CN103957895A - Complex agent containing clopidogrel and aspirin - Google Patents
Complex agent containing clopidogrel and aspirin Download PDFInfo
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- CN103957895A CN103957895A CN201280053817.4A CN201280053817A CN103957895A CN 103957895 A CN103957895 A CN 103957895A CN 201280053817 A CN201280053817 A CN 201280053817A CN 103957895 A CN103957895 A CN 103957895A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4743—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having sulfur as a ring hetero atom
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- A—HUMAN NECESSITIES
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- 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
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- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
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Abstract
The present invention relates to a complex agent of clopidogrel and aspirin, and more particularly, to a complex agent including a capsule containing a granule obtained by coating a clopidogrel layer with a layer for preventing rapid release, and an aspirin granule obtained by coating an aspirin layer with an enteric layer. The physical contact between the clopidogrel and the aspirin may be blocked, and the eutectic phenomenon may be fundamentally blocked. In the short term, a change in the amount, elution properties, and bioequivalence of the agent may be prevented, and in the long term, the stability of the agent may be ensured. In addition, damage to the stomach wall may be prevented by coating the aspirin with the enteric layer.
Description
Technical field
The present invention relates to the compound formulation that comprises clopidogrel and aspirin.Specifically, relate to stable and guaranteed the compound formulation of bioavailability, this compound formulation is by carrying out the granule of coating with rapid release protective layer to clopidogrel layer and incapsulating with the aspirin granule that enteric layer carries out coating to aspirin layer.
Background technology
Clopidogrel, i.e. (+)-(S)-α-(2-chlorphenyl)-6,7-dihydro-thiophene also [3,2-c] pyridine-5 (4H)-methyl acetate is anticoagulant, it is not only effective to the treatment of the peripheral arterial disease such as apoplexy, thrombosis and thromboembolism disease, and effective to the treatment of the coronary artery disease such as apoplexy, thrombosis, thromboembolism disease and myocardial infarction.Clopidogrel is combined with ADP by directly suppressing adenosine diphosphate (ADP) receptor, and directly suppresses the activation of the glycoprotein GPIIb/IIa complex of the ADP-mediation of secondary, thereby suppresses the platelet aggregation of ADP-induction.In addition, the amplification of the platelet activation that clopidogrel is caused by the ADP discharging by blocking-up, suppresses the platelet aggregation being brought out by the agonist except ADP (agonist).
The pharmacological action of such clopidogrel is to be realized by its active metabolite, and this active metabolite is after clopidogrel oral administration, in liver, carry out metabolism and form.This active metabolite optionally and non reversibility make to be present in the adp receptor modification in platelet, be combined with adp receptor thereby hinder ADP.Therefore the effect of clopidogrel depends on the enzyme that makes clopidogrel metabolism in liver to a great extent.
Chemical name as the bisulfate clopidogrel of the representative pharmaceutical raw material of clopidogrel is (+)-(S)-α-(2-chlorphenyl)-6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-methyl acetate disulfate (1:1) also.The chemical formula of bisulfate clopidogrel is C
16h
16clNO
2sH
2sO
4, its molecular weight is 419.9.
Bisulfate clopidogrel is white or Lycoperdon polymorphum Vitt powder.It is almost insoluble in the water of neutral pH, but very easily holds in the time of pH1.0.And it easily holds (freely soluble) in methanol, slightly soluble in dichloromethane, in ether almost insoluble (practically insoluble).
Known, bisulfate clopidogrel is in order to reduce such as acute (recent) myocardial infarction (myocardial infarction, MI), there is (thromboticevent) and administration in the thrombosis of acute apoplexy (stroke) or (established) arterial disease (arterial disease) of making a definite diagnosis and so on, it reduces new (new) cerebral infarction (ischemic stroke), the speed of the composite end points (combined end point) of new MI and other vascular death (vascular death).In the case of the patient with acute coronary syndrome, known bisulfate clopidogrel not only reduces the speed because of the composite end points of the death that cardiovascular causes, MI or apoplexy, and reduces the speed of the composite end points of cardiovascular death, MI, apoplexy or intractable ischemia (refractory ischemia).
In addition, be called as acetysalicylic aspirin and be typically used as analgesic (for slight pain disease and pain), antipyretic (for heating) and anti-inflammatory agent.In addition, aspirin has anticoagulation (dilute blood, blood thinning) effect, and low dosage long term administration can prevention of cardiac outbreak (heart attack).
The aspirin of CAS numbering (Number): 50-78-2 is chemically being called as Aspirin.The molecular formula of aspirin is C
9h
8o
4, molecular weight is 180.16.
