CN116440132A - Medicament containing amlodipine and azilsartan and preparation method thereof - Google Patents

Medicament containing amlodipine and azilsartan and preparation method thereof Download PDF

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Publication number
CN116440132A
CN116440132A CN202211643634.XA CN202211643634A CN116440132A CN 116440132 A CN116440132 A CN 116440132A CN 202211643634 A CN202211643634 A CN 202211643634A CN 116440132 A CN116440132 A CN 116440132A
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azilsartan
amlodipine
medicament
preparation
mixture
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尹九灵
朱润峰
王刚
褚襄萍
焦金红
许洁
王丹
杨学敏
周巧云
李洪明
张燕华
苏葳
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Fujian Ruitailai Pharmaceutical Technology Co ltd
Fujian Cosunter Pharmaceutical Co Ltd
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Fujian Ruitailai Pharmaceutical Technology Co ltd
Fujian Cosunter Pharmaceutical Co Ltd
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Priority to CN202211643634.XA priority Critical patent/CN116440132A/en
Publication of CN116440132A publication Critical patent/CN116440132A/en
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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
    • 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
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Organic Chemistry (AREA)
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Abstract

The invention relates to the technical field of medicines, in particular to a medicament containing amlodipine and azilsartan and a preparation method thereof, wherein the medicament comprises more than two mutually independent mechanisms, and the mechanism is provided with one of an amlodipine medicament and an azilsartan medicament; the amlodipine medicament is amlodipine or/and pharmaceutically acceptable salt thereof; the azilsartan medicine is azilsartan or/and pharmaceutically acceptable salt thereof. The preparation method comprises the following steps: preparing a first mixture from amlodipine and a first auxiliary material; spraying the azilsartan medicine and the second auxiliary material into particles prepared by the first adhesive in the granulating process, crushing, adding the third auxiliary material containing the second adhesive, and uniformly mixing to prepare a second mixture; the second mixture and the first mixture are pressed into a medicament. The invention is provided with mutually independent mechanisms, reduces the contact area of two kinds of medicines and improves the stability. The method of direct compression and fluid bed granulation ensures that the preparation process is simple and the stability is better.

Description

Medicament containing amlodipine and azilsartan and preparation method thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a medicament containing amlodipine and azilsartan.
Background
Hypertension is a disease caused by various complex factors, the occurrence and duration of the hypertension are related to various factors such as blood volume, heart function, blood vessel tension and the like, the action mechanisms of the existing clinically applied antihypertensive drugs are different, and the antihypertensive drugs generally can only sound to partial mechanism of the hypertension, so that the antihypertensive effect has a certain limitation. In recent years, whether it is an international or domestic guideline for hypertension, it has been uniformly recommended to initiate SPC (novel monolithic combination formulation) therapy, because it can simply and efficiently solve two key problems of combination therapy and compliance faced by hypertension management. 2018 European Society of Cardiology (ESC)/society of hypertension (ESH) guidelines: SPC combined with two drugs is the initial treatment preference for all hypertensive patients.
The number of patients suffering from hypertension in China is large, the control rate is low, most patients need to be combined for medication in order to achieve the standard of blood pressure, but the compliance is inversely proportional to the number of medications and the number of times of medications. The investigation shows that the hypertension drug treatment in China faces the serious problems of low combined use rate (only 30%) and poor compliance. Although SPC treatment can bring multiple benefits and is recommended in agreement for numerous authoritative guidelines, SPC utilization rate of hypertension patients in China is less than 10%. This is a great concern in clinical management, and improvements are needed in the current state of SPC use.
There are several fixed combinations containing calcium channel blockers ("calcium antagonists") and angiotensin ii receptor antagonists, such as tablets containing amlodipine and valsartan or amlodipine and azilsartan, on the market today for the treatment of hypertension and angina.
