CN104523710A - Compound clopidogrel hydrogen sulphate and aspirin double-layer tablet and preparation method thereof - Google Patents
Compound clopidogrel hydrogen sulphate and aspirin double-layer tablet and preparation method thereof Download PDFInfo
- Publication number
- CN104523710A CN104523710A CN201410840875.2A CN201410840875A CN104523710A CN 104523710 A CN104523710 A CN 104523710A CN 201410840875 A CN201410840875 A CN 201410840875A CN 104523710 A CN104523710 A CN 104523710A
- Authority
- CN
- China
- Prior art keywords
- granule
- aspirin
- bisulfate clopidogrel
- glyceryl behenate
- filler
- 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
Links
Classifications
-
- 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
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic 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
- A61K9/20—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
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of medicines, and relates to a compound clopidogrel hydrogen sulphate and aspirin double-layer tablet and a preparation method thereof. The compound clopidogrel hydrogen sulphate and aspirin double-layer tablet disclosed by the invention is formed by taking clopidogrel hydrogen sulphate and aspirin as the active components, adding glyceryl behenate and cholesteryl hemisuccinate and combining a filling agent, a disintegrating agent and a lubricating agent. The material prepared by the preparation process has good fluidity and anti-sticking property; the sticking problem of the compound clopidogrel hydrogen sulphate and aspirin double-layer tablet is solved; the anti-platelet aggregation effects of effective components are also improved; furthermore, the quality stability of drugs is good; and safe and effective drug use can be realized.
Description
Technical field
The invention belongs to medical art, relate to a kind of pharmaceutical preparation of antiplatelet aggregation.More specifically, a kind of bisulfate clopidogrel aspirin Composite Double synusia and preparation method thereof is related to.
Background technology
Along with the prolongation of people's average life, the change of living environment and dietary, cardiovascular and cerebrovascular disease sickness rate raises year by year, and its pharmaceutical market demand is increasing.Thrombotic disease belongs to cardiovascular and cerebrovascular disease, that the intravascular space that causes due to thrombosis is narrow in obturation, make main organs generation ischemia and infraction and cause the various diseases of malfunction, show as myocardial infarction, coronary heart disease, atherosclerosis, apoplexy or cerebral infarction and peripheral angiopathy, have that occurred frequently and height is disabled, lethal feature.The generation of thrombotic disease changes with blood vessel internal membrane damage, regional flow, the change of blood constituent is relevant.After there is severe trauma, puerperal and major operation, platelet and thrombin increase, and blood coagulability increases greatly, and blood solidifies at cardiovascular intracavity, cause forming thrombosis.The formation of thrombosis is the common basis of cardiovascular and cerebrovascular disease, is also cause cardiovascular and cerebrovascular disease morbidity and dead first cause.Therefore, antiplatelet aggregation for prevention and therapy thrombotic disease and the various cardiovascular and cerebrovascular diseases that cause significant.
Aspirin is first generation antiplatelet drug; by there is irreversible acetylization reaction with cyclooxygenase activity part serine; make enzyme deactivation; suppress arachidonic acid metabolic; reduce the generation of the TXA2. (TXA2) platelet being had to powerful short aggregation, platelet function is suppressed.The aspirin on platelet hyperfunctioning of low dose of (75-300mg) and cause thrombotic disease effect certainly, clinical can be used for, prevents temporal cerebral ischemia seizure, myocardial infarction, atrial fibrillation, Cardiac valve prosthesis, arteriovenous fistula or other postoperative thrombosis, also can be used for treating unstable angina pectoris.
Clopidogrel is antiplatelet drug of new generation, chemistry (2S)-2-(2-chlorphenyl)-2-(4 by name, 5, 6, 7-Tetramethylene sulfide [3, 2-c] and pyridine-5-base) acetate hydrogensulfate, structural formula is as implied above, belong to thiophene pyridine derivatives, it is a kind of prodrug, by optionally with adenosine diphosphate (ADP) (ADP) receptors bind of platelet surface adenyl cyclase coupling, Fibrinogen is suppressed to be combined with its platelet receptor GP II b/ III a and to play the effect of anticoagulant, be applicable to the apoplexy of outbreak in the recent period, myocardial infarction and the patient making a definite diagnosis peripheral arterial disease, the generation of atherosclerotic event can be reduced.Current clopidogrel has been the standard care medicine of antiplatelet aggregation clinically.
Clinical trial proves to accept, compared with clopidogrel hydrogen aspirin therapy and the independent patient applying clopidogrel or aspirin, in the events such as reduction cardiovascular death, myocardial infarction or apoplexy, to be better than independent treatment group.European Union in 2010 has gone on the market clopidogrel aspirin compound tablet, and prescription is: bisulfate clopidogrel, aspirin, mannitol, polyethylene glycol 6000, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, corn starch, castor oil hydrogenated, stearic acid, silicon dioxide.After deliberation, said preparation is Shortcomings in the material fluidity of preparation process, resistance to bond and quality stability, haves much room for improvement.
