CN106176723A - A kind of solid composite medicament and preparation method thereof - Google Patents

Abstract

The invention discloses a kind of solid composite medicament, containing compound A and more than one pharmaceutically acceptable pharmaceutic adjuvants, the impurity E weight percentage in this solid composite medicament is less than 1.0%.The solid composite medicament that the present invention provides, has good stability, thus is effectively guaranteed the safety and efficacy of drug use.Reduce the generation of untoward reaction during pharmaceutical composition uses simultaneously, be effectively guaranteed the quality of product, drug safety and effectiveness are provided good guarantee.

Description

A kind of solid composite medicament and preparation method thereof

Technical field

The invention belongs to medicinal chemistry art, particularly to a kind of solid composite medicament, its inclusion compound A and Pharmaceutically acceptable pharmaceutic adjuvant more than kind, and preparation method thereof.

Background technology

Heart failure (abbreviation heart failure)) it is owing to any cardiac structure or dysfunction cause ventricular filling or penetrate blood ability One group of impaired complex clinical syndrome, for various cardiopathic severe stage, its sickness rate is high, and 5 annual survival rates are swollen with pernicious Tumor is similar, is one of current most important cardiovascular disease.

Since two thousand five, popular due to cardiovascular risk factors, the number of the infected of China cardiovascular diseases is in continuing The situation increased.According to statistics, China's cardiovascular patient is about 2.9 hundred million people, and wherein heart failure sufferer there are about 4,500,000 people (in " State cardiovascular diseases report 2013 ").Angiotensin-convertion enzyme inhibitor (ACEI) is being proved and reducing patient's case fatality rate One class medicine, is also that evidence-based medical accumulates most medicines, is the choice drug of the treatment heart failure of workman, and Enalapril is i.e. For being usually used in one of ACEI of clinical heart failure treatment.

Compound A (its structural formula is shown in formula I), is a kind of medicine for anti-heart failure researched and developed by Novartis Co., Ltd, its Structure is first public in patent WO2007056546A1.This compound is by N-valeryl-N-[[2'-(1H-tetrazole-5-base) [1,1'-biphenyl]-4-base] methyl]-Valine and (2R, 4S)-5-biphenyl-4-base-(3-carboxy-propionylamino)-2-first The supramolecular complex (complex) that base-ethyl valerate is combined by non-covalent bond, has angiotensin receptor and blocks Dual function is suppressed with neutral endopeptidase.

Clinical trial results shows, compared with Enalapril treatment group, compound A makes experimenter because of heart failure admission rate Have dropped 21%, and decrease the symptom of heart failure and health limits, reducing the mortality rate of heart failure patient and be in hospital Rate aspect is better than Enalapril (N Engl J Med, 2014,371 (1): 993-1004).Therefore, compound A is a kind of great Market potential cardiotonic agents.This clinical drug is used for reducing chronic heart failure heart of patient and dies of illness and die and because heart failure is in hospital risk, It has the untoward reaction such as neurotoxicity and vasodilation, hypotension, impaired renal function, hyperkalemia.

Impurity majority in medicine have potential source biomolecule activity, can with drug interaction, affect Drug safety with Effectiveness, even produces toxicity.The impurity E of compound A is the impurity that we detect in preparation prescription stability sample, its Structural formula is as shown in Formula II.

International monopoly WO2009061713A1 discloses a kind of solid oral forms preparation containing compound A, this solid port Take type preparation by filler microcrystalline Cellulose, disintegrating agent polyvinylpolypyrrolidone, binding agent hydroxypropylcellulose, magnesium stearate lubricant, Colloidal silica anhydrous and Pulvis Talci composition.But stability, impurity and the content of this solid oral forms preparation is controlled not Did research.The present inventor to the impurity E content in the solid composite medicament containing compound A to pharmaceutical composition The impact of stability and safety conducts in-depth research, and thus completes the present invention.

Summary of the invention

It is an object of the invention to provide a kind of solid composite medicament containing compound A, this solid composite medicament There is specific impurity E content.The present inventor finds, containing the solid medicine of compound A through substantial amounts of checking test The stability of compositions is affected substantially by the content of pharmaceutical composition impurity E, and the impurity E produced in composition sample Safety and the effectiveness of this solid composite medicament can be badly influenced.Therefore, impurity E is controlled at the solid containing compound A Content in compositions becomes the key ensureing this solid composite quality.

The solid composite medicament containing compound A that the present invention provides, it has good stability, controls miscellaneous simultaneously The content of matter E, can be effectively improved the product quality of this pharmaceutical composition, reduces the incidence rate of untoward reaction, thus more preferably Ground guarantees the clinical drug safety of this pharmaceutical composition.

The above-mentioned beneficial effect of the present invention is achieved through the following technical solutions:

A kind of solid composite medicament, its inclusion compound A and more than one pharmaceutically acceptable pharmaceutic adjuvants, should Impurity E weight percentage in solid composite medicament be less than 1.0%, wherein compound A and impurity E respectively as Formulas I with Shown in Formula II:

The above-mentioned solid composite medicament containing compound A, preferably its impurity E weight percentage are less than 0.8%.

The above-mentioned solid composite medicament containing compound A, preferably its impurity E weight percentage are less than 0.3%.

Described " weight percentage " refers to the weight percentage relative to compound A.

The control of the impurity E weight percentage in the above-mentioned solid composite medicament containing compound A, can be by control Make different raw material batch, and pharmaceutic adjuvant forms and consumption, or optimize preparation process thereof, or said method Combination prioritization scheme obtain.

Above-mentioned pharmaceutically acceptable pharmaceutic adjuvant (be called for short " pharmaceutically acceptable auxiliaries ") include filler, binding agent, disintegrating agent, One or more kinds of mixture in lubricant, fluidizer and stabilizer etc..

Described filler is selected from microcrystalline Cellulose, lactose, mannitol, starch, pregelatinized Starch, sucrose, dextrin, phosphoric acid hydrogen One or more in calcium, sorbitol are with the mixing of arbitrary proportion.When the mass parts of compound A is 1, described filler Mass parts consumption be 0.5～2.75 part (without coating consumption).

One or more in polyvidone, hydroxypropylcellulose, the hypromellose of described binding agent are with arbitrarily The mixing of ratio.The preferred low-substituted hydroxypropyl cellulose of hydroxypropylcellulose.When the mass parts of compound A is 1, described binding agent Mass parts consumption is 0.02～0.2 part (without coating consumption).

On the one hand binding agent and the use of filler, can make the solid composite medicament of the present invention be more easy to be prepared as various Solid preparation, the dissolution on the other hand making the solid composite medicament of the present invention is more steady.

Described disintegrating agent one in polyvinylpolypyrrolidone, crosslinked carboxymethyl fecula sodium, cross-linking sodium carboxymethyl cellulose Or the two or more mixing with arbitrary proportion.When the mass parts of compound A is 1, the mass parts consumption of described disintegrating agent is 0.03～0.2 part (without coating consumption).

The described solid composite medicament containing compound A can contain fluidizer further, and described fluidizer is selected from dioxy One or more in SiClx, Pulvis Talci are with the mixing of arbitrary proportion.When the mass parts of compound A is 1, described fluidizer The mass parts consumption of agent is 0.002～0.05 part (without coating consumption).

Solid composite medicament containing compound A of the present invention can also be considered as prescription needs to comprise further lubrication Agent.Described lubricant is in magnesium stearate, hydrogenated vegetable oil, polyethylene glycols, stearic acid, Palmic acid, Brazil wax One or more are with the mixing of arbitrary proportion.The amount of described lubricant with the lubricant effect that can realize well known in the art is Accurate, it is preferred that when the mass parts of compound A is 1, the mass parts consumption of described lubricant be 0.01～0.1 part (without coating Consumption).

Solid composite medicament containing compound A of the present invention can also be considered as prescription needs to comprise further plasticising One or more in agent, preservative, correctives, solubilizing agent, coloring agent, dispersant, rate of release regulator etc. are above-mentioned The mixture of material.

Described plasticizer includes but not limited to Polyethylene Glycol, propylene glycol, glycerol.

Described preservative includes but not limited to benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, potassium sorbate sodium, propanoic acid Calcium, sodium propionate, p-hydroxybenzoic acid, p-hydroxybenzoic acid isopropyl ester.

Described correctives includes sweeting agent, aromatic, mucilage and effervescent, and wherein sweeting agent can be sucrose, sweet Echinacoside, simple syrup, syrupus aromaticus, glycerol, sorbitol, saccharin sodium, protein sugar；Mucilage can be sodium alginate, arabic gum, Gelatin, methylcellulose, sodium carboxymethyl cellulose；Effervescent can be organic acid such as citric acid, tartaric acid, sodium bicarbonate.

Described solubilizing agent includes but not limited to the smooth class of fatty acid Pyrusussuriensis, poly yamanashi esters, polyoxyethylene fatty acid ester class, phosphorus Fat, cholesterol, stearate (such as sodium stearate), oleate (such as enuatrol), sodium lauryl sulphate, dodecyl sodium sulfonate Sodium.

Described coloring agent includes but not limited to beet red, carmine, carotene, lemon yellow, Folium Pini orchid, copper chlorophyllin Sodium salt, caramel, aluminum color lake, yellow ferric oxide, light blue.

Described dispersant includes but not limited to sodium tripolyphosphate, sodium hexameta phosphate, sodium pyrophosphate, silicates, three second Base hexyl phosphoric acid, methyl anyl alcohol, cellulose derivative, polyacrylamide, guar gum, fatty acid polyethylene glycol ester.

Opacifier includes but not limited to titanium dioxide, zinc oxide, yellow ferric oxide.

Described rate of release regulator is selected from sucrose, sodium chloride, surfactant, Polyethylene Glycol (PEG).

In order to the effect making concrete preparation formulation is more perfect, the present invention can suitably increase above-mentioned one or more Adjuvant.To those skilled in the art, the ordinary technical knowledge grasped according to it and common knowledge can be suitable The above-mentioned adjuvant of use, the present invention is no longer described further.

By preparation technique knowledge, have and multiple can control the method for impurity E in pharmaceutical composition, can be said method Further derivative and amendment adjust, but for the solid composite medicament containing compound A of the present invention, control impurity E Purpose≤1.0% is improve the stability of pharmaceutical composition and reduce adverse reaction rate, pharmaceutically acceptable auxiliary with above-mentioned Material restriction, preparation technology and raw material batch do not have directly contact.Therefore, as long as effectively control the impurity of described pharmaceutical composition E, in the range of≤1.0%, should be understood as identical with the spirit of present inventive concept, belongs to protection scope of the present invention.

Preferably (in the present invention, the consumption of active compound component A is all with pure rear calculating of giving money as a gift, i.e. to remove for active component The Mass Calculation of effective ingredient after slaine and water of crystallization) unit dose in the range of every day about 1 to about 1000mg, such as 40 To 400mg (such as, 50mg, 100mg, 200mg, 400mg).Or less dosage, such as 0.5 to 100mg every day can be provided； 0.5 to 50mg；Or 0.5 to 20mg.

The described solid composite medicament containing compound A can be prepared as oral solid formulation；Described oral administration solid Preparation is tablet (including conventional tablet, coated tablet), capsule, granule, pill.

The preparation method of a kind of solid composite medicament containing compound A, the method comprises as follows: by pharmaceutical composition In after each component weighs, mixing granulation, sieve the solid composite medicament obtained containing compound A.Granulation can use dry method Pelletizing, its process can use the method for routine, such as: put in mixer granulator, stirring at low speed and shear-mixed, mixture mistake Sieve.

Above-mentioned solid composite medicament, can be coated, tableting step further, prepares conventional tablet, coating Tablet, granule and capsule or employing extrusion spheronization method prepare micropill.Preparation-obtained formulation products stability is good Good, thus it is effectively guaranteed the safety and efficacy of drug use.Coating uses conventional coating method, and its coating material can Selected from cellulose acetate, ethyl cellulose, hypromellose, hydroxypropyl cellulose, Polyethylene Glycol, cellulose acetate benzene three Ester, cellulose acetate-phthalate, polyvinylpyrrolidone, acrylic resin, methacrylic acid copolymer, polyvinyl acetate Phthalic acid ester, Hydroxypropyl Methyl Cellulose Phthalate, succinic acid acetic acid hydroxypropyl methylcellulose, zein ethanol solution, Lac ethanol solution, gelatin, methacrylic acid-acrylic acid methyl ester (or ethyl ester, butyl ester) copolymer, methacrylic acid-methyl-prop E pioic acid methyl ester copolymer, ethyl acrylate-methacrylate copolymer, ethyl acrylate-methyl methacrylate (2:l) are altogether Polymers.

Described tabletting can use dry granulation tabletting, or powder vertical compression.

The preparation technology of described dry granulation tabletting is preferably as follows, but can do accommodation according to actual needs.One Planting the method that compound A pharmaceutical composition prepared by the dry granulation tabletting optimized, described method comprises the steps of:

1), pharmaceutically acceptable auxiliaries is sieved by 40 mesh sieves, obtain mixture；

2), by said mixture and active component put in hopper mixer and mix, cross 40 mesh sieves；

3), shred after tablet machine pressure sheet, cross 40 mesh sieves；

4), with the tablet of the tablet machine described specification of compacting, then coating.

