CN114209675A - Clopidogrel hydrogen sulfate and aspirin micro-tablet capsule and preparation method thereof - Google Patents

Clopidogrel hydrogen sulfate and aspirin micro-tablet capsule and preparation method thereof Download PDF

Info

Publication number
CN114209675A
CN114209675A CN202210064244.0A CN202210064244A CN114209675A CN 114209675 A CN114209675 A CN 114209675A CN 202210064244 A CN202210064244 A CN 202210064244A CN 114209675 A CN114209675 A CN 114209675A
Authority
CN
China
Prior art keywords
aspirin
clopidogrel
microtablets
micro
clopidogrel bisulfate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202210064244.0A
Other languages
Chinese (zh)
Other versions
CN114209675B (en
Inventor
宁宗超
徐德海
郭全禄
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing Weizhirui Pharmaceutical Technology Co ltd
Original Assignee
Beijing Weizhirui Pharmaceutical Technology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beijing Weizhirui Pharmaceutical Technology Co ltd filed Critical Beijing Weizhirui Pharmaceutical Technology Co ltd
Priority to CN202210064244.0A priority Critical patent/CN114209675B/en
Publication of CN114209675A publication Critical patent/CN114209675A/en
Application granted granted Critical
Publication of CN114209675B publication Critical patent/CN114209675B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • 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 clopidogrel bisulfate aspirin microtablet comprises a clopidogrel bisulfate microtablet, an aspirin microtablet and a capsule shell, wherein active ingredients are clopidogrel bisulfate and aspirin; the auxiliary materials are filler, disintegrant, glidant and/or lubricant. The aspirin and the clopidogrel hydrogen sulfate are respectively pressed into two micro-tablets, and then the two micro-tablets are filled into the same capsule according to the specification requirement, compared with a double-layer tablet which is a commercially available preparation, the micro-tablet capsule can physically and absolutely isolate the aspirin and the clopidogrel hydrogen sulfate, can stop the interaction of the aspirin and the clopidogrel hydrogen sulfate, greatly improve the stability of the clopidogrel hydrogen sulfate, and has more controllable process compared with the double-layer tablet.