Summary of the invention
In view of this, the invention provides a kind of bisulfate clopidogrel aspirin Composite Double synusia and preparation method thereof, described bisulfate clopidogrel aspirin composite double layer sheet material good fluidity, resistance to bond are good, tabletting time not sticking, constant product quality is good, and antiplatelet aggregative activity strengthens.
In order to realize foregoing invention object, the invention provides following technical scheme:
A kind of bisulfate clopidogrel aspirin Composite Double synusia, with bisulfate clopidogrel and aspirin for active component, adds Glyceryl Behenate, cholesteryl hemisuccinate, then is equipped with filler, disintegrating agent and lubricant combination and forms.
Described filler is selected from one or more the mixture in lactose, mannitol, microcrystalline Cellulose, pregelatinized Starch, corn starch.
Described disintegrating agent is selected from one or more the mixture in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium.
Described lubricant is selected from one or more the mixture in magnesium stearate, stearic acid, silicon dioxide, polyethylene glycol 6000, Macrogol 4000, castor oil hydrogenated, Pulvis Talci, micropowder silica gel.
Optional, bisulfate clopidogrel aspirin Composite Double synusia of the present invention, can also use dehydrated alcohol as binding agent.
The present invention is by adding specific adjuvant Glyceryl Behenate and cholesteryl hemisuccinate, and specific consumption proportion, not only improve the mobility of material, resistance to bond, have also obtained good stability, and the bisulfate clopidogrel aspirin Composite Double synusia that antiplatelet aggregative activity strengthens.Sticking when obtained bisulfate clopidogrel aspirin Composite Double synusia can avoid tabletting, can also strengthen the antiplatelet aggregative activity of effective ingredient, and the quality stability of medicine is good, can reach safe and effective for medication.Test shows, bisulfate clopidogrel aspirin Composite Double synusia of the present invention has stronger platelet aggregation inhibitory activity, and compared with commercially available prod, bisulfate clopidogrel aspirin Composite Double synusia antiplatelet aggregative activity of the present invention strengthens.
As preferably, in bisulfate clopidogrel aspirin Composite Double synusia unit formulation provided by the invention, bisulfate clopidogrel is 98 weight portions, and aspirin is 75 weight portions or 100 weight portions; 0.4 times that Glyceryl Behenate is 5 ~ 30 weight portions, cholesteryl hemisuccinate weight portion is Glyceryl Behenate weight portion; Filler is 240 ~ 320 weight portions; Disintegrating agent is 5 ~ 18 weight portions; Lubricant is 6 ~ 20 weight portions.
As preferably, in bisulfate clopidogrel aspirin Composite Double synusia provided by the invention, Glyceryl Behenate is 15 weight portions, cholesteryl hemisuccinate is 6 weight portions; Filler is 275 weight portions; Disintegrating agent is 15 weight portions; Lubricant is 16 weight portions.
Present invention also offers the preparation method of bisulfate clopidogrel aspirin Composite Double synusia:
In certain embodiments, bisulfate clopidogrel aspirin composite double layer piece preparation method provided by the invention, comprises the steps:
1) prepared by granule 1: first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler by bisulfate clopidogrel, then with disintegrating agent, mix lubricant after dry granulation obtain granule 1; Or first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent by bisulfate clopidogrel, then after adding mix lubricant, dry granulation obtains granule 1;
2) prepared by granule 2: first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler by aspirin, then with disintegrating agent, mix lubricant after dry granulation obtain granule 2; Or aspirin is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent, then with mix lubricant after dry granulation obtain granule 2;
3) tabletting: ground floor and the second layer material feeder of respectively granule 1 and granule 2 being put into bi-layer tablet press, be pressed into the tablet of hardness within the scope of 80N ~ 120N;
4) coating and get final product.
In further embodiments, the preparation method of bisulfate clopidogrel aspirin Composite Double synusia provided by the invention, comprises the steps:
1) prepared by granule 1: first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler by bisulfate clopidogrel, then add appropriate dehydrated alcohol wet granulation, dryly must do granule, then obtains granule 1 with disintegrating agent, mix lubricant; Or bisulfate clopidogrel is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent, then add appropriate dehydrated alcohol wet granulation, dryly must do granule, then obtain granule 1 with mix lubricant;
2) prepared by granule 2: first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler by aspirin, then add appropriate dehydrated alcohol wet granulation, dryly must do granule, then obtains granule 2 with disintegrating agent, mix lubricant; Or aspirin is mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent, then add appropriate dehydrated alcohol wet granulation, dryly must do granule, then obtain granule 2 with mix lubricant;
3) tabletting: ground floor and the second layer material feeder of respectively granule 1 and granule 2 being put into bi-layer tablet press, be pressed into the tablet of hardness within the scope of 80N ~ 120N;
4) coating and get final product.
