CN106176654A - Solid composite medicament containing compound A and preparation method thereof - Google Patents
Solid composite medicament containing compound A and preparation method thereof Download PDFInfo
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- CN106176654A CN106176654A CN201610534130.2A CN201610534130A CN106176654A CN 106176654 A CN106176654 A CN 106176654A CN 201610534130 A CN201610534130 A CN 201610534130A CN 106176654 A CN106176654 A CN 106176654A
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- compound
- solid composite
- composite medicament
- containing compound
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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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
The invention discloses a kind of solid composite medicament containing compound A, the impurity E weight percentage in this solid composite medicament is less than 1.0%, and moisture weight percentage composition is in the range of 2.5 7.0%.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
Technical field
The invention belongs to medicinal chemistry art, particularly to a kind of solid composite medicament containing compound A and system thereof
Preparation Method.
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, moisture and the content control to this solid oral forms preparation
System did not did research.The present inventor is to the impurity E in the solid composite medicament containing compound A and moisture pair
The impact of pharmaceutical composition 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 and moisture.The present inventor finds, containing compound through substantial amounts of checking test
The stability of the solid composite medicament of A is affected substantially by the content of pharmaceutical composition impurity E and compositions moisture, and
The impurity E produced in composition sample and moisture can badly influence safety and the effectiveness of this solid composite medicament.Cause
This, control impurity E and moisture content in the solid composite containing compound A becomes the pass ensureing this solid composite quality
Key.
The solid composite medicament containing compound A that the present invention provides, it has good stability, controls miscellaneous simultaneously
Matter E and the content of moisture, can be effectively improved the product quality of this pharmaceutical composition, reduces the incidence rate of untoward reaction, from
And better assure that 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 containing compound A, its inclusion compound A and more than one are pharmaceutically acceptable
Pharmaceutic adjuvant.Impurity E weight percentage in this solid composite medicament is less than 1.0%, and moisture weight percentage contains
Amount controls at 2.5-7.0%, and wherein compound A and impurity E are respectively as shown in Formulas I and Formula II:
The above-mentioned solid composite medicament containing compound A, preferably its impurity E weight percentage are less than 0.8%, more
Preferably more than 0.3%.
The above-mentioned solid composite medicament containing compound A, preferably its moisture weight percentage composition are 3.0-6.0%, more
It is preferably 4.0-6.0%.
Described " impurity E weight percentage " refers to the weight percentage relative to compound A, described " water
Divide weight percentage " refer to the percentage composition relative to pharmaceutical composition weight.
Impurity E in the above-mentioned solid composite medicament containing compound A and the control of moisture weight percentage composition, permissible
By controlling different raw material batch, and pharmaceutic adjuvant forms and consumption, or optimizes preparation process thereof, or control
The moisture of pharmaceutical purpose adjuvant, or increase suitable drying means, or the combination prioritization scheme of said method obtains
Arrive.
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 need to comprise further lubricant depending on prescription.
Described lubricant one in magnesium stearate, hydrogenated vegetable oil, polyethylene glycols, stearic acid, Palmic acid, Brazil wax
Or the two or more mixing with arbitrary proportion.The amount of described lubricant is as the criterion with the lubricant effect that can realize well known in the art, excellent
Choosing, when the mass parts of compound A is 1, the mass parts consumption of described lubricant is 0.01～0.1 part and (uses without coating
Amount).
Solid composite medicament containing compound A of the present invention can also depending on prescription need to comprise further plasticizer,
One or more above-mentioned substances in preservative, correctives, solubilizing agent, coloring agent, dispersant, rate of release regulator etc.
Mixture.
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 impurity E content and the method for moisture in pharmaceutical composition,
Can be the most derivative of said method and amendment adjustment, but for the solid drugs group containing compound A of the present invention
Compound, controls impurity E weight percentage≤1.0% and moisture weight percentage composition purpose in the range of 2.5-7.0%
It is improve the stability of pharmaceutical composition and reduce adverse reaction rate, with the restriction of above-mentioned pharmaceutically acceptable auxiliaries, preparation technology
Directly contact is not had with raw material batch.Therefore, as long as the impurity E weight percentage effectively controlling described pharmaceutical composition exists
≤ 1.0% and moisture weight percentage composition in the range of 2.5-7.0%, should be understood as the spirit phase with present inventive concept
With, belong 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%, moisture weight percentage composition, in the range of 2.5-7.0%, is placed 2 months, its pharmaceutical composition under acceleration conditions
Moisture content change is less, all within 0.08%；Particularly, its impurity E weight percentage is controlled within 0.8%, water
When dividing weight percentage in the range of 3.0-6.0%, pharmaceutical composition moisture content change is less, all within 0.04%；
Control its impurity E weight percentage within 0.3%, moisture weight percentage composition in the range of 4.0-6.0% time, medicine group
Compound moisture content change is the most unchanged, all within 0.01%.