Azilsartan (azilsartan) with chemical name of 2-ethoxy-1- [ [2' - (5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) biphenyl-4-yl ] methyl ] -1H-benzimidazole-7-carboxylic acid, has a structure shown in formula I, and belongs to angiotensin ii receptor antagonists.
Amlodipine besylate (amlodipine besylate), chemical name: 3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4 dihydro-6-methyl-3, 5-pyridine dicarboxylic acid ester benzene sulfonate has a structure shown in formula I1, belongs to a calcium channel blocker, and can selectively inhibit calcium ions from entering smooth muscle cells and myocardial cells through a membrane.
Azilsartan amlodipine tablet developed by the Kagaku pharmaceutical industry Co., ltd., japan, 3 months in 2014, is approved for market in Japan under the trade name ofCan be used for treating hypertension. The compound is researched, and the azilsartan and the amlodipine besylate are both stable, but the stability of a compound preparation obtained by mixing the azilsartan and the amlodipine besylate is poor.
Disclosure of Invention
First, the technical problem to be solved
In view of the above-mentioned drawbacks and shortcomings of the prior art, the present invention provides a medicament comprising amlodipine and azilsartan, wherein the medicament is provided with two or more independent mechanisms for respectively storing the amlodipine and the azilsartan, so as to isolate the two mechanisms from contacting and improve the stability of the medicament;
correspondingly, the invention also provides a preparation method of the medicament containing amlodipine and azilsartan, which improves the dissolution rate of the amlodipine and the azilsartan by a direct compression method and a mode of adding an adhesive separately, reduces the occurrence of impurities and improves the storage stability.
(II) technical scheme
In order to achieve the above purpose, the main technical scheme adopted by the invention comprises the following steps:
in a first aspect, an embodiment of the present invention provides a medicament comprising amlodipine and azilsartan, which is characterized in that the medicament comprises more than two mutually independent mechanisms, wherein the mechanism is provided with one of an amlodipine medicament and an azilsartan medicament;
the amlodipine medicament is amlodipine or/and pharmaceutically acceptable salt thereof;
the azilsartan medicine is azilsartan or/and pharmaceutically acceptable salt thereof.
Optionally, the mechanism is a capsule capable of accommodating the medicine, or an integrated structure made of the medicine and auxiliary materials.
Alternatively, the medicament is a multi-layer structure formed by sequentially and tightly connecting more than two mutually independent mechanisms from inside to outside.
Alternatively, the ratio of the contact area of the two mechanisms to the volume of the medicament is 12-17:100.
Alternatively, the medicament is a cylinder and the bottom surface has a diameter of 9mm and a height of 4 to 6mm.
Optionally, the medicament volume is less than 500mm 3 Preferably less than 450mm 3 And more preferably less than 420mm 3 。
Optionally, a barrier is provided between the two mechanisms.
Optionally, the interlayer is mainly prepared from one or a combination of more than two of the following components: hydroxypropyl methylcellulose, polyvinyl alcohol, polyethylene glycol, glyceryl triacetate, titanium dioxide and talcum powder.
In a second aspect, the present invention also provides a process for the preparation of a medicament comprising amlodipine and azilsartan, comprising the steps of:
s1, preparing a first mixture from amlodipine medicines and first auxiliary materials;
s2, spraying the azilsartan medicine and the second auxiliary material into a first adhesive in the fluidized bed granulation process to prepare granules; pulverizing the prepared particles, adding a third auxiliary material containing a second adhesive, and uniformly mixing to prepare a second mixture;
s3, preparing a first mechanism from the first mixture by a direct compression method, and coating a second mixture on the outer side of the first mechanism by a tablet press to form a second mechanism;
or (b)
And preparing the second mixed material into a second mechanism by a direct compression method, and coating the first mixed material on the outer side of the second mechanism by a tablet press to form a first mechanism.
The invention obviously reduces the dosage of the first adhesive, and the mode of adding the second adhesive after crushing the prepared particles can lead the dissolution effect to be better and can endow the particles with better storage stability. The addition amount of the first adhesive is 2-5% of the weight of the medicament, and the addition amount of the second adhesive is 5-10% of the weight of the medicament.
Optionally, the first adhesive is a mixed solution of high-substituted hydroxypropyl cellulose and polyethylene glycol, and the mass concentration of the high-substituted hydroxypropyl cellulose is 5-12%.
Optionally, the second binder is highly substituted hydroxypropyl cellulose.
Optionally, the third auxiliary material is a mixture of low-substituted hydroxypropyl cellulose, high-substituted hydroxypropyl cellulose and microcrystalline cellulose.
Alternatively, the high substituted hydroxypropylcellulose has a molecular weight of less than 90000.
The molecular weight of the high-substituted hydroxypropyl cellulose is less than 90000, so that the prepared medicament has better dissolution, the occurrence of impurities is reduced, and the storage stability is improved.
Alternatively, in step S2, the amount of small particles smaller than 90 μm in the small particles obtained by pulverizing the particles is 30% or less, and the amount of small particles larger than 250 μm in the small particles is 10% or less.
Alternatively, the pulverization was carried out using a hammer mill, and the fluidized bed particles were pulverized into the above-mentioned particle size range using a 2.0mm sieve at a rotation speed of 2500 revolutions. The content of azilsartan in the tablets at the front, middle and later stages in the tabletting process can reach 98.0-102.0% in the particle size range.
Optionally, the first binder is added in an amount of 2-5% of the medicament content, and the second binder is added in an amount of 5-10% of the medicament content.
Optionally, the second auxiliary material comprises lactose, corn starch, microcrystalline cellulose, mannitol, pregelatinized starch.
Optionally, the first auxiliary material comprises anhydrous calcium hydrogen phosphate, microcrystalline cellulose, sodium carboxymethyl starch, calcium carboxymethyl cellulose, colloidal silicon dioxide, red ferric oxide and magnesium stearate.
Optionally, the third auxiliary material comprises high-substituted hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose and magnesium stearate.
(III) beneficial effects
The beneficial effects of the invention are as follows:
1. according to the medicament containing amlodipine and azilsartan, through arranging the mutually independent mechanisms for placing the amlodipine medicaments and the azilsartan medicaments, the contact area of the two medicaments is reduced, and the stability of the medicament serving as a compound preparation is improved.
2. In the preparation method of the medicament, the direct compression and fluid bed granulation methods not only lead the preparation process to be simple, but also have the advantages of increasing the stability and better technical effect of in vitro dissolution compared with other methods;
the first adhesive and the second adhesive are respectively added in the granulating and total mixing processes, so that the in-vitro dissolution effect is better.
In addition, the invention adopts a hammer crushing mode during the granulation, thereby not only ensuring good fluidity of the granules, but also perfectly solving the problem that the content of azilsartan in the medicament is less than 98.0-102.0% due to the layering of the granules in the tabletting process.
Detailed Description
The present invention will be described in detail below with reference to specific embodiments for better explaining the present invention.
The high-substituted hydroxypropyl cellulose in the embodiment of the invention is hydroxypropyl etherate of cellulose, contains 53.4 to 77.5 percent of hydroxypropyl, is white powder, is easy to dissolve in cold water, can be dissolved in methanol, ethanol, isopropanol and propylene glycol, has good inertia, does not react with medicines, and is an adhesive with excellent performance.
The low-substituted hydroxypropyl cellulose contains 7-9% of hydroxypropyl, has large surface area and porosity, good water absorption speed and water absorption capacity, the water absorption expansion rate is 500-700%, and the disintegrated particles are finer, so that the dissolution of the medicine is facilitated. The preparation is mainly used as a tablet disintegrating agent, and is characterized by easy molding, strong applicability, capability of increasing the hardness and appearance of the tablet, capability of enabling the tablet to disintegrate rapidly, and insusceptibility of the tablet to long-term storage.