In further embodiments, bisulfate clopidogrel aspirin composite double layer piece preparation method provided by the invention, comprises the steps:
1) prepared by granule 1: first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler by bisulfate clopidogrel, then with disintegrating agent, mix lubricant after dry granulation obtain granule 1; Or first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent by bisulfate clopidogrel, then dry granulation obtains granule 1 after adding mix lubricant;
2) prepared by granule 2: first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler by aspirin, then add appropriate dehydrated alcohol wet granulation, dryly must do granule, then obtains granule 2 with disintegrating agent, mix lubricant; Or aspirin is mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent, then add appropriate dehydrated alcohol wet granulation, dryly must do granule, then obtain granule 2 with mix lubricant;
3) tabletting: ground floor and the second layer material feeder of respectively granule 1 and granule 2 being put into bi-layer tablet press, be pressed into the tablet of hardness within the scope of 80N ~ 120N;
4) coating and get final product.
In further embodiments, bisulfate clopidogrel aspirin composite double layer piece preparation method provided by the invention, comprises the steps:
1) prepared by granule 1: first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler by bisulfate clopidogrel, then add appropriate dehydrated alcohol wet granulation, dryly must do granule, then obtains granule 1 with disintegrating agent, mix lubricant; Or bisulfate clopidogrel is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent, then add appropriate dehydrated alcohol wet granulation, dryly must do granule, then obtain granule 1 with mix lubricant;
2) prepared by granule 2: first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler by aspirin, then with disintegrating agent, mix lubricant after dry granulation obtain granule 2; Or aspirin is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent, then with mix lubricant after dry granulation obtain granule 2;
3) tabletting: ground floor and the second layer material feeder of respectively granule 1 and granule 2 being put into bi-layer tablet press, be pressed into the tablet of hardness within the scope of 80N ~ 120N;
4) namely coating obtains bisulfate clopidogrel aspirin Composite Double synusia.
As preferably, in the preparation method of bisulfate clopidogrel aspirin Composite Double synusia provided by the invention, described step 1) in the consumption of Glyceryl Behenate and cholesteryl hemisuccinate be respectively 50% of respective full dose, the consumption of filler is 45% of full dose, the consumption of disintegrating agent is the 70%-100% of full dose, and the consumption of lubricant is 60% of full dose; Described step 2) in the consumption of above-mentioned each adjuvant be surplus.
As preferably, in the preparation method of bisulfate clopidogrel aspirin Composite Double synusia provided by the invention, the particle drying condition of wet granulation is 40 DEG C ~ 50 DEG C.
Present invention also offers the bisulfate clopidogrel aspirin Composite Double synusia that above-mentioned preparation method is obtained.
The invention provides a kind of bisulfate clopidogrel aspirin Composite Double synusia, comprise bisulfate clopidogrel, aspirin, Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent and lubricant.By adding adjuvant Glyceryl Behenate and the cholesteryl hemisuccinate of special ratios, not only improve the mobility of material, resistance to bond, have also obtained the bisulfate clopidogrel aspirin Composite Double synusia that quality stability is good, antiplatelet aggregative activity strengthens.Obtained bisulfate clopidogrel aspirin Composite Double synusia can avoid material sticking, and can also strengthen the antiplatelet aggregative activity of bisulfate clopidogrel aspirin, and the quality stability of medicine is good, can reach the safe, effective of medication.Test shows, bisulfate clopidogrel aspirin Composite Double synusia of the present invention has stronger platelet aggregation inhibitory activity, compared with existing bisulfate clopidogrel aspirin tablet, bisulfate clopidogrel aspirin Composite Double synusia antiplatelet aggregative activity of the present invention strengthens.
Detailed description of the invention
Below in conjunction with embodiment, set forth the present invention further.
In bisulfate clopidogrel aspirin Composite Double synusia provided by the invention and preparation method thereof, raw materials used medicine and pharmaceutically acceptable adjuvant all can be buied by market.
The preparation of embodiment 1 bisulfate clopidogrel aspirin Composite Double synusia
| Title | Consumption | Granule 1 consumption | Granule 2 consumption |
| Bisulfate clopidogrel | 98g | 98g | -- |
| Aspirin | 75g | -- | 75g |
| Glyceryl Behenate | 15g | 7.5g | 7.5g |
| Cholesteryl hemisuccinate | 6g | 3g | 3g |
| Mannitol | 130g | 58.5g | 71.5g |
| Corn starch | 145g | 65.25g | 79.75g |
| Low-substituted hydroxypropyl cellulose | 15g | 9g | 6g |
| Castor oil hydrogenated | 10g | 6g | 4g |
| Magnesium stearate | 6g | 3.6g | 2.4g |
Preparation: bisulfate clopidogrel is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent, then adds appropriate dehydrated alcohol wet granulation, 50 DEG C dry must do granule, then obtains granule 1 with mix lubricant; Aspirin is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, then with disintegrating agent, mix lubricant after dry granulation obtain granule 2; Respectively granule 1 and granule 2 are put into ground floor and the second layer material feeder of bi-layer tablet press, be pressed into 1000, the tablet of hardness within the scope of 80N ~ 120N; Coating and get final product.