Description

Clopidogrel hydrogen sulfate and aspirin micro-tablet capsule and preparation method thereof
Technical Field
The application relates to the technical field of medicines, in particular to a clopidogrel hydrogen sulfate and aspirin micro-tablet capsule and a preparation method thereof.
Background
Aspirin can inhibit platelet release reaction and platelet aggregation, thereby reducing thromboxane A2(TXA2) production, and is mainly used for preventing and treating ischemic heart disease, angina pectoris, cardiopulmonary infarction, and cerebral thrombosis.
Clopidogrel hydrogen sulfate can selectively inhibit the binding of Adenosine Diphosphate (ADP) to platelet receptors, and then inhibit and activate ADP and glycoprotein GP IIb/IIIalpha complex, thereby inhibiting the aggregation of platelets, and is mainly used for treating patients suffering from stroke, myocardial infarction and peripheral arterial diseases.
Research shows that the combination of aspirin and clopidogrel hydrogen sulfate can obviously enhance the antiplatelet activity, can be used for treating diseases caused by platelet aggregation, including stable or unstable angina, and cardiovascular and cerebrovascular diseases, and has definite curative effect.
The currently marketed clopidogrel bisulfate aspirin tablet is a double-layer tablet, because the compatibility of aspirin and clopidogrel bisulfate is poor, the contact of two raw material medicines is greatly increased by directly mixing and tabletting, and further the character change and the related substances are increased. The stability of the double-layer tablet can be effectively improved by preparing the double-layer tablet, 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 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 bisulfate aspirin microtablet and a preparation method thereof, which are used for solving the problem that two kinds of raw materials cannot be completely isolated because the phenomenon of local raw material contact cannot be avoided in the existing clopidogrel bisulfate aspirin double-layer tablet preparation process.
On one hand, the clopidogrel bisulfate aspirin microtablet consists of clopidogrel bisulfate microtablets, aspirin microtablets and capsule shells, wherein active ingredients are clopidogrel bisulfate and aspirin; the auxiliary materials are filler, disintegrant, glidant and/or lubricant.
Optionally, the active ingredient accounts for 30-60%, filler 25-40%, disintegrant 4-20%, glidant and/or lubricant 0.8-2.5%; in the active ingredients, aspirin accounts for 12-42%; the percentage of clopidogrel hydrogen sulfate is 18-48%.
Optionally, the filler is one or more of microcrystalline cellulose, lactose, corn starch, silicified microcrystalline cellulose, and mannitol; the disintegrating agent is one or more of microcrystalline cellulose and low-substituted hydroxypropyl cellulose.
Optionally, the glidant is one or more of silicon dioxide and talcum powder; the lubricant is one or more of stearic acid, zinc stearate, magnesium stearate, polyethylene glycol and glyceryl behenate.
Optionally, the capsule comprises clopidogrel hydrogen sulfate micro-tablets, aspirin micro-tablets and a capsule shell; wherein, the number of the clopidogrel bisulfate micro-tablets is 10-20, the number of the aspirin micro-tablets is 8-20, and the capsule shells are enteric-coated capsule shells of No. 1, No. 0 and No. 00.
Optionally, the clopidogrel bisulfate microtablets are 5-10mg in specification, 10-25mg in tablet weight and 2-3mm in diameter.
Optionally, the aspirin micro-tablet has specification of 5-10mg, tablet weight of 10-25mg, and diameter of 2-3 mm.
In a second aspect, the application provides a preparation method of clopidogrel hydrogen sulfate aspirin micro-tablet capsules, which comprises the following steps:
sieving aspirin with a 80-mesh sieve, and mixing with a first filler, a first disintegrant and a first glidant to obtain a first mixture; adding a first lubricant into the first mixture and mixing to obtain aspirin micro-tablets;
sieving clopidogrel hydrogen sulfate by a sieve of 80 meshes, and mixing the sieved clopidogrel hydrogen sulfate with a second filling agent, a second disintegrating agent and a second flow aid to obtain a second mixture; adding a second lubricant into the second mixture and mixing to obtain clopidogrel bisulfate microtablets;
filling the aspirin microtablets and the clopidogrel hydrogen sulfate microtablets into capsule shells to prepare microtablets.
Optionally, in the aspirin micro-tablet, the aspirin is 36-52% by weight, the first filler is 24-44% by weight, the first disintegrant is 6-20% by weight, the first glidant is 0.8-2.5% by weight, and the first lubricant is 0.8-2.5% by weight.
Optionally, in the clopidogrel bisulfate microtablets, the clopidogrel bisulfate is 38-66 wt%, the filler is 24-45 wt%, the disintegrant is 4-8 wt%, the second flow aid is 0.8-2.5 wt%, and the second lubricant is 0.8-2.5 wt%.
According to the technical scheme, the clopidogrel bisulfate aspirin microtablet and the preparation method thereof are provided, the clopidogrel bisulfate aspirin microtablet provided by the application is composed of clopidogrel bisulfate microtablets, aspirin microtablets and a capsule shell, wherein active ingredients are clopidogrel bisulfate and aspirin; the auxiliary materials are filler, disintegrant, glidant and/or lubricant. The aspirin and the clopidogrel hydrogen sulfate 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 hydrogen sulfate can be absolutely isolated physically, the interaction of the aspirin and the clopidogrel hydrogen sulfate can be avoided, the stability of the clopidogrel hydrogen sulfate capsule is greatly improved, and the process is more controllable compared with a double-layer tablet. And the capsule body of the clopidogrel bisulfate aspirin microtablet is selected as an enteric capsule, so that adverse reactions caused by stimulation of aspirin to gastric mucosa can be avoided, and an enteric coating procedure with high process difficulty can be avoided.
Drawings
In order to more clearly explain the technical solution of the present application, the drawings needed to be used in the embodiments will be briefly described below, and it is obvious to those skilled in the art that other drawings can be obtained according to the drawings without creative efforts.
Fig. 1 is a schematic diagram of clopidogrel bisulfate aspirin microtablets provided herein.
Detailed Description
Reference will now be made in detail to embodiments, examples of which are illustrated in the accompanying drawings. When the following description refers to the accompanying drawings, like numbers in different drawings represent the same or similar elements unless otherwise indicated. The embodiments described in the following examples do not represent all embodiments consistent with the present application. But merely as exemplifications of systems and methods consistent with certain aspects of the application, as recited in the claims.
At present, clopidogrel hydrogen sulfate aspirin tablets are developed and developed by the company cinonafiran under the trade name of Duoplavin, and the product is approved to be sold on the market by the human medical product Committee (CHMP) of the European drug administration (EMA) on 12-month and 17-day 2009, and the compound tablet comprises 2 dose combinations, namely clopidogrel 75 mg/aspirin 75mg and clopidogrel 75 mg/aspirin 100 mg.
The currently marketed clopidogrel bisulfate aspirin tablet is a double-layer tablet, because the compatibility of aspirin and clopidogrel bisulfate is poor, the contact of two raw material medicines is greatly increased by directly mixing and tabletting, and further the character change and the related substances are increased. The double-layer tablet can effectively improve the stability. However, the double-layer tablet process has higher requirements on equipment and auxiliary materials, and the phenomenon of local contact cannot be avoided in the preparation process. Oral aspirin can directly affect and stimulate gastric mucosa to cause nausea and vomiting, and long-term use can cause gastric ulcer, gastrorrhagia and other symptoms caused by damage of a gastritis membrane.
In order to solve the technical problems, the clopidogrel bisulfate and aspirin micro-tablet capsule and the preparation method thereof are provided.
On one hand, the clopidogrel bisulfate aspirin microtablet consists of clopidogrel bisulfate microtablets, aspirin microtablets and capsule shells, wherein active ingredients are clopidogrel bisulfate and aspirin; the auxiliary materials are filler, disintegrant, glidant and/or lubricant.
Specifically, the active ingredients account for 30-60%, the filling agent 25-40%, the disintegrating agent 4-20%, and the glidant and/or lubricant 0.8-2.5%; in the active ingredients, aspirin accounts for 12-42%; the percentage of clopidogrel hydrogen sulfate is 18-48%.
Specifically, the filler is one or more of microcrystalline cellulose, lactose, corn starch, silicified microcrystalline cellulose and mannitol; the disintegrating agent is one or more of microcrystalline cellulose and low-substituted hydroxypropyl cellulose.
Specifically, the glidant is one or more of silicon dioxide and talcum powder; the lubricant is one or more of stearic acid, zinc stearate, magnesium stearate, polyethylene glycol and glyceryl behenate.
Specifically, the capsule comprises clopidogrel hydrogen sulfate micro-tablets, aspirin micro-tablets and a capsule shell; wherein, the number of the clopidogrel bisulfate micro-tablets is 10-20, the number of the aspirin micro-tablets is 8-20, and the capsule shells are enteric-coated capsule shells of No. 1, No. 0 and No. 00.
Specifically, the clopidogrel bisulfate microtablets are 5-10mg, 10-25mg in tablet weight and 2-3mm in diameter.
Specifically, the aspirin micro-tablet has a specification of 5-10mg, a tablet weight of 10-25mg and a diameter of 2-3 mm.
In a second aspect, the application provides a preparation method of clopidogrel hydrogen sulfate aspirin micro-tablet capsules, which comprises the following steps:
sieving aspirin with a 80-mesh sieve, and mixing with a first filler, a first disintegrant and a first glidant to obtain a first mixture; adding a first lubricant into the first mixture and mixing to obtain aspirin micro-tablets;
sieving clopidogrel hydrogen sulfate by a sieve of 80 meshes, and mixing the sieved clopidogrel hydrogen sulfate with a second filling agent, a second disintegrating agent and a second flow aid to obtain a second mixture; adding a second lubricant into the second mixture and mixing to obtain clopidogrel bisulfate microtablets;
filling the aspirin microtablets and the clopidogrel hydrogen sulfate microtablets into capsule shells to prepare microtablets.
Specifically, in the aspirin micro-tablet, the aspirin is 36-52% by weight, the first filler is 24-44% by weight, the first disintegrant is 6-20% by weight, the first glidant is 0.8-2.5% by weight, and the first lubricant is 0.8-2.5% by weight.
Specifically, in the clopidogrel bisulfate microtablets, the clopidogrel bisulfate is 38-66 wt%, the filling agent is 24-45 wt%, the disintegrating agent is 4-8 wt%, the flow aid is 0.8-2.5 wt%, and the lubricant is 0.8-2.5 wt%.
Fig. 1 is a schematic diagram of clopidogrel bisulfate aspirin microtablets, small No. 1 capsules and large No. 0 capsules provided by the present application.
Specific examples are given below for a detailed description.
Example 1
TABLE 1
Figure BDA0003479624350000041
Figure BDA0003479624350000051
Wherein, the compositions and the proportions of the components of the example 1 are shown in the table 1.
The process comprises the following steps:
preparation of aspirin mini-tablets:
sieving aspirin with 80 mesh sieve, sieving with lactose, microcrystalline cellulose and silicon dioxide with 40 mesh sieve, mixing, adding stearic acid, and sieving with 40 mesh sieve. Making into micro-tablet with diameter of 2mm and weight of 10mg, each tablet containing aspirin 5 mg.
Preparing clopidogrel hydrogen sulfate micro-tablets:
sieving clopidogrel hydrogen sulfate with a 80-mesh sieve, sieving with mannitol, low-substituted hydroxypropyl cellulose and silicon dioxide with a 40-mesh sieve, mixing, adding zinc stearate, and sieving with a 40-mesh sieve. Making into micro-tablet with diameter of 2mm and weight of 10mg, each tablet containing clopidogrel 5 mg.
Preparing a compound capsule:
taking 15 aspirin micro tablets and 15 clopidogrel hydrogen sulfate micro tablets, and filling into a No. 1 enteric capsule to prepare 75 mg: 75mg clopidogrel hydrogen sulfate aspirin microtablets.
Example 2
TABLE 2
Figure BDA0003479624350000052
Figure BDA0003479624350000061
Wherein, the compositions and the proportions of the components of the example 2 are shown in the table 2.
The process comprises the following steps:
preparation of aspirin mini-tablets:
sieving aspirin with 60 mesh sieve, sieving with 40 mesh sieve together with corn starch, microcrystalline cellulose and silicon dioxide, adding stearic acid, and sieving with 40 mesh sieve. Making into micro-tablet with diameter of 2mm and weight of 10mg, each tablet containing aspirin 5 mg.
Preparing clopidogrel hydrogen sulfate micro-tablets:
sieving clopidogrel hydrogen sulfate with 60 mesh sieve, mixing with silicified microcrystalline cellulose, low-substituted hydroxypropyl cellulose and talc powder, sieving with 40 mesh sieve, adding polyethylene glycol 6000, and sieving with 40 mesh sieve. Making into micro-tablet with diameter of 2mm and weight of 10mg, each tablet containing clopidogrel 5 mg.
Preparing a compound capsule:
taking 15 aspirin micro-tablets and 20 clopidogrel hydrogen sulfate micro-tablets, and filling into a No. 0 enteric-coated capsule to prepare 75 mg: a clopidogrel bisulfate aspirin microtablet enteric capsule of 100mg specification.
Example 3
TABLE 3
Figure BDA0003479624350000062
Wherein, the compositions and the proportions of the components of the example 3 are shown in the table 3.
The process comprises the following steps:
preparation of aspirin mini-tablets:
sieving aspirin with 60 mesh sieve, sieving with microcrystalline cellulose, polyvidone K30 and silicon dioxide with 40 mesh sieve, mixing, adding stearic acid, and sieving with 40 mesh sieve. Making into micro-tablet with diameter of 2mm and weight of 10mg, each tablet containing aspirin 5 mg.
Preparing clopidogrel hydrogen sulfate micro-tablets:
sieving clopidogrel hydrogen sulfate with a 60-mesh sieve, sieving with silicified microcrystalline cellulose, sodium carboxymethyl starch and talcum powder with a 40-mesh sieve, mixing, adding glyceryl behenate, and sieving with a 40-mesh sieve. Making into micro-tablet with diameter of 2mm and weight of 10mg, each tablet containing clopidogrel 5 mg.
Preparing a compound capsule:
taking 15 aspirin micro tablets and 15 clopidogrel hydrogen sulfate micro tablets, and filling into No. 1 enteric-coated capsules to obtain 75 mg; 75mg clopidogrel hydrogen sulfate aspirin microtablets.
Example 4
The aspirin microtablets and clopidogrel bisulfate microtablets in example 3 are coated, and the opadry film coating premixes with different colors are used for isolating coating, so that the aspirin microtablets and the clopidogrel bisulfate microtablets are further completely isolated. Coating parameters: the solid content of the coating liquid is 12 percent, the material temperature is 30-40 ℃, the rotating speed of a main engine is 6-15rpm, and the weight gain of the coating is 2-3 percent. Obtaining light blue aspirin film coating micro-tablets, wherein the coating weight is increased by 2.6%; the yellow clopidogrel bisulfate film coated micro-tablets have the coating weight increased by 2.4 percent. Respectively taking 15 tablets of the light blue aspirin film-coated micro-tablets and 15 tablets of the yellow clopidogrel hydrogen sulfate film-coated micro-tablets, and filling into a No. 1 enteric-coated capsule to prepare 75 mg: 75mg clopidogrel hydrogen sulfate aspirin microtablets.
Comparative example 1
TABLE 4
Prescription composition Function of Ratio of
Aspirin Active ingredient 20％(5mg)
Clopidogrel hydrogen sulfate Active ingredient 26.1％(6.52mg)
Lactose Filler 34％
Microcrystalline cellulose Disintegrating agent 18％
Silicon dioxide Glidants 1.1％
Stearic acid Lubricant agent 0.8％
Wherein, table 4 shows the composition and the ratio of each component of comparative example 1.
The difference is that aspirin and clopidogrel hydrogen sulfate are directly mixed and tabletted.
The process comprises the following steps:
the aspirin and the clopidogrel bisulfate are sieved by a 60-mesh sieve, mixed with the lactose, the microcrystalline cellulose and the silicon dioxide which are sieved by a 40-mesh sieve, and finally, the stearic acid is added and mixed with the mixture which is sieved by a 40-mesh sieve.
Making into micro-tablet with diameter of 3mm and weight of 25mg, each tablet containing aspirin 5mg and clopidogrel 5 mg.
Taking 15 tablets of clopidogrel hydrogen sulfate aspirin micro-tablets, and filling into a No. 0 gelatin capsule to obtain 75 mg; 75mg clopidogrel hydrogen sulfate aspirin microtablets.
Comparative example 2
TABLE 5
Figure BDA0003479624350000081
Wherein, table 5 shows the composition and the ratio of each component of comparative example 2.
The difference is that aspirin and clopidogrel hydrogen sulfate are pressed into a double-layer tablet.
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 hydrogen sulfate with a 60-mesh sieve, sieving with mannitol, low-substituted hydroxypropyl cellulose and silicon dioxide with a 40-mesh sieve, mixing, adding zinc stearate, and sieving with a 40-mesh sieve.
And (3) pressing the double-layer tablets by using a tablet press, filling aspirin mixed powder, prepressing the mixture to form tablets, filling clopidogrel hydrogen sulfate mixed powder, and pressing the mixture to form the tablets. The diameter is 10mm, the tablet weight is 500mg, each tablet contains 75mg of aspirin and 75mg of clopidogrel.
Comparative example 3
Except that the tablets of comparative example 2 were used for enteric coating.
Coating with opadry enteric coating premix, coating parameters: the solid content of the coating liquid is 7 percent, the material temperature is 30-40 ℃, the rotating speed of a main engine is 6-15rpm, and the weight gain of the coating is 6-8 percent. The coating weight gain of the obtained enteric coated tablet is 6.9%.
The types and parameters of the capsule shells used in examples 1 to 4 are shown in Table 6.
TABLE 6
Item 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
Cap 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 mouth 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
Capacity (ml) 0.95 0.68 0.5
The following analysis was performed in conjunction with the specific effect evaluation data.
Effect evaluation data:
1. disintegration time limit
Enteric-coated capsules: taking 6 samples, firstly checking for 2 hours without adding a baffle in a hydrochloric acid solution (9 → 1000), wherein the capsule shell of each sample cannot crack or disintegrate; taking out the hanging basket, washing with small amount of water, adding baffle plate into each tube, and examining in artificial intestinal juice according to the above method, wherein the total disintegration should be completed within 1 hr. If 1 granule can not be completely disintegrated, another 6 granules should be taken for retesting, and all the results are in accordance with the regulations.
Enteric-coated tablets: taking 6 test pieces, and checking in hydrochloric acid solution (9 → 1000) for 2 hr to prevent cracking, disintegration or softening; the basket was then removed, washed with a small amount of water, and examined in artificial intestinal fluid as described above, and the whole mass should disintegrate within 1 hour. If 1 tablet can not be completely disintegrated, 6 tablets should be taken for retesting, and all the results are in accordance with the regulations. The disintegration test data are shown in tables 7-8.
TABLE 7 disintegration test in hydrochloric acid solution
Figure BDA0003479624350000091
Figure BDA0003479624350000101
TABLE 8 disintegration test in artificial intestinal fluids
Test group Disintegration time limit
Example 1 10min
Example 2 13min
Example 3 14min
Example 4 13min
Comparative example 1 /
Comparative example 2 /
Comparative example 3 30min
And (4) conclusion: from the above data, it can be seen that the enteric capsules used in the examples have no cracks and disintegration in hydrochloric acid solution and can disintegrate and release faster in phosphate buffer solution, while the enteric coating in the comparative examples has no cracks and disintegration in hydrochloric acid solution but disintegrates and releases slower in phosphate buffer solution.
2. Dissolution of
The dissolution method comprises the following steps: the rotation speed is 75rpm, and the dissolution medium is phosphate buffer solution with pH6.8.
A chromatographic column: an 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: 235 nm; flow rate: 1.0 mL/min-1(ii) a Sample introduction amount: 10 μ L. The theoretical plate number under the chromatographic conditions should be not less than 2000 in terms of relative retention time. Tables 9-15 show the dissolution data for examples 1-4 and comparative examples 1-3, respectively.
Table 9 example 1 dissolution results
Figure BDA0003479624350000102
Figure BDA0003479624350000111
Table 10 example 2 dissolution results
Figure BDA0003479624350000112
Table 11 example 3 dissolution results
Figure BDA0003479624350000113
Table 12 example 4 dissolution results
Figure BDA0003479624350000114
Figure BDA0003479624350000121
TABLE 13 dissolution results of comparative example 1
Figure BDA0003479624350000122
Table 14 dissolution results of comparative example 2
Figure BDA0003479624350000123
TABLE 15 dissolution results of comparative example 3
Figure BDA0003479624350000124
Figure BDA0003479624350000131
And (4) conclusion: from the above data, it can be seen that the inventive examples all dissolved faster in phosphate buffer at pH6.8 than the comparative examples, and the within-batch uniformity of the examples was better than the comparative examples.
3. Related substances
The method for preparing aspirin related substances comprises the following steps:
chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent; gradient elution is carried out according to the following table by taking acetonitrile-tetrahydrofuran-glacial acetic acid-water (20: 5: 5: 70) as a mobile phase A and acetonitrile as a mobile phase B; the detection wavelength is 276 nm; the injection volume is 10. mu.L.
Limitation: if an impurity peak exists in the chromatogram of the test solution, the sum of the peak areas of other impurities except the salicylic acid peak is not more than the main peak area (0.5%) of the control solution, and chromatographic peaks smaller than the main peak area of the sensitivity solution are ignored. The limit of salicylic acid is 0.3%.
The related substance method of clopidogrel hydrogen sulfate comprises the following steps:
chromatographic conditions are as follows: chiral chromatographic column (ULTRONES-OVM) with ovomucin bonded silica gel as filler; acetonitrile-0.01 mol/L potassium dihydrogen phosphate solution (20: 80) is used as a mobile phase; the detection wavelength is 220 nm; the injection volume is 10. mu.L.
Limitation: if an impurity peak exists in a chromatogram of a test solution, calculating according to an external standard method by using the peak area, wherein the clopidogrel impurity I can not pass 0.5 percent of the labeled amount of the clopidogrel, and the clopidogrel impurity III can not pass 1.0 percent of the labeled amount of the clopidogrel; calculating other single impurities by peak area according to a main component external standard method, and multiplying the result by 0.766 to obtain 0.2% of the labeled amount of clopidogrel; the total amount of impurities is not more than 1.5 percent of the labeled amount of clopidogrel (except for clopidogrel impurity II). The data are shown in tables 16-17.
TABLE 16 results for aspirin related substances
Figure BDA0003479624350000132
TABLE 17 clopidogrel hydrogen sulfate related substance results
Figure BDA0003479624350000141
And (4) conclusion: from the above data, it can be seen that the inventive examples are superior in stability to the comparative examples.
And (3) analyzing the data effect:
examples 1-3 all use two uncoated microtablets for enteric capsules, and example 4 first film-coats the two microtablets and then encapsulates them. Comparative example 1 aspirin and clopidogrel hydrogen sulfate were directly mixed and tableted, comparative example 2 aspirin and clopidogrel hydrogen sulfate were compressed into a double-layered tablet, and comparative example 3 enteric-coated the double-layered tablet directly.
Stability (related substances): examples 1-4 are essentially identical and are the most stable products; comparative example 1 is worst; comparative examples 2-3 are more stable and still have a larger gap than 1-4.
Dissolution: the dissolution uniformity of the double-layer tablet and the coated tablet is poor, and the dissolution uniformity of the micro-tablet filled into the enteric-coated capsule is better.
The production process comparison:
and (3) performing mixed tabletting of aspirin and clopidogrel hydrogen sulfate: the simplest process, but the worst stability;
double-layer tablets: the tabletting process has high difficulty, the enteric coating has high difficulty and long time, the enteric performance is controlled difficultly, and the stability is good;
micro-tablet capsules: the tablet pressing process is less in difficulty, the direct capsule filling process is simple and controllable, the enteric solubility can be easily controlled, and the stability is best.
In summary, the application provides a clopidogrel bisulfate aspirin microtablet and a preparation method thereof, the clopidogrel bisulfate aspirin microtablet provided by the application consists of clopidogrel bisulfate microtablets, aspirin microtablets and a capsule shell, wherein active ingredients are clopidogrel bisulfate and aspirin; the auxiliary materials are filler, disintegrant, glidant and/or lubricant. The aspirin and the clopidogrel hydrogen sulfate 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 hydrogen sulfate can be absolutely isolated physically, the interaction of the aspirin and the clopidogrel hydrogen sulfate can be avoided, the stability of the clopidogrel hydrogen sulfate capsule is greatly improved, and the process is more controllable compared with a double-layer tablet. And the capsule shell of the clopidogrel bisulfate aspirin microtablet is selected as an enteric capsule, so that adverse reaction caused by stimulation of aspirin to gastric mucosa can be avoided, and an enteric coating procedure with high process difficulty can be avoided.
The embodiments provided in the present application are only a few examples of the general concept of the present application, and do not limit the scope of the present application. Any other embodiments extended according to the scheme of the present application without inventive efforts will be within the scope of protection of the present application for a person skilled in the art.

Claims (10)

1. The clopidogrel bisulfate aspirin microtablet is characterized in that the clopidogrel bisulfate aspirin microtablet consists of clopidogrel bisulfate microtablets, aspirin microtablets and capsule shells, wherein active ingredients are clopidogrel bisulfate and aspirin; the auxiliary materials are filler, disintegrant, glidant and/or lubricant.
2. The clopidogrel bisulfate aspirin micro-tablet capsule according to claim 1, wherein the active ingredients account for 30-60%, the filling agent accounts for 25-40%, the disintegrating agent accounts for 4-20%, and the flow aid and/or the lubricant accounts for 0.8-2.5%; in the active ingredients, aspirin accounts for 12-42%; the percentage of clopidogrel hydrogen sulfate is 18-48%.
3. The clopidogrel bisulfate aspirin mini-tablet capsule according to claim 1, wherein the filler is one or more of microcrystalline cellulose, lactose, corn starch, silicified microcrystalline cellulose, mannitol; the disintegrating agent is one or more of microcrystalline cellulose and low-substituted hydroxypropyl cellulose.
4. The clopidogrel bisulfate aspirin micro-tablet capsule according to claim 1, wherein the glidant is one or more of silicon dioxide and talcum powder; the lubricant is one or more of stearic acid, zinc stearate, magnesium stearate, polyethylene glycol and glyceryl behenate.
5. The clopidogrel bisulfate aspirin microtablets capsule of claim 1, wherein the capsule comprises clopidogrel bisulfate microtablets, aspirin microtablets, and a capsule shell; wherein, the number of the clopidogrel bisulfate micro-tablets is 10-20, the number of the aspirin micro-tablets is 8-20, and the capsule shells are enteric-coated capsule shells of No. 1, No. 0 and No. 00.
6. The clopidogrel bisulfate aspirin microtablets of claim 5, wherein the clopidogrel bisulfate microtablets are 5-10mg in size, 10-25mg in tablet weight and 2-3mm in diameter.
7. The clopidogrel bisulfate aspirin microtablets of claim 5, wherein the aspirin microtablets are 5-10mg in size, 10-25mg in tablet weight, and 2-3mm in diameter.
8. A preparation method of clopidogrel hydrogen sulfate aspirin micro-tablet capsules is characterized by comprising the following steps:
sieving aspirin with a 80-mesh sieve, and mixing with a first filler, a first disintegrant and a first glidant to obtain a first mixture; adding a first lubricant into the first mixture and mixing to obtain aspirin micro-tablets;
sieving clopidogrel hydrogen sulfate by a sieve of 80 meshes, and mixing the sieved clopidogrel hydrogen sulfate with a second filling agent, a second disintegrating agent and a second flow aid to obtain a second mixture; adding a second lubricant into the second mixture and mixing to obtain clopidogrel bisulfate microtablets;
filling the aspirin microtablets and the clopidogrel hydrogen sulfate microtablets into capsule shells to prepare microtablets.
9. The preparation method of the clopidogrel bisulfate aspirin micro-tablet capsule according to claim 8, wherein in the aspirin micro-tablet, the aspirin is 36-52% in parts by weight, the first filler is 24-44% in parts by weight, the first disintegrant is 6-20% in parts by weight, the first glidant is 0.8-2.5% in parts by weight, and the first lubricant is 0.8-2.5% in parts by weight.
10. The preparation method of the clopidogrel bisulfate aspirin microtablets of claim 8, wherein the clopidogrel bisulfate microtablets contain 38-66% by weight of clopidogrel bisulfate, 24-45% by weight of a second filler, 4-8% by weight of a second disintegrant, 0.8-2.5% by weight of a second flow aid, and 0.8-2.5% by weight of a second lubricant.
CN202210064244.0A 2022-01-20 2022-01-20 Clopidogrel hydrogen sulfate aspirin microchip capsule and preparation method thereof Active CN114209675B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210064244.0A CN114209675B (en) 2022-01-20 2022-01-20 Clopidogrel hydrogen sulfate aspirin microchip capsule and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210064244.0A CN114209675B (en) 2022-01-20 2022-01-20 Clopidogrel hydrogen sulfate aspirin microchip capsule and preparation method thereof

Publications (2)

Publication Number Publication Date
CN114209675A true CN114209675A (en) 2022-03-22
CN114209675B CN114209675B (en) 2023-06-02

Family

ID=80708663

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210064244.0A Active CN114209675B (en) 2022-01-20 2022-01-20 Clopidogrel hydrogen sulfate aspirin microchip capsule and preparation method thereof

Country Status (1)

Country Link
CN (1) CN114209675B (en)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008129468A2 (en) * 2007-04-20 2008-10-30 Wockhardt Research Centre Pharmaceutical compositions of clopidogrel
US20090060996A1 (en) * 2006-02-10 2009-03-05 Kristjansson Torfi E Formulations of Clopidogrel Bisulphate
CN101703513A (en) * 2009-11-10 2010-05-12 沈阳药科大学 Compound sustained-release preparation of aspirin and clopidogrel or pharmaceutically acceptable salt thereof
KR20130048335A (en) * 2011-11-02 2013-05-10 한국유나이티드제약 주식회사 Combination of clopidogrel and aspirin
CN109069436A (en) * 2016-03-16 2018-12-21 韩国联合制药株式会社 Compound formulation containing 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
CN112451531A (en) * 2020-12-09 2021-03-09 乐普药业股份有限公司 Aspirin and rivaroxaban compound preparation and preparation method thereof

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090060996A1 (en) * 2006-02-10 2009-03-05 Kristjansson Torfi E Formulations of Clopidogrel Bisulphate
WO2008129468A2 (en) * 2007-04-20 2008-10-30 Wockhardt Research Centre Pharmaceutical compositions of clopidogrel
CN101703513A (en) * 2009-11-10 2010-05-12 沈阳药科大学 Compound sustained-release preparation of aspirin and clopidogrel or pharmaceutically acceptable salt thereof
KR20130048335A (en) * 2011-11-02 2013-05-10 한국유나이티드제약 주식회사 Combination of clopidogrel and aspirin
CN109069436A (en) * 2016-03-16 2018-12-21 韩国联合制药株式会社 Compound formulation containing 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
CN112451531A (en) * 2020-12-09 2021-03-09 乐普药业股份有限公司 Aspirin and rivaroxaban compound preparation and preparation method thereof

Also Published As

Publication number Publication date
CN114209675B (en) 2023-06-02

Similar Documents

Publication Publication Date Title
KR101213345B1 (en) Composition containing anti-dementia drug
AU777705B2 (en) Pharmaceutical compositions
JP4260370B2 (en) Oral sustained release formulation of fasudil hydrochloride
NZ201008A (en) Oral preparations containing dipyridamole and at least 5 molar equivalents of orally acceptable acidic excipient
JP2005512997A (en) Tamsulosin tablets
EP4106732A1 (en) Pharmaceutical composition comprising dapagliflozin
CN100488515C (en) Ground erythromycin enteric micropill and its preparation method
KR20110117199A (en) Galenic formulations of organic compounds
CZ298851B6 (en) Controlled-release tablet for oral administration of active substances
CN104873473A (en) Potassium chloride sustained-release tablet and preparation method thereof
KR20190000657A (en) Sustained-release formulation comprising mosapride having a broad molecular weight distribution
CN111939136A (en) Compound preparation containing ticagrelor and aspirin and preparation method thereof
CN114209675A (en) Clopidogrel hydrogen sulfate and aspirin micro-tablet capsule and preparation method thereof
ITMI970047A1 (en) ANTI-TUBERCULAR PHARMACEUTICAL COMPOSITION AND PROCEDURE FOR ITS PRODUCTION
CN101636153A (en) Time-specific delayed/pulsatile release dosage forms
JP2020023505A (en) Composite preparation of mosapride and rabeprazole
CN105687157A (en) Levofloxacin hydrochloride capsule and preparation method thereof
CN102247366A (en) Medicinal composition comprising quick-release pellets containing Enalapril or Enalapril-acid addition salt and slow-release pellets containing Felodipine
CN102106856A (en) Entecavir medicinal composition and preparation method thereof
JP2018090510A (en) Orally disintegrable tablet containing duloxetine hydrochloride
CN103550182B (en) Enteric-coated sustained release composition
CN112353784A (en) Aspirin enteric-coated micro-tablet capsule and preparation method thereof
CN101897678B (en) Sustained-release composition of cefaclor
CN102204917B (en) Pharmaceutical composition containing fasudil and sildenafil, and preparation method and application thereof
RU2303980C2 (en) Medicinal formulation showing anti-aggregating effect and method for its preparing

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant