CN114209675B - Clopidogrel hydrogen sulfate aspirin microchip capsule and preparation method thereof - Google Patents

Clopidogrel hydrogen sulfate aspirin microchip capsule and preparation method thereof Download PDF

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CN114209675B
CN114209675B CN202210064244.0A CN202210064244A CN114209675B CN 114209675 B CN114209675 B CN 114209675B CN 202210064244 A CN202210064244 A CN 202210064244A CN 114209675 B CN114209675 B CN 114209675B
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aspirin
clopidogrel bisulfate
microchip
capsule
clopidogrel
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CN114209675A (en
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宁宗超
徐德海
郭全禄
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Beijing Weizhirui Pharmaceutical Technology Co ltd
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Beijing Weizhirui Pharmaceutical Technology Co ltd
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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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

Abstract

The application provides a clopidogrel bisulfate aspirin microchip capsule and a preparation method thereof, wherein the clopidogrel bisulfate aspirin microchip capsule comprises clopidogrel bisulfate, aspirin microchip and a capsule shell, wherein active ingredients are clopidogrel bisulfate and aspirin; the auxiliary materials are filler, disintegrating agent, glidant and/or lubricant. The aspirin and the clopidogrel bisulfate are respectively pressed into two micro tablets, and then the two micro tablets are filled into the same capsule according to the specification requirement, and compared with a double-layer tablet of a commercially available preparation, the micro tablet capsule can be used for physically and absolutely isolating the aspirin and the clopidogrel bisulfate, so that the interaction of the aspirin and the clopidogrel bisulfate can be avoided, the stability of the clopidogrel bisulfate tablet is greatly improved, and the process is more controllable compared with the double-layer tablet.

Description

Clopidogrel hydrogen sulfate aspirin microchip capsule and preparation method thereof
Technical Field
The application relates to the technical field of medicines, in particular to clopidogrel bisulfate aspirin microchip capsules and a preparation method thereof.
Background
Aspirin can inhibit the release reaction of blood platelets and inhibit the aggregation of blood platelets, thereby reducing the generation of thromboxane A2 (TXA 2), and is mainly used for preventing and treating ischemic heart disease, angina pectoris, heart-lung infarction and cerebral thrombosis.
Clopidogrel bisulfate can selectively inhibit the combination of adenosine diphosphate (adenosine diphosphate, ADP) and platelet receptors, and then inhibit and activate ADP and glycoprotein GPIIb/IIIa complex, thereby inhibiting the aggregation of platelets, and is mainly used for treating patients suffering from apoplexy, myocardial infarction and peripheral arterial diseases.
Research shows that aspirin and clopidogrel bisulfate are combined, so that the antiplatelet activity is obviously enhanced, and the clopidogrel sodium bisulfate can be used for treating diseases caused by platelet aggregation, including stable or unstable angina pectoris, cardiovascular and cerebrovascular diseases, and has definite curative effect.
The clopidogrel bisulfate aspirin tablet sold in the market at present is a double-layer tablet, because aspirin and clopidogrel bisulfate have poor compatibility, and the two raw materials are directly mixed and tableted, the contact of the clopidogrel bisulfate and the aspirin is greatly increased, and further, the properties are changed and related substances are increased. The stability of the prepared double-layer tablet can be effectively improved, but the process of the double-layer tablet has higher requirements on equipment and auxiliary materials, and the phenomenon of mixing local raw material medicines still cannot be avoided in the preparation process, so that the two raw material medicines cannot be completely isolated.
Disclosure of Invention
The application provides a clopidogrel hydrogen sulfate aspirin micro-tablet capsule and a preparation method thereof, which are used for solving the problem that the contact phenomenon of local raw materials can not be avoided in the existing preparation process of a clopidogrel hydrogen sulfate aspirin double-layer tablet, so that the two raw materials can not be completely isolated.