The preparation of embodiment 2 bisulfate clopidogrel aspirin Composite Double synusia
| Title | Consumption | Granule 1 consumption | Granule 2 consumption |
| Bisulfate clopidogrel | 98g | 98g | -- |
[0049]
| Aspirin | 100g | -- | 100g |
| Glyceryl Behenate | 30g | 15g | 15g |
| Cholesteryl hemisuccinate | 12g | 6g | 6g |
| Pregelatinized Starch | 140g | 63g | 77g |
| Microcrystalline Cellulose | 100g | 45g | 55g |
| Polyvinylpolypyrrolidone | 18g | 12.6g | 5.4g |
| Silicon dioxide | 10g | 8g | 2g |
| Stearic acid | 10g | 8g | 2g |
Preparation: bisulfate clopidogrel is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, then adds appropriate dehydrated alcohol wet granulation, 45 DEG C dry must do granule, then obtains granule 1 with disintegrating agent, mix lubricant; Aspirin is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, then with disintegrating agent, mix lubricant after dry granulation obtain granule 2; Respectively granule 1 and granule 2 are put into ground floor and the second layer material feeder of bi-layer tablet press, be pressed into 1000, the tablet of hardness within the scope of 80N ~ 120N; Coating and get final product.
The preparation of embodiment 3 bisulfate clopidogrel aspirin Composite Double synusia
| Title | Consumption | Granule 1 consumption | Granule 2 consumption |
| Bisulfate clopidogrel | 98g | 98g | -- |
| Aspirin | 75g | -- | 75g |
| Glyceryl Behenate | 20g | 15g | 15g |
| Cholesteryl hemisuccinate | 8g | 4g | 4g |
| Lactose | 125g | 56.25g | 68.75g |
| Pregelatinized Starch | 125g | 56.25g | 68.75g |
| Cross-linking sodium carboxymethyl cellulose | 10g | 7g | 3g |
| Polyethylene glycol 6000 | 6g | 3.6g | 2.4g |
| Micropowder silica gel | 4g | 2.4g | 1.6g |
Preparation: bisulfate clopidogrel is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, then with disintegrating agent, mix lubricant after dry granulation obtain granule 1; First mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler by aspirin, then add appropriate dehydrated alcohol wet granulation, 45 DEG C dry must do granule, then obtains granule 2 with disintegrating agent, mix lubricant; Respectively granule 1 and granule 2 are put into ground floor and the second layer material feeder of bi-layer tablet press, be pressed into 1000 tablets of hardness within the scope of 80N ~ 120N; Coating and get final product.
The preparation of embodiment 4 bisulfate clopidogrel aspirin Composite Double synusia
| Title | Consumption | Granule 1 consumption | Granule 2 consumption |
[0056]
| Bisulfate clopidogrel | 98g | 98g | -- |
| Aspirin | 75g | -- | 75g |
| Glyceryl Behenate | 10g | 5g | 5g |
| Cholesteryl hemisuccinate | 4g | 2g | 2g |
| Microcrystalline Cellulose | 120g | 54g | 66g |
| Mannitol | 160g | 72g | 88g |
| Carboxymethyl starch sodium | 7g | 7g | 0 |
| Macrogol 4000 | 6g | 3.6g | 2.4g |
Preparation: bisulfate clopidogrel is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent, then after adding mix lubricant, dry granulation obtains granule 1; Aspirin is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent, then with mix lubricant after dry granulation obtain granule 2; Respectively granule 1 and granule 2 are put into ground floor and the second layer material feeder of bi-layer tablet press, be pressed into 1000, the tablet of hardness within the scope of 80N ~ 120N; Coating and get final product.
The preparation of embodiment 5 bisulfate clopidogrel aspirin Composite Double synusia
| Title | Consumption | Granule 1 consumption | Granule 2 consumption |
| Bisulfate clopidogrel | 98g | 98g | -- |
| Aspirin | 100g | -- | 100g |
| Glyceryl Behenate | 25g | 12.5g | 12.5g |
| Cholesteryl hemisuccinate | 10g | 5g | 5g |
| Microcrystalline Cellulose | 260g | 117g | 143g |
| Polyvinylpolypyrrolidone | 12g | 10g | 2g |
| Micropowder silica gel | 9g | 5.4g | 3.6g |
| Silicon dioxide | 6g | 3.6g | 2.4g |
Preparation: bisulfate clopidogrel is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent, then adds appropriate dehydrated alcohol wet granulation, 40 DEG C dry must do granule, then obtains granule 1 with mix lubricant; Mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent by aspirin, then add appropriate dehydrated alcohol wet granulation, 40 DEG C dry must do granule, then obtains granule 2 with mix lubricant; Respectively granule 1 and granule 2 are put into ground floor and the second layer material feeder of bi-layer tablet press, be pressed into 1000, the tablet of hardness within the scope of 80N ~ 120N; Coating and get final product.
The preparation of embodiment 6 bisulfate clopidogrel aspirin Composite Double synusia
| Title | Consumption | Granule 1 consumption | Granule 2 consumption |
[0063]
| Bisulfate clopidogrel | 98g | 98g | -- |
| Aspirin | 100g | -- | 100g |
| Glyceryl Behenate | 5g | 2.5g | 2.5g |
| Cholesteryl hemisuccinate | 2g | 1g | 1g |
| Corn starch | 320g | 131.9g | 135.1g |
| Low-substituted hydroxypropyl cellulose | 5g | 3.8g | 1.2g |
| Pulvis Talci | 12g | 7.2g | 4.8g |
Preparation: bisulfate clopidogrel is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, then adds appropriate dehydrated alcohol wet granulation, 50 DEG C dry must do granule, then obtains granule 1 with disintegrating agent, mix lubricant; Aspirin is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, then with disintegrating agent, mix lubricant after dry granulation obtain granule 2; Respectively granule 1 and granule 2 are put into ground floor and the second layer material feeder of bi-layer tablet press, be pressed into 1000, the tablet of hardness within the scope of 80N ~ 120N; Coating and get final product.
The preparation of embodiment 7 bisulfate clopidogrel aspirin Composite Double synusia
| Title | Consumption | Granule 1 consumption | Granule 2 consumption |
| Bisulfate clopidogrel | 98g | 98g | -- |
| Aspirin | 100g | -- | 100g |
| Glyceryl Behenate | 12g | 10g | 10g |
| Cholesteryl hemisuccinate | 4.8g | 2.4g | 2.4g |
| Pregelatinized Starch | 300g | 135g | 165g |
| Cross-linking sodium carboxymethyl cellulose | 14g | 11g | 3g |
| Silicon dioxide | 9g | 5.4g | 3.6g |
| Magnesium stearate | 9g | 5.4g | 3.6g |
Preparation: bisulfate clopidogrel is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent, then adds appropriate dehydrated alcohol wet granulation, 45 DEG C dry must do granule, then obtains granule 1 with mix lubricant; Aspirin is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent, then with mix lubricant after dry granulation obtain granule 2; Respectively granule 1 and granule 2 are put into ground floor and the second layer material feeder of bi-layer tablet press, be pressed into 1000, the tablet of hardness within the scope of 80N ~ 120N; Coating and get final product.
The preparation of embodiment 8 bisulfate clopidogrel aspirin Composite Double synusia
| Title | Consumption | Granule 1 consumption | Granule 2 consumption |
| Bisulfate clopidogrel | 98g | 98g | -- |
| Aspirin | 75g | -- | 75g |
[0070]
| Glyceryl Behenate | 18g | 9g | 9g |
| Cholesteryl hemisuccinate | 2.1 | 1.05g | 1.05g |
| Mannitol | 270g | 121.5g | 148.5g |
| Polyvinylpolypyrrolidone | 16g | 12.8g | 3.2g |
| Polyethylene glycol 6000 | 17g | 10.2g | 6.8g |
Preparation: bisulfate clopidogrel is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent, then after adding mix lubricant, dry granulation obtains granule 1; Mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent by aspirin, then add appropriate dehydrated alcohol wet granulation, 50 DEG C dry must do granule, then obtains granule 2 with mix lubricant; Respectively granule 1 and granule 2 are put into ground floor and the second layer material feeder of bi-layer tablet press, be pressed into 1000, the tablet of hardness within the scope of 80N ~ 120N; Coating and get final product.
The antiplatelet aggregative activity test of embodiment 9 bisulfate clopidogrel aspirin Composite Double synusia
Extracting male Wistar rat, body weight 240-280g, is divided into three groups at random, often organizes 10.Be respectively test A group, test B group, matched group.Test A group: the bisulfate clopidogrel aspirin Composite Double synusia that the embodiment of the present invention 1 provides; Test B group: existing bisulfate clopidogrel aspirin tablet (prescription comprises bisulfate clopidogrel, aspirin, mannitol, microcrystalline Cellulose, silicon dioxide, magnesium stearate, castor oil hydrogenated, low-substituted hydroxypropyl cellulose, corn starch); Matched group: distilled water.
Often organize and gavage administration respectively 5 days, 2h after last administration, with 20% urethane intraperitoneal anesthesia, from abdominal aortic blood, 3.8% sodium citrate mixes by 1:9 with whole blood, the centrifugal 7min of 1000r/m prepares platelet rich plasma (PRP), the centrifugal 10min of 3000r/m prepares platelet poor plasma (PPP), application SPA-3 type PPP autobalance platelet aggregation instrument, the platelet aggregation percent of being induced by each derivant is adjusted to 60% ~ 70%, derivant ADP, arachidonic acid, collagen final concentration is respectively 4 μm of ol/L, 2mmol/L, 20mg/ml, the results are shown in Table 1.
Table 1 bisulfate clopidogrel aspirin Composite Double synusia is on the impact of platelet aggregation rate
From table 1 result, the bisulfate clopidogrel aspirin Composite Double synusia that the embodiment of the present invention 1 provides has stronger antiplatelet aggregative activity, shows that bisulfate clopidogrel aspirin Composite Double synusia pharmacologically active provided by the invention strengthens.
Carry out antiplatelet aggregation experiment to bisulfate clopidogrel aspirin Composite Double synusia prepared by embodiment 2-8 according to the method described above, action effect is all close with embodiment 1.
To sum up, the antiplatelet aggregation effect of bisulfate clopidogrel aspirin Composite Double synusia provided by the invention is better than existing bisulfate clopidogrel aspirin Composite Double synusia.
The fluidity determining of embodiment 10 material particles
The mobility of solid is commonly used and is represented angle of repose (θ), typically refers to the maximum angular that the free inclined-plane of powder body accumulation horizon and horizontal plane are formed.Angle of repose is less, and frictional force is less, and mobility is better, and good fluidity when it is generally acknowledged θ≤30 degree, can meet the need for liquidity in production process during θ≤40 degree.The mobility of powder body is to the weight differential of the preparations such as tablet, granule, capsule and normally Influence of production is larger.
The bisulfate clopidogrel aspirin composite double layer sheet material granule of embodiment 1, existing product prescription material particles, the material particles prepared according to CN102389436A embodiment 1 method are measured angle of repose respectively.Method adopts injection method, is slowly added by powder body above funnel, and the inclination angle that the material spilt from funnel bottom forms coniform accumulation body is in the horizontal plane angle of repose, the results are shown in Table 2.
Table 2 measurement result angle of repose
| Complex | The embodiment of the present invention 1 | Existing product | CN102389436 A embodiment 1 |
| Angle of repose | 29.5° | 37.5° | 39 degree |
From table 2 result, the bisulfate clopidogrel aspirin material particles that the embodiment of the present invention 1 provides is less than 30 ° angle of repose, be significantly less than existing product prescription, bisulfate clopidogrel aspirin material particles prepared by patented method, show that the mobility of the bisulfate clopidogrel aspirin composite double layer sheet material that the embodiment of the present invention 1 provides is more excellent.
Carry out mobility-detected to bisulfate clopidogrel aspirin compound material particles prepared by embodiment 2-8 according to the method described above, result is all close with embodiment 1.
To sum up, the mobility of bisulfate clopidogrel aspirin composite double layer sheet material provided by the invention is better than existing bisulfate clopidogrel aspirin complex.
The stability study of embodiment 11 bisulfate clopidogrel aspirin Composite Double synusia
With the bisulfate clopidogrel aspirin Composite Double synusia prepared by the embodiment of the present invention 1 for object of study, carry out study on the stability, comprising: accelerated test, long-term stable experiment.Study on the stability experimental condition and method are all with reference to the relevant regulations of 2010 editions " Chinese Pharmacopoeia " annex, and accelerated test investigates 6 months, and long-time stability were investigated to 12 months, and result is as follows:
Table 5 accelerated test (temperature 40 DEG C ± 2 DEG C, relative humidity 75% ± 5%)
Table 6 long-term stable experiment (temperature 25 DEG C ± 2 DEG C, relative humidity 60% ± 10%)
From table 5 ~ 6 result, bisulfate clopidogrel aspirin Composite Double synusia prepared by the embodiment of the present invention 1 is at 40 DEG C, 6 months are investigated under the acceleration environment of relative humidity 75%, at 25 DEG C ± 2 DEG C, 12 months are investigated under relative humidity 60% ± 10% condition, primary quality measure, without significant change, shows bisulfate clopidogrel aspirin composite double layer tablet quality good stability prepared by the embodiment of the present invention 1.
Carry out Detection of Stability to bisulfate clopidogrel aspirin Composite Double synusia prepared by embodiment 2 ~ 8 according to the method described above, the stability of the bisulfate clopidogrel aspirin Composite Double synusia that result all provides with embodiment 1 is close.
To sum up, bisulfate clopidogrel aspirin Composite Double synusia provided by the invention has good quality stability.
Below be only the preferred embodiment of the present invention; not in order to limit the present invention, to those skilled in the art, under the premise without departing from the principles of the invention; the some improvement that can also make, retouching, equivalent replacement, all should be included within protection scope of the present invention.
Claims (10)
1. a bisulfate clopidogrel aspirin Composite Double synusia, with bisulfate clopidogrel and aspirin for active component, it is characterized in that, add Glyceryl Behenate, cholesteryl hemisuccinate, then be equipped with filler, disintegrating agent and lubricant combination and form.
2. bisulfate clopidogrel aspirin Composite Double synusia according to claim 1, it is characterized in that, described bisulfate clopidogrel is 98 weight portions; Described aspirin is 75 weight portions or 100 weight portions.
3. bisulfate clopidogrel aspirin Composite Double synusia according to claim 1, it is characterized in that, described Glyceryl Behenate is 5 ~ 30 weight portions, cholesteryl hemisuccinate weight portion is Glyceryl Behenate weight portion 0.4 times.
4. bisulfate clopidogrel aspirin Composite Double synusia according to claim 1, it is characterized in that, described filler is selected from one or more the mixture in lactose, mannitol, microcrystalline Cellulose, pregelatinized Starch, corn starch, and its weight portion is 240 ~ 320.
5. bisulfate clopidogrel aspirin Composite Double synusia according to claim 1, it is characterized in that, described disintegrating agent is selected from one or more the mixture in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, and its weight portion is 5 ~ 18.
6. bisulfate clopidogrel aspirin Composite Double synusia according to claim 1, it is characterized in that, described lubricant is selected from one or more the mixture in magnesium stearate, stearic acid, silicon dioxide, polyethylene glycol 6000, Macrogol 4000, castor oil hydrogenated, Pulvis Talci, micropowder silica gel, and its weight portion is 6 ~ 20.
7. bisulfate clopidogrel aspirin Composite Double synusia according to claim 1, is characterized in that, dehydrated alcohol can be used as binding agent.
8. the preparation method of the bisulfate clopidogrel aspirin Composite Double synusia according to any one of claim 1-8, comprises the steps:
1) prepared by granule 1: first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler by bisulfate clopidogrel, then with disintegrating agent, mix lubricant after dry granulation obtain granule 1; Or first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent by bisulfate clopidogrel, then after adding mix lubricant, dry granulation obtains granule 1; Or bisulfate clopidogrel is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, then add appropriate dehydrated alcohol wet granulation, dryly must do granule, then obtain granule 1 with disintegrating agent, mix lubricant; Or bisulfate clopidogrel is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent, then add appropriate dehydrated alcohol wet granulation, dryly must do granule, then obtain granule 1 with mix lubricant;
2) prepared by granule 2: first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler by aspirin, then with disintegrating agent, mix lubricant after dry granulation obtain granule 2; Or aspirin is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent, then with mix lubricant after dry granulation obtain granule 2; Or aspirin is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, then add appropriate dehydrated alcohol wet granulation, dryly must do granule, then obtain granule 2 with disintegrating agent, mix lubricant; Or aspirin is first mixed with Glyceryl Behenate, cholesteryl hemisuccinate, filler, disintegrating agent, then add appropriate dehydrated alcohol wet granulation, dryly must do granule, then obtain granule 2 with mix lubricant;
3) tabletting: ground floor and the second layer material feeder of respectively granule 1 and granule 2 being put into bi-layer tablet press, be pressed into the tablet of hardness within the scope of 80N ~ 120N;
4) namely coating obtains bisulfate clopidogrel aspirin Composite Double synusia.
9. the preparation method of bisulfate clopidogrel aspirin Composite Double synusia according to claim 8, it is characterized in that, described step 1) in the consumption of Glyceryl Behenate and cholesteryl hemisuccinate be respectively 50% of respective full dose, the consumption of filler is 45% of full dose, the consumption of disintegrating agent is the 70%-100% of full dose, and the consumption of lubricant is 60% of full dose; Described step 2) in the consumption of above-mentioned adjuvant be surplus.
10. the preparation method of bisulfate clopidogrel aspirin Composite Double synusia according to claim 8, the particle drying condition of described wet granulation is 40 DEG C ~ 50 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410840875.2A CN104523710B (en) | 2014-12-30 | 2014-12-30 | A kind of bisulfate clopidogrel aspirin Composite Double synusia and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410840875.2A CN104523710B (en) | 2014-12-30 | 2014-12-30 | A kind of bisulfate clopidogrel aspirin Composite Double synusia and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104523710A true CN104523710A (en) | 2015-04-22 |
| CN104523710B CN104523710B (en) | 2018-05-25 |
Family
ID=52839468
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410840875.2A Active CN104523710B (en) | 2014-12-30 | 2014-12-30 | A kind of bisulfate clopidogrel aspirin Composite Double synusia and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104523710B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106619549A (en) * | 2017-01-03 | 2017-05-10 | 江苏吴中医药集团有限公司苏州制药厂 | Ticagrelor and aspirin compound tablet and preparation method thereof |
| CN115581679A (en) * | 2021-07-05 | 2023-01-10 | 上海复星星泰医药科技有限公司 | Preparation method of anti-sticking tablet and tablet |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101632647A (en) * | 2008-07-21 | 2010-01-27 | 北京迈劲医药科技有限公司 | Preparation method for compound preparation comprising aspirin and alkaline drugs |
| CN201426858Y (en) * | 2009-07-06 | 2010-03-24 | 沈阳亿灵医药科技有限公司 | Clopidogrel hydrogen shlfate and aspirin double-layer tablet |
| CN102389436A (en) * | 2011-09-09 | 2012-03-28 | 北京阜康仁生物制药科技有限公司 | Medicinal composition for resisting platelet aggregation |
| WO2014027334A2 (en) * | 2012-08-17 | 2014-02-20 | Laboratorios Senosiain, S.A. De C.V. | Oral pharmaceutical composition in the form of microspheres and preparation method |
-
2014
- 2014-12-30 CN CN201410840875.2A patent/CN104523710B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101632647A (en) * | 2008-07-21 | 2010-01-27 | 北京迈劲医药科技有限公司 | Preparation method for compound preparation comprising aspirin and alkaline drugs |
| CN201426858Y (en) * | 2009-07-06 | 2010-03-24 | 沈阳亿灵医药科技有限公司 | Clopidogrel hydrogen shlfate and aspirin double-layer tablet |
| CN102389436A (en) * | 2011-09-09 | 2012-03-28 | 北京阜康仁生物制药科技有限公司 | Medicinal composition for resisting platelet aggregation |
| WO2014027334A2 (en) * | 2012-08-17 | 2014-02-20 | Laboratorios Senosiain, S.A. De C.V. | Oral pharmaceutical composition in the form of microspheres and preparation method |
Non-Patent Citations (2)
| Title |
|---|
| 杨怡静等: "山嵛酸甘油酯作为片剂润滑剂的研究", 《中国现代应用药学》 * |
| 王玉等: "复方阿司匹林/硫酸氢氯吡格雷双层缓释片的制备", 《中国药剂学杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106619549A (en) * | 2017-01-03 | 2017-05-10 | 江苏吴中医药集团有限公司苏州制药厂 | Ticagrelor and aspirin compound tablet and preparation method thereof |
| CN106619549B (en) * | 2017-01-03 | 2019-12-06 | 江苏吴中医药集团有限公司苏州制药厂 | ticagrelor and aspirin composite tablet and preparation method thereof |
| CN115581679A (en) * | 2021-07-05 | 2023-01-10 | 上海复星星泰医药科技有限公司 | Preparation method of anti-sticking tablet and tablet |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104523710B (en) | 2018-05-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2022022369A1 (en) | Sustained-release formulation of tofacitinib or salt thereof and preparation method therefor | |
| JP2019069981A (en) | Pharmaceutical composition containing irbesartan and amlodipine or salt thereof | |
| CN101703513B (en) | Compound sustained-release preparation of aspirin and clopidogrel or pharmaceutically acceptable salt thereof | |
| CN101972236A (en) | Sustained release preparation containing pirfenidone | |
| CN110035757A (en) | A kind of olaparib takes orally sustained and controlled release medicament composition and application thereof | |
| KR20160054216A (en) | Pharmaceutical tablet comprising Choline Alphoscerate and method for manufacturing the same | |
| KR101473268B1 (en) | Pharmaceutical composition comprising clopidogrel and aspirin and process for preparing the same | |
| US20140363512A1 (en) | Oral pharmaceutical composition | |
| CN1682719B (en) | Enteric soluble coating slow releasing tablet containing huperzine A and preparing method | |
| CA3010778A1 (en) | Galenic formulations of organic compounds | |
| US20120141586A1 (en) | Thrombin receptor antagonist and clopidogrel fixed dose tablet | |
| CN115518066A (en) | Pharmaceutical composition for treating anticoagulation and application | |
| CN104146978A (en) | Disulfiram enteric coated tablet and preparation method thereof | |
| CN104523710A (en) | Compound clopidogrel hydrogen sulphate and aspirin double-layer tablet and preparation method thereof | |
| CN109414423A (en) | Delayed release medicine preparation comprising valproic acid and its purposes | |
| CN106420738B (en) | A kind of sustained release preparation of levamlodipine or its salt and preparation method thereof | |
| EP3437645A1 (en) | Film-coated tablet having high chemical stability of active ingredient | |
| RU2414903C1 (en) | Pharmaceutical composition of prolonged action based on clozapine of peroral introduction | |
| US20170333352A1 (en) | Rapidly disintegrating tablet, and method for producing same | |
| CN104644595A (en) | Solid pharmaceutical composition with clopidogrel | |
| CN100496606C (en) | Composite preparation containing nitrate esters medicine and HMG-CoA reductase inhibitor | |
| JP6469234B2 (en) | Super-fast disintegrating tablet and method for producing the same | |
| CN105582546B (en) | A kind of Entecavir phosphatide complexes and the compound enteric-coated tablet of diammonium glycyrrhizinate | |
| CA3207049A1 (en) | Irak4 degraders and uses thereof | |
| RU2663460C2 (en) | Complex preparation including valsartan and rosuvastatin calcium and manufacturing method therefor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |