CN111419810B - High-stability perindopril tert-butylamine tablet and preparation method thereof - Google Patents
High-stability perindopril tert-butylamine tablet and preparation method thereof Download PDFInfo
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- 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
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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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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- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- 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
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- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Abstract
The invention discloses a high-stability perindopril tert-butylamine tablet and a preparation method thereof. The tablet according to the invention, perindopril tert-butylamine starting material, needs to be prepared into granules with high density and capable of passing 30 mesh (600 μm) but not 80 mesh (180 μm) before being put into the tablet formulation. According to the invention, by controlling the density of the perindopril tert-butylamine raw material, the stability of the perindopril tert-butylamine tablet is greatly improved, the perindopril tert-butylamine tablet is more stable in storage, and the effectiveness and safety of the medicine in administration are ensured. The preparation method is simple, has no special requirements on equipment, and is suitable for large-scale production.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparation research, and particularly relates to a high-stability perindopril tert-butylamine tablet and a preparation method thereof.
Background
Perindopril tert-butylamine (perindopril tert-butylamine) as a second-generation angiotensin converting enzyme inhibitor is clinically commonly used for treating essential hypertension, symptomatic heart failure and coronary artery diseases, and has the advantages of small dosage, wide treatment range, quick and lasting curative effect, small adverse reaction and the like.
Perindopril tert-butylamine has various impurities in the raw material, and the known impurities comprise impurity B, impurity K, main peak, impurity E, impurity F and impurity H, and have the following structures and names:
impurity B:
(2S,3 α S,7 α S) -1- ((S) -N- [ (S) -1-carboxybutyl ] alanyl) octahydro-1H-indole-2-carboxylic acid impurity C:
(2S) -2- [ (3S,5 α S,9 α S,10 α S) -3-methyl-1, 4-dioxoperhydropyrazino [1,2- α ] indol-2-yl ] pentanoic acid impurity D:
(2S) -2- [ (3S,5 α S,9 α S,10 α R) -3-methyl-1, 4-dioxoperhydropyrazino [1,2- α ] indol-2-yl ] pentanoic acid impurity E:
(2S, 3. alpha. S, 7. alpha. S) -l- [ (S) -N- [ (S) -1-methylethoxycarbonylbutyl ] alanyl ] octahydro-2-indolecarboxylic acid impurity F:
(2S) -2- [ (3S, 5. alpha. S, 9. alpha. S, 10. alpha. S) -3-methyl-1, 4-dioxo-decahydropyrazin [1, 2. alpha ] indol-2 (1H) -yl ] pentanoic acid ethyl ester
Impurity H:
(2S, 3. alpha. S, 7. alpha. S) -1- [ (2S) -2- [ (5RS) -3-cyclohexyl-2- (cyclohexylidene) -4-oxo-5-propylimidazolin-1-yl ] propanoyl ] octahydro-1H-indole-2-carboxylic acid
Impurity K:
(3S, 5. alpha. S, 9. alpha. S, 10. alpha. S) -3-methyldecahydro-pyrazino [1, 2-alpha ] indole-1, 4-dione.
It is known from patent EP-a0308341 that perindopril tert-butylamine salt is a relatively heat and moisture sensitive drug and is susceptible to degradation by two routes, the main degradation products of which are impurity B and impurity F. The stability of the tablets prepared therefrom is also a general problem due to the chemical instability of perindopril tert-butylamine salt.
Studies in patent CN200680031342.3 show that the particle size of the starting material affects the stability of perindopril tert-butylamine tablets, and that the stability of tablets prepared with larger than smaller particle size starting material is better, which suggests controlling the particle size of perindopril tert-butylamine to have a particle size above the median particle size of 7 μm, preferably 8 μm to 20 μm. However, the examples show that when tablets prepared from large-particle materials are placed at 40 ℃/75% RH for 1 month, the content of impurity B increases from < 0.05% to 0.13%, the content of impurity F increases from 0.07% to 0.28%, and further improvement in stability is still required. While other patents disclose the addition of different stabilizers to control the stability of perindopril tert-butylamine tablets, which are more complex in formulation.
Disclosure of Invention
The invention aims to solve the problem of poor stability of perindopril tert-butylamine tablets in the prior art, and provides a perindopril tert-butylamine tablet and a preparation method thereof, so that the stability of the perindopril tert-butylamine tablet is greatly improved.
