CN109464442A - One seed sand library Ba Qu Valsartan sodium pharmaceutical composition and preparation method thereof - Google Patents
One seed sand library Ba Qu Valsartan sodium pharmaceutical composition and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to pharmaceutical preparations technology fields, in particular to seed sand library Ba Qu Valsartan sodium pharmaceutical composition and preparation method thereof.The preparation method includes the solvent using the acetone of special ratios as the independent wet granulation of supplementary material, then mixing granulation, and combine the decompression drying method of lower temperature to the particle drying after granulation, a kind of reproducibility excellent technique when can amplify/reduce scale mould is obtained, and guarantees that drug is not damaged during the preparation process.The stability and homogeneity of gained pharmaceutical composition are excellent, can be conducive to the drug and well promote in treatment heart failure and hypertension etc..
Description
Technical field
The invention belongs to pharmaceutical preparations technology field, in particular to a seed sand library Ba Qu Valsartan sodium pharmaceutical composition and its
Preparation method.
Background technique
According to " Chinese cardiovascular disease report 2013 ") statistics, China's cardiovascular patient is about 2.9 hundred million people, wherein heart failure
Exhausting sufferer, there are about 4,500,000 people.Angiotensin converting enzyme inhibitors (ACEI) are to be proved that heart failure patient death can be reduced
The first kind drug and evidence-based medical of rate accumulate most drugs, are the choice drugs for the treatment heart failure generally acknowledged early stage,
Such as Enalapril.
Sha Kuba song Valsartan sodium, also referred to as LCZ696 are that have angiotensin receptor by one kind of Novartis Co., Ltd's research and development
The cardiotonic agents for inhibiting double action with neutral endopeptidase are blocked, structure (such as following formula) is in patent WO2007056546A1
It is first public.The clinical trial results having disclosed show compared with Enalapril treatment group, Sha Kuba song Valsartan sodium make by
Examination person reduces the symptom and body limitation of heart failure because heart failure admission rate has dropped 21%, is reducing heart failure
The death rate and admission rate aspect for exhausting patient are better than Enalapril (N Engl J Med, 2014,371 (1): 993-1004).It can
To find out, Sha Kuba song Valsartan sodium is a kind of great market potential cardiotonic agents, and product is on the second half year in 2015 is granted
City.Presently commercially available LCZ696 (trade (brand) name ENTRESTOTM) can be to release film-coated tablet as 200,100 and 50mg
Peroral dosage form obtains.
Since Sha Kuba song Valsartan sodium is a kind of special drug, with special bonding and at salt mode, so that
It can be dissociated to wet, thermally labile, and in solution system.
Known Sha Kuba song Valsartan preparation of sodium scheme includes: that patent WO2009061713 discloses a seed sand library Ba Qu
The preparation and preparation method thereof of Valsartan sodium then will mixing by mixing therapeutic agent at least one pharmaceutically acceptable excipient
Object is directly compressed with suitable equipment such as tablet press machine or suppresses mixture with suitable equipment such as roller press and prepare, however according to
There are poor reproducibilities after the ratio amplifications such as according to Figure of description as it can be seen that the program haves the defects that.
In addition, the dosage form of WO2017/134597A1, suitable for paediatrics or need low individual dosage or encounter to gulp down
Swallow other patients of difficult (such as due to disease or due to the age), the Sha Kuba comprising 1:1 molar ratio is bent and Valsartan is (excellent
Choosing is the form of so-called angiotensin receptor Neprilysin inhibitor (ARNI) LCZ696, illustrates small dimension for this medicine
Using also there is more urgent demand.
Based on the aforementioned prior art, other derivative prior arts are all made of dry granulation technology scheme, by auxiliary
The adjustment of material and technological parameter, improves the stability etc. of product, still, however it remains reappear between amplification/diminution scale mould
Property difference problem, different size may need different generation technique, be unfavorable for the overall performance control of product, may cause use
Effect after medicine is unbalanced.
Summary of the invention
In view of the problems existing in the prior art, it is of the invention provide new Sha Kuba song Valsartan sodium pharmaceutical composition and
Preparation method, the solvent using the acetone of special ratios as the independent wet granulation of supplementary material, then mixing granulation, and combine
For the decompression drying method of lower temperature to the particle drying after granulation, scale mould Shi Chongxian can be amplified/reduce by obtaining one kind
The excellent technique of property, and guarantee that drug is not damaged during the preparation process.
The present invention realizes the beneficial effects such as above-mentioned, is achieved through the following technical solutions:
Firstly, the present invention provides a seed sand library Ba Qu Valsartan sodium pharmaceutical compositions, comprising:
(1) add a small amount of acetone that 10-20 purpose wet particle is made in Sha Kuba song Valsartan sodium；
(2) hydrophilic filler, adhesive, disintegrating agent are crossed into 80 meshes respectively, a small amount of acetone is added, 10-20 purpose is made
Wet particle；
(3) the wet particle of step (1) and (2) is mixed, granulation, then in the decompression drying method of lower temperature to granulation
Particle drying afterwards removes acetone, and after then addition mix lubricant is uniform, tabletting is coated using proper auxiliary materials.
As a preferred technical solution of the present invention, the usage amount of a small amount of acetone in step (1) are as follows: LCZ696: acetone
=1:0.1-0.2g/mL.
As a preferred technical solution of the present invention, the usage amount of a small amount of acetone in step (2) are as follows: hydrophily filling
Agent, adhesive, disintegrating agent quality sum: acetone=1:0.2-0.8g/mL.
As a preferred technical solution of the present invention, lower temperature refers to 30-40 DEG C, and drying time is less than 1h.
By aforementioned solvents usage amount and drying temperature, auxiliary material can not only be made to pass through conventional wet processing mixing
Uniformly, also, be found surprisingly that overcome this drug can not wet granulation difficulty, obtained supplementary material stuff and other stuff through detecting
It was found that LCZ696 still by special bonding and at salt in a manner of exist.
Method through a large number of experiments, when acetone usage amount is respectively smaller than the usage amount, it is difficult to effective to guarantee that original is auxiliary
Material uniformly mixing, and when usage amount increase, it is easy the extension because of subsequent drying time, LCZ696 is easy to cause to be decomposed into figured silk fabrics
Sha Tan and Sha Ku is than bent individual compound.
It is more found surprisingly that, when the solvent using aforementioned usage amount, if used after directly mixing supplementary material
The solvent granulation, without preparing wet particle respectively in advance, is also easy to cause LCZ696 to be decomposed into Valsartan and Sha Ku ratio Qu Dan
Only compound, it may be possible to LCZ696 prepare wet particle using acetone, makes it that one kind " saturation " state be presented, avoid it is direct with it is auxiliary
Expect mixed ionization, reduces the possibility of drug decomposition.
As a preferred technical solution of the present invention, the hydrophilic filler is selected from mannitol, calcium monohydrogen phosphate, sorb
One or more of alcohol, microcrystalline cellulose are with the mixing of arbitrary proportion.The mass ratio of LCZ696 and hydrophilic filler
Preferably 1:0.7-0.8, particularly preferred sorbierite.
As a preferred technical solution of the present invention, described adhesive is selected from povidone, low-substituted hydroxypropyl cellulose, hydroxyl
One or more of third methylcellulose is with the mixing of arbitrary proportion.The mass ratio of LCZ696 and adhesive is preferably 1:
0.05-0.08, particularly preferred hydroxypropyl methylcellulose.
As a preferred technical solution of the present invention, the disintegrating agent is selected from crospovidone, crosslinked carboxymethyl fecula
One or more of sodium is with the mixing of arbitrary proportion.The mass ratio of LCZ696 and disintegrating agent is preferably 1:0.05-0.08,
Particularly preferred crosslinked carboxymethyl fecula sodium.
As a preferred technical solution of the present invention, when the mass ratio of LCZ696 and hydrophilic filler sorbierite are preferred
For 1:0.7-0.8；And the mass ratio of LCZ696 and adhesive hydroxypropyl methylcellulose is preferably 1:0.06-0.07；And LCZ696 with
When the mass ratio of disintegrating agent crosslinked carboxymethyl fecula sodium is preferably 1:0.06-0.07, guarantee pharmaceutical granulation that can be best is with after
Mobility in continuous step, and homogeneity of pelletizing, difference is reduced as far as possible between the batch of gained pharmaceutical composition.
As a preferred technical solution of the present invention, the present invention selects aforementioned ratio to combine, and is made using magnesium stearate
For lubricant, it is preferable to use it is the 1-3% of LCZ696 mass that amount, which is the usage amount of pharmaceutical composition lubricant, press after mixing
Piece, after being coated after tabletting using Opadry, coating weight gain 0.3-1.5%.
The dissolution of gained pharmaceutical composition is approximate with commercial product, and stability further improves, and Light absorbing impurty is as far as possible
Reduction, it is contemplated that meet the related request of Conformance Assessment.
Another object of the present invention is to provide the preparation method of aforementioned seed sand library Ba Qu Valsartan sodium pharmaceutical composition, wrap
It includes:
(1) add a small amount of acetone that 10-20 purpose wet particle is made in Sha Kuba song Valsartan sodium；
(2) hydrophilic filler, adhesive, disintegrating agent are crossed into 80 meshes respectively, a small amount of acetone is added, 10-20 purpose is made
Wet particle；
(3) the wet particle of step (1) and (2) is mixed, granulation, then in the decompression drying method of lower temperature to granulation
Particle drying afterwards removes acetone, and after then addition mix lubricant is uniform, tabletting is coated using proper auxiliary materials.
The preparation method of described pharmaceutical composition further comprises that foregoing pharmaceutical composition obtains various optimal technical schemes.
Specifically, as a preferred technical solution of the present invention, the usage amount of a small amount of acetone in step (1) are as follows:
LCZ696: acetone=1:0.1-0.2g/mL.
As a preferred technical solution of the present invention, the usage amount of a small amount of acetone in step (2) are as follows: hydrophily filling
Agent, adhesive, disintegrating agent quality sum: acetone=1:0.2-0.8g/mL.
As a preferred technical solution of the present invention, lower temperature refers to 30-40 DEG C, and drying time is less than 1h.
By aforementioned solvents usage amount and drying temperature, auxiliary material can not only be made to pass through conventional wet processing mixing
Uniformly, also, be found surprisingly that overcome this drug can not wet granulation difficulty, obtained supplementary material stuff and other stuff through detecting
It was found that LCZ696 still by special bonding and at salt in a manner of exist.
Method through a large number of experiments, when acetone usage amount is respectively smaller than the usage amount, it is difficult to effective to guarantee that original is auxiliary
Material uniformly mixing, and when usage amount increase, it is easy the extension because of subsequent drying time, LCZ696 is easy to cause to be decomposed into figured silk fabrics
Sha Tan and Sha Ku is than bent individual compound.
It is more found surprisingly that, when the solvent using aforementioned usage amount, if used after directly mixing supplementary material
The solvent granulation, without preparing wet particle respectively in advance, is also easy to cause LCZ696 to be decomposed into Valsartan and Sha Ku ratio Qu Dan
Only compound, it may be possible to LCZ696 prepare wet particle using acetone, makes it that one kind " saturation " state be presented, avoid it is direct with it is auxiliary
Expect mixed ionization, reduces the possibility of drug decomposition.
As a preferred technical solution of the present invention, the hydrophilic filler is selected from mannitol, calcium monohydrogen phosphate, sorb
One or more of alcohol, microcrystalline cellulose are with the mixing of arbitrary proportion.The mass ratio of LCZ696 and hydrophilic filler
Preferably 1:0.7-0.8, particularly preferred sorbierite.
As a preferred technical solution of the present invention, described adhesive is selected from povidone, low-substituted hydroxypropyl cellulose, hydroxyl
One or more of third methylcellulose is with the mixing of arbitrary proportion.The mass ratio of LCZ696 and adhesive is preferably 1:
0.05-0.08, particularly preferred hydroxypropyl methylcellulose.
As a preferred technical solution of the present invention, the disintegrating agent is selected from crospovidone, crosslinked carboxymethyl fecula
One or more of sodium is with the mixing of arbitrary proportion.The mass ratio of LCZ696 and disintegrating agent is preferably 1:0.05-0.08,
Particularly preferred crosslinked carboxymethyl fecula sodium.
As a preferred technical solution of the present invention, when the mass ratio of LCZ696 and hydrophilic filler sorbierite are preferred
For 1:0.7-0.8；And the mass ratio of LCZ696 and adhesive hydroxypropyl methylcellulose is preferably 1:0.06-0.07；And LCZ696 with
When the mass ratio of disintegrating agent crosslinked carboxymethyl fecula sodium is preferably 1:0.06-0.07, guarantee pharmaceutical granulation that can be best is with after
Mobility in continuous step, and homogeneity of pelletizing, difference is reduced as far as possible between the batch of gained pharmaceutical composition.
As a preferred technical solution of the present invention, the present invention selects aforementioned ratio to combine, and is made using magnesium stearate
For lubricant, it is preferable to use it is the 1-3% of LCZ696 mass that amount, which is the usage amount of pharmaceutical composition lubricant, press after mixing
Piece, after being coated after tabletting using Opadry, coating weight gain 0.3-1.5%.
The pharmaceutical composition dissolution that the method obtains is approximate with commercial product, and stability further improves, impurity
Limitation reduces as far as possible, it is contemplated that meets the related request of Conformance Assessment.
Pharmaceutical composition of the present invention can be applied to prevent and/or treat hypertension, heart failure, hypertension and heart failure
Drug in use.
Gained pharmaceutical composition substantially reduces the type of auxiliary material, prepares not only simple process, so that product is because of specification difference
And amplification/diminution scale mould reproducibility is excellent, reduces production cost, is easy to industrial application, and the different state of an illness are effectively ensured
Patient take the drug of different size after guarantee pharmaceutically-active harmony.
Indicate: the present invention is outer except as otherwise illustrating, and the Sha Kuba song Valsartan sodium refers both to the compound of formula:
Compared with the prior art, the beneficial effects of the invention include:
(1) present invention uses solvent of the acetone of special ratios as the independent wet granulation of supplementary material, then mixing granulation,
And combining the decompression drying method of lower temperature to the particle drying after granulation, scale mould can be amplified/reduce by obtaining one kind
When the excellent technique of reproducibility, and guarantee that drug is not damaged during the preparation process, so that wet granulation is applied to this drug
It is possibly realized.
(2) by aforementioned preparation process, the quality of gained pharmaceutical composition is stablized, show as granulation particle good fluidity,
Homogeneity is good, and pharmaceutical composition stability is good, difference reduces as far as possible between piece, to improve the validity and equilibrium of clinical application
Property；
(3) present invention greatly reduces the supplementary material composition of prescription, not only reduces process costs, but also simple process, is conducive to
Extensive industrial application.
Detailed description of the invention
Fig. 1, Sha Kuba song raw material X-ray spectrogram；
Fig. 2, Valsartan raw material X-ray spectrogram；
Fig. 3, Sha Kuba song Valsartan sodium raw materials X-ray spectrogram.
Specific embodiment
Below with reference to embodiment and attached drawing, the present invention is described in further detail, but the embodiment invented is not limited to
This.
Embodiment 1
One seed sand library Ba Qu Valsartan sodium pharmaceutical composition and preparation method thereof, comprising:
(1) add a small amount of acetone that 20 purposes wet particle was made in Sha Kuba song Valsartan sodium, LCZ696: acetone=1:
0.15g/mL；
(2) by hydrophilic filler-sorbierite, adhesive-hydroxypropyl methylcellulose, disintegrating agent-crosslinked carboxymethyl fecula sodium
Cross 80 meshes respectively, a small amount of acetone be added and was made the wet particle of 20 purposes, hydrophilic filler, adhesive, disintegrating agent quality it
With: acetone=1:0.5g/mL；
(3) the wet particle of step (1) and (2) is uniformly mixed, granulation, then to the particle after granulation at 30-40 DEG C
It is dried under reduced pressure 30min, removes acetone, after then addition mix lubricant is uniform, according to specification tabletting needed for drug, using Europe bar
Generation coating, weight gain 1%.
Embodiment 2
One seed sand library Ba Qu Valsartan sodium pharmaceutical composition and preparation method thereof, comprising:
(1) add a small amount of acetone that 20 purposes wet particle was made in Sha Kuba song Valsartan sodium, LCZ696: acetone=1:
0.15g/mL；
(2) by hydrophilic filler-mannitol, adhesive-hydroxypropyl methylcellulose, disintegrating agent-crosslinked carboxymethyl fecula sodium
Cross 80 meshes respectively, a small amount of acetone be added and was made the wet particle of 20 purposes, hydrophilic filler, adhesive, disintegrating agent quality it
With: acetone=1:0.5g/mL；
(3) the wet particle of step (1) and (2) is uniformly mixed, granulation, then to the particle after granulation at 30-40 DEG C
It is dried under reduced pressure 30min, removes acetone, after then addition mix lubricant is uniform, according to specification tabletting needed for drug, using Europe bar
Generation coating, weight gain 1%.
Embodiment 3
One seed sand library Ba Qu Valsartan sodium pharmaceutical composition and preparation method thereof, comprising:
(1) add a small amount of acetone that 20 purposes wet particle was made in Sha Kuba song Valsartan sodium, LCZ696: acetone=1:
0.15g/mL；
(2) hydrophilic filler-microcrystalline cellulose, adhesive-hydroxypropyl methylcellulose, disintegrating agent-cross-linked carboxymethyl are formed sediment
Powder sodium crosses 80 meshes respectively, a small amount of acetone is added, the wet particle of 20 purposes, hydrophilic filler, adhesive, disintegrating agent matter was made
The sum of amount: acetone=1:0.5g/mL；
(3) the wet particle of step (1) and (2) is uniformly mixed, granulation, then to the particle after granulation at 30-40 DEG C
It is dried under reduced pressure 30min, removes acetone, after then addition mix lubricant is uniform, according to specification tabletting needed for drug, using Europe bar
Generation coating, weight gain 1%.
Embodiment 4
One seed sand library Ba Qu Valsartan sodium pharmaceutical composition and preparation method thereof, comprising:
(1) add a small amount of acetone that 20 purposes wet particle was made in Sha Kuba song Valsartan sodium, LCZ696: acetone=1:
0.15g/mL；
(2) by hydrophilic filler-sorbierite, adhesive-povidone, disintegrating agent-crosslinked carboxymethyl fecula sodium mistake respectively
80 meshes are added a small amount of acetone and the wet particle of 20 purposes, hydrophilic filler, adhesive, disintegrating agent quality sum: acetone were made
=1:0.5g/mL；
(3) the wet particle of step (1) and (2) is uniformly mixed, granulation, then to the particle after granulation at 30-40 DEG C
It is dried under reduced pressure 30min, removes acetone, after then addition mix lubricant is uniform, according to specification tabletting needed for drug, using Europe bar
Generation coating, weight gain 1%.
Embodiment 5-20
Using the technical solution of embodiment 1,2,3 and 4, is prepared respectively according to specification needed for following drug, respectively obtain reality
A 5-20 is applied,
Comparative example 1
Referring to the prescription and preparation method of WO2009/061713 embodiment 3, according to following prescription:
Magnesium stearate, talcum powder, colloidal silicon dioxide and microcrystalline cellulose are sieved by 30 meshes first.Then
Said mixture, LCZ696, Crospovidone and low substituted hydroxypropylcellulose are mixed about 120 turns in hopper mixing machine.So
Afterwards, obtained mixture is sieved by 30 meshes.Then the mixture sieved is mixed about in hopper mixing machine
120 turns.The mixture is suppressed using the roller press pressure of 30kN.After compacting, grinds the mixture and sieved through 18 meshes
Point, obtain final interior phase particle.By particle and the Crospovidone sieved through 30 meshes and talcum powder (additional particle) in hopper
About 50 turns are mixed in mixing machine.Then, obtained mixture is being expected with the magnesium stearate (additional particle) sieved through 30 meshes
About 50 turns are mixed in bucket mixing machine.Then obtained final mixture is compressed using Fette3090 equipment in blocks.Use Europe bar
It is coated weight gain 1% for coating polymer, obtains coating tablet.
Comparative example 2-5
It using the technical solution of comparative example 1, is prepared respectively according to specification needed for following drug, it is real to respectively obtain comparison
A 2-5 is applied,
Embodiment 21
Dissolution rate detection
Using Chinese Pharmacopoeia (2010 editions) annex XC dissolution determination method the second method paddle method detect respectively embodiment 6,10,
14,18 and 3 gained LCZ696 vertical compression tablet of comparative example dissolution rate situation, the data obtained is as shown in the table:
| Project | 15min | 30min | 45min |
| Embodiment 6 | 83.71 | 93.65 | 99.49 |
| Embodiment 10 | 80.71 | 91.36 | 99.12 |
| Embodiment 14 | 81.51 | 92.82 | 98.72 |
| Embodiment 18 | 79.29 | 92.71 | 98.85 |
| Comparative example 3 | 78.94 | 86.21 | 96.63 |
As can be seen that embodiment 6,10,14,18 and 3 gained preparation of comparative example have preferable dissolving out capability, and have
More consistent dissolution characteristic dissolves about 80% in 15min, meets clinical application requirement.
Embodiment 22
Stability experiment
By embodiment 6,10,14,18 and 3 obtained solid oral type preparation (100mg) of comparative example in acceleration environment (40
DEG C ± 2 DEG C, RH75% ± 5%) under place 30 days, medicine group is detected using the HPLC method that Chinese Pharmacopoeia (2010 editions) annex is recorded
The situation of change of the impurity A of object is closed, acquired results are as follows:
By stability experiment as can be seen that embodiment 6,10,14,18 is clearly more excellent relative to having than embodiment 3
Quality stability.
Wherein, the chemical structural formula of the impurity A is as follows:
Embodiment 23
Embodiment 6,10,14,18 and comparative example 3 are taken into particle before final tabletting, using 2010 editions " drug's GMPs
Guide " (oral solid formulation) 5.2.4 record distribution of particles method of testing measure angle of repose, mixture homogeneity, it is as a result as follows:
| Particle angle of repose (°) | It mixes uniformity (%) | |
| Embodiment 6 | 24.6 | 1.4 |
| Embodiment 10 | 28.8 | 1.7 |
| Embodiment 14 | 29.3 | 1.9 |
| Embodiment 18 | 27.6 | 2.1 |
| Comparative example 3 | 42.3 | 4.8 |
It is found that embodiment 6,10,14,18 is relative to having clearly more excellent mobility and uniform content than embodiment 3
Property, quality is more balanced.
Embodiment 24:
Using Chinese Pharmacopoeia (2010 editions) annex XC dissolution determination method the second method paddle method detect respectively embodiment 6,10,
14,18 and 3 each 6 of gained LCZ696 vertical compression tablet of comparative example dissolution rate situation.
It is found that embodiment 6,10,14,18 is relative to there is uniformity between clearly more excellent piece than embodiment 3, it is poor between piece
Different smaller, quality is more balanced.
Embodiment 25:
X-ray detection is carried out using measuring method below, individual Sha Kuba song is not found in granulation and figured silk fabrics is husky
Smooth strong characteristic peak, and have the characteristic peak for seeing that Sha Kuba song Valsartan sodium is strong, so, that can confirm is 1- of the embodiment of the present invention
There is not apparent compound key to be broken in 20 pelletizations, Sha Kuba song Valsartan sodium is retained completely, so that being carried out using solvent
Wet granulation is applied to drug of the invention and is possibly realized.
Specifically, referring to Fig. 1-Sha Kuba song raw material X-ray spectrogram, Fig. 2-Valsartan raw material X-ray spectrogram, Fig. 3-Sha Ku
Ba Qu Valsartan sodium raw materials X-ray spectrogram.
X-ray diffraction testing conditions:
X-ray diffraction uses sharp shadow (Empyrean) X-ray diffractometer, in Cu target K alpha ray, voltage: 40.0kV, electric current:
40.0mA, 1/32 ° of divergent slit, 1/16 ° of antiscatter slits, antiscatter slits 7.5mm, 0.02 ° of step-length, every step residence time
Measure 2 θ ranges under the conditions of 40s: 2 ° -40 °.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention,
It should be equivalent substitute mode, be included within the scope of the present invention.
Claims (9)
1. a seed sand library Ba Qu Valsartan sodium pharmaceutical composition, comprising:
(1) add a small amount of acetone that 10-20 purpose wet particle is made in Sha Kuba song Valsartan sodium；
(2) hydrophilic filler, adhesive, disintegrating agent are crossed into 80 meshes respectively, a small amount of acetone is added, the wet grain of 10-20 purpose is made
Son；
(3) the wet particle of step (1) and (2) is mixed, granulation, then after the decompression drying method of lower temperature is to granulation
Particle drying removes acetone, and after then addition mix lubricant is uniform, tabletting is coated using proper auxiliary materials.
2. pharmaceutical composition according to claim 1, which is characterized in that the usage amount of a small amount of acetone in the step (1)
Are as follows: LCZ696: acetone=1:0.1-0.2g/mL.
3. pharmaceutical composition according to claim 1, which is characterized in that the usage amount of a small amount of acetone in the step (2)
Are as follows: hydrophilic filler, adhesive, disintegrating agent quality sum: acetone=1:0.2-0.8g/mL.
4. pharmaceutical composition according to claim 1, which is characterized in that lower temperature refers to 30-40 DEG C, drying time
Less than 1h.
5. pharmaceutical composition according to claim 1-4, which is characterized in that the hydrophilic filler is selected from sweet
Reveal one or more of alcohol, calcium monohydrogen phosphate, sorbierite, microcrystalline cellulose with the mixing of arbitrary proportion, LCZ696 and parent
The mass ratio of aqueous filler is preferably 1:0.7-0.8；Described adhesive is selected from povidone, low-substituted hydroxypropyl cellulose, hydroxypropyl
For one or more of methylcellulose with the mixing of arbitrary proportion, the mass ratio of LCZ696 and adhesive is preferably 1:
0.05-0.08；The disintegrating agent is selected from one or more of crospovidone, crosslinked carboxymethyl fecula sodium arbitrarily to compare
The mass ratio of the mixing of example, LCZ696 and disintegrating agent is preferably 1:0.05-0.08.
6. pharmaceutical composition according to claim 5, which is characterized in that the matter of LCZ696 and hydrophilic filler sorbierite
Amount is than being preferably 1:0.7-0.8；And the mass ratio of LCZ696 and adhesive hydroxypropyl methylcellulose is preferably 1:0.06-0.07；And
LCZ696 and the mass ratio of disintegrating agent crosslinked carboxymethyl fecula sodium are preferably 1:0.06-0.07.
7. pharmaceutical composition according to claim 6, which is characterized in that using magnesium stearate as lubricant, preferably
The usage amount of pharmaceutical composition lubricant be LCZ696 mass 1-3%, tabletting after mixing, after tabletting using Opadry into
After row coating, coating weight gain 0.3-1.5%.
8. a kind of preparation method of Sha Kuba song Valsartan sodium pharmaceutical composition according to claim 1-7,
It is characterized in that, comprising:
(1) add a small amount of acetone that 10-20 purpose wet particle is made in Sha Kuba song Valsartan sodium；
(2) hydrophilic filler, adhesive, disintegrating agent are crossed into 80 meshes respectively, a small amount of acetone is added, the wet grain of 10-20 purpose is made
Son；
(3) the wet particle of step (1) and (2) is mixed, granulation, then after the decompression drying method of lower temperature is to granulation
Particle drying removes acetone, and after then addition mix lubricant is uniform, tabletting is coated using proper auxiliary materials.
9. a kind of purposes of pharmaceutical composition, which is characterized in that pharmaceutical composition according to claim 1-7 exists
Preparation prevents and/or treats the application in the drug of hypertension, heart failure, hypertension and heart failure.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110031568A (en) * | 2019-03-20 | 2019-07-19 | 石药集团中奇制药技术（石家庄）有限公司 | Sha Kuba is bent in a kind of measurement human plasma, goes ethyl Sha Kuba bent and the method for Determination of valsartan in human |
| CN113456607A (en) * | 2021-07-08 | 2021-10-01 | 南京康川济医药科技有限公司 | Sacubitril valsartan sodium monolayer osmotic pump controlled release tablet and preparation method thereof |
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| CN101272777A (en) * | 2005-05-18 | 2008-09-24 | 兰贝克赛实验室有限公司 | Stable dosage forms of spiro and dispiro 1,2,4-trioxolane antimalarials |
| CN105997994A (en) * | 2015-07-11 | 2016-10-12 | 凌莉 | Solid oral preparation and preparation method thereof |
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- 2018-11-19 CN CN201811373100.3A patent/CN109464442B/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101272777A (en) * | 2005-05-18 | 2008-09-24 | 兰贝克赛实验室有限公司 | Stable dosage forms of spiro and dispiro 1,2,4-trioxolane antimalarials |
| CN105997994A (en) * | 2015-07-11 | 2016-10-12 | 凌莉 | Solid oral preparation and preparation method thereof |
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| 韦超等: "《药剂学 第2版》", 31 August 2012 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110031568A (en) * | 2019-03-20 | 2019-07-19 | 石药集团中奇制药技术（石家庄）有限公司 | Sha Kuba is bent in a kind of measurement human plasma, goes ethyl Sha Kuba bent and the method for Determination of valsartan in human |
| CN113456607A (en) * | 2021-07-08 | 2021-10-01 | 南京康川济医药科技有限公司 | Sacubitril valsartan sodium monolayer osmotic pump controlled release tablet and preparation method thereof |
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| CN109464442B (en) | 2020-02-28 |
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