On one hand, the application provides a clopidogrel bisulfate aspirin microchip capsule which consists of clopidogrel bisulfate microchip, aspirin microchip and a capsule shell, wherein active ingredients are clopidogrel bisulfate and aspirin; the auxiliary materials are filler, disintegrating agent, glidant and/or lubricant.
Optionally, the active ingredient accounts for 30-60%, the filling agent accounts for 25-40%, the disintegrating agent accounts for 4-20%, and the glidant and/or the lubricant accounts for 0.8-2.5%; the active ingredient comprises 12-42% of aspirin; clopidogrel bisulfate accounts for 18-48 percent.
Optionally, the capsule comprises clopidogrel bisulfate micro tablets, aspirin micro tablets and a capsule shell; wherein, the number of clopidogrel bisulfate micro tablets is 10-20, the number of aspirin micro tablets is 8-20, and the capsule shells are enteric capsule shells of No. 1, no. 0 and No. 00; wherein, the clopidogrel bisulfate micro tablet has the specification of 5-10mg, the tablet weight of 10-25mg and the diameter of 2-3mm; the aspirin micro tablet has a specification of 5-10mg, a tablet weight of 10-25mg and a diameter of 2-3mm.
Optionally, the filler is one of microcrystalline cellulose, lactose, corn starch, silicified microcrystalline cellulose and mannitol; the disintegrating agent is microcrystalline cellulose or low-substituted hydroxypropyl cellulose.
Optionally, the glidant is silicon dioxide or talcum powder; the lubricant is one of stearic acid, zinc stearate, magnesium stearate, polyethylene glycol and glyceryl behenate.
In a second aspect, the present application provides a method for preparing clopidogrel bisulfate aspirin microchip capsule, comprising the following steps:
sieving aspirin with 80 mesh sieve, mixing with a first filler, a first disintegrating agent and a first glidant to obtain a first mixture; adding a first lubricant into the first mixture, and mixing to obtain an aspirin micro tablet;
sieving clopidogrel bisulfate with an 80-mesh sieve, and mixing with a second filler, a second disintegrating agent and a second glidant to obtain a second mixture; adding a second lubricant into the second mixture and mixing to obtain clopidogrel bisulfate micro-tablets;
filling aspirin microchip and clopidogrel bisulfate Lei Weipian into capsule shells to prepare the microchip capsules.
Optionally, in the aspirin micro tablet, 36-52% of aspirin, 24-44% of a first filler, 6-20% of a first disintegrating agent, 0.8-2.5% of a first glidant and 0.8-2.5% of a first lubricant.
Optionally, in the clopidogrel bisulfate micro tablet, the clopidogrel bisulfate is 38-66% by weight, the filler is 24-45% by weight, the disintegrating agent is 4-8% by weight, the second glidant is 0.8-2.5% by weight, and the second lubricant is 0.8-2.5% by weight.
According to the technical scheme, the clopidogrel hydrogen sulfate aspirin microchip capsule and the preparation method thereof are provided, wherein the clopidogrel hydrogen sulfate aspirin microchip capsule consists of clopidogrel hydrogen sulfate microchip, aspirin microchip and a capsule shell, and active ingredients are clopidogrel hydrogen sulfate and aspirin; the auxiliary materials are filler, disintegrating agent, glidant and/or lubricant. The aspirin and the clopidogrel bisulfate are respectively pressed into two micro tablets, and then the two micro tablets are filled into the same capsule according to the specification requirement, so that the aspirin and the clopidogrel bisulfate can be physically and absolutely isolated, the interaction of the aspirin and the clopidogrel bisulfate can be stopped, the stability of the clopidogrel bisulfate tablet is greatly improved, and the process is more controllable compared with a double-layer tablet. And the capsule body of the clopidogrel hydrogen sulfate aspirin microchip capsule is selected as an enteric capsule, so that adverse reaction caused by the irritation of aspirin to gastric mucosa can be avoided, and the enteric coating procedure with high technological difficulty can be avoided.
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In order to more clearly illustrate the technical solutions of the present application, the drawings that are needed in the embodiments will be briefly described below, and it will be obvious to those skilled in the art that other drawings can be obtained from these drawings without inventive effort.
Fig. 1 is a schematic diagram of clopidogrel bisulfate aspirin microchip capsule provided herein.
Detailed Description
Reference will now be made in detail to the embodiments, examples of which are illustrated in the accompanying drawings. When the following description refers to the accompanying drawings, the same numbers in different drawings refer to the same or similar elements, unless otherwise indicated. The embodiments described in the examples below do not represent all embodiments consistent with the present application. Merely as examples of systems and methods consistent with some aspects of the present application as detailed in the claims.
Currently, clopidogrel hydrogen sulfate aspirin tablets are developed by the company of minofei amont under the trade name Duoplavin, which obtains the marketing approval of the human pharmaceutical products Committee (CHMP) of the European Medicines Agency (EMA) at 12 months of 2009, and the compound tablet comprises 2 dose combinations, namely 75mg of clopidogrel/75 mg of aspirin and 75mg of clopidogrel/100 mg of aspirin.
The clopidogrel bisulfate aspirin tablet sold in the market at present is a double-layer tablet, because aspirin and clopidogrel bisulfate have poor compatibility, and the two raw materials are directly mixed and tableted, the contact of the clopidogrel bisulfate and the aspirin is greatly increased, and further, the properties are changed and related substances are increased. The stability of the prepared double-layer tablet can be effectively improved. However, the process of the double-layer tablet has high requirements on equipment and auxiliary materials, and the phenomenon of local contact still cannot be avoided in the preparation process. The oral aspirin can directly influence the symptoms of nausea and vomiting caused by gastric mucosa irritation, gastric ulcer, gastrorrhagia and the like caused by gastric membrane damage after long-term use.
In order to solve the technical problems, the clopidogrel bisulfate aspirin microchip capsule and the preparation method thereof are provided.
On one hand, the application provides a clopidogrel bisulfate aspirin microchip capsule which consists of clopidogrel bisulfate microchip, aspirin microchip and a capsule shell, wherein active ingredients are clopidogrel bisulfate and aspirin; the auxiliary materials are filler, disintegrating agent, glidant and/or lubricant.
Specifically, the active ingredient accounts for 30-60%, the filling agent accounts for 25-40%, the disintegrating agent accounts for 4-20%, and the glidant and/or the lubricant accounts for 0.8-2.5%; the active ingredient comprises 12-42% of aspirin; clopidogrel bisulfate accounts for 18-48 percent.
Specifically, the capsule comprises clopidogrel bisulfate micro tablets, aspirin micro tablets and a capsule shell; wherein, the number of clopidogrel bisulfate micro tablets is 10-20, the number of aspirin micro tablets is 8-20, and the capsule shells are enteric capsule shells of No. 1, no. 0 and No. 00; wherein, the clopidogrel bisulfate micro tablet has the specification of 5-10mg, the tablet weight of 10-25mg and the diameter of 2-3mm; the aspirin micro tablet has a specification of 5-10mg, a tablet weight of 10-25mg and a diameter of 2-3mm.
Specifically, the filler is one of microcrystalline cellulose, lactose, corn starch, silicified microcrystalline cellulose and mannitol; the disintegrating agent is microcrystalline cellulose or low-substituted hydroxypropyl cellulose.
Specifically, the glidant is silicon dioxide or talcum powder; the lubricant is one of stearic acid, zinc stearate, magnesium stearate, polyethylene glycol and glyceryl behenate.
In a second aspect, the present application provides a method for preparing clopidogrel bisulfate aspirin microchip capsule, comprising the following steps:
sieving aspirin with 80 mesh sieve, mixing with a first filler, a first disintegrating agent and a first glidant to obtain a first mixture; adding a first lubricant into the first mixture, and mixing to obtain an aspirin micro tablet;
sieving clopidogrel bisulfate with an 80-mesh sieve, and mixing with a second filler, a second disintegrating agent and a second glidant to obtain a second mixture; adding a second lubricant into the second mixture and mixing to obtain clopidogrel bisulfate micro-tablets;
filling aspirin microchip and clopidogrel bisulfate Lei Weipian into capsule shells to prepare the microchip capsules.
Specifically, in the aspirin micro tablet, 36-52% of aspirin, 24-44% of a first filler, 6-20% of a first disintegrating agent, 0.8-2.5% of a first glidant and 0.8-2.5% of a first lubricant.
Specifically, in the clopidogrel bisulfate micro tablet, the weight part of clopidogrel bisulfate is 38-66%, the weight part of filler is 24-45%, the weight part of disintegrating agent is 4-8%, the weight part of glidant is 0.8-2.5%, and the weight part of lubricant is 0.8-2.5%.
Fig. 1 is a schematic diagram of clopidogrel bisulfate aspirin microtablet capsules provided in the present application, small capsule No. 1 and large capsule No. 0.
Specific examples are given below for details.
Example 1
TABLE 1
Figure GDA0004214326490000041
Figure GDA0004214326490000051
Wherein, table 1 is the composition and ratio of each component of example 1.
The process comprises the following steps:
preparation of aspirin micro-tablets:
sieving aspirin with 80 mesh sieve, mixing with lactose, microcrystalline cellulose and silicon dioxide, sieving with 40 mesh sieve, adding stearic acid, and sieving with 40 mesh sieve. Making into microtablets with diameter of 2mm and weight of 10mg, each tablet containing 5mg of aspirin.
Clopidogrel bisulfate micro-tablets are prepared:
sieving clopidogrel bisulfate with a 80-mesh sieve, mixing with mannitol, low-substituted hydroxypropyl cellulose and silicon dioxide with a 40-mesh sieve, adding zinc stearate, and mixing with 40-mesh sieve. Making into microtablets with diameter of 2mm and weight of 10mg, each tablet containing clopidogrel 5mg.
Making into compound capsule:
taking the 15 pieces of aspirin micro-tablets, 15 pieces of clopidogrel bisulfate micro-tablets, and filling the tablets into No. 1 enteric-coated capsules to prepare 75mg: clopidogrel bisulfate and aspirin microtablets with 75mg specification.
Example 2
TABLE 2
Figure GDA0004214326490000052
Wherein, table 2 is the composition and ratio of each component of example 2.
The process comprises the following steps:
preparation of aspirin micro-tablets:
sieving aspirin with 60 mesh sieve, mixing with corn starch, microcrystalline cellulose and silicon dioxide, sieving with 40 mesh sieve, adding stearic acid, and sieving with 40 mesh sieve. Making into microtablets with diameter of 2mm and weight of 10mg, each tablet containing 5mg of aspirin.
Clopidogrel bisulfate micro-tablets are prepared:
sieving clopidogrel hydrogen sulfate with 60 mesh sieve, mixing with silicified microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and pulvis Talci with 40 mesh sieve, adding polyethylene glycol 6000, and sieving with 40 mesh sieve. Making into microtablets with diameter of 2mm and weight of 10mg, each tablet containing clopidogrel 5mg.
Making into compound capsule:
taking 15 pieces of the aspirin micro tablet, 20 pieces of clopidogrel bisulfate micro tablet, and filling into a No. 0 enteric capsule to prepare 75mg: clopidogrel bisulfate aspirin micro-tablet enteric-coated capsule with 100mg specification.
Example 3
TABLE 3 Table 3
Figure GDA0004214326490000061
Wherein, table 3 is the composition and ratio of each component of example 3.
The process comprises the following steps:
preparation of aspirin micro-tablets:
sieving aspirin with 60 mesh sieve, mixing with microcrystalline cellulose, povidone K30 and silicon dioxide, sieving with 40 mesh sieve, adding stearic acid, and sieving with 40 mesh sieve. Making into microtablets with diameter of 2mm and weight of 10mg, each tablet containing 5mg of aspirin.
Clopidogrel bisulfate micro-tablets are prepared:
clopidogrel bisulfate is sieved by a 60-mesh sieve, mixed with silicified microcrystalline cellulose, sodium carboxymethyl starch and silicon dioxide by a 40-mesh sieve, added with glyceryl behenate and sieved by a 40-mesh sieve. Making into microtablets with diameter of 2mm and weight of 10mg, each tablet containing clopidogrel 5mg.
Making into compound capsule:
taking the 15 aspirin micro-tablets, namely 15 clopidogrel bisulfate micro-tablets, and filling the 15 clopidogrel bisulfate micro-tablets into a No. 1 enteric capsule to prepare 75mg; clopidogrel bisulfate and aspirin microtablets with 75mg specification.
Example 4
The aspirin microtablets and clopidogrel bisulfate microtablets in example 3 were coated, and the aspirin microtablets and the clopidogrel bisulfate microtablets were further completely separated from each other by barrier coating using different colors of the opadry film coating premixes. Coating parameters: the solid content of the coating liquid is 12%, the material temperature is 30-40 ℃, the rotating speed of a host machine is 6-15rpm, and the coating weight gain is 2-3%. Obtaining light blue aspirin film coated micro-tablets, wherein the coating weight is increased by 2.6%; the clopidogrel bisulfate film coated micro-tablets have the weight gain of 2.4 percent. Taking the light blue aspirin film coated micro-tablets 15 tablets respectively, and loading the yellow clopidogrel bisulfate film coated micro-tablets 15 tablets into No. 1 enteric-coated capsules to prepare 75mg: clopidogrel bisulfate and aspirin microtablets with 75mg specification.
Comparative example 1
TABLE 4 Table 4
Prescription composition Action Proportion of
Aspirin Active ingredient 20％(5mg)
Clopidogrel bisulfate Active ingredient 26.1％(6.52mg)
Lactose and lactose Filler (B) 34％
Microcrystalline cellulose Disintegrating agent 18％
Silica dioxide Glidant 1.1％
Stearic acid Lubricant 0.8％
Wherein, table 4 is the composition and ratio of each component of comparative example 1.
The difference is that aspirin and clopidogrel bisulfate are directly mixed and tableted.
The process comprises the following steps:
sieving aspirin and clopidogrel bisulfate with a 60-mesh sieve, mixing with lactose, microcrystalline cellulose and silicon dioxide with a 40-mesh sieve, adding stearic acid, and mixing with 40-mesh sieve.
Making into microtablets with diameter of 3mm, tablet weight of 25mg, each tablet containing 5mg of aspirin and 5mg of clopidogrel containing.
Taking 15 clopidogrel hydrogen sulfate aspirin micro tablets, and filling the clopidogrel hydrogen sulfate aspirin micro tablets into a size 0 gelatin capsule to prepare 75mg; clopidogrel bisulfate and aspirin microtablets with 75mg specification.
Comparative example 2
TABLE 5
Figure GDA0004214326490000081
Wherein, table 5 is the composition and ratio of each component of comparative example 2.
The difference is that aspirin and clopidogrel bisulfate are pressed into double-layer tablets.
The process comprises the following steps:
sieving aspirin with 60 mesh sieve, mixing with microcrystalline cellulose and silicon dioxide with 40 mesh sieve, adding stearic acid, and sieving with 40 mesh sieve.
Sieving clopidogrel bisulfate with a 60-mesh sieve, mixing with mannitol, low-substituted hydroxypropyl cellulose and silicon dioxide with a 40-mesh sieve, adding zinc stearate, and mixing with 40-mesh sieve for standby.