The embodiments 1-12 of the invention provide a medicament containing amlodipine and azilsartan and a preparation method thereof, wherein the medicament is formed by a tablet core layer prepared from amlodipine and auxiliary materials, a shell layer coated on the tablet core layer and a coating layer coated on the outer surface of the shell layer prepared from azilsartan and auxiliary materials;
the respective parts by weight of the components in the core layer, the shell layer and the coating layer of the tablets in examples 1 to 12 are shown in Table 1;
the specific preparation method comprises the following steps:
s1, preparation of a core layer: using a 60-mesh sieve, mixing corresponding parts by weight of amlodipine besylate, amlodipine maleate, first microcrystalline cellulose, anhydrous calcium hydrophosphate, sodium carboxymethyl starch, carboxymethyl cellulose calcium, colloidal silicon dioxide and red ferric oxide for 3 times by adopting an equivalent progressive method, adding corresponding parts by weight of first magnesium stearate, mixing for 3 minutes to obtain a first mixture, and directly tabletting the first mixture into an amlodipine tablet core layer by adopting powder;
s2 preparation of a shell layer:
s21, sieving and mixing corresponding parts by weight of azilsartan, second microcrystalline cellulose, lactose and corn starch by using a 60-mesh sieve, placing the sieved and mixed materials in a fluidized bed granulation pot, spraying a first adhesive solution prepared by mixing corresponding parts by weight of first high-substituted hydroxypropyl cellulose and first polyethylene glycol, and performing fluidized bed granulation to obtain fluidized bed granules of an azilsartan layer;
s22, crushing the fluidized bed particles by using a 2500-turn hammer crusher and a 2.0 screen, adding the mixture of the low-substituted hydroxypropyl cellulose, the second high-substituted hydroxypropyl cellulose (second adhesive) and the third microcrystalline cellulose which are mixed for 3 times by using a 60-mesh screen again, mixing for 20 minutes, adding the second magnesium stearate, and mixing for 3 minutes to obtain a second mixed material;
s23, coating the second mixture on the outer side of an amlodipine tablet core through a tablet press with a core-in-tablet machine to form an azilsartan shell;
s3, coating the corresponding parts by weight of the mixture of the hypromellose, the second polyethylene glycol, the titanium dioxide and the iron oxide on the outer side of the azilsartan shell to form a coating layer, and preparing the medicament containing the amlodipine and the azilsartan.
Wherein the preparation of the coating layer is not necessary.
The embodiments 13-15 of the present invention provide a medicament comprising amlodipine and azilsartan and a preparation method thereof, wherein the medicament comprises a tablet core layer made of azilsartan and auxiliary materials, an isolation layer coated on the outer surface of the tablet core layer, and a shell layer coated on the tablet core layer made of amlodipine and auxiliary materials
The respective parts by weight of the components in the core layer, the shell layer and the separator in examples 13 to 15 are shown in Table 2;
the specific preparation method comprises the following steps:
s1, preparation of a core layer:
s11, sieving and mixing corresponding parts by weight of azilsartan, first microcrystalline cellulose, lactose and corn starch by using a 60-mesh sieve, placing the sieved and mixed materials in a fluidized bed granulation pot, spraying a first adhesive solution prepared by mixing corresponding parts by weight of first high-substituted hydroxypropyl cellulose and first polyethylene glycol, and performing fluidized bed granulation to obtain fluidized bed granules of an azilsartan layer;
s12, crushing the fluidized bed particles by using a 2500-turn hammer crusher and a 2.0 screen, adding the mixture of the low-substituted hydroxypropyl cellulose, the second high-substituted hydroxypropyl cellulose (second adhesive) and the second microcrystalline cellulose which are mixed for 3 times by using a 60-mesh screen again, mixing for 20 minutes, adding the first magnesium stearate, and mixing for 3 minutes to obtain a second mixed material;
s13, tabletting the second mixture to obtain an azilsartan tablet core;
s14, coating an isolation layer on the outer side of the azilsartan medoxomil tablet core by using a mixture of hydroxypropyl methylcellulose and second polyethylene glycol in corresponding parts by weight;
s2 preparation of a shell layer: and (3) sieving corresponding parts by weight of amlodipine besylate, amlodipine maleate, third microcrystalline cellulose, anhydrous calcium hydrophosphate, carboxymethyl starch sodium, carboxymethyl cellulose calcium, colloidal silicon dioxide and red ferric oxide by an equivalent progressive method for 3 times for mixing, adding corresponding parts by weight of second magnesium stearate for mixing for 3 minutes to obtain a first mixture, and coating the first mixture on the outer side of an azilsartan tablet core by a tablet press to form an amlodipine shell layer to obtain the medicament containing amlodipine and azilsartan.
Wherein the preparation of the isolating layer is not necessary.
TABLE 2
Comparative example 1
Other components and preparation methods were the same as in example 1, except that: the shell components and corresponding parts by weight of comparative example 1 are shown in Table 3, wherein the first highly substituted hydroxypropylcellulose was added in an amount of 25.7, and the second highly substituted hydroxypropylcellulose ELF was added in an amount of 0.
TABLE 3 Table 3
The components of the shell layer Parts by weight of
Azilsartan 20
Second microcrystalline cellulose 8
Lactose and lactose 119.95
CornStarch 35
First highly substituted hydroxypropyl cellulose ELF 25.7
First polyethylene glycol 7.7
Low substituted hydroxypropyl cellulose 13
Second highly substituted hydroxypropyl cellulose ELF 0
Third microcrystalline cellulose 19.4
Second magnesium stearate 1.25
Comparative example 2
Other components and preparation methods were the same as in example 1, except that: in comparative example 2, the first highly substituted hydroxypropylcellulose and the second highly substituted hydroxypropylcellulose were all of JXF type.
Wherein the molecular weight of the highly substituted hydroxypropyl cellulose JXF used in comparative example 2 is greater than 90000 and the molecular weight of the highly substituted ELF hydroxypropyl cellulose used in example 1 is less than 90000.
Test one the comparative dissolution tests of the agents comprising amlodipine and azilsartan obtained in examples 1-15 and comparative examples 1 and 2 of the present invention were carried out to determine dissolution profiles of azilsartan at 75rpm by paddle method under different pH media (pH 1.2 hydrochloric acid solution, pH4.5 acetate buffer, pH5.8 phosphate buffer, pH6.8 phosphate buffer), and the results are shown in tables 4-7 (wherein the values are dissolution percentages); the dissolution of amlodipine in each medium at 75rpm by paddle method was measured for 15 minutes, and the results are shown in table 8.
Wherein the control medicine is azilsartan amlodipine tablet produced by Wuta of Japan.
TABLE 4 Azilsartan elution results (pH 5.8 phosphate buffer)
Dissolution time (min) 0 5 10 15 30 60
Control drug 0 6.4 32.6 58.7 87.9 98.0
Example 1 0 7.2 33.1 59.6 89.8 99.5
Example 2 0 16.7 47.2 65.4 90.2 100.5
Example 3 0 36.2 75.3 90.7 98.2 98.9
Example 4 0 18.2 50.3 70.9 92.3 99.7
Example 5 0 4.4 28.4 52.3 85.4 99.1
Example 6 0 8.7 37.7 64.3 92.7 99.8
Example 7 0 8.5 36.7 63.3 91.7 100.2
Example 8 0 5.1 17.8 43.3 78.7 97.6
Example 9 0 8.1 33.7 60.2 89.7 99.8
Example 10 0 6.5 31.7 57.2 85.1 100.7
Example 11 0 4.5 19.7 45.2 79.9 98.2
Example 12 0 7.3 34.1 60.4 91.1 100.8
Example 13 0 12.4 54.7 85.4 99.7 98.9
Example 14 0 12.7 55.6 87.4 100.3 99.8
Example 15 0 32.6 67.8 93.5 100.6 100.7
Comparative example 1 0 29.2 52.8 72.4 93.7 99.7
Comparative example 2 0 3.1 21.2 48.5 81.3 99.5
TABLE 5 Azilsartan elution results (pH 6.8 phosphate buffer)
Dissolution time (min) 0 5 10 15 30 60
Control drug 0 13.3 64.0 92.5 98.7 99.8
Example 1 0 14.2 65.7 92.1 98.4 99.5
Example 5 0 10.2 56.7 84.7 94.3 99.5
Example 6 0 15.7 71.3 94.7 98.7 99.8
Example 7 0 15.6 71.7 94.3 99.1 100.2
Example 9 0 15.1 70.9 94.5 98.3 99.4
Example 10 0 13.7 62.2 87.1 95.4 100.1
Example 12 0 14.4 65.7 93.1 98.2 99.7
Comparative example 1 0 43.9 84.7 93.7 98.7 100.1
Comparative example 2 0 5.6 44.5 88.5 97.8 99.8
TABLE 6 Azilsartan dissolution results (pH 1.2 hydrochloric acid solution)
TABLE 7 Azilsartan dissolution results (pH 4.5 acetate buffer)
Dissolution time (min) 0 5 10 15 30 60
Control drug 0 0.8 6.1 10.2 14.3 16.4
Example 1 0 0.7 5.9 10.3 14.2 16.3
Example 5 0 0.7 5.4 9.7 13.6 15.9
Example 6 0 1.0 6.7 10.9 14.9 16.7
Example 7 0 0.8 6.3 10.4 14.3 16.2
Example 9 0 0.9 6.5 10.9 15.1 16.9
Example 10 0 1.0 6.5 10.7 14.6 16.2
Example 12 0 1.2 6.9 10.6 14.9 16.5
Comparative example 1 0 5.7 10.2 11.5 14.3 16.1
Comparative example 2 0 0.8 6.3 10.3 14.1 16.6
TABLE 8 results of 15 minute dissolution of amlodipine in various media
The dissolution rate of the control drug may represent a dissolution rate which has been clinically proven to have little side effects on the human body and good efficacy, and deviations from the dissolution rate of the control drug are considered to have a greater potential safety risk to the human body or poor efficacy.
As can be seen from tables 4 to 5, the dissolution rates of azilsartan of examples 1, 5, 6, 7, 9, 10 and 12 at the respective time points of the control drugs are similar to those of the control drugs under the conditions of ph5.8 and ph6.8, and the dissolution rates of comparative examples 1,2 and the control drugs are different from each other;
from this, it can be seen that: in example 1, the dissolution rate of the binder highly substituted hydroxypropyl cellulose ELF was consistent with that of the control drug at each time point by adding the binder highly substituted hydroxypropyl cellulose ELF separately (adding granulation and adding total mixing), while the dissolution rate was significantly affected by adding the binder highly substituted hydroxypropyl cellulose ELF at one time in comparative example 1, and the dissolution rate was greatly different from that of the control drug; the preparation of highly substituted hydroxypropylcellulose JXF also does not improve dissolution.
Tables 6 to 7 show that the dissolution rate of azilsartan within 60min is low at pH1.2 and pH4.5, which is related to the apparent influence of pH on the solubility of the drug itself and the in vivo pK properties of the drug. The dissolution rates of the examples and the control drug at these two pH conditions were also highly consistent.
As can be seen from Table 8, the amlodipine dissolution of each of the examples and the control drug in a plurality of media having pH5.8, pH6.8, pH4.5 and pH1.2 satisfies 15 minutes and the cumulative dissolution rate is more than 85%, and thus the in vivo absorption and the efficacy can be ensured.
Test two the medicaments comprising amlodipine and azilsartan obtained in examples 1-15 and comparative examples 1 and 2 of the present invention were subjected to a test under severe test conditions (without packaging, die placement, 40 ℃ ± 2 ℃ and relative humidity 75% ± 5%) to examine stability, and the results were shown in table 9.
Wherein the control medicine is azilsartan amlodipine tablet produced by Wuta of Japan.
TABLE 9 comparative drug, example, comparative impurity results
As shown in table 9, examples 1 to 15 of the present invention can be obtained, and azilsartan amlodipine impurity can be controlled at a low level. Under severe inspection conditions (without packaging, die placement, 40 ℃ ± 2 ℃ and relative humidity 75% ± 5%) lofting inspection, the impurities of the examples remain at a lower level, no significant increase is seen, and stability is significantly improved compared to the control drug.
Thirdly, granulating the fluidized bed particles in the step S22 of the embodiment 1 of the invention by using a hammer mill, sieving, treating by using screens with different rotation speeds and different specifications, and measuring the content of azilsartan and the material fluidity during tabletting; and the fluidized bed particles are processed by using a hammer mill and screens with different specifications by using a granulator, and the content of azilsartan and the material fluidity during tabletting in the step S23 are measured; the results are shown in Table 10.
Table 10 particle size distribution and Effect of different pulverizing and granulating methods of example 1
As shown in Table 10, according to the embodiment of the invention, the azilsartan shell fluidized bed particles are crushed under the condition of a 2.0mm screen and 2500 turns, the content of the azilsartan in the obtained medicament can reach 98.0-102.0%, and the flowability of the material during tabletting can be ensured.
In step S2, the fluidized bed particles were pulverized by a hammer mill at a rotational speed of 2500 rpm with a 2.0mm screen, to obtain the following particle size distribution: not more than 30% of the particles are smaller than 90 μm, and not more than 10% of the particles are larger than 250 μm. The content of azilsartan in the pre-medicament, the middle medicament and the post-medicament in the tabletting process can reach 98.0-102.0 percent within the particle size range.
The content calculation method of the azilsartan is as follows:
the content of azilsartan in the medicament= (mass of azilsartan in actual detection/mass of actual medicament)/(mass of theoretical medicament/mass of theoretical medicament) ×100%. For example: the weight of the agent is theoretically 300mg and azilsartan is theoretically 20mg. However, in the actual tabletting process, the weight of the prepared tablet may be 290-310 mg due to deviation of equipment, so that the content of azilsartan is 97-103%. Theoretically, when the content reaches 98.0% or more, it can be said that the loss rate is almost zero.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.

Claims (9)

1. The medicament containing amlodipine and azilsartan is characterized by comprising more than two mutually independent mechanisms, wherein the mechanisms are provided with one of amlodipine medicaments and azilsartan medicaments;
the amlodipine medicament is amlodipine or/and pharmaceutically acceptable salt thereof;
the azilsartan medicine is azilsartan or/and pharmaceutically acceptable salt thereof.
2. The medicament comprising amlodipine and azilsartan as defined in claim 1, wherein: the mechanism is a capsule capable of containing the medicine or an integrated structure made of the medicine and auxiliary materials.
3. The pharmaceutical preparation comprising amlodipine and azilsartan according to claim 1, wherein the pharmaceutical preparation is a multi-layered structure formed by sequentially and tightly connecting two or more mutually independent mechanisms from inside to outside.
4. A process for the preparation of a medicament comprising amlodipine and azilsartan as claimed in claim 1, comprising the steps of:
s1, preparing a first mixture from amlodipine medicines and first auxiliary materials;
s2, spraying the azilsartan medicine and the second auxiliary material into a first adhesive in the fluidized bed granulation process to prepare granules; pulverizing the prepared particles, adding a third auxiliary material containing a second adhesive, and uniformly mixing to prepare a second mixture;
s3, preparing a first mechanism from the first mixture by a direct compression method, and coating a second mixture on the outer side of the first mechanism by a tablet press to form a second mechanism;
or (b)
And preparing the second mixed material into a second mechanism by a direct compression method, and coating the first mixed material on the outer side of the second mechanism by a tablet press to form a first mechanism.
5. A process for the preparation of a medicament comprising amlodipine and azilsartan as defined in claim 4, wherein: the first adhesive is a mixed solution of high-substituted hydroxypropyl cellulose and polyethylene glycol, and the mass concentration of the high-substituted hydroxypropyl cellulose is 5-12%.
6. A process for the preparation of a medicament comprising amlodipine and azilsartan as defined in claim 4, wherein: the second binder is highly substituted hydroxypropyl cellulose.
7. A process for the preparation of a medicament comprising amlodipine and azilsartan as defined in claim 5 or 6, wherein: the molecular weight of the high-substituted hydroxypropyl cellulose is less than 90000.
8. A process for the preparation of a medicament comprising amlodipine and azilsartan as defined in claim 4, wherein: in the step S2, the amount of small particles smaller than 90 μm is 30% or less, and the amount of small particles larger than 250 μm is 10% or less.
9. A process for the preparation of a medicament comprising amlodipine and azilsartan as defined in claim 4, wherein: the addition amount of the first adhesive is 2-5% of the weight of the medicament, and the addition amount of the second adhesive is 5-10% of the weight of the medicament.
CN202211643634.XA 2022-12-20 2022-12-20 Medicament containing amlodipine and azilsartan and preparation method thereof Pending CN116440132A (en)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103169701A (en) * 2011-12-22 2013-06-26 天津康鸿医药科技发展有限公司 Telmisartan amlodipine double-layer tablet and preparation method thereof
WO2015051771A1 (en) * 2013-10-08 2015-04-16 Zentiva, K.S. A stable pharmaceutical composition containing amlodipine and valsartan
CN106668016A (en) * 2015-11-11 2017-05-17 江苏先声药业有限公司 Solid preparation of azilsartan and levamlodpine besylate composition and preparation method of solid preparation
CN109432034A (en) * 2018-12-28 2019-03-08 乐普制药科技有限公司 A kind of valsartan amlodipine tri-layer tablets and preparation method thereof
JP2020094025A (en) * 2018-12-11 2020-06-18 日本ジェネリック株式会社 Solid preparations containing azilsartan and amlodipine besilate and methods for producing solid formulations
JP2021161103A (en) * 2020-03-31 2021-10-11 日本ジェネリック株式会社 Film coated tablet containing azisartan and amlodipine besylate
CN114224859A (en) * 2020-12-29 2022-03-25 深圳信立泰药业股份有限公司 Compound antihypertensive medicinal composition and preparation method thereof
CN114668760A (en) * 2022-03-11 2022-06-28 福建瑞泰来医药科技有限公司 Medicament containing amlodipine and bisoprolol and preparation method thereof

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103169701A (en) * 2011-12-22 2013-06-26 天津康鸿医药科技发展有限公司 Telmisartan amlodipine double-layer tablet and preparation method thereof
WO2015051771A1 (en) * 2013-10-08 2015-04-16 Zentiva, K.S. A stable pharmaceutical composition containing amlodipine and valsartan
CN106668016A (en) * 2015-11-11 2017-05-17 江苏先声药业有限公司 Solid preparation of azilsartan and levamlodpine besylate composition and preparation method of solid preparation
JP2020094025A (en) * 2018-12-11 2020-06-18 日本ジェネリック株式会社 Solid preparations containing azilsartan and amlodipine besilate and methods for producing solid formulations
CN109432034A (en) * 2018-12-28 2019-03-08 乐普制药科技有限公司 A kind of valsartan amlodipine tri-layer tablets and preparation method thereof
JP2021161103A (en) * 2020-03-31 2021-10-11 日本ジェネリック株式会社 Film coated tablet containing azisartan and amlodipine besylate
CN114224859A (en) * 2020-12-29 2022-03-25 深圳信立泰药业股份有限公司 Compound antihypertensive medicinal composition and preparation method thereof
CN114668760A (en) * 2022-03-11 2022-06-28 福建瑞泰来医药科技有限公司 Medicament containing amlodipine and bisoprolol and preparation method thereof

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