The above object of the present invention is achieved by the following technical means:
a high stability perindopril tert-butylamine tablet wherein the perindopril tert-butylamine starting material needs to be prepared into granules having a high density and capable of passing 30 mesh (600 μm) but not 80 mesh (180 μm) before being put into the tablet formulation.
In some preferred embodiments of the invention, the perindopril tert-butylamine starting material needs to be prepared into granules having a high density and capable of passing 60 mesh (250 μm) but not 80 mesh (180 μm) before being dosed into the tablet formulation.
The high density of the invention means that the bulk density is 0.8-1.0 g/ml, and the tap density is 1.0-1.5 g/ml; in some specific embodiments, the bulk density is 0.90-0.95 g/ml, and the tap density is 1.20-1.50 g/ml; in some embodiments, the high density of the present invention refers to a bulk density of 0.90-0.95 g/ml and a tap density of 1.20-1.30 g/ml; in a specific embodiment, the high density of the present invention refers to a bulk density of 0.93g/ml and a tap density of 1.25 g/ml.
The perindopril tert-butylamine raw material of the present invention prepared into granules having high density and capable of passing 30 mesh (600 μm) but not 80 mesh (180 μm) can be obtained by conventional methods of the prior art, in one embodiment of the present invention, by tabletting or rolling to prepare relatively hard flakes, followed by crushing and sieving.
The inventors found that compression of perindopril tert-butylamine salt resulted in a significant increase in the density of the granules, which resulted in a significant increase in tablet stability, but when larger particles were present, the mixing uniformity decreased, and therefore, granules that could pass through a 60 mesh but not 80 mesh screen were preferred, both ensuring uniformity and significantly improving stability.
The perindopril tert-butylamine tablet provided by the invention can also contain pharmaceutically acceptable auxiliary materials, and in some embodiments, the perindopril tert-butylamine tablet provided by the invention comprises the following raw materials in parts by weight:
6-10 parts of perindopril tert-butylamine high-density particles;
170 parts of a filling agent 160;
2-5 parts of a lubricant.
In some embodiments, the filler of the present invention is selected from the group consisting of one, two or more of lactose, mannitol, microcrystalline cellulose, xylitol, maltitol, dextrin or pregelatinized starch.
In some embodiments, the lubricant of the present invention is selected from a combination of one, two or more of stearic acid, magnesium stearate, zinc stearate, silicon dioxide, colloidal silicon dioxide or talc.
The perindopril tert-butylamine tablet provided by the invention can realize remarkable stability improvement by controlling the density of the raw materials and mixing the raw materials with simple auxiliary materials.
In some specific embodiments, the perindopril erbumine tablet according to the invention comprises the following raw materials in parts by weight:
the invention also provides a preparation method of the high-stability perindopril tert-butylamine tablet, which is characterized in that a formula amount of perindopril tert-butylamine salt raw material is prepared into granules which have high density and can pass through 30 meshes (600 mu m) but not 80 meshes (180 mu m) before being put into a tablet formula, and then the granules are mixed and tableted with formula amount of fillers and lubricants.
In one embodiment, the present invention provides a more specific process for the preparation of a highly stable tablet of perindopril tert-butylamine comprising the steps of:
(1) placing a perindopril tert-butylamine salt raw material into a dry rolling granulator, selecting a whole sieve with the aperture of 1.2-1.6 mm, adjusting the oil pressure to 11 MPa-20 Mpa at a feeding speed of 45-55 Hz, continuously adding the material into a hopper of the dry rolling granulator, receiving the material from a discharge port, screening by using 30-mesh (600 mu m) and 80-mesh (180 mu m) steel sieves, and taking high-density particles with the particle size capable of passing through the 30-mesh sieve but not capable of passing through the 80-mesh sieve;
(2) uniformly mixing perindopril tert-butylamine salt particles screened in the step (1) with a filler and a lubricant in a formula amount, and tabletting by using a phi 6-10 mm punch in an environment with the humidity lower than 40% RH, wherein the tabletting hardness is as follows: 40-70N.
The high density in the production method of the present invention is as described above.
In some preferred embodiments of the invention, the perindopril tert-butylamine starting material needs to be prepared into granules having a high density and capable of passing 60 mesh (250 μm) but not 80 mesh (180 μm) before being dosed into the tablet formulation.
The perindopril tert-butylamine tablet can be packaged in a form of aluminum-plastic blister package and an aluminum bag, and a molecular sieve desiccant is added into the aluminum bag.
The invention also provides the use of perindopril erbumine tablets in the invention as a medicament for treating hypertension and congestive heart failure.
The inventors have found through studies that stable perindopril tert-butylamine tablets can be obtained by a simpler process. Specifically, the compactness of perindopril tert-butylamine raw material particles plays a crucial role in tablet stability, the high-compactness raw material is beneficial to inhibiting the degradation of the tablets in the storage process, particularly the reduction of impurities B and F, the high-compactness raw material particles can be obtained by a tabletting method or a rolling method, and the stability of perindopril tert-butylamine tablets can be remarkably improved by controlling the density of the raw material.
Detailed description of the invention
The following are specific embodiments of the present invention, which are intended to further illustrate the invention and not to limit it.
The following examples are experimental methods without specifying specific conditions, and generally follow the methods known in the art. The test materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified.
Wherein the particle diameter of the raw material of perindopril tert-butylamine is D102.16 μm, D509.61 μm, D90It was 28.16 μm. The measurement method is as follows: according to the particle size and particle size distribution measurement method (the 2015 edition of Chinese pharmacopoeia, the fourth general rule of 0982, thThree methods) (SYMPA HELOS/RODOS/M or laser particle size analyzer with equivalent performance), taking about 1.5g of the product, detecting the light shielding rate of the detector within the range of 5-15%, and measuring according to a dry method, wherein the dispersion pressure is 2.0bar, the vibration speed is 50%, and taking the average value of continuous measurement for 3 times.
The terms used in the following examples, unless otherwise specified, are defined as follows:
the term "low density granules" is commercially available perindopril tert-butylamine raw material without tabletting and rolling, having a bulk density of 0.21g/ml and a tap density of 0.34 g/ml.
The term "high-density particles" refers to high-density particles which are prepared by preparing the raw materials into sheets with higher hardness by a tabletting method or a rolling method, and then crushing and screening the sheets to obtain the particles with high compactness, wherein the bulk density is 0.8-1.0 g/ml, and the tap density is 1.0-1.5 g/ml.
The density in the following examples was measured using an intelligent powder property tester manufactured by dandongbautt instruments ltd, and the measurement method was as follows:
bulk density: passing a sufficient amount of the powder required for the determination through a sieve having a pore size of not more than 1.0mm, if necessary to break up agglomerates formed during storage; the action in the operation must be gentle so as not to change the properties of the material. In a dry 250ml graduated cylinder (accurate to 2ml), slowly pouring a sample accurately weighed to 0.1% in an appropriate amount (m) without compaction so that the apparent volume is in the range of 150-250 ml, and if necessary, under the condition of no compaction, leveling the powder layer, and reading the closest scale value as the untreated apparent volume (V0). Bulk density (g/ml) was calculated according to the formula m/V0. Generally, parallel measurements should be made when measuring this parameter.
Tap density: the measuring cylinder is fixed on a device which can realize 250 +/-15 times of tap motion within 1 minute from the height of 3 +/-0.2 mm, 10 times, 500 times and 1250 times of tap motion are carried out on the same powder sample, and the corresponding volume V is read10,V500And V1250And accurate to the minimum scale. If V500And V1250Is less than 2mL, V1250Is the tap volume. If V500And V1250The difference of (3) is more than 2mL, and the tapping is repeated according to the previous 1250 times of tapping until the difference of two measured values is less than 2 mL. According to m/VfThe tap density (g/mL), V, was calculated from the formulafIs the final tapped volume.
Example 1
The process comprises the following steps:
(1) perindopril tert-butylamine raw material (bulk density 0.21g/ml, tap density 0.34g/ml) which is not tabletted and rolled is weighed.
(2) Mixing the above raw materials with lactose, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate, tabletting with phi 8mm punch, controlling environment humidity to be lower than 40% RH, and tabletting hardness: 40-70N;
(3) the packaging form of aluminum-plastic blister packaging and an aluminum bag is adopted, and a molecular sieve desiccant is added into the aluminum bag.
Example 2
The process comprises the following steps:
(1) pressing perindopril tert-butylamine into sheets with proper hardness by using a dry granulator, grinding, sieving, specifically placing the raw materials into a GK-40 dry rolling granulator, selecting a whole sieve with the aperture of 1.5mm, adjusting the oil pressure to be more than 11MPa, continuously adding the materials into a hopper of the dry rolling granulator at a feeding speed of 50Hz, receiving the materials from a discharge port, sieving by using 60-mesh (250 mu m) and 80-mesh (180 mu m) steel sieves, and taking particles (the bulk density is 0.93g/ml, and the tap density is 1.25g/ml) with the particle size capable of passing through the 60-mesh but not 80-mesh sieves.
(2) Weighing high-density perindopril tert-butylamine particles after granulation according to the prescription amount, uniformly mixing with lactose, microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate, tabletting by adopting a phi 8mm punch, controlling the environmental humidity to be lower than 40% RH, and controlling the tabletting hardness as follows: 40-70N;
(3) the packaging form of aluminum-plastic blister packaging and an aluminum bag is adopted, and a molecular sieve desiccant is added into the aluminum bag.
Example 3
The process comprises the following steps:
(1) pressing perindopril tert-butylamine salt into sheets with proper hardness by using a dry granulator, grinding, sieving, specifically placing the raw materials into a GK-40 dry rolling granulator, selecting a whole sieve with the aperture of 1.5mm, adjusting the oil pressure to be more than 11MPa, continuously adding the materials into a hopper of the dry rolling granulator at a feeding speed of 50Hz, receiving the materials from a discharge port, sieving by using 30-mesh (600 mu m) and 60-mesh (250 mu m) steel sieves, and taking particles (the bulk density is 0.89g/ml, and the tap density is 1.12g/ml) with the particle size of being capable of passing through the 30-mesh sieve but not capable of passing through the 60-mesh sieve.
(2) Weighing high-density perindopril tert-butylamine particles granulated according to the prescription amount, uniformly mixing with lactose, microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate, tabletting by using a phi 8mm punch, controlling the environmental humidity to be lower than 40% RH, and controlling the tabletting hardness to be: 40-70N;
(3) the packaging form of aluminum-plastic blister packaging and an aluminum bag is adopted, and a molecular sieve desiccant is added into the aluminum bag.
Product performance detection
(1) Mixing uniformity: after the total mixing is finished, sampling is carried out at 9 different positions in the mixer, the content of the sample is measured, and the RSD of the content is calculated, wherein the smaller the RSD is, the more uniform the mixing is.
(2) The properties, content uniformity, dissolution rate, moisture and friability of the tablets are determined according to the method of Chinese pharmacopoeia 2015 edition.
(3) Method for measuring substance concerned
The samples were taken either fresh or using a low temperature sample injector (5 ℃).
Taking a proper amount of the fine powder (about 30mg of perindopril tert-butylamine) obtained in the example 1-3, placing the fine powder in a 10ml measuring flask, adding a proper amount of solvent water (the pH value is adjusted to 2.5 by using a 50% perchloric acid solution), dissolving perindopril tert-butylamine by ultrasonic treatment, cooling, diluting the solution to a scale by using a solvent, shaking up the solution, filtering, and taking a subsequent filtrate as a sample solution. Precisely measuring 1ml of the test solution, placing the test solution in a 200ml measuring flask, adding a solvent to dilute the test solution to a scale, and shaking the test solution uniformly to serve as a control solution. Precisely measuring 1ml of the control solution, placing the control solution in a 10ml measuring flask, adding a solvent to dilute the control solution to a scale, and shaking up the control solution to obtain a sensitivity solution. Taking another appropriate amount of perindopril peak identification reference substance, adding a solvent to dissolve and dilute the perindopril peak identification reference substance to prepare a solution containing about 3mg in each 1ml, and taking the solution as a system applicability solution 1; taking a proper amount of perindopril impurity standard substance, adding a solvent to dissolve and dilute the perindopril impurity standard substance to prepare a solution containing about 0.1mg in each 1ml as a system applicability solution 2. Measuring by high performance liquid chromatography (China pharmacopoeia 2015 edition general rules 0512). Octyl silane bonded silica gel as packing (Intersil C8-3 column, 4.0mm 150mm, 5 μm or equivalent performance column); mobile phase a was water (pH adjusted to 3.5 with 50% perchloric acid solution) and mobile phase B was acetonitrile (containing 0.03% perchloric acid).
TABLE 1 mobile phase gradient elution Table
Gradient elution was carried out as in Table 1, detection wavelength 215nm and column temperature 60 ℃. Injecting 120 mu l of the system applicability solution into a liquid chromatograph, wherein the retention time of a perindopril peak is about 25min, the impurity B, the impurity K, a main peak, the impurity E, the impurity F and the impurity H sequentially generate peaks, and the ratio of the peak height of the impurity B to the valley height between the impurity B and the impurity K is not less than 3.0; injecting 220 μ l of the system applicability solution into a liquid chromatograph, wherein the retention time of perindopril peak is about 25min, impurities C and D are in turn discharged, and the relative retention time of each impurity is shown in Table 2. Injecting 20 μ l of the sensitive solution into a liquid chromatograph, wherein the signal-to-noise ratio of the main component chromatographic peak should not be less than 10. Precisely measuring 20 μ l of each of the test solution and the reference solution, respectively injecting into a liquid chromatograph, and recording chromatogram. In the chromatogram of the test solution, the content limits of each impurity and the total impurities are shown in Table 2.
Table 2 relative retention times and limits for each of the known impurities
(4) Content determination method
Measured by high performance liquid chromatography (2015 version of Chinese pharmacopoeia 0512), the product contains perindopril tert-butylamine (C)19H32N2O5·C4H11N) should be between 90.0% and 110.0% of the indicated amount.
Chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as filler (recommended Agilent Zorbax SB-C18 column, 4.6mm 250mm, 5 μm or equivalent chromatographic column), and methanol-phosphate buffer solution (taking 2g potassium dihydrogen phosphate, adding water to dissolve, adding 3ml phosphoric acid and 3ml triethylamine, diluting with water to 1000ml) (48:52) is used as mobile phase; the column temperature was 50 ℃ and the detection wavelength was 215 nm. Taking a proper amount of perindopril tert-butylamine and an impurity B reference substance respectively, adding a mobile phase for dissolving and diluting to prepare a mixed solution containing 0.2mg of perindopril tert-butylamine and impurity B reference substances in each 1ml as a system applicability solution, taking 20 mu l of the mixed solution to be injected into a liquid chromatograph, and adjusting a chromatographic system to ensure that the retention time of a perindopril peak is about 12 minutes and the separation degree of the perindopril peak and the impurity B peak is more than 6.0. The theoretical plate number should not be lower than 3000 calculated as perindopril peak.
The determination method comprises the following steps: taking a proper amount (about 20mg of perindopril tert-butylamine) in examples 1-3, precisely weighing, placing in a 100ml measuring flask, dissolving perindopril tert-butylamine in a proper amount of mobile phase by using ultrasonic waves, cooling, diluting to a scale with the mobile phase, shaking uniformly, filtering, taking subsequent filtrate as a sample solution, precisely measuring 20 mu l, injecting into a liquid chromatograph, and recording a chromatogram. Taking a proper amount of perindopril tert-butylamine reference substance, adding a proper amount of mobile phase, dissolving by ultrasonic, cooling, quantitatively diluting by using the mobile phase to prepare a solution containing 0.2mg in each 1ml, and measuring by the same method. Calculating according to the peak area by an external standard method to obtain the product.
(5) Stability inspection method
The formulations of the above examples 1 to 3 were packaged by aluminum plastic blister and aluminum bag, and then placed under 40 ℃/75% RH for 1 month to measure the related substances, contents, etc.
The results are as follows:
tablets were prepared according to the methods of examples 1,2, and 3, and the mixing uniformity results show that: the high-density raw material particles of 60-80 meshes are easy to be uniformly mixed in the process of preparing the tablet, the mixing uniformity is better, and the mixing uniformity of the low-density raw material particles and the high-density raw material particles of 30-60 meshes is slightly poor. See table 3 for details.
Table 3 blend uniformity results
| Measurement items | Example 1 | Example 2 | Example 3 |
| RSD | 1.9％ | 0.9％ | 2.1％ |
Meanwhile, the properties, content uniformity, dissolution rate, moisture, hardness, friability and related substances of the tablets prepared by the methods of examples 1,2 and 3 were measured, and the results show that the quality of each tablet meets the standard requirements (table 4).
Table 4 tablet quality results
The stability tests were carried out by subjecting examples 1,2, 3 to accelerated conditions (40 ℃, RH 75%) for 1 month, and the results show that: tablets prepared from low-density perindopril tert-butylamine raw material particles are set out at 40 ℃ and RH 75% for 1 month, the impurity B, the impurity F and other maximum single impurities and total impurities are all obviously increased, and the increase amplitude of the tablets prepared from the high-density raw material particles is obviously smaller than that of the tablets prepared from the high-density raw material particles. Therefore, the stability of the tablet prepared from the high-density raw material particles is better. The results are shown in Table 5.
TABLE 5 tablet stability test results
In summary, the following steps: the high-density particles can obviously improve the stability, preferably 60-80 meshes of high-density raw material particles, have the best mixing uniformity in the process of preparing tablets, and the prepared tablets have the quality meeting the standard and obviously improve the stability in the storage process.
Claims (4)
1. A preparation method of perindopril tert-butylamine tablets is characterized by comprising the following steps:
(1) placing a perindopril tert-butylamine salt raw material into a dry rolling granulator, selecting a whole screen with the aperture of 1.2-1.6 mm, adjusting oil pressure to 11 MPa-20 Mpa at a feeding speed of 45-55 Hz, continuously adding the perindopril tert-butylamine salt raw material into a hopper of the dry rolling granulator, screening by using 30-mesh and 80-mesh steel screens after receiving materials, and taking high-density particles with the particle size capable of passing through the 30-mesh screen but not capable of passing through the 80-mesh screen;
(2) uniformly mixing perindopril tert-butylamine salt particles screened in the step (1) with a filler and a lubricant in a formula amount, and tabletting by using a phi 6-10 mm punch in an environment with the humidity lower than 40% RH, wherein the tabletting hardness is as follows: 40-70N.
2. A process for the preparation of perindopril tert-butylamine tablets according to claim 1, wherein the parts by weight of the starting materials are as follows:
6-10 parts of perindopril tert-butylamine;
170 parts of a filling agent 160;
2-5 parts of a lubricant.
3. A process for the preparation of perindopril tert-butylamine tablets according to claim 1, wherein the tablets are prepared in the form of aluminium blister packs with an aluminium bag in which a molecular sieve drying agent is added.
4. Use of perindopril tert-butylamine tablets prepared by the preparation method according to any one of claims 1 to 3 for the preparation of a medicament for the treatment of hypertension and congestive heart failure.
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| US20050142196A1 (en) * | 2003-07-11 | 2005-06-30 | Patel Ashish A. | Stable pharmaceutical compositions containing an ACE inhibitor |
| CN101166516A (en) * | 2005-01-21 | 2008-04-23 | 特瓦制药工业有限公司 | Stable pharmaceutical formulations of zonisamide and methods for their manufacture |
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| CN102482184A (en) * | 2009-09-01 | 2012-05-30 | 罗盖特公司 | Mannitol crystal powder having a low fine-particle content, and method for producing same |
| CN105395497A (en) * | 2015-12-04 | 2016-03-16 | 杭州新诺华医药有限公司 | Stable alpha-crystalline form perindopril tert-butylamine tablet and preparation method thereof |
| CN106620644A (en) * | 2016-12-13 | 2017-05-10 | 杭州新诺华医药有限公司 | Stable perindopril indapamide tablet and preparation technology |
| CN110229138A (en) * | 2018-03-05 | 2019-09-13 | 华东理工大学 | Lipoic acid spheroidal particle and its preparation method and application |
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2020
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|---|---|---|---|---|
| US20050142196A1 (en) * | 2003-07-11 | 2005-06-30 | Patel Ashish A. | Stable pharmaceutical compositions containing an ACE inhibitor |
| CN101166516A (en) * | 2005-01-21 | 2008-04-23 | 特瓦制药工业有限公司 | Stable pharmaceutical formulations of zonisamide and methods for their manufacture |
| CN101252915A (en) * | 2005-08-30 | 2008-08-27 | 力奇制药公司 | Pharmaceutical composition comprising perindopril or its salts |
| CN102482184A (en) * | 2009-09-01 | 2012-05-30 | 罗盖特公司 | Mannitol crystal powder having a low fine-particle content, and method for producing same |
| CN105395497A (en) * | 2015-12-04 | 2016-03-16 | 杭州新诺华医药有限公司 | Stable alpha-crystalline form perindopril tert-butylamine tablet and preparation method thereof |
| CN106620644A (en) * | 2016-12-13 | 2017-05-10 | 杭州新诺华医药有限公司 | Stable perindopril indapamide tablet and preparation technology |
| CN110229138A (en) * | 2018-03-05 | 2019-09-13 | 华东理工大学 | Lipoic acid spheroidal particle and its preparation method and application |
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| CN111419810A (en) | 2020-07-17 |
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