CN109157526A - A kind of valsartan amlodipine compound preparation and its preparation process - Google Patents
A kind of valsartan amlodipine compound preparation and its preparation process Download PDFInfo
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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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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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
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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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
- A61K9/2009—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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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
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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
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The invention discloses a kind of valsartan amlodipine compound preparations, including active constituent Valsartan and Amlodipine and its salt and pharmaceutically acceptable auxiliary material, the Valsartan is amorphous state, and particle shape is powdered and/or dendroid and/or non-spherical aggregation under an optical microscope.Also disclose preparation method.Technological means disclosed by the invention effectively by the optical detection of material with production technology is organic combines, and then reaching control finished product preparation quality, technological means disclosed by the invention effectively overcomes finished product preparation dissolution rate in valsartan amlodipine compound preparation production process and detects uncontrollable and unstable technological deficiency.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of valsartan amlodipine compound preparation and its preparation work
Skill.
Background technique
Valsartan is angiotensin II receptor antagonist anti-hypertension class drug, which is to play to make angiotensins
II I type (AT1) receptor blockade, angiotensinⅡ blood plasma level increase, and stimulate unclosed AT2 receptor, while the AT1 that contends with
The effect of receptor, to achieve the effect that expanding blood vessel reduces blood pressure.
Amlodipine is widely used long-acting calcium antagonist (CCB), can expand periphery parteriole, make peripheral resistance
(afterload) reduces, to reduce cardiac muscle energy consumption and oxygen demand, and can expand normal and ischemic region coronary artery and come of age
Shape parteriole.
Valsartan is combined with amlodipine in clinical application and is prepared into valsartan amlodipine compound preparation, for fitting
Answering disease is the treatment of essential hypertension.
For, for valsartan amlodipine, especially its compound preparation, dissolution rate medicine generation in human body for drug
Dynamic characteristic is affected, and dissolution rate directly affects the bioavilability of drug.Therefore, valsartan amlodipine compound preparation
Human body is acted on relatively stable, effective dissolution characteristics, it is most important for the drug effect for increasing drug.
However, the detection of pharmaceutical preparation includes raw material instantly for the production about valsartan amlodipine compound preparation
Medicine, preparation intermediate and finished product preparation are detected according to the detection scheme that " Chinese Pharmacopoeia " is recorded.However, according to " China
Pharmacopeia " detection scheme recorded, often detection display bulk pharmaceutical chemicals, the detection of preparation intermediate are qualified, but final finished preparation dissolves out
It is unstable that degree but detects unqualified and batch finished product preparation qualification rate, in turn result in do over again, waste material the problem of.
Above-mentioned technical problem is always the technical bottleneck of valsartan amlodipine compound preparation production, seriously hinders Valsartan
The production of Amlodipine compound preparation.
Therefore, it develops a kind of valsartan amlodipine compound preparation quality control detection and the united Quality Control of production technology is raw
Production. art solves dissolution rate detection in production process for improving valsartan amlodipine compound preparation finished product preparation qualification rate
Uncontrollable and unstable technological deficiency is most important.
Summary of the invention
Technical problem to be solved by the present invention lies in how overcoming in valsartan amlodipine compound preparation production process,
Finished product preparation dissolution rate detects uncontrollable and unstable technological deficiency.
The present invention solves above-mentioned technical problem by the following technical programs:
A kind of valsartan amlodipine compound preparation, including active constituent Valsartan and Amlodipine and its salt and pharmacy
Upper acceptable auxiliary material, the Valsartan are amorphous state, under an optical microscope particle shape be powdered and/or dendroid and/or
Non-spherical aggregation.It is preferred that the particle shape as described in attached drawing 2a.
Preferably, valsartan amlodipine compound preparation, wherein the median D50 of Valsartan uses laser diffraction particle size
Method measurement, the ratio of the median D50 measured in decentralized medium 1%SDS and atoleine is less than 10.
Preferably, valsartan amlodipine compound preparation has following In Vitro Dissolution features:
Valsartan amlodipine compound preparation is placed in medicament dissolution instrument, using phosphate buffer as dissolution medium, control
The pH4.5 of producing phosphate buffer, the revolving speed for controlling medicament dissolution instrument is 50rpm, timing sampling detection；
It is had the feature that by the result that above-mentioned dissolving-out method measures
Valsartan, Amlodipine are calculated in the average dissolution rate of 10min, 30min, 60min and following standard dissolution rate
Similar factors are not less than 50, and dissolve out difference and be respectively less than the 10% of labelled amount；
Valsartan is in 10min, 30min, 60min standard dissolution rate are as follows: 31.92%, 61.13%, 79.05%；
Amlodipine is in 10min, 30min, 60min standard dissolution rate are as follows: 23.35%, 54.33%, 74.10%.
Preferably, valsartan amlodipine compound preparation, which is characterized in that the raw material including following parts by weight: Valsartan
75-85, Amlodipine Besylate Tablet 6-8, microcrystalline cellulose 50-60, crospovidone 18-22, colloidal silicon dioxide 1.2-1.6,
Magnesium stearate 4.0-5.0.
More there is the valsartan amlodipine compound preparation of choosing, which is characterized in that the raw material including following parts by weight: Valsartan
80, Amlodipine Besylate Tablet 6.94, microcrystalline cellulose 54.06, crospovidone 20, colloidal silicon dioxide 1.5, magnesium stearate
4.5。
The present invention also provides the preparation methods of the valsartan amlodipine compound preparation, comprising the following steps:
S1, Valsartan selection, select crystal form to be amorphous, and particle shape is powdered and/or dendroid under an optical microscope
And/or non-spherical aggregation, and the median measured in decentralized medium 1%SDS and atoleine with laser diffraction particle size method
The ratio of D50 is less than 10；It does not meet such as and increases S1a step；
S1a, it takes Valsartan and Amlodipine Besylate Tablet to be placed in high speed disintegrator after crushing 0.5-5min, samples, carry out
The micro- detection of optics particle shape, until the particle shape of the micro- detection display valsartan particles of optics particle shape is disappeared substantially by ball；
S2, the Valsartan of S1 is mixed to obtain to first mixing with Amlodipine Besylate Tablet and other auxiliary materials；Or by the material of S1a with
Other auxiliary materials mix to obtain first mixing；
S3, the first mixing dry granulation by S2；
S4, step S3 is made pellet and mix lubricant, obtains total mixing；
S5, plain piece is made in total mixing tabletting obtained by step S4；
S6, to the coating of plain piece obtained by step S5 to get.
Preferably, optical microphotograph in the preparation method of valsartan amlodipine compound preparation, the step S1 and step S1a
The method of detection is as follows: the powder of step S1 or step S1a respectively is shaken off glass slide, is placed in particle image analyzer, light
It learns microscope and amplifies 100 times, LED light source shoots reflected image, observes particle shape by micro-image.
Preferably, the preparation method of valsartan amlodipine compound preparation, the step S3 increase S3a step,
S3a, particle is made in S3, by 60 meshes, fine powder continues to repeat S3 step 1 time, gained particle and fine powder and cut
Particle is stayed to merge stand-by.Certainly repeating S3 step can be with 2 times, 3 times or more time, so that the weight ratio that fine powder accounts for total amount exists
In the range of 10%-40%.It is very little then tablet is not clean, it is too many to influence mobility and tablet weight variation etc.
Preferably, the preparation method of valsartan amlodipine compound preparation, the sieve of whole grain in the step S3 dry granulation
Screen distance is 0.5-2.0mm.Preferred aperture is 0.9mm, 1.2mm, 1.5mm；Most preferably 0.9mm.
Compared with the existing technology the invention has the following advantages:
1, technical solution disclosed by the invention, which successfully discloses, causes Valsartan raw material and preparation premix according to pharmacopeia
Examination criteria, detection is qualified, but the reason that the dissolution rate of final finished compound preparation detection qualification rate is unstable.Reason is exactly
The difference of particle shape, and the D50 ratio under different medium.
2, the present invention produces use in conjunction by microimage detection technology and preparation, effectively overcomes pharmacopeia examination criteria
In, because of the detection means being not directed to, the finished product preparation dissolution rate of different production batch is caused to detect the unstable technology of qualification rate
Problem.Detection means disclosed by the invention selects suitable raw material in advance, avoids unqualified raw material from feeding intake and causes preparation molten
Underproof disadvantage out substantially increases the qualification rate of finished product preparation.
3, it proposes to merge disintegrating process for unqualified raw material, overcomes raw material defect.
Detailed description of the invention
Fig. 1 Valsartan batch 1 (under) and batches 2 (on) PXRD scheme.
Fig. 2 micro-powder particle shape figure；1 micro-powder particle shape figure of 2a Valsartan batch；2 micro-powder particle shapes of 2b Valsartan batch
Figure；1 Valsartan of the 2c comparative example batch micro- particle shape figure of 1 premix；2 Valsartan of 2d comparative example batch, 2 premix Microscopic Graineds
Shape figure；4 Valsartan of 2e embodiment batch 2 and Amlodipine are through the cooking machine crushing micro- particle shape figure of 1min；2 Valsartan of 2f embodiment batch
2 and Amlodipine through pulverizer crush the micro- particle shape figure of 1min.
The micro- particle shape figure of Fig. 3 liquid dispersion；3a Valsartan batch 1 is dispersed in microscopic morphology figure in 1%SDS；3b Valsartan
It criticizes 2 and is dispersed in microscopic morphology figure in 1%SDS；3c Valsartan batch 1 is dispersed in microscopic morphology figure in atoleine；3d Valsartan batch 2
It is dispersed in microscopic morphology figure in atoleine.
Specific embodiment
For convenient for those skilled in the art understand that technical solution of the present invention, now in conjunction with Figure of description to the technology of the present invention side
Case is described further.
Comparative example 1
(1) Valsartan (criticizing 1) 800g, Amlodipine Besylate Tablet 69.4g, microcrystalline cellulose 540.6g, crospovidone
Then 200g, colloidal silicon dioxide 15g, magnesium stearate 30g diffusion mixing are sieved 30 mesh 1 time as premix, it is mixed to be further continued for diffusion
Close to obtain premix；
(2) dry granulation: taking the first mixing dry granulating machine (DP-5 dry granulating machine, Shenzhen Xinyi are special) of step (1),
It is rolled into ribbon, integrates broken, whole grain (the integrated taper of DP-5 dry granulating machine rotates pelletizing machine), whole grain mesh size is
0.9mm；
(2A): being made particle for step (2) and use 60 mesh sieves, sieve fine powder repeats step (2) once, collect all
Particle and fine powder；
(3) it total mix: makes pellet and mixes using magnesium stearate 15g as lubricant with step (2) and (2A), obtain total mixing；
(4) total mixing obtained by step (3) tabletting: is used into diameter 10mm round punch tabletting (the rotary tabletting of ZPW-23
Machine, Shanghai Tian Qi pharmaceutical machine Co., Ltd), tablet hardness 90N is controlled, plain piece is made；
(5) be coated: using seed-coating machine (II high-efficiency coating machine of Labcoat, Shenzhen Xinyi special) to plain piece obtained by step (4) with
Opadry be coating material be coated to get.
Comparative example 2
With comparative example 1, only Valsartan lot number becomes criticizing 2 from criticizing 1, and even sieve number of sneaking out changes.
(1) Valsartan (criticizing 2) 800g, Amlodipine Besylate Tablet 69.4g, microcrystalline cellulose 540.6g, crospovidone
Then 200g, colloidal silicon dioxide 15g, magnesium stearate 30g diffusion mixing are sieved 30 mesh 1 time as premix, it is mixed to be further continued for diffusion
Close to obtain premix；
(2) dry granulation: taking the first mixing dry granulating machine (DP-5 dry granulating machine, Shenzhen Xinyi are special) of step (1),
It is rolled into ribbon, integrates broken, whole grain (the integrated taper of DP-5 dry granulating machine rotates pelletizing machine), whole grain mesh size is
0.9mm；
(2A): being made particle for step (2) and use 60 mesh sieves, sieve fine powder repeats step (2) once, collect all
Particle and fine powder；
(3) it total mix: makes pellet and mixes using magnesium stearate 15g as lubricant with step (2) and (2A), obtain total mixing；
(4) total mixing obtained by step (3) tabletting: is used into diameter 10mm round punch tabletting (the rotary tabletting of ZPW-23
Machine, Shanghai Tian Qi pharmaceutical machine Co., Ltd), tablet hardness 90N is controlled, plain piece is made；
(5) be coated: using seed-coating machine (II high-efficiency coating machine of Labcoat, Shenzhen Xinyi special) to plain piece obtained by step (4) with
Opadry be coating material be coated to get.
2 parts of identical supplementary material is separately taken, is sieved respectively in step (1) 30 mesh 4 times or 8 times, subsequent step is same as above.
Above-mentioned 3 groups of tests are as 81 mixing of screening, 4 mixing of screening, screening mixing.
Comparative example 3
(1) Valsartan (criticizing 1) 800g, Amlodipine Besylate Tablet 69.4g, microcrystalline cellulose 540.6g, crospovidone
200g, colloidal silicon dioxide 15g, magnesium stearate 30g are placed in efficient wet mixer-granulator (G10 efficient wet mixing granulation
Machine, Shenzhen Xinyi are special) in, speed of agitator 4r/s, cutter rotating velocity 30r/s mix 10min, obtain premix；
(2) dry granulation: taking the first mixing dry granulating machine (DP-5 dry granulating machine, Shenzhen Xinyi are special) of step (1),
It is rolled into ribbon, integrates broken, whole grain (the integrated taper of DP-5 dry granulating machine rotates pelletizing machine), whole grain mesh size is
0.9mm；
(2A): being made particle for step (2) and use 60 mesh sieves, sieve fine powder repeats step (2) once, collect all
Particle and fine powder；
(3) it total mix: makes pellet and mixes using magnesium stearate 15g as lubricant with step (2) and (2A), obtain total mixing；
(4) total mixing obtained by step (3) tabletting: is used into diameter 10mm round punch tabletting (the rotary tabletting of ZPW-23
Machine, Shanghai Tian Qi pharmaceutical machine Co., Ltd), tablet hardness 90N is controlled, plain piece is made；
(5) be coated: using seed-coating machine (II high-efficiency coating machine of Labcoat, Shenzhen Xinyi special) to plain piece obtained by step (4) with
Opadry be coating material be coated to get.
Comparative example 4
(1) Valsartan (criticizing 2) 800g, Amlodipine Besylate Tablet 69.4g, microcrystalline cellulose 540.6g, crospovidone
200g, colloidal silicon dioxide 15g, magnesium stearate 30g are placed in efficient wet mixer-granulator (G10 efficient wet mixing granulation
Machine, Shenzhen Xinyi are special) in, speed of agitator 4r/s, cutter rotating velocity 30r/s mix 10min, obtain premix；
(2) dry granulation: taking the first mixing dry granulating machine (DP-5 dry granulating machine, Shenzhen Xinyi are special) of step (1),
It is rolled into ribbon, integrates broken, whole grain (the integrated taper of DP-5 dry granulating machine rotates pelletizing machine), whole grain mesh size is
0.9mm；
(2A): being made particle for step (2) and use 60 mesh sieves, sieve fine powder repeats step (2) once, collect all
Particle and fine powder；
(3) it total mix: makes pellet and mixes using magnesium stearate 15g as lubricant with step (2) and (2A), obtain total mixing；
(4) total mixing obtained by step (3) tabletting: is used into diameter 10mm round punch tabletting (the rotary tabletting of ZPW-23
Machine, Shanghai Tian Qi pharmaceutical machine Co., Ltd), tablet hardness 90N is controlled, plain piece is made；
(5) be coated: using seed-coating machine (II high-efficiency coating machine of Labcoat, Shenzhen Xinyi special) to plain piece obtained by step (4) with
Opadry be coating material be coated to get.
3 parts of identical supplementary material is separately taken, difference shear-mixed 3min, 7min, 30min, subsequent step are same as above in step (1).
Above-mentioned 4 groups of tests are as shearing 3min mixing, shearing 7min mixing, shearing 10min mixing, shearing 30min mixing.
Embodiment 1
A kind of valsartan amlodipine piece, is made of the raw material of following parts by weight: Valsartan (criticizing 2) 75, benzene sulfonic acid ammonia chlorine
Horizon 5, microcrystalline cellulose 50, crospovidone 18, colloidal silicon dioxide 1.2, magnesium stearate 4.0.
The valsartan amlodipine piece is made by following method:
(1) Valsartan, Amlodipine Besylate Tablet are used into pulverizer (LFP-1000A high-speed multifunctional pulverizer, Lai Fu
Board), at revolving speed 25000rpm crush 1min after premix, then with microcrystalline cellulose, crospovidone, colloidal silicon dioxide
And the 60% of total magnesium stearate quality mixes to obtain first mixing；
(2) dry granulation: taking the first mixing dry granulating machine (DP-5 dry granulating machine, Shenzhen Xinyi are special) of step (1),
It is rolled into ribbon, integrates broken, whole grain (the integrated taper of DP-5 dry granulating machine rotates pelletizing machine), whole grain mesh size is
0.9mm；
(3) total mix: remaining magnesium stearate is made pellet as lubricant with step (2) and is mixed, total mixing is obtained；
(4) total mixing obtained by step (3) tabletting: is used into diameter 10mm round punch tabletting (the rotary tabletting of ZPW-23
Machine, Shanghai Tian Qi pharmaceutical machine Co., Ltd), tablet hardness 90N is controlled, plain piece is made；
(5) be coated: using seed-coating machine (II high-efficiency coating machine of Labcoat, Shenzhen Xinyi special) to plain piece obtained by step (4) with
Opadry be coating material be coated to get.
Embodiment 2
A kind of valsartan amlodipine piece, is made of the raw material of following parts by weight: Valsartan (criticizing 2) 80, benzene sulfonic acid ammonia chlorine
Horizon 6.94, microcrystalline cellulose 54.06, crospovidone 20, colloidal silicon dioxide 1.5, magnesium stearate 4.5.
The valsartan amlodipine piece is made by following method:
(1) Valsartan, Amlodipine Besylate Tablet are used into pulverizer (LFP-1000A high-speed multifunctional pulverizer, Lai Fu
Board), at revolving speed 25000rpm crush 1min after premix, then with microcrystalline cellulose, crospovidone, colloidal silicon dioxide
And the 60% of total magnesium stearate quality mixes to obtain first mixing；
(2) dry granulation: taking the first mixing dry granulating machine (DP-5 dry granulating machine, Shenzhen Xinyi are special) of step (1),
It is rolled into ribbon, integrates broken, whole grain (the integrated taper of DP-5 dry granulating machine rotates pelletizing machine), whole grain mesh size is
0.9mm；
(2A): being made particle for step (2) and use 60 mesh sieves, sieve fine powder repeats step (2) once, collect all
Particle and fine powder；
(3) it total mix: makes pellet and mixes using remaining magnesium stearate as lubricant with step (2) and (2A), obtain total mix
Material；
(4) total mixing obtained by step (3) tabletting: is used into diameter 10mm round punch tabletting (the rotary tabletting of ZPW-23
Machine, Shanghai Tian Qi pharmaceutical machine Co., Ltd), tablet hardness 90N is controlled, plain piece is made；
(5) be coated: using seed-coating machine (II high-efficiency coating machine of Labcoat, Shenzhen Xinyi special) to plain piece obtained by step (4) with
Opadry be coating material be coated to get.
Embodiment 3
Prescription, technique are same as Example 2, and only Valsartan batch is different.
A kind of valsartan amlodipine piece, is made of the raw material of following parts by weight: Valsartan (criticizing 1) 80, benzene sulfonic acid ammonia chlorine
Horizon 6.94, microcrystalline cellulose 54.06, crospovidone 20, colloidal silicon dioxide 1.5, magnesium stearate 4.5.
The valsartan amlodipine piece is made by following method:
(1) Valsartan, Amlodipine Besylate Tablet are used into pulverizer (LFP-1000A high-speed multifunctional pulverizer, Lai Fu
Board), at revolving speed 25000rpm crush 1min after premix, then with microcrystalline cellulose, crospovidone, colloidal silicon dioxide
And the 60% of total magnesium stearate quality mixes to obtain first mixing；
(2) dry granulation: taking the first mixing dry granulating machine (DP-5 dry granulating machine, Shenzhen Xinyi are special) of step (1),
It is rolled into ribbon, integrates broken, whole grain (the integrated taper of DP-5 dry granulating machine rotates pelletizing machine), whole grain mesh size is
0.9mm；
(2A): being made particle for step (2) and use 60 mesh sieves, sieve fine powder repeats step (2) once, collect all
Particle and fine powder；
(3) it total mix: makes pellet and mixes using remaining magnesium stearate as lubricant with step (2) and (2A), obtain total mix
Material；
(4) total mixing obtained by step (3) tabletting: is used into diameter 10mm round punch tabletting (the rotary tabletting of ZPW-23
Machine, Shanghai Tian Qi pharmaceutical machine Co., Ltd), tablet hardness 90N is controlled, plain piece is made；
(5) be coated: using seed-coating machine (II high-efficiency coating machine of Labcoat, Shenzhen Xinyi special) to plain piece obtained by step (4) with
Opadry be coating material be coated to get.
Embodiment 4
A kind of valsartan amlodipine piece, is made of the raw material of following parts by weight: Valsartan (criticizing 2) 80, benzene sulfonic acid ammonia chlorine
Horizon 6.94, microcrystalline cellulose 54.06, crospovidone 20, colloidal silicon dioxide 1.5, magnesium stearate 4.5.
The valsartan amlodipine piece is made by following method:
(1) by Valsartan, Amlodipine Besylate Tablet using cooking machine (JYL-C022 cooking machine (the nine limited public affairs of positive share
Department), at revolving speed 18000-23000rpm crush 1min after premix, then with microcrystalline cellulose, crospovidone, colloidal state two
The 60% of silica and total magnesium stearate quality mixes to obtain just mixing；
(2) dry granulation: taking the first mixing dry granulating machine (DP-5 dry granulating machine, Shenzhen Xinyi are special) of step (1),
It is rolled into ribbon, integrates broken, whole grain (the integrated taper of DP-5 dry granulating machine rotates pelletizing machine), whole grain mesh size is
1.5mm；
(3) total mix: remaining magnesium stearate is made pellet as lubricant with step (2) and is mixed, total mixing is obtained；
(4) total mixing obtained by step (3) tabletting: is used into diameter 10mm round punch tabletting (the rotary tabletting of ZPW-23
Machine, Shanghai Tian Qi pharmaceutical machine Co., Ltd), tablet hardness 90N is controlled, plain piece is made；
(5) be coated: using seed-coating machine (II high-efficiency coating machine of Labcoat, Shenzhen Xinyi special) to plain piece obtained by step (4) with
Opadry be coating material be coated to get.
Embodiment 5
A kind of valsartan amlodipine piece, each raw material dosage proportion are as follows: Valsartan (criticizing 2) 80g, Amlodipine Besylate Tablet
6.94g, microcrystalline cellulose 54.06g, crospovidone 20g, colloidal silicon dioxide 1.5g, magnesium stearate 4.5g.
A kind of preparation method of valsartan amlodipine piece, comprising the following steps:
(1) Valsartan, Amlodipine Besylate Tablet are used into pulverizer (LFP-1000A high-speed multifunctional pulverizer, Lai Fu
Board), at revolving speed 25000rpm crush 2min after premix, then with microcrystalline cellulose, crospovidone, colloidal silicon dioxide
And the 60% of total magnesium stearate quality mixes to obtain first mixing；
(2) dry granulation: taking the first mixing dry granulating machine (DP-5 dry granulating machine, Shenzhen Xinyi are special) of step (1),
It is rolled into ribbon, integrates broken, whole grain (the integrated taper of DP-5 dry granulating machine rotates pelletizing machine), whole grain mesh size is
0.9mm；
(3) total mix: remaining magnesium stearate is made pellet as lubricant with step (2) and is mixed, total mixing is obtained；
(4) total mixing obtained by step (3) tabletting: is used into diameter 10mm round punch tabletting (the rotary tabletting of ZPW-23
Machine, Shanghai Tian Qi pharmaceutical machine Co., Ltd), tablet hardness 90N is controlled, plain piece is made；
(5) be coated: using seed-coating machine (II high-efficiency coating machine of Labcoat, Shenzhen Xinyi special) to plain piece obtained by step (4) with
Opadry be coating material be coated to get.
Embodiment 6
Dissolution measurement and similarity evaluation
According to dissolution rate and drug release determination method (four general rules of Chinese Pharmacopoeia version in 2015,0,931 second method), with phosphate
Buffer (pH4.5, PBS4.5) 1000ml is dissolution medium, and revolving speed 50rpm is operated according to methods, through 5,10,15,30,60 Hes
When 120min, solution 15ml is taken, and supplements mutually synthermal and volume dissolution medium immediately, discards primary filtrate 10ml, precision amount
Subsequent filtrate 2ml is taken, precision is added 50% acetonitrile solution of 2ml, shakes up, as test solution；Separately take Amlodipine Besylate Tablet pair
It is appropriate according to product and Valsartan reference substance, it is accurately weighed, add 50% acetonitrile solution to dissolve and quantify dilution and is made in every 1ml containing about ammonia
The mixed solution of Flordipine 0.1mg, Valsartan 1.6mg, as reference substance mother liquor；Precision measures reference substance mother liquor 2ml, and precision adds
Enter 2ml dissolution medium, shake up, as reference substance solution.Referring to high effective liquid chromatography for measuring, with octadecylsilane bonded silica
Glue is filler；With acetonitrile-water-trifluoroacetic acid (500: 500: 2) for mobile phase；Flow velocity 1.2ml per minute；Detection wavelength is
237nm；Column temperature is 40 DEG C.Precision measures above two each 10 μ l of solution, injects liquid chromatograph, records chromatogram.By external standard
Method calculates separately the amount of dissolution of every middle Amlodipine and Valsartan with peak area.
Comparative example 1-4 is measured in accordance with the law, Valsartan ammonia chlorine made from different premix mode described in embodiment 2-5
Plain film, and the dissolution of former triturate valsartan amlodipine piece (Novartis Co., Ltd, Bei Bote).
It lists 10,30,60min dissolution data and similar factors f2 is calculated with this, similar factors determine phase not less than 50
Seemingly, otherwise dissimilar.
F2 calculation formula is as follows
Rt is that t time reference sample is averaged the amount of dissolution；
Tt is that t time given the test agent is averaged the amount of dissolution；
N is the number of sampling time point.
The difference at corresponding time point and RLD dissolution is calculated simultaneously, if is greater than 10%.
The influence of 1 premixing process of table and the dissolution of raw material batch P-TOLUENE SULFO ACID 99's Amlodipine
1 using batch 1 Valsartan, remaining is using batch 2 Valsartans
The influence that 2 premixing process of table and raw material batch dissolve out Valsartan
1 using batch 1 Valsartan, remaining is using batch 2 Valsartans
Premixing process uses screening or shear-mixed mode to the dissolution no significant difference of Valsartan and Amlodipine.Criticize 1
Two components are similar to RLD dissolution (f2 > 50) when Valsartan, and batch 2 Valsartans, the dissolution of two components are accelerated, Amlodipine dissolution
(f2 < 50) no longer similar to RLD.1-8 number or shear time 3-30min are sieved, the dissolution of two components is all had no significant effect,
And the change of hybrid parameter dissolution fluid is also not present tendency variation, Amlodipine dissolution is still dissimilar with RLD.
Thus the application design crushes Valsartan, increases Valsartan surface area, to wrap up Amlodipine and block it
Dissolution.Valsartan after crushed as the result is shown, so that Amlodipine discharges.
In conjunction with micro- particle shape, different medium D50 ratio, powdered and/or dendritic and/or non-spherical Valsartan is excellent
The raw material of choosing, different medium D50 are also preferred raw material than the Valsartan greater than 10.
Embodiment 7
Particle size determination
Claim this product (Valsartan or Amlodipine Besylate Tablet) about 0.1g, 1% lauryl sodium sulfate of bonus point dispersion media (SDS)
Or simultaneously suspension solution is made in ultrasound 15s for atoleine shaking.In laser granulometry (BT9300 laser particle size analyzer, pellet
The special Instrument Ltd. in east hundred) appropriate decentralized medium is added in sample cell, the correction of instrument blank background is carried out, then into sample cell
Appropriate suspension is added, makes shading rate 20-40%, opens sample cell stirring, measures the size distribution of sample, the results are shown in Table 3.
As a result visible the surveyed partial size of Valsartan two batches raw material in decentralized medium 1%SDS and atoleine is without obvious poor
Different, instant difference out can not be explained with partial size difference.In addition find that partial size differs greatly under different medium, atoleine measures grain
Only institute's measured value obtains 1/10th to diameter under about 1%SDS.Further analysis find crowd 2 Valsartan D50 in 1%SDS (85.23 μm) and
Ratio 85.23:7.331=11.6 in atoleine (7.331 μm) is greater than 10.1 ratio 77.09:9.942=7.8 is criticized,
Less than 10.
It therefore can area using the Valsartan D50 ratio measured in 1%SDS (85.23 μm) and atoleine (7.331 μm)
Materials variance in two batches, decision content 10, ratio adapt to a variety of premixing process greater than 10 raw material, must be using height less than 10
Fast disintegrating process, it is similar that dissolution feature could grind reference to original.
The particle diameter distribution of table 3 Valsartan and Amlodipine
Embodiment 9
Crystal form measurement
Two batches crystalline form of Valsartan, the result is shown in Figure 1 are measured using X-ray powder diffraction (PXRD) instrument.It can be seen that two batches Valsartan
It is amorphous, PXRD figure (Fig. 1) no significant difference.
Embodiment 10
Particle shape optical observation
Two batches batch Valsartan partial size, crystal form no significant difference, no method interpretation wherein accelerate by Valsartan and Amlodipine dissolution
The reason of, therefore attempt observation particle shape.
It takes Valsartan, Amlodipine, screening mixed powder powder to shake off glass slide, is analyzed using particle image analyzer,
Optical microscopy (JX-2000A type particle image analyzer, Jingxin Power Testing Apparatus Co., Ltd., Chengdu) amplifies 100 times
(10 × 10), additional LED light source shoot reflected light image, as a result see Fig. 2.
It can be seen that the micro- particle shape of two batches Valsartan has notable difference, and batch 1 predominantly powdered, dendroid (2a), non-spherical, and
Criticize 2 predominantly nodular (2b).Screening mixed powder micrograph show, 1 batch of 1 obtained mixed powder uniform and smooth of comparative example,
Without obvious agglomerate, Amlodipine column crystal form is well coated (2c)；And 2 batches of 2 obtained mixed powders of comparative example have obviously
Valsartan group's ball successfully blocks bonding (2d) by other auxiliary materials.And group's ball through batch 2 Valsartans crushed is broken up, but shape
At the biggish bonding block (2f) of some intensity.
Separately Valsartan particle size determination solution is taken to be placed on glass slide, is analyzed using particle image analyzer, optical microscopy,
Amplify 100 times (10 × 10), additional LED light source shoots reflected light image, as a result sees Fig. 3.It shows in 1%SDS medium, batch 2 powder
Group's ball under last current state disappears (3b), and the dendroid under batch 1 pulverulence also disappears (3a), is respectively formed unordered particle buildup,
Two batches Valsartan assembles particle shape, and no significant difference is consistent with particle size determination result.And in atoleine, the equal shape of two batches Valsartan
At fines, nothing is significantly built up, indifference between batch.This can also explain that surveyed partial size is about the surveyed grain of 1%SDS in atoleine
/ 10th of diameter, Valsartan freely disperses in atoleine, and surveyed partial size is the partial size of original individual particle, and 1%SDS
Middle Valsartan can not fine dispersion, surveyed partial size be conglomerate grain graininess.
By microexamination in the premix technical process of valsartan amlodipine compound preparation Valsartan-Amlodipine
Package degree, Optimizing Process Parameters can significantly improve the qualification rate of the dissolution rate of finished product preparation.But when the life of prescribe medicine enterprise
Production. art is not directed to above-mentioned quality control process.
The above embodiments are merely illustrative of the technical solutions of the present invention, rather than its limitations, although with reference to the foregoing embodiments
Invention is explained in detail, those skilled in the art should understand that: it still can be to aforementioned each implementation
Technical solution documented by example is modified or equivalent replacement of some of the technical features；And these modification or
Replacement, the spirit and scope for technical solution of various embodiments of the present invention that it does not separate the essence of the corresponding technical solution.
Claims (10)
1. a kind of valsartan amlodipine compound preparation, which is characterized in that including active constituent Valsartan and Amlodipine and its
Salt and pharmaceutically acceptable auxiliary material, the Valsartan be amorphous state, under an optical microscope particle shape be it is powdered and/or
Dendroid and/or non-spherical aggregation.
2. valsartan amlodipine compound preparation according to claim 1, which is characterized in that figured silk fabrics is husky in the compound preparation
Smooth median D50 is measured using laser diffraction particle size method, the middle position measured in decentralized medium 1%SDS and atoleine
The ratio of partial size D50 is less than 10.
3. valsartan amlodipine compound preparation according to claim 1, which is characterized in that have following In Vitro Dissolutions special
Sign:
Valsartan amlodipine compound preparation is placed in medicament dissolution instrument, using phosphate buffer as dissolution medium, controls phosphorus
The pH4.5 of phthalate buffer, the revolving speed for controlling medicament dissolution instrument is 50rpm, timing sampling detection；
It is had the feature that by the result that above-mentioned dissolving-out method measures
Valsartan, Amlodipine calculate in the average dissolution rate of 10min, 30min, 60min to following standard dissolution rate similar
The factor is not less than 50, and dissolves out difference and be respectively less than the 10% of labelled amount；
Valsartan is in 10min, 30min, 60min standard dissolution rate are as follows: 31.92%, 61.13%, 79.05%；
Amlodipine is in 10min, 30min, 60min standard dissolution rate are as follows: 23.35%, 54.33%, 74.10%.
4. valsartan amlodipine compound preparation according to claim 1, which is characterized in that the original including following parts by weight
Material: Valsartan 75-85, Amlodipine Besylate Tablet 6-8, microcrystalline cellulose 50-60, crospovidone 18-22, colloidal silicon dioxide
1.2-1.6, magnesium stearate 4.0-5.0.
5. valsartan amlodipine compound preparation according to claim 4, which is characterized in that the original including following parts by weight
Material: Valsartan 80, Amlodipine Besylate Tablet 6.94, microcrystalline cellulose 54.06, crospovidone 20, colloidal silicon dioxide 1.5,
Magnesium stearate 4.5.
6. the preparation method of valsartan amlodipine compound preparation according to claim 1, comprising the following steps:
S1, Valsartan selection, selects crystal form to be amorphous, and under an optical microscope particle shape for powdered and/or dendroid and/or
Non-spherical aggregation, and the median D50 measured in decentralized medium 1%SDS and atoleine with laser diffraction particle size method
Ratio less than 10；It does not meet such as and increases S1a step；
S1a, Valsartan and Amlodipine Besylate Tablet is taken to be placed in high speed disintegrator after crushing 0.5-5min, sampling carries out optics
The micro- detection of particle shape, until the particle shape of the micro- detection display valsartan particles of optics particle shape is disappeared substantially by ball；
S2, the Valsartan of S1 is mixed to obtain to first mixing with Amlodipine Besylate Tablet and other auxiliary materials；Or by the material of S1a and other
Auxiliary material mixes to obtain first mixing；
S3, the first mixing dry granulation by S2；
S4, step S3 is made pellet and mix lubricant, obtains total mixing；
S5, plain piece is made in total mixing tabletting obtained by step S4；
S6, to the coating of plain piece obtained by step S5 to get.
7. the preparation method of valsartan amlodipine compound preparation according to claim 6, which is characterized in that the step
The method that optical microphotograph detects in S1 and step S1a is as follows: the powder of step S1 or step S1a respectively is shaken off glass slide, is set
In particle image analyzer, optical microscopy amplifies 100 times, and LED light source shoots reflected image, observes grain by micro-image
Shape.
8. the preparation method of valsartan amlodipine compound preparation according to claim 6, which is characterized in that the step
S3 increases S3a step,
S3a, particle is made in S3, by 60 meshes, fine powder continues to repeat S3 step 1 time, gained particle and fine powder and retention
Grain merges stand-by.
9. the preparation method of valsartan amlodipine compound preparation according to claim 6, which is characterized in that the step
The mesh size of whole grain is 0.5-2.0mm in S3 dry granulation.
10. the preparation method of valsartan amlodipine compound preparation according to claim 9, which is characterized in that the step
The mesh size of whole grain is 0.9mm in rapid S3 dry granulation.
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| CN101103006A (en) * | 2005-01-11 | 2008-01-09 | 特瓦制药工业有限公司 | Process for preparing amorphous valsartan |
| CN101237859A (en) * | 2005-08-17 | 2008-08-06 | 诺瓦提斯公司 | Solid dosage forms of valsartan and amlo dipine and method of making the same |
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| CN101103006A (en) * | 2005-01-11 | 2008-01-09 | 特瓦制药工业有限公司 | Process for preparing amorphous valsartan |
| CN101237859A (en) * | 2005-08-17 | 2008-08-06 | 诺瓦提斯公司 | Solid dosage forms of valsartan and amlo dipine and method of making the same |
| CN101485657A (en) * | 2009-03-04 | 2009-07-22 | 浙江华海药业股份有限公司 | Diovan compound preparation and preparation method thereof |
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