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%, and its moisture weight percentage composition be in the range of 2.5-7.0%, reduce pharmaceutical composition use during not
The generation of good reaction, is effectively guaranteed the quality of product, and drug safety and effectiveness are provided 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, Pulvis Talci, stearic acid, press
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, Pulvis Talci, 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.
Embodiment 13
Preparation containing the pharmaceutical composition of compound A:
(1) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, polyvidone, Pulvis Talci are crossed 40 mesh sieve use, according to recipe quantity
Weigh, 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 14
Preparation containing the pharmaceutical composition of compound A:
(1) microcrystalline Cellulose, polyvinylpolypyrrolidone, hypromellose, magnesium stearate are crossed 40 mesh sieve use, according to recipe quantity
Weigh, 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 1-14, wherein, compound A Materials Example 1,3-14 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 4,6,10,12-14 use dry granulation process.
The assay of the impurity of the embodiment 15 pharmaceutical composition containing compound A
The pharmaceutical composition that the HPLC method detection embodiment 1-14 gained using Chinese Pharmacopoeia annex to record contains compound A
The impurity E of preparation and the weight percentage (%) of moisture, 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
Dividing content all≤1.0%, moisture weight percentage composition is all in the range of 2.5-7.0%；Even if embodiment 3,7,12,14 use with
Embodiment 1, the compound A of 4-6,8-11 same batch, but affected by prescription composition and ratio and preparation process, gained
In solid composite medicament, impurity E weight percentage is but more than 1.0%, and moisture weight percentage composition is also by prescription composition and ratio
Example and the impact of preparation process, embodiment 2,3,7,13 moisture is more than 7.0%, and embodiment 12 moisture is less than
2.5%.
Embodiment 16 study on the stability is tested
Embodiment 1-14 gained preparation is placed 2 months under acceleration environment (40 DEG C ± 2 DEG C, RH75% ± 5%), uses
The moisture weight percentage composition (%) 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 and moisture weight percentage composition were in the range of 2.5-7.0%, through 2 months
Acceleration environment preserve after, the total miscellaneous changes of contents of pharmaceutical composition is less, all within 0.08%, particularly, for control miscellaneous
Matter E weight percentage is while moisture weight percentage composition is in the range of 3.0-6.0% within 0.8%, and pharmaceutical composition is total
Miscellaneous changes of contents is less, all within 0.04%；For controlling impurity E weight percentage within 0.3% and moisture weight
Percentage composition is in the range of 4.0-6.0%, and the total miscellaneous changes of contents of pharmaceutical composition is the most unchanged, all within 0.01%.And
For do not control impurity E weight percentage 1.0%, moisture weight percentage composition medicine group in the range of 2.5-7.0%
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
Compound moisture 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.Or control the most simultaneously impurity E and moisture pharmaceutical composition (i.e. embodiment 13,
The pharmaceutical composition of 14), its total miscellaneous changes of contents is the most very fast.So, pharmaceutical composition of the present invention by effectively control impurity E and
The content of moisture, preparation stability is higher, more meets the requirement of clinical application correlated quality regulation.
Experiment (Behaviors survey) is investigated in embodiment 17 untoward reaction
Laboratory sample: test sample: compound A pharmaceutical composition (embodiment 1-14)；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.
| 0 grade | Normal stand |
| 1 grade | 5 times have 1～2 time in lying on one's side |
| 2 grades | 5 times have 3～4 times in lying on one's side |
| 3 grades | 5 times complete in lying on one's side |
| 4 grades | 5 times have 1～2 time in carrying ground |
| 5 grades | 5 times have 3～4 times in carrying ground |
| 6 grades | 5 times complete in carrying ground |
| 7 grades | Carry ground and right slow |
| 8 grades | Can not right |
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 2,3,7,12-14 be 3 grade-5
Level, 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 impurity E and the moisture of pharmaceutical composition, and pharmaceutical composition adverse reaction rate is the least；
And embodiment 2,3,7,12,13 and 14, impurity E or the moisture of higher amount may be contained, therefore affect pharmaceutical composition and produce
Other specificity impurity or due to the collaborative restrictive function between medicine, so that adverse reaction rate substantially increases, but
Concrete reason is unknown, absolutely proves that in control pharmaceutical composition, impurity E and moisture are in the scope of protection of present invention,
The generation of untoward reaction can be reduced, 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. containing a solid composite medicament of compound A, its inclusion compound A and more than one are pharmaceutically acceptable
Pharmaceutic adjuvant, it is characterised in that the impurity E weight percentage in this solid composite medicament is less than 1.0%, moisture weight
Percentage composition is in the range of 2.5-7.0%, and wherein compound A and impurity E are respectively as shown in Formulas I and Formula II:
Solid composite medicament containing compound A the most according to claim 1, it is characterised in that this solid drugs group
Impurity E weight percentage in compound is less than 0.8%, preferably more than 0.3%.
Solid composite medicament containing compound A the most according to claim 1, it is characterised in that this solid drugs group
Moisture weight percentage composition in compound is in the range of 3.0-6.0%, preferably in the range of 4.0-6.0%.
4., according to the solid composite medicament containing compound A described in claim 1-3 any claim, its feature exists
In, described pharmaceutically acceptable pharmaceutic adjuvant includes in filler, binding agent, disintegrating agent, lubricant, fluidizer and stabilizer
One or more kinds of mixture.
Solid composite medicament containing compound A the most according to claim 4, it is characterised in that described filler selects
One in microcrystalline Cellulose, lactose, mannitol, starch, pregelatinized Starch, sucrose, dextrin, calcium hydrogen phosphate, sorbitol or
The two or more mixing with arbitrary proportion；When the mass parts of compound A is 1, the mass parts consumption of described filler be 0.5～
2.75 parts (without coat weight).
Solid composite medicament containing compound A the most according to claim 4, it is characterised in that described binding agent selects
One or more in polyvidone, hydroxypropylcellulose, hypromellose are with the mixing of arbitrary proportion；As compound A
Mass parts when being 1, the mass parts consumption of described binding agent is 0.02～0.2 part (without coat weight).
Solid composite medicament containing compound A the most according to claim 4, it is characterised in that described disintegrating agent selects
One or more in crospovidone, crosslinked carboxymethyl fecula sodium, cross-linking sodium carboxymethyl cellulose are with arbitrary proportion
Mixing；When the mass parts of compound A is 1, the mass parts consumption of described disintegrating agent be 0.03～0.2 part (without coating weight
Amount).
Solid composite medicament containing compound A the most according to claim 4, it is characterised in that described fluidizer selects
One or more in silicon dioxide, Pulvis Talci are with the mixing of arbitrary proportion；When the mass parts of compound A is 1, institute
The mass parts consumption stating fluidizer is 0.002～0.05 part (without coat weight).
Solid composite medicament containing compound A the most according to claim 4, it is characterised in that described lubricant selects
In magnesium stearate, hydrogenated vegetable oil, polyethylene glycols, stearic acid, Palmic acid, Brazil wax one or more with
The mixing of arbitrary proportion；When the mass parts of compound A is 1, the mass parts consumption of described lubricant be 0.01～0.1 part (no
Containing coat weight).
10. the side of the solid composite medicament containing compound A prepared as described in claim 1-9 any claim
Method, it is characterised in that the method comprises: after component each in pharmaceutical composition is weighed, mixing granulation, sieves and obtains containing chemical combination
The solid composite medicament of thing A.
11. solid composite medicaments containing compound A as described in claim 1-9 any claim are being controlled for preparation
Treating cardiovascular and cerebrovascular vessel and the application of relevant disease medicine, described disease is selected from hypertension, acute and chronic heart failure, left ventricular function not
Entirely, hypertrophic cardiomyopathy, diabetic cardiomyopathy, room mo(u)ld top half and ventricle type arrhythmia, atrial fibrillation, atrial flutter, harmful blood
Pipe is reinvented, myocardial infarction and sequela, arteriosclerosis, instability or stable type angor, Secondary cases aldosteronism, former
The property sent out and secondary pulmonary hypertension, diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, Primary Nephrosis egg
Albiduria, renovascular hypertension, diabetic retinopathy, migraine, peripheral blood vessel, Raynaud disease, chamber hypertrophy, cognitive barrier
Hinder, glaucoma and apoplexy.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670485A (en) * | 2012-06-11 | 2012-09-19 | 华润赛科药业有限责任公司 | Method for researching and controlling hydrolysis impurity H in solid composition containing valsartan |
| CN101098689B (en) * | 2005-11-09 | 2013-02-13 | 诺瓦提斯公司 | Pharmaceutical combinations of an angiotensin receptor antagonist and an nep inhibitor |
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2016
- 2016-07-07 CN CN201610534130.2A patent/CN106176654A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101098689B (en) * | 2005-11-09 | 2013-02-13 | 诺瓦提斯公司 | Pharmaceutical combinations of an angiotensin receptor antagonist and an nep inhibitor |
| CN102670485A (en) * | 2012-06-11 | 2012-09-19 | 华润赛科药业有限责任公司 | Method for researching and controlling hydrolysis impurity H in solid composition containing valsartan |
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