The preparation technology of described powder vertical compression is preferably as follows, but can do accommodation according to actual needs.A kind of excellent The method that the preparation changed is suitable for powder vertical compression compound A pharmaceutical composition, described method comprises the steps of:

1), by compound A, pharmaceutically acceptable auxiliaries cross 40 mesh sieves, and carry out weighing by recipe quantity and get the raw materials ready；

2), take recipe quantity binding agent, disintegrating agent and 1/2 recipe quantity filler mix homogeneously and must mix powder a；

3), take recipe quantity crude drug, fluidizer (if any), filler mix homogeneously must mix powder b；

4), by step 2 gained mix powder a add step 3 gained mix in powder b, and add recipe quantity lubricant (if any) mixing Uniformly, obtain and always mix powder, tabletting, coating.

Pharmaceutical composition of the present invention may be used for following disease or disease: selected from hypertension, acute and chronic heart failure, Left ventricular insufficiency, hypertrophic cardiomyopathy, diabetic cardiomyopathy, room mo(u)ld top half and ventricle type arrhythmia, atrial fibrillation, atrium are flutterred Dynamic, harmful vascular remodeling, myocardial infarction and sequela thereof, arteriosclerosis, instability or stable type angor, Secondary cases aldehyde steroid Hyperketosis disease, constitutional and secondary pulmonary hypertension, diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, Primary Nephrosis albuminuria, renovascular hypertension, diabetic retinopathy, migraine, peripheral blood vessel, Raynaud disease, Chamber hypertrophy, cognitive disorder, glaucoma and apoplexy.

The present invention has such advantages as and beneficial effect compared to existing technology:

1, the solid composite medicament containing compound A that the present invention provides, controls its impurity E weight percentage and does not surpasses Crossing 1.0%, place 2 months under acceleration conditions, the total miscellaneous changes of contents of its pharmaceutical composition is less, all within 0.1%；Especially , control its impurity E weight percentage within 0.8% time, the total miscellaneous changes of contents of pharmaceutical composition is less, all 0.05% Within；Control its impurity E weight percentage within 0.3% time, the total miscellaneous changes of contents of pharmaceutical composition is the most unchanged, all Within 0.02%.

2, the solid composite medicament containing compound A that the present invention provides, controls its impurity E weight percentage and does not surpasses Cross 1.0%, reduce the generation of untoward reaction during pharmaceutical composition uses, be effectively guaranteed the quality of product, to Medicine safety and effectiveness provide good guarantee.

3, the preparation that the solid composite medicament that the present invention provides is made, has good stability, thus is effectively guaranteed medicine The safety and efficacy that thing uses.

Detailed description of the invention

Below in conjunction with embodiment, the present invention is described in further detail, but the embodiment of invention is not limited to this.

Embodiment 1

Preparation containing the pharmaceutical composition of compound A:

(1) 40 mesh sieve use crossed by microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, silicon dioxide, stearic acid, Carry out weighing standby according to recipe quantity；

(2) take recipe quantity polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose and 1/2 recipe quantity microcrystalline Cellulose mix homogeneously to obtain Mixed powder a；

(3) take recipe quantity crude drug, silicon dioxide, 1/2 recipe quantity microcrystalline Cellulose mix homogeneously must mix powder b；

(4) being added by mixed powder a in mixed powder b, the another recipe quantity stearic acid that adds mixes, and must contain the pharmaceutical composition of compound A Mixed powder.

The preparation of tablet

Aforementioned pharmaceutical compositions is always mixed powder uses powder vertical compression technique to be prepared as the tablet that specification is 100mg, coating, The Hardness Control of described tablet is 5～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets " Chinese Pharmacopoeia " (2010 Version) related request of second annex IA.

Embodiment 2

Preparation containing the pharmaceutical composition of compound A:

(1) microcrystalline Cellulose, polyvinylpolypyrrolidone, polyvidone, silicon dioxide, magnesium stearate cross 40 mesh sieve use, according to prescription Amount carries out weighing standby；

(2) take recipe quantity polyvinylpolypyrrolidone, polyvidone and 1/2 recipe quantity microcrystalline Cellulose mix homogeneously and must mix powder a；

(3) take recipe quantity crude drug, silicon dioxide, 1/2 recipe quantity microcrystalline Cellulose mix homogeneously must mix powder b；

(4) being added by mixed powder a in mixed powder b, the another recipe quantity magnesium stearate that adds mixes, and must contain the drug regimen of compound A Thing mixes powder.

The preparation of tablet

Powder vertical compression technique is used to be prepared as the tablet that specification is 100mg, coating, the hardness of described tablet by always mixing powder Control 5～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets " Chinese Pharmacopoeia " (2010 editions) second annex IA Related request.

Embodiment 3

Preparation containing the medicinal composition tablets of compound A:

(1) calcium hydrogen phosphate, cross-linking sodium carboxymethyl cellulose, hypromellose, magnesium stearate cross 40 mesh sieve use, according to place Side's amount carries out weighing and gets the raw materials ready；

(2) taking recipe quantity crude drug, calcium hydrogen phosphate, cross-linking sodium carboxymethyl cellulose, hypromellose use equivalent to pass Increasing method adds mixing, pelletizes with 75% appropriate amount of ethanol；

(3) it is dried, crosses 40 mesh sieves, add magnesium stearate mix homogeneously, tabletting, coating.

Embodiment 4

Preparation containing the pharmaceutical composition of compound A:

(1) lactose, cross-linking sodium carboxymethyl cellulose, hydroxypropylcellulose, stearic acid are crossed 40 mesh sieve use, enter according to recipe quantity Row weighs, mixing；

(2) said mixture and crude drug are put in hopper mixer and mix, cross 40 mesh sieves；

(3) shredding after tablet machine pressure sheet, cross 40 mesh sieves, the pharmaceutical composition that must contain compound A mixes powder.

The preparation of tablet

With tablet machine, above-mentioned mixed powder being pressed into the tablet that specification is 100mg, coating, the Hardness Control of described tablet is 5 ～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets the relevant of " Chinese Pharmacopoeia " (2010 editions) second annex IA and want Ask.

Embodiment 5

Preparation containing the pharmaceutical composition of compound A:

(1) sucrose, polyvinylpolypyrrolidone, hypromellose, silicon dioxide cross 40 mesh sieve use, weigh according to recipe quantity Standby；

(2) take recipe quantity polyvinylpolypyrrolidone, hypromellose and 1/2 recipe quantity sucrose mix homogeneously and must mix powder a；

(3) take recipe quantity crude drug, silicon dioxide, 1/2 recipe quantity sucrose mix homogeneously must mix powder b；

(4) being added in mixed powder b by mixed powder a, the pharmaceutical composition that must contain compound A mixes powder.

The preparation of tablet

Powder vertical compression technique is used to be prepared as the tablet that specification is 100mg, coating, the hardness of described tablet by always mixing powder Control 5～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets " Chinese Pharmacopoeia " (2010 editions) second annex IA Related request.

Embodiment 6

Preparation containing the pharmaceutical composition of compound A:

(1) calcium hydrogen phosphate, polyvinylpolypyrrolidone, hypromellose, magnesium stearate are crossed 40 mesh sieve use, enter according to recipe quantity Row weighs, mixing；

(2) said mixture and crude drug are put in hopper mixer and mix, cross 40 mesh sieves；

(3) shredding after tablet machine pressure sheet, cross 40 mesh sieves, the pharmaceutical composition that must contain compound A mixes powder.

The preparation of tablet

With tablet machine, above-mentioned mixed powder being pressed into the tablet that specification is 100mg, coating, the Hardness Control of described tablet is 5 ～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets the relevant of " Chinese Pharmacopoeia " (2010 editions) second annex IA and want Ask.

Embodiment 7

Preparation containing the pharmaceutical composition of compound A:

(1) mannitol, alginate, hypromellose, silicon dioxide, magnesium stearate cross 40 mesh sieve use, according to recipe quantity Carry out weighing standby；

(2) take recipe quantity alginate, hypromellose and 1/2 recipe quantity mannitol mix homogeneously and must mix powder a；

(3) take recipe quantity crude drug, silicon dioxide, 1/2 recipe quantity mannitol mix homogeneously must mix powder b；

(4) being added by mixed powder a in mixed powder b, the another recipe quantity magnesium stearate that adds mixes, and must contain the drug regimen of compound A Thing mixes powder.

The preparation of tablet

Powder vertical compression technique is used to be prepared as the tablet that specification is 100mg, coating, the hardness of described tablet by always mixing powder Control 5～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets " Chinese Pharmacopoeia " (2010 editions) second annex IA Related request.

Embodiment 8

Preparation containing the pharmaceutical composition of compound A:

(1) microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, Pulvis Talci, beta-schardinger dextrin-cross 40 mesh sieve use, Carry out weighing standby according to recipe quantity；

(2) take recipe quantity polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose and 1/2 recipe quantity microcrystalline Cellulose mix homogeneously to obtain Mixed powder a；

(3) take recipe quantity crude drug, 1/2 recipe quantity microcrystalline Cellulose mix homogeneously must mix powder b；

(4) being added by mixed powder a in mixed powder b, the another recipe quantity Pulvis Talci that adds mixes, and must contain the pharmaceutical composition of compound A Mixed powder.

The preparation of tablet

Powder vertical compression technique is used to be prepared as the tablet that specification is 100mg, coating, the hardness of described tablet by always mixing powder Control 5～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets " Chinese Pharmacopoeia " (2010 editions) second annex IA Related request.

Embodiment 9

Preparation containing the pharmaceutical composition of compound A:

(1) lactose, crosslinked carboxymethyl fecula sodium, hypromellose, magnesium stearate cross 40 mesh sieve use, enter according to recipe quantity Row weighing is got the raw materials ready；

(2) take recipe quantity crosslinked carboxymethyl fecula sodium, hypromellose and 1/2 recipe quantity lactose mix homogeneously and must mix powder a；

(3) take recipe quantity crude drug, 1/2 recipe quantity lactose mix homogeneously must mix powder b；

(4) being added by mixed powder a in mixed powder b, the another recipe quantity magnesium stearate that adds mixes, and must contain the drug regimen of compound A Thing.

The preparation of tablet

Powder vertical compression technique is used to be prepared as the tablet that specification is 100mg, coating, the hardness of described tablet by always mixing powder Control 5～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets " Chinese Pharmacopoeia " (2010 editions) second annex IA Related request.

Embodiment 10

Preparation containing the pharmaceutical composition of compound A:

(1) starch, cross-linking sodium carboxymethyl cellulose, hydroxypropylcellulose, hydrogenated vegetable oil are crossed 40 mesh sieve use, according to prescription Amount weighs, mixing；

(2) said mixture and crude drug are put in hopper mixer and mix, cross 40 mesh sieves；

(3) shredding after tablet machine pressure sheet, cross 40 mesh sieves, the pharmaceutical composition that must contain compound A mixes powder.

The preparation of tablet

With tablet machine, above-mentioned mixed powder being pressed into the tablet that specification is 100mg, coating, the Hardness Control of described tablet is 5 ～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets the relevant of " Chinese Pharmacopoeia " (2010 editions) second annex IA and want Ask.

Embodiment 11

Preparation containing the pharmaceutical composition of compound A:

(1) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose are crossed 40 mesh sieve use, according to place Side's amount carries out weighing standby；

(2) recipe quantity cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and 1/2 recipe quantity microcrystalline Cellulose are taken mixed Close and uniform must mix powder a；

(3) take recipe quantity crude drug, 1/2 recipe quantity microcrystalline Cellulose mix homogeneously must mix powder b；

(4) being added in mixed powder b by mixed powder a, the pharmaceutical composition that must contain compound A mixes powder.

The preparation of tablet

Powder vertical compression technique is used to be prepared as the tablet that specification is 100mg, coating, the hardness of described tablet by always mixing powder Control 5～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets " Chinese Pharmacopoeia " (2010 editions) second annex IA Related request.

Embodiment 12

Preparation containing the pharmaceutical composition of compound A:

(1) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, acrylic resin, magnesium stearate are crossed 40 mesh sieve use, according to Recipe quantity weighs, mixing；

(2) said mixture and crude drug are put in hopper mixer and mix, cross 40 mesh sieves；

(3) shredding after tablet machine pressure sheet, cross 40 mesh sieves, the pharmaceutical composition that must contain compound A mixes powder.

The preparation of tablet

With tablet machine, above-mentioned mixed powder being pressed into the tablet that specification is 100mg, coating, the Hardness Control of described tablet is 5 ～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets the relevant of " Chinese Pharmacopoeia " (2010 editions) second annex IA and want Ask.

Note: above-described embodiment 1-12, wherein, compound A Materials Example 1,3-12 select same batch, and embodiment 2 is selected Select another batch.Embodiment 1,2,5,7-9,11 use powder vertical compression techniques to prepare tablet, embodiment 3 uses wet granulation work Skill, embodiment 4,6,10,12 uses dry granulation process.

The assay of the impurity E of the embodiment 13 pharmaceutical composition containing compound A

The pharmaceutical composition that the HPLC method detection embodiment 1-12 gained using Chinese Pharmacopoeia annex to record contains compound A The impurity E weight percentage (%) of preparation, acquired results is as follows:

From the above it is known that embodiment 1,4-6,8-11 all use same batch compound A, impurity E weight hundred Divide content all≤1.0%；Even if embodiment 3,7,12 uses and embodiment 1,4-6,8-11 same batch compound A, but is subject to Prescription composition and ratio and the impact of preparation process, in gained solid composite medicament, impurity E weight percentage is but more than 1.0%；The compound A raw material for different batches that embodiment 2 is selected, in its pharmaceutical composition, impurity E weight percentage is big In 1.0%.

Embodiment 14 study on the stability is tested

Embodiment 1-12 gained preparation is placed 2 months under acceleration environment (40 DEG C ± 2 DEG C, RH75% ± 5%), uses The total miscellaneous weight percentage (%) of the HPLC method detection pharmaceutical composition that Chinese Pharmacopoeia annex is recorded, and observe pharmaceutical composition Cosmetic variation, acquired results is as follows:

Understanding from the above, in Acceleration study, embodiment 1,4,5,6,8,9,10 and 11 is by effectively controlling medicine Impurity E weight percentage≤1.0% of compositions, after preserving, the total miscellaneous changes of contents of pharmaceutical composition is less, all exists Within 0.1%, particularly, for control impurity E weight percentage within 0.8%, the total miscellaneous changes of contents of pharmaceutical composition Less, all within 0.05%, for control impurity E weight percentage within 0.3%, pharmaceutical composition is the most miscellaneous containing quantitative change Change the most unchanged, all within 0.02%.And for not controlling impurity E weight percentage medicine group within 1.0% Compound (i.e. the pharmaceutical composition of embodiment 2,3,7,12), its formulation aesthetics its colour changed into yellow, have even becomes deep yellow, medicine group The total miscellaneous content of compound dramatically increases, and amplification reaches more than 0.3%, and the quality of pharmaceutical composition is substantially deteriorated, and has a strong impact on medicine The effectiveness used and safety.So, pharmaceutical composition of the present invention is by effectively controlling the content of impurity E, preparation stability Higher, more meet the requirement of clinical application correlated quality regulation.

Experiment (Behaviors survey) is investigated in embodiment 15 untoward reaction

Laboratory sample: test sample: compound A pharmaceutical composition (embodiment 1-12)；Negative controls: use Vehicle controls Product--deionized water (prepared by laboratory).

Laboratory animal: ICR mice, SPF level, for Animal Sex and the quantity of test, jenny: 25, male dynamic Thing: 25.Body weight and the range of age when buying, jenny: 9.6～13.5g, 3 week old；Buck: 10.0～13.0g, 3 Week old.

Dosage: Vehicle controls group 0mg/kg, compound A pharmaceutical composition pulverizing, by low dose of active compound component A Amount group 1.0mg/kg, middle dosage group 10mg/kg, high dose group 110mg/kg gastric infusion, successive administration one week.

Test procedure: pole-jump test operates: (diameter is about 0.9cm to the metal bar smooth with a root surface, and length is about 72cm), stand vertically.The different time points pole-jump test operation laggard line space of end is turned over after one week with successive administration before being administered Normal reflection operates: mention mousetail, and mice of dishing out after rotating 4 circles, (side or the back side the abnormal attitude that observation mice lands Ground), continuously repeat 5 times, and mark according to Irwin ' s behavior rank scores standard.Before being administered, successive administration one Within after week 0.5,1,2,4,6,24 hours, respectively observe a pole-climbing and aerial righting reflex.After experiment terminates, use excess CO₂Anesthesia Put to death this test surviving animals used.Neurological deficit score result all represents with frequency.Above-mentioned data should use SAS9.1 to unite Meter is analyzed.

Standards of grading: Irwin ' s behavior rank scores standard.

Result and discussion:

Embodiment 1, the pharmaceutical composition of 4-6,8-11, use compound A 1.0,10 and 110mg/kg treated animal respectively to observe Time point pole-climbing and aerial righting reflex observed result equal no significant difference (P > 0.05) compared with Vehicle controls group (0mg/kg).

Compound A 1.0,10 and 110mg/kg treated animal each observing time in embodiment 1,4-6,8-11 pharmaceutical composition In some pole-climbing and aerial righting reflex observed result and embodiment 2,3,7,12 pharmaceutical composition compound A 1.0,10 and 110mg/kg group is compared, and embodiment 1,4-6,8-11 pharmaceutical composition are 0 grade-1 grade, and embodiment 2,3,7,12 is 3 grades-5 grades, Some Animals observes Novel presentation.

From above-mentioned statistical result, by untoward reaction the effects, embodiment 1,4,5,6,8,9,10 and 11 medicine Compositions is by effectively controlling the impurity E content of pharmaceutical composition, and pharmaceutical composition adverse reaction rate is the least；And implement Example 2,3,7 and 12, may containing the impurity E of higher amount, therefore affect pharmaceutical composition produce other specificity impurity or by Collaborative restrictive function between medicine, so that adverse reaction rate substantially increases, but concrete reason is unknown, absolutely proves In control pharmaceutical composition, impurity E content is in the scope of protection of present invention, it is possible to reduce the generation of untoward reaction, it is ensured that The effectiveness of medication and safety.

Above-described embodiment is the present invention preferably embodiment, but embodiments of the present invention are not by above-described embodiment Limit, the change made under other any spirit without departing from the present invention and principle, modify, substitute, combine, simplify, All should be the substitute mode of equivalence, within being included in protection scope of the present invention.

Claims (11)

1. a solid composite medicament, its inclusion compound A and more than one pharmaceutically acceptable pharmaceutic adjuvants, it is special Levying and be, the impurity E weight percentage in this solid composite medicament is less than 1.0%, and wherein compound A and impurity E divide Not as shown in Formulas I and Formula II:

Solid composite medicament the most according to claim 1, it is characterised in that the impurity E in this solid composite medicament Weight percentage is less than 0.8%.

Solid composite medicament the most according to claim 1, it is characterised in that in this solid composite medicament；Impurity E Weight percentage is less than 0.3%.

4. according to the solid composite medicament described in claim 1-3 any claim, it is characterised in that described pharmaceutically may be used The pharmaceutic adjuvant accepted includes the one or two kinds of in filler, binding agent, disintegrating agent, lubricant, fluidizer and stabilizer Above mixture.

Solid composite medicament the most according to claim 4, it is characterised in that described filler selected from microcrystalline Cellulose, One or more in lactose, mannitol, starch, pregelatinized Starch, sucrose, dextrin, calcium hydrogen phosphate, sorbitol are with arbitrarily The mixing of ratio；When the mass parts of compound A is 1, the mass parts consumption of described filler is 0.5～2.75 part and (does not contains bag Clothing weight).

Solid composite medicament the most according to claim 4, it is characterised in that described binding agent is selected from polyvidone, hydroxypropyl One or more in cellulose, hypromellose are with the mixing of arbitrary proportion；When the mass parts of compound A is 1, The mass parts consumption of described binding agent is 0.02～0.2 part (without coat weight).

Solid composite medicament the most according to claim 4, it is characterised in that described disintegrating agent selected from polyvinylpolypyrrolidone, One or more in crosslinked carboxymethyl fecula sodium, cross-linking sodium carboxymethyl cellulose are with the mixing of arbitrary proportion；Work as chemical combination When the mass parts of thing A is 1, the mass parts consumption of described disintegrating agent is 0.03～0.2 part (without coat weight).

Solid composite medicament the most according to claim 4, it is characterised in that described fluidizer is selected from silicon dioxide, cunning One or more in stone powder are with the mixing of arbitrary proportion；When the mass parts of compound A is 1, the matter of described fluidizer Amount part consumption is 0.002～0.05 part (without coat weight).

Solid composite medicament the most according to claim 4, it is characterised in that described lubricant is selected from magnesium stearate, hydrogen Change one or more the mixing with arbitrary proportion in vegetable oil, polyethylene glycols, stearic acid, Palmic acid, Brazil wax Close；When the mass parts of compound A is 1, the mass parts consumption of described lubricant is 0.01～0.1 part (without coat weight).

10. the method for the solid composite medicament prepared as described in claim 1-9 any claim, it is characterised in that The method comprises: after component each in pharmaceutical composition being weighed, mixing granulation, and sieve the solid drugs obtained containing compound A Compositions.

11. solid composite medicaments as described in claim 1-9 any claim be used for preparing treatment cardiovascular and cerebrovascular vessel and The application of relevant disease medicine, described disease is selected from hypertension, acute and chronic heart failure, left ventricular insufficiency, the hypertrophic heart Myopathy, diabetic cardiomyopathy, room mo(u)ld top half and ventricle type arrhythmia, atrial fibrillation, atrial flutter, harmful vascular remodeling, cardiac muscle Infraction and sequela, arteriosclerosis, instability or stable type angor, Secondary cases aldosteronism, constitutional and secondary Property pulmonary hypertension, diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, Primary Nephrosis albuminuria, kidney blood Pipe hypertension, diabetic retinopathy, migraine, peripheral blood vessel, Raynaud disease, chamber hypertrophy, cognitive disorder, glaucoma And apoplexy.