And (3) pressing the double-layer tablet by using a tablet press, filling aspirin mixed powder, pre-pressing the tablet, filling clopidogrel bisulfate mixed powder, and pressing the tablet. The tablet has a diameter of 10mm, a tablet weight of 500mg, and each tablet contains 75mg of aspirin and 75mg of clopidogrel.
Comparative example 3
The only difference was that the tablets of comparative example 2 were enteric coated.
Coating using an opadry enteric coating premix, coating parameters: the solid content of the coating liquid is 7%, the material temperature is 30-40 ℃, the rotating speed of the main machine is 6-15rpm, and the coating weight gain is 6-8%. The coating weight gain of the obtained enteric coated tablet is 6.9%.
The capsule shell types and parameters used in examples 1-4 above are shown in Table 6.
TABLE 6
Project 00 # 0 # 1 #
Cap length (mm) 11.6±0.4 10.8±0.4 9.8±0.4
Body length (mm) 19.8±0.4 18.4±0.4 16.4±0.4
Wall thickness (mm) 0.110±0.015 0.110±0.015 0.110±0.015
Body wall thickness (mm) 0.110±0.015 0.110±0.015 0.110±0.015
Riser part outer diameter (mm) 8.48±0.03 7.58±0.03 6.83±0.03
Body opening external diameter (mm) 8.15±0.03 7.34±0.03 6.61±0.03
Lock and rear total length (mm) 23.3±0.03 21.2±0.03 19.0±0.03
Average weight (mg) 122±10 97±8 77±6
Volume (ml) 0.95 0.68 0.5
The analysis is performed in conjunction with specific effect evaluation data.
Effect evaluation data:
1. time limit of disintegration
Enteric capsule: taking 6 grains of a test sample, firstly, checking for 2 hours in a hydrochloric acid solution (9-1000) without adding a baffle, wherein the capsule shell of each grain cannot crack or disintegrate; taking out the basket, washing with small amount of water, adding baffle plate into each tube, and checking in artificial intestinal juice according to the above method, wherein the whole tube should disintegrate within 1 hr. If 1 granule can not be completely disintegrated, 6 granules should be taken for repeated tests, and all the granules should meet the regulations.
Enteric coated tablets: taking 6 tablets of a test sample, firstly checking in hydrochloric acid solution (9-1000) for 2 hours, wherein each tablet cannot crack, disintegrate or soften; and taking out the hanging basket, washing with a small amount of water, and then, checking in artificial intestinal juice according to the method, wherein the whole basket should be disintegrated within 1 hour. If 1 tablet can not be completely disintegrated, 6 tablets should be taken for repeated tests, and all the tablets should meet the regulations. The disintegration test data are shown in tables 7-8.
TABLE 7 disintegration test in hydrochloric acid solution
Test group Time limit of disintegration
Example 1 No cracking and disintegration
Example 2 No cracking and disintegration
Example 3 No cracking and disintegration
Figure GDA0004214326490000101
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Table 8 disintegration test in artificial intestinal juice
Figure GDA0004214326490000102
Conclusion: from the above data, it is clear that the enteric capsules used in the examples have no cracking and disintegration in hydrochloric acid solution and can be disintegrated and released more rapidly in phosphate buffer, whereas the enteric coatings used in the comparative examples have no cracking and disintegration in hydrochloric acid solution but have a slower disintegration and release in phosphate buffer.
2. Dissolution out
The dissolution method comprises the following steps: the dissolution medium was phosphate buffer at pH6.8 at 75 rpm.
Chromatographic column: ultimate XB-C18 column (250 mm. Times.4.6 mm,5 μm); mobile phase: acetonitrile-water-phosphoric acid (volume ratio 40:60:2); detection wavelength: 235nm; flow rate: 1.0 mL/min -1 The method comprises the steps of carrying out a first treatment on the surface of the Sample injection amount: 10 mu L. The theoretical plate number under the chromatographic conditions should be not less than 2000 in terms of relative retention time. Tables 9 to 15 show the elution data of examples 1 to 4 and comparative examples 1 to 3, respectively.
TABLE 9 elution results for example 1
Figure GDA0004214326490000103
Figure GDA0004214326490000111
TABLE 10 elution results for example 2
Figure GDA0004214326490000112
TABLE 11 elution results of example 3
Figure GDA0004214326490000113
TABLE 12 elution results for example 4
Figure GDA0004214326490000114
TABLE 13 comparative example 1 elution results
Figure GDA0004214326490000121
Table 14 comparative example 2 elution results
Figure GDA0004214326490000122
TABLE 15 comparative example 3 elution results
Figure GDA0004214326490000123
Conclusion: from the above data, the examples of the present invention all dissolved faster in ph=6.8 phosphate buffer than the comparative examples, and the examples had better batch uniformity than the comparative examples.
3. Related substances
Aspirin related substance method:
chromatographic conditions: octadecylsilane chemically bonded silica is used as a filler; gradient elution was performed using acetonitrile-tetrahydrofuran-glacial acetic acid-water (20:5:5:70) as mobile phase a and acetonitrile as mobile phase B according to the following table; the detection wavelength is 276nm; the sample volume was 10. Mu.L.
Limit: the chromatogram of the sample solution has impurity peaks, except Yang Suanfeng, the sum of the areas of other impurity peaks is not more than the main peak area (0.5%) of the control solution, and the chromatographic peak less than the main peak area of the sensitivity solution is ignored. Salicylic acid limit 0.3%. The clopidogrel bisulfate related substances method comprises the following steps:
chromatographic conditions: chiral chromatographic column (ULTRONES-OVM) with ovomucin-bonded silica gel as filler; acetonitrile-0.01 mol/L potassium dihydrogen phosphate solution (20:80) is taken as a mobile phase; the detection wavelength is 220nm; the sample volume was 10. Mu.L.
Limit: the chromatogram of the sample solution has impurity peaks, the peak area is calculated according to an external standard method, the clopidogrel impurity I is not more than 0.5% of the clopidogrel mark amount, and the clopidogrel impurity III is not more than 1.0% of the clopidogrel mark amount; calculating other single impurities according to a main component external standard method and the peak area, and multiplying the result by 0.766 to obtain 0.2% of the marked quantity of clopidogrel; the sum of the impurities is not 1.5% of the marked amount of clopidogrel (all except clopidogrel impurity II). Specific data are shown in tables 16-17.
TABLE 16 aspirin related substance results
Figure GDA0004214326490000131
TABLE 17 clopidogrel bisulfate related substance results
Figure GDA0004214326490000132
Figure GDA0004214326490000141
Conclusion: from the above data, the stability of the examples of the present invention is better than that of the comparative examples.
And (3) data effect analysis:
examples 1-3 used uncoated two microtablets for enteric capsules, and example 4 coated the two microtablets first with a film and then encapsulated. Comparative example 1 aspirin and clopidogrel bisulfate were directly mixed and tableted, comparative example 2 aspirin and clopidogrel bisulfate were compressed into a bilayer tablet, and comparative example 3 the bilayer tablet was directly enteric-coated.
Stability (related substances): examples 1-4 were essentially identical and were the most stable products; comparative example 1 was worst; comparative examples 2-3 were more stable and still have a larger gap than examples 1-4.
And (3) dissolving out: the double-layer tablet and the coated tablet have poor dissolution uniformity, and the micro tablet filled into the enteric capsule has better dissolution uniformity.
Comparison of production process:
aspirin and clopidogrel bisulfate mixed tablet: the process is the simplest, but the stability is the worst;
double-layer sheet: the tabletting process has the advantages of high difficulty, high enteric coating difficulty, long time, high enteric performance control difficulty and high stability;
microchip capsule: the tabletting process has the advantages of low difficulty, simple and controllable process of directly encapsulating, easy control of enteric solubility and best stability.
In summary, the present application provides a clopidogrel bisulfate aspirin microchip capsule and a preparation method thereof, wherein the clopidogrel bisulfate aspirin microchip capsule provided by the present application is composed of clopidogrel bisulfate microchip, aspirin microchip and a capsule shell, wherein active ingredients are clopidogrel bisulfate and aspirin; the auxiliary materials are filler, disintegrating agent, glidant and/or lubricant. The aspirin and the clopidogrel bisulfate are respectively pressed into two micro tablets, and then the two micro tablets are filled into the same capsule according to the specification requirement, so that the aspirin and the clopidogrel bisulfate can be physically and absolutely isolated, the interaction of the aspirin and the clopidogrel bisulfate can be stopped, the stability of the clopidogrel bisulfate tablet is greatly improved, and the process is more controllable compared with a double-layer tablet. And the capsule shell of the clopidogrel hydrogen sulfate aspirin microchip capsule is selected as an enteric capsule, so that adverse reaction caused by the irritation of aspirin to gastric mucosa can be avoided, and the enteric coating procedure with high technological difficulty can be avoided.
The detailed description provided above refers to the accompanying drawings, which are presented by way of illustration only
Please refer to several examples under the general concept, and do not constitute a limitation of the protection scope of the present application. Any other embodiments developed in accordance with the present application without inventive effort are within the scope of the present application for those skilled in the art.

Claims (3)

1. The clopidogrel hydrogen sulfate aspirin microchip capsule is characterized by comprising clopidogrel hydrogen sulfate microchip, an aspirin microchip and a capsule shell, wherein the aspirin microchip comprises 50% w/w of aspirin, 40% w/w of microcrystalline cellulose, 8% w/w of povidone K30, 1.2% w/w of silicon dioxide and 0.8% w/w of stearic acid; clopidogrel bisulfate micro-tablets consist of 65.2% w/w clopidogrel bisulfate, 25% w/w silicified microcrystalline cellulose, 7% w/w sodium carboxymethyl starch, 0.8% w/w silicon dioxide and 2% w/w glyceryl behenate; wherein each clopidogrel bisulfate micro tablet contains 5-10mg of clopidogrel bisulfate, the tablet weight is 10-25mg, and the diameter is 2-3mm; each aspirin micro tablet contains 5-10mg of aspirin, the tablet weight is 10-25mg, and the diameter is 2-3mm.
2. Clopidogrel bisulfate aspirin microchip capsule according to claim 1; wherein, the number of clopidogrel bisulfate micro-tablets in each capsule is 10-20, and the number of aspirin micro-tablets is 8-20; the capsule shell is selected from enteric capsule shells No. 1, no. 0 and No. 00.
3. The preparation method of clopidogrel bisulfate aspirin microchip capsule according to any one of claims 1 to 2, characterized in that the method comprises the following steps:
sieving aspirin with 60 mesh sieve, mixing with microcrystalline cellulose, povidone K30 and silicon dioxide, sieving with 40 mesh sieve, adding stearic acid, sieving with 40 mesh sieve, and mixing; making into microchip;
sieving clopidogrel hydrogen sulfate with a 60-mesh sieve, mixing with silicified microcrystalline cellulose, sodium carboxymethyl starch and silicon dioxide with a 40-mesh sieve, adding glyceryl behenate, and mixing with 40-mesh sieve; making into microchip;
filling aspirin microchip and clopidogrel bisulfate Lei Weipian into capsule shells to prepare the microchip capsules.
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CN101703513B (en) * 2009-11-10 2014-04-23 沈阳药科大学 Compound sustained-release preparation of aspirin and clopidogrel or pharmaceutically acceptable salt thereof
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KR20130048335A (en) * 2011-11-02 2013-05-10 한국유나이티드제약 주식회사 Combination of clopidogrel and aspirin
CN112353784A (en) * 2020-11-10 2021-02-12 湖南慧泽生物医药科技有限公司 Aspirin enteric-coated micro-tablet capsule and preparation method thereof

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