Aspirin is colourless or white crystals or white crystalline powder or granule.Aspirin odorless or slightly tart flavour.The fusing point of aspirin is 136 DEG C, and boiling point is 140 DEG C.Aspirin and free acid (free acid), acetanilide, aminophenazone, phenazone (phenazone), hexamine, iron salt, sodium phenobarbital, quinine salt, potassium iodide and sodium iodide and alkaline hydrated oxide (alkali hydroxide), carbonic ester and stearate are immiscible.Aspirin is stable in dry air, if but contact with dampness, be hydrolyzed gradually, and form acetic acid and salicylic acid.In alkaline solution, hydrolysis is carried out rapidly, and the clear solution forming is likely made up of acetas and salicylate completely.Aspirin decomposes rapidly in ammonium acetate or alkali-metal acetate, carbonate, citrate or hydroxide solution.
Aspirin is used for the treatment of the slight moderate pain that arrives as analgesic, is used for the treatment of soft tissue (soft tissue) and arthritis as anti-inflammatory agent, and as antipyretic.For the adult who has pain and heating, aspirin is every 4 hours administration 300-1000mg conventionally, at most administration every day 4g.Acute multiple rheumatic arthritis (acute polyarthritis rheumatica) in the situation that, common one day 1g, point 6 administrations, maximum one day 8g.The in the situation that of rheumatic arthritis, common one day 0.5g to 1g, point 6 administrations, maximum one day 8g.In order to prevent transient ischemic attack and prevention of arterial thrombosis, common one day 300mg to 1200mg, point 2 times or 3 administrations.
Aspirin can be used for reducing heart attack, apoplexy or the chance of the other problem that may occur in the time that blood vessel is blocked by blood clot (blood clot).Aspirin prevents the formation of dangerous blood clot.
The formation of TXA2. in non reversibility ground resistance hemostasis platelet of low dosage long-term taking aspirin, produces inhibitory action to platelet aggregation, the characteristic of this dilute blood on reducing aspect the incidence rate of heart attack effectively.
Known aspirin activates and in liver, makes clopidogrel be converted into the enzyme of active metabolite.Therefore, to the dosage form of clopidogrel administration together with aspirin has been carried out to a lot of research, but there is the problem that produces eutectic (eutectic) phenomenon in the time that two kinds of medicines directly contact.First, because aspirin is to absorb few material in gastrointestinal, and more than needing administration ormal weight, but aspirin itself has the character of damage gastrointestinal, and therefore very large to its consumption restriction.Such problem becomes more serious in the metabolism in order to increase clopidogrel in the dosage form of the first stripping of aspirin.
,, although aspirin promotes the generation of clopidogrel active metabolite in liver, there is individual differences in the generation of such active metabolite, also likely the blood level of medicine is produced to unexpected deviation, is not therefore always preferred.Particularly, with regard to Cytochrome P450 2C19 (CYP4502C19) the liver metabolism enzyme activating with regard to the aspirin first discharging, in the generation degree of its active metabolite, have individual differences, such individual differences makes the blood level of the medicine of above-mentioned active metabolite produce deviation inevitably.And such deviation is uncontrollable, patient is caused to unpredictable impact, therefore not preferred.
(prior art document)
Patent documentation 1:KR10-2009-0091076A (HANAL Pharmaceutical Co., Ltd) 2009.8.26
Patent documentation 2:WO2006/138214A (Elan Pharma Int Ltd) 2006.12.28
Patent documentation 3:WO2000/66130A (Sanofi-Synthelabo) 2000.11.9
Patent documentation 4:WO1997/29753A (Sanofi d.Kkoswi) 1997.8.21
Summary of the invention
Technical problem
The present invention proposes in order to solve problem as above; its object is; provide a kind of stable and guaranteed the compound formulation of bioavailability, this compound formulation is by carrying out the granule of coating with rapid release protective layer to clopidogrel layer and incapsulating with the aspirin granule that enteric layer carries out coating to aspirin layer.
The means of dealing with problems
In order to realize object as above, compound formulation of the present invention is characterised in that, comprises:
(A) clopidogrel granule, (B) aspirin granule and (C) hold the capsule of described clopidogrel granule and aspirin granule,
Described (A) clopidogrel granule comprises:
The kernel that contains excipient;
Clopidogrel outer core, the outside of itself and above-mentioned kernel is adjacent, and contains clopidogrel, its isomer or its pharmaceutically useful salt and the first bonding agent as pharmacologically active principles; And
Rapid release protective layer, the outside of itself and above-mentioned outer core is adjacent, and contains the second bonding agent and the first plasticizer,
Described (B) aspirin granule comprises:
The kernel that contains excipient;
Aspirin outer core, the outside of itself and above-mentioned kernel is adjacent, and contains aspirin or its pharmaceutically useful salt and the 3rd bonding agent as pharmacologically active principles; And
Enteric layer, the outside of itself and above-mentioned outer core is adjacent, and contains enteric coatings agent and the second plasticizer.
In addition, above-mentioned clopidogrel outer core can further comprise the 3rd plasticizer.
In addition, above-mentioned aspirin outer core can further comprise the 4th plasticizer.
In addition, above-mentioned excipient can select the group of free sugar, starch, microcrystalline Cellulose, lactose, Brazil wax, mannitol, tartaric acid, xylitol and composition thereof composition.
In addition, the pharmaceutically useful salt of above-mentioned clopidogrel can select disulfate, resinate, camsilate (camsylate), benzene sulfonate, the napadisilate monohydrate of free clopidogrel) group of (napadisilate monohydrate), hydrochlorate and composition thereof composition.
In addition, above-mentioned the first bonding agent, the second bonding agent and the 3rd bonding agent can select independently of one another and freely replace or the group of unsubstituted alkylcellulose or its salt, polythene derivative (polyvinyl derivative), poly alkylene glycol (polyalkyleneglycol), polymethylacrylic acid and composition thereof composition.
In addition, above-mentioned replacement or unsubstituted alkylcellulose or its salt can select the group of free methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, methyl hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose and composition thereof composition.
In addition, above-mentioned polythene derivative can select the group of free polyvinylpyrrolidone, polyvinyl alcohol and composition thereof composition.
In addition, above-mentioned poly alkylene glycol can be selected the group of free Polyethylene Glycol, polypropylene glycol and composition thereof composition.
In addition, above-mentioned polymethylacrylic acid can select freely the group of gathering (butyl methacrylate-copolymerization-(2-dimethyl aminoethyl) methacrylate-copolymerization-methyl methacrylate), poly-(ethyl acrylate-copolymerization-methyl methacrylate), poly-(ethyl acrylate-copolymerization-methyl methacrylate-copolymerization-methacrylic acid chlorination trimethylamine groups ethyl ester (trimethylamino ethyl methacrylate chloride)) and composition thereof composition.
In addition, above-mentioned the first plasticizer, the second plasticizer, the 3rd plasticizer and the 4th plasticizer can select the group of free glycol, ester, oil, glycerol, glycerol derivatives and composition thereof composition independently of one another.
In addition, above-mentioned glycol can select the group of free propylene glycol, Polyethylene Glycol and composition thereof composition.
In addition, above-mentioned ester selects the group of free diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, glyceryl triacetate and composition thereof composition.
In addition, above-mentioned oil can select the group of free Oleum Ricini, Oleum Cocois and composition thereof composition.
In addition, above-mentioned glycerol and glycerol derivatives can select the group of free glycerol, glyceryl monostearate and composition thereof composition.
In addition, above-mentioned enteric coatings agent can be selected the group of free Lac, HPMCAS, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalic acid ester, cellulose acetate, polyvinyl alcohol phthalic acid ester, poly-(methacrylate-copolymerization-methyl methacrylate), poly-(acrylic acid methyl ester .-copolymerization-methyl methacrylate-copolymerization-methacrylic acid), poly-(methacrylate-copolymerization-ethyl acrylate) and composition thereof composition.
In addition, above-mentioned clopidogrel outer core, aspirin outer core, rapid release protective layer or enteric layer can further comprise the additive in the group of selecting free diluent, lubricant, stabilizing agent, film coating agent and composition thereof composition.
In addition,, with respect to above-mentioned clopidogrel 100 weight portions, aspirin can be 10 to 1000 weight portions.
In addition, above-mentioned capsule can be hard capsules.
On the other hand; term as used in this specification " rapid release protective layer " refers to following layer: be coated on the outer surface of clopidogrel outer core and blocking-up clopidogrel directly contacts (protective layer) with aspirin, and play help clopidogrel and can first discharge under one's belt the effect of (rapid release).
Invention effect
The maximum of compound formulation of the present invention is characterised in that, by clopidogrel and aspirin are filled in a capsule, and taking clopidogrel as immediate release granule, fill taking aspirin as enteric solubility granule, be designed to as the clopidogrel of main constituent and aspirin not direct physical contact, thereby fundamentally block the eutectic phenomenon of two kinds of compositions.So, by eliminating eutectic phenomenon, prevent the variation of the physicochemical properties of each composition, thereby have the variation of the content that prevents preparation, dissolution characteristic, bioequivalence (bioequivalence) short-termly, chronicity ground improves the effect of the stability of preparation.
And compound formulation of the present invention causes the problem of damage in order to prevent because aspirin stimulates coat of the stomach, aspirin is carried out to coating with enteric layer, make aspirin only in enteral stripping and not stripping under one's belt.Therefore, if oral administration compound formulation of the present invention, clopidogrel first stripping under one's belt, aspirin is stripping after enteral, thereby has the effect of prevention coat of the stomach damage.
Finally, compound formulation of the present invention has advantages of as follows: with simultaneously or separate the situation that the time takes clopidogrel and aspirin and compare, can increase convenience and the compliance taken, and due to the complementary pharmacological action of two kinds of medicines, even if therefore employing is compared lower consumption and also can be demonstrated identical result with preparation in the past, and can reduce the side effect and the manufacturing expense that are caused by pharmaceutical component.
Brief description of the drawings
Fig. 1 is the skeleton diagram about compound formulation structure of the present invention.
Fig. 2 is the differential scanning calorimetry (DSC) figure of bisulfate clopidogrel.
Fig. 3 is the differential scanning calorimetry (DSC) figure of aspirin.
Fig. 4 is the differential scanning calorimetry (DSC) figure of bisulfate clopidogrel and aspirin mixture.
Fig. 5 is the changes of contents figure of clopidogrel in the accelerated test of 6 months.
Fig. 6 is the changes of contents figure of aspirin in the accelerated test of 6 months.
Fig. 7 is the dissolution rate variation diagram of clopidogrel in the accelerated test of 6 months.
Fig. 8 is the dissolution rate variation diagram of aspirin in 0.1N HCl in the accelerated test of 6 months.
Fig. 9 is the dissolution rate variation diagram of aspirin in the time of pH6.8 in the accelerated test of 6 months.
Figure 10 is total analog changes of contents figure of clopidogrel in the accelerated test of 6 months.
Figure 11 is total analog changes of contents figure of aspirin in the accelerated test of 6 months.
Figure 12 is the comparison stripping figure when the pH1.2 about clopidogrel granule and Plavix (Plavix) tablet.
Figure 13 is the comparison stripping figure when the pH4.0 about clopidogrel granule and Plavix tablet.
Figure 14 is the comparison stripping figure when the pH6.8 about clopidogrel granule and Plavix tablet.
Figure 15 is the comparison stripping figure in water about clopidogrel granule and Plavix tablet.
Figure 16 is the comparison stripping figure when the pH1.2 about aspirin granule and Astrix capsule.
Figure 17 is the comparison stripping figure when the pH6.0 about aspirin granule and Astrix capsule.
Figure 18 is the comparison stripping figure when the pH6.8 about aspirin granule and Astrix capsule.
Figure 19 is the blood level figure of clopidogrel.
Figure 20 is the blood level figure of aspirin.
Figure 21 is salicylic blood level figure.
Detailed description of the invention
Below, to a preferred embodiment of the present invention will be described in detail.In addition, in following explanation, although the description of a lot of specific items such as concrete elements, but this is just in order to help more comprehensively understanding of the present invention to provide, in affiliated technical field, have and conventionally know the knowledgeable and it is evident that, also can implement the present invention even without so specific item.In addition, in explanation time of the present invention, in the case of be judged as to illustrating of relevant known function or formation likely unnecessarily make main idea of the present invention fuzzy, description is omitted.
As shown in Figure 1, compound formulation of the present invention comprises clopidogrel granule and aspirin granule in capsule, and above-mentioned clopidogrel granule comprises: the kernel that contains excipient; Clopidogrel outer core, the outside of itself and above-mentioned kernel is adjacent, and contains clopidogrel, its isomer or its pharmaceutically useful salt and the first bonding agent as pharmacologically active principles; And rapid release protective layer, the outside of itself and above-mentioned outer core is adjacent, and contains the second bonding agent and the first plasticizer.In addition, aspirin granule comprises: the kernel that contains excipient; Aspirin outer core, the outside of itself and above-mentioned kernel is adjacent, and contains aspirin or its pharmaceutically useful salt and the 3rd bonding agent as pharmacologically active principles; And enteric layer, the outside of itself and above-mentioned outer core is adjacent, and contains enteric coatings agent and the second plasticizer.
The first stripping clopidogrel granule under one's belt of compound formulation of the present invention like this, afterwards at enteral stripping aspirin granule.Therefore, not only can show the complementary pharmacological effect of clopidogrel and aspirin, and can prevent that the coat of the stomach being caused by aspirin from damaging.And then, by blocking-up clopidogrel directly contact with aspirin, can prevent eutectic phenomenon, prevent content or dissolution characteristic variation, raising medicine stability.
In compound formulation of the present invention, above-mentioned clopidogrel outer core can further comprise the 3rd plasticizer, and above-mentioned aspirin outer core can further comprise the 4th plasticizer.Such plasticizer is given plasticity to upright and outspoken macromolecule and is improved processability, plays the flexible effect that strengthens coating tunicle in the time that tablet and granule are carried out to coating.
In addition, above-mentioned excipient can select the group of free sugar, starch, microcrystalline Cellulose, lactose, Brazil wax, mannitol, tartaric acid, xylitol and composition thereof composition, is particularly preferably sugar.
In addition, the pharmaceutically useful salt of above-mentioned clopidogrel can select disulfate, resinate, camsilate, benzene sulfonate, the napadisilate monohydrate of free clopidogrel, the group of hydrochlorate and composition thereof composition, is particularly preferably disulfate and benzene sulfonate.
In addition, above-mentioned the first bonding agent, the second bonding agent and the 3rd bonding agent can select independently of one another and freely replace or unsubstituted alkylcellulose or its salt, polythene derivative, poly alkylene glycol, the group of polymethylacrylic acid and composition thereof composition, wherein, above-mentioned replacement or unsubstituted alkylcellulose or its salt can select free methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, methyl hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, the group of its salt and composition thereof composition, be particularly preferably hydroxypropyl emthylcellulose.
In addition, above-mentioned polythene derivative can select the group of free polyvinylpyrrolidone, polyvinyl alcohol and composition thereof composition, and above-mentioned poly alkylene glycol can be selected the group of free Polyethylene Glycol, polypropylene glycol and composition thereof composition.
In addition, above-mentioned polymethylacrylic acid can select freely the group of gathering (butyl methacrylate-copolymerization-(2-dimethyl aminoethyl) methacrylate-copolymerization-methyl methacrylate), poly-(ethyl acrylate-copolymerization-methyl methacrylate), poly-(ethyl acrylate-copolymerization-methyl methacrylate-copolymerization-methacrylic acid chlorination trimethylamine groups ethyl ester) and composition thereof composition.
In above-mentioned polymethylacrylic acid, poly-(butyl methacrylate-copolymerization-(2-dimethyl aminoethyl) methacrylate-copolymerization-methyl methacrylate) be poly-(butyl methacrylate-copolymerization-(2-dimethyl aminoethyl) methacrylate-copolymerization-methyl methacrylate) 1:2:1 such as Eudragit E100, Eudragit E12.5 or the Eudragit E PO of Evonik Degussa (Germany) more preferably.
In addition above-mentioned poly-(ethyl acrylate-copolymerization-methyl methacrylate) more preferably poly-(ethyl acrylate-copolymerization-methyl methacrylate) 2:1 such as Eudragit NE30D, Eudragit NE40D, the Eudragit NM30D of Evonik Degussa (Germany).
In addition, above-mentioned poly-(ethyl acrylate-copolymerization-methyl methacrylate-copolymerization-methacrylic acid chlorination trimethylamine groups ethyl ester) is more preferably such as the Eudragit RL100 of Evonik Degussa (Germany), Eudragit RL PO, Eudragit RL30D, above-mentioned poly-(ethyl acrylate-copolymerization-methyl methacrylate-copolymerization-methacrylic acid chlorination trimethylamine groups ethyl ester) 1:2:0.2 of Eudragit RL12.5 and so on or such as Eudragit RS100, Eudragit RSPO, Eudragit RS30D, poly-(ethyl acrylate-copolymerization-methyl methacrylate-copolymerization-methacrylic acid chlorination trimethylamine groups ethyl ester) 1:2:0.1 of Eudragit RS12.5 and so on.
In addition; above-mentioned the first plasticizer, the second plasticizer, the 3rd plasticizer and the 4th plasticizer can select the group of free glycol, ester, oil, glycerol, glycerol derivatives and composition thereof composition independently of one another; wherein; glycol can select the group of free propylene glycol, Polyethylene Glycol and composition thereof composition, and ester can select the group of free diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, glyceryl triacetate and composition thereof composition.
In addition, above-mentioned oil can select the group of free Oleum Ricini, Oleum Cocois and composition thereof composition, and glycerol and glycerol derivatives can select the group of free glycerol, glyceryl monostearate and composition thