulators, cytotoxin/cell inhibit Agent, antiproliferative, protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV kinases inhibitors, reverse transcriptase suppression The drug and Apoptosis of preparation, angiogenesis inhibitors, cell Proliferation and survival signaling inhibitor, interference cell cycle check Derivant, cytotoxic drug, tyrosine protein inhibitor, EGFR inhibitor, VEGFR inhibitor, serine/threonine protein Inhibitor, Bcr-Abl inhibitor, c-Kit inhibitor, Met inhibitor, Raf inhibitor, mek inhibitor, MMP inhibitor, topology Isomerase inhibitors, Histone deacetylase inhibitor, proteasome inhibitor, CDK inhibitor, the suppression of Bcl-2 family proteins Preparation, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitor, AKT suppressions Preparation, integrin retarding agent, interferon-' alpha ', IL-12, cox 2 inhibitor, p53, p53 activator, VEGF antibody, EGF Antibody etc..
Main advantages of the present invention are：
(1) Pharmaceutical composition of the invention molding is easy, can utilize direct powder compression obtain content uniformly, piece weight The Pharmaceutical composition of compound shown in the Formulas I of stable tablet form.
(2) Pharmaceutical composition disintegration time of the invention is short, and dissolution rate is fast, and has extraordinary chemical stability.
(3) Pharmaceutical composition of the invention is easy to process, and the sieving time is short, in preparation process it is less occur slice it is difficult, Phenomena such as sticking, is highly suitable for industrialized production.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.
The Study of Liquidity of compound shown in 1 Formulas I of test example
The mobility of raw materials of compound shown in Formulas I has been investigated using Brookfield engineering instruments, flows letter The mobility of compound is in low consolidation stress (consolidating shown in number figure (Flow Function Graph) display type I Stress it is to bond (cohesive) under), between bonding under middle consolidation stress (consolidating stress) (cohesive) it and is easy between flowing (easy flowing), shows that the mobility of raw materials of compound shown in Formulas I is poor.
Irregular column structure is presented mostly by compound, compound shown in discoverable type I shown in Electronic Speculum observation type I, There is not needle-shaped crystal structure, so crystal structure is not the reason for causing powder flowbility difference.
The chemical stability of compound shown in 2 Formulas I of test example
Table 1 is to the test result of the forced degradation of raw materials of compound medicine shown in Formulas I, and compound shown in Formulas I is in high temperature, illumination Under the conditions of stablize, acid, alkali conditional stability it is relatively poor, it is degradable in oxidizing condition.
Table 1
Project Forced degradation condition It is total miscellaneous
It does not destroy It does not destroy 0.15%
Acid destroys 60 DEG C of HCl, 3h 2.37%
Alkali destroys 60 DEG C of NaOH, 5h 1.28%
High temperature 100 DEG C, 7h 0.17%
Illumination destroys 6h 0.16%
Oxidative demage 1%H2O2, 1h 5.35%
Influence of the granularity of 1 bulk pharmaceutical chemicals of embodiment to preparation dissolution rate
Raw materials of compound medicine shown in the Formulas I of 3 lot numbers is taken, measures particle diameter distribution, the results are shown in Table 2.By 3 lot numbers Raw materials of compound medicine shown in Formulas I prepares label (chemical combination shown in every middle Formulas I with identical prescription, by direct powder compression The content of object is 80mg).The composition of label is (w/w)：Compound 15% shown in Formulas I, colloidal silicon dioxide 3%, sweet dew Alcohol 61.5%, microcrystalline cellulose 8.1%, low-substituted hydroxypropyl cellulose 9.4%, sodium stearyl fumarate 3%.
Table 2
Compound lot shown in Formulas I D50μm D90μm Label lot number
73-06S 18.1 37.8 20160106
74-05S 51.2 117 20160201
81-01S 26.6 77.1 20160202
PH1.2,4.5 dissolution medium and FASSIF media in, using slurry processes, measured with 75 turns of rotating speed per minute The stripping curve of each lot number label, as a result as shown in Figures 1 to 3.Compound label is at 3 kinds shown in the Formulas I prepared from different-grain diameter It can see in dissolution results in different pH value media：
In the acid medium of pH1.2, since solubility of the drug in this medium is very big, so 3 of different-grain diameter are molten Go out curve almost without difference.
In the dissolution medium of pH4.5, dissolution most slow is 74-05S groups.81-01S groups and 73-06S groups are molten at 30 minutes Dissolution rate when out-degree is respectively 74%, 68%, 45 minutes is respectively 79%, 75%；Dissolution rate at 60 minutes is respectively 84%, 80%, the two is not much different.
In the simulated intestinal fluid FASSIF media of pH6.5,74-05S groups are still slower than other 2 groups.81-01S groups and 73- Dissolution rate of the 06S groups at 45 minutes is respectively 42%, 47%；Dissolution rate at 60 minutes is respectively 49%, 56%, and the two is molten Go out relatively.
So in the medium of pH4.5 or more, the grain size of raw material has an impact the dissolution of drug.At 30 minutes to 60 points In clock time section, raw material particle size D90Relatively for 37.8 μm and 77.1 μm of drug-eluting curves, raw material particle size D90For 117 μm of dissolution is then relatively slow.But raw material particle size D90When being 117 μm, dissolution remains to meet the needs of of the invention.
2 uniformity of dosage units of embodiment is investigated
3 groups in Example 1, the intermediate powder before tabletting, the content for investigating compound shown in Formulas I are uniform Property；The results are shown in Table 3.As a result raw materials of compound medicine D shown in display type I90At 37.8~117 μm, assay result Relative standard deviation RSD is respectively less than 5%.Due to having selected suitable auxiliary material and hybrid technique, raw material particle size to be distributed to content The influence of the uniformity can reduce.
Table 3
Group Content RSD
73-06S 13.99% 2.55%
74-05S 14.86% 3.19%
81-01S 14.10% 1.62%
The investigation of 3 bulk pharmaceutical chemicals processing mode of embodiment
Raw materials of compound medicine shown in Formulas I is handled by mechanical crushing and sieving two ways, the results are shown in Table 4. Compound materials shown in discoverable type I are very easy to crush, and mechanical crushing will make the grain size D of raw material for 10 seconds90Less than 30 μm.
Table 4
The investigation of embodiment 4A core fillers
Label is prepared according to the prescription of embodiment 1, wherein shown in the Formulas I of selection two different batches of 73-06S, 81-01S Compound, it is respectively the mannitol of 100 μm, 180 μm two kinds of specifications to select average grain diameter.
The compound shown in the Formulas I is 73-06S (D90=37.8 μm), when mannitol average grain diameter is 180 μm, extract compacting Label 20, weigh piece weight.As a result it shows：With average piece heavy phase ratio, all tablet weight variations are respectively less than 5%, 19 piece method of double differences It is different to be less than 4%, 16 tablet weight variation less than 3%.The label 10 of compacting is extracted, measures the content of compound shown in Formulas I, relatively Standard deviation RSD is 2.55%.
The compound shown in the Formulas I is 81-01S (D90=77.1 μm), when mannitol average grain diameter is 180 μm, extract tabletting Start, is intermediate, each 10 of label that is terminating three phases, measuring the content of compound shown in Formulas I respectively.Start, is intermediate, terminating The relative standard deviation RSD in 3 stages is respectively 0.8%, 0.4%, 2.8%.
The compound shown in the Formulas I is 81-01S (D90=77.1 μm), when mannitol average grain diameter is 100 μm, extract tabletting Start, is intermediate, each 10 of label that is terminating three phases, measuring the content of compound shown in Formulas I respectively.Start, is intermediate, terminating The relative standard deviation RSD in 3 stages is respectively 0.1%, 0.1%, 0.2%.
The result shows that prescription according to the present invention so that the grain size and density of mannitol not will produce tablet quality aobvious Writing influences.
The investigation of embodiment 4B core fillers
Core formulation group becomes (w/w)：Compound 15% shown in Formulas I, colloidal silicon dioxide 3%, low substituted hydroxy-propyl are fine Dimension element 9.4%, sodium stearyl fumarate 3%, 69.6% mannitol+microcrystalline cellulose (mass ratio 7.6:1~1.8:1) or 69.6% lactose pre-mixing agent.Lactose pre-mixing agent selects commercialization 80 lactose celluloses of Cellactose, lactose and cellulose ratios About 3：1.
Using direct powder compression, the projects such as the mobility, compressibility, disintegration of prescription are assessed.The result shows that sweet dew Alcohol combines similar to lactose pre-mixing agent major part project result as filler with microcrystalline cellulose.But lactose pre-mixing agent prescription phase It is less than mannitol prescription with hardness under compression force.
The influence of the mannitol and microcrystalline cellulose of different proportion as filler to dissolution rate has also been investigated, the results are shown in Table 5.In the dissolution medium of pH4.5, the selection result of dissolution rate shows：The ratio of mannitol and microcrystalline cellulose is 36：10 or 76：When 10, dissolution does not change significantly, but in mannitol：Microcrystalline cellulose (w/w) is 18：When 10, dissolution is declined, But dissolution rate has still reached 57% when 20min.
Table 5
The investigation of 5 label glidant of embodiment
Since compound flow shown in Formulas I is poor, influence of the glidant to label production technology is investigated.When using colloidal state When silica is glidant, the mobility of powder can be improved；But sieve can be also blocked simultaneously, makes mixed-powder first time mistake The time lengthening of sieve.
《Pharmaceutic adjuvant handbook (fourth edition)》(Handbook of Pharmaceutical Excipients,4th Edition, edited by Raymond C Rowe, Paul J Sheskey, and Paul J Weller) in recorded glue When state silica improves dry powder flow as glidant, dosage is generally 0.1~0.5%.
The prescription of each batch label is (w/w)：Compound 15% shown in Formulas I, colloidal silicon dioxide 0~3%, crosslinking carboxylic first Base sodium cellulosate 3%, sodium stearyl fumarate 3%, surplus are mannitol and microcrystalline cellulose, wherein mannitol and microcrystalline cellulose Mass ratio be 3.25：1.
Tableting processes find that the prescription compressibility for being not added with glidant is deteriorated, and dead punching is susceptible to after increasing compression force.Work as glue When the dosage of state silica is 0.6%, prescription compressibility is significantly improved.
When the dosage of colloidal silicon dioxide is 1.5% or 3%, tablet weight variation, uniformity of dosage units are without marked difference.Wherein When the dosage of silica is 1.5%, 10 10mg specification labels are extracted, the relative standard deviation RSD of piece weight is 2.3%；With When amount is 3%, corresponding relative standard deviation RSD is 4.5%.The label of two different colloidal silica silicone contents, shown in Formulas I The assay result of compound all shows that uniformity of dosage units is stablized.
When the dosage of colloidal silicon dioxide is 3%, when decreasing, but being disintegrated for 1.5% disintegration and dissolution than dosage Between still less than 2 minutes, and 20 minutes dissolution also reached 57.4% (dissolution medium pH=4.5,75rpm).
When the dosage of colloidal silicon dioxide is 1.5%, powder crosses 60 mesh sieve after mixing, does not occur showing for sieving time length As；When dosage is 3%, observes sieving time lengthening for the first time, but still can receive in range in industrialization.
The investigation of 6 sodium stearyl fumarate of embodiment
The prescription of each batch label is (w/w)：Compound 15% shown in Formulas I, colloidal silicon dioxide 3%, cross-linked carboxymethyl Sodium cellulosate 3%, sodium stearyl fumarate 0.75%~3%, surplus are mannitol and microcrystalline cellulose, wherein mannitol and crystallite The mass ratio of cellulose is 3.25：1.
《Pharmaceutic adjuvant handbook (fourth edition)》(Handbook of Pharmaceutical Excipients,4th Edition, edited by Raymond C Rowe, Paul J Sheskey, and Paul J Weller) in recorded it is hard Fat fumaric acid sodium is generally 0.5~2.0% as tablet or the lubricant of capsule, dosage.
Tableting processes are found, when sodium stearyl fumarate dosage is 0.75%, slice difficulty occur in tableting processes, and have viscous Rush phenomenon appearance.When sodium stearyl fumarate dosage is 1.5%, slice is difficult, sticking phenomenon still occurs, but has been industrialization Process can bear.When sodium stearyl fumarate dosage is 3%, do not occur slice difficulty, sticking phenomenon.
Influence of 7 coating weight gain of embodiment to tablet
Different coating weight gains are investigated to influence of the tablet in relation to substance, while investigating influence of the coating weight gain to dissolution rate. It selects Opadry 85F640013 as coating powder, as a result shows that dissolution of the sample in pH3.8 when coating weight gain 3% and 4% is situated between In matter, the dissolution rate of different time points is very close, and 20 minutes dissolution rates are respectively 89%, 88%.At 60 DEG C, 75%RH conditions It is lower place 10 days, the variation in relation to substance also very close to.
8 exemplary industrialization prescription of embodiment and technique
Accurately weigh compound 222.0g shown in Formulas I, colloidal silicon dioxide 22.0g, mannitol 863.5g, microcrystalline cellulose 265.76g, sodium stearyl fumarate 44.0g, croscarmellose sodium 51.26g, Opadry film-coating premixing powder 61.6g, Check that supplementary material whether there is particle or caking phenomenon when weighing, and if it exists, be sieved, then weighed first.
First colloidal silicon dioxide, microcrystalline cellulose, croscarmellose sodium are mixed, sieving；Sequentially add Formulas I Shown compound and mannitol, are added sodium stearyl fumarate after mixing, continue to be uniformly mixed, obtain intermediate powder.
It carries out the content detection of intermediate powder, piece weight, tabletting core is calculated according to intermediate product assay result after qualified. Timing monitoring piece weight and hardness in tableting processes.Such as the label between 10mg~240mg specifications can be pressed into.
Qualified label is placed in coating pan, taking coating pre-mixing agent, (Opadry 85F640013 increases weight by theoretical label 3% 1.3~1.4 times of samplings), prepare coating suspensions.After label weightening 3~4%, stop coating.
9 dissolution rate of embodiment is investigated
Each 6 of 10mg, 80mg the specification tablet every batch of prepared according to embodiment 8 is taken, carrying out dissolution rate investigation, (dissolution is situated between Matter pH=3.8,75rpm), as a result as shown in Figures 4 and 5.According to embodiment 8 prepare tablet dissolution in 30 minutes reach 90% with On.
10,80mg specifications tablet prepared by embodiment 8 is extracted, uses 50mL water to be disintegrated into suspension respectively, observes disintegration (all samples are all disintegrated in 3 minutes) rapidly.Measure the dissolution of suspension after being disintegrated, the results showed that suspension after disintegration Than identical tablet under normal leaching condition, dissolution in incipient 5 minutes is slightly fast for dissolution, and the dissolution of remaining time point and tablet is bent Line does not have difference；f2Similar factors are 53, and dissolution rate is consistent.
10 study on the stability of embodiment
Stability to obtaining compound film coating tablet shown in Formulas I in embodiment 8 is investigated.Thin membrane coated tablet is placed in High-density polyethylene bottle (screws bottle cap, there is paper bag powder charge drier in bottle)；Setting-out condition is 40 ± 2 DEG C of temperature, relatively wet Degree 75 ± 5%；(0M) and (1M) after 1 month total miscellaneous variation with content when starting are measured, the results are shown in Table 6.It has completed Accelerated stability test show the list in all 6 batches of samples it is miscellaneous and it is total it is miscellaneous do not change significantly, 10mg's is total miscellaneous small In total miscellaneous respectively less than the 0.4% of 0.6%, 80mg specifications；Dissolution rate variation is less than 10%, and product stability is good.
Table 6
1 wet granule compression tablet method of comparative example
According to following prescription, tablet is prepared by conventional wet lay granulating tabletting process.Prescription is (w/w)：Compound shown in Formulas I 15.4%, mannitol 47% (interior plus), microcrystalline cellulose 18.5% (interior plus), low-substituted hydroxypropyl cellulose 5.4% (interior plus), 1% hydroxypropyl cellulose (being made into 3% solution for pelletizing), microcrystalline cellulose 6.2% (additional), low-substituted hydroxypropyl cellulose 4.3% (additional), sodium stearyl fumarate 2.3% (additional).
Compared with tablet in embodiment 8, wet granule compression tablet good fluidity and hardness is big；But disintegration is slow, 10 minutes Dissolution is significantly less than direct powder compression, and dissolution in 10 minutes is only 7.6% (pH=4.5,75rpm).
All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To be made various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims (12)

1. a kind of Pharmaceutical composition containing compound shown in Formulas I,
It is characterized in that, the Pharmaceutical composition is prepared via direct powder compression, the Pharmaceutical composition includes Formulas I chemical combination Object, filler, glidant, lubricant, disintegrant.
2. Pharmaceutical composition as described in claim 1, which is characterized in that the filler is selected from the group：Starch, sucrose, paste Essence, lactose, pregelatinized starch, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, sorbierite, mannitol, or combinations thereof；And/or
The glidant is talcum powder or colloidal silicon dioxide；It is preferred that colloidal silicon dioxide；And/or
The lubricant is selected from the group：Magnesium stearate, calcium stearate, zinc stearate, odium stearate, stearic acid, stearyl fumarate Sodium, polyethylene glycol, lauryl sodium sulfate, or combinations thereof；It is preferred that sodium stearyl fumarate；And/or
The disintegrant is selected from the group：Dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl fiber It is one or more in plain sodium, crospovidone；It is preferred that low-substituted hydroxypropyl cellulose and/or croscarmellose sodium； More preferably low-substituted hydroxypropyl cellulose or croscarmellose sodium.
3. Pharmaceutical composition as claimed in claim 2, which is characterized in that the filler is mannitol and microcrystalline cellulose； Preferably, in the filler, the weight ratio of mannitol and microcrystalline cellulose is (1.5~9)：1, it is therefore preferable to (1.8~8)： 1, more preferably (3~7.6)：1.
4. Pharmaceutical composition as described in claim 1, which is characterized in that the weight ratio of the filler and compound of formula I is (3~7)：1, it is therefore preferable to (4~6)：1, more preferably (4.5~5.5)：1；And/or
The weight ratio of the glidant and compound of formula I is (0.04~0.2)：1, it is therefore preferable to (0.06~0.2)：1, more preferably Ground is (0.08~0.15)：1；And/or
The weight ratio of the lubricant and compound of formula I is (0.08~0.44)：1, it is therefore preferable to (0.09~0.33)：1, it is more excellent Selection of land is (0.1~0.22)：1；And/or
The weight ratio of the disintegrant and compound of formula I is (0.15~0.8)：1, it is therefore preferable to (0.18~0.7)：1, more preferably Ground is (0.2~0.65)：1.
5. Pharmaceutical composition as described in any one of claims 1-3, which is characterized in that the Pharmaceutical composition includes：
6. Pharmaceutical composition as described in any one of claims 1-3, which is characterized in that the Pharmaceutical composition includes：
And the filler includes mannitol and microcrystalline cellulose, and the weight ratio of the mannitol and microcrystalline cellulose is (1.8 ~8)：1；
And the disintegrant is selected from the group：Low-substituted hydroxypropyl cellulose or croscarmellose sodium.
7. Pharmaceutical composition as described in any one of claims 1-3, which is characterized in that the Pharmaceutical composition is by following components Composition：
And the filler includes mannitol and microcrystalline cellulose, and the weight ratio of the mannitol and microcrystalline cellulose is (1.8 ~8)：1；
And the disintegrant is selected from the group：Low-substituted hydroxypropyl cellulose or croscarmellose sodium.
8. a kind of method preparing any one of claim 1-7 Pharmaceutical compositions, which is characterized in that the preparation method packet It includes：
(1) first glidant, first part's filler, disintegrant are mixed, sieving；
(2) compound of formula I and second part filler are added, lubricant is added after mixing, continues to be uniformly mixed, in obtaining Mesosome powder；
(3) content detection for carrying out intermediate powder calculates piece weight according to intermediate product assay result, carries out tabletting.
9. method as claimed in claim 8, which is characterized in that the filler is mannitol and microcrystalline cellulose, and described First part's filler is microcrystalline cellulose, and second part filler is mannitol.
10. a kind of medicinal tablets, which is characterized in that the medicinal tablets include the medicine as described in any one of claim 1 to 7 Use composition.
11. medicinal tablets as claimed in claim 10, which is characterized in that the medicinal tablets include：Label, the label are Pharmaceutical composition described in any one of claim 1 to 7, and the coating that is coated on outside the label.
12. a kind of medicine box, which is characterized in that the medicine box includes：
The Pharmaceutical composition as described in any one of claim 1 to 7；With
For with the Pharmaceutical composition associated with second therapeutic agent.
CN201710108703.XA 2017-02-27 2017-02-27 A kind of Pharmaceutical composition and preparation method thereof of 2- amino-metadiazine compounds Pending CN108498477A (en)

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WO2020038434A1 (en) * 2018-08-23 2020-02-27 江苏奥赛康药业有限公司 Pharmaceutical composition of 2-aminopyrimidine compounds

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DK2361248T3 (en) * 2008-06-27 2019-01-14 Celgene Car Llc Heteroberl compounds and uses thereof
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WO2020038434A1 (en) * 2018-08-23 2020-02-27 江苏奥赛康药业有限公司 Pharmaceutical composition of 2-aminopyrimidine compounds
CN110856719A (en) * 2018-08-23 2020-03-03 江苏奥赛康药业有限公司 Medicinal composition of 2-aminopyrimidine compounds

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Application publication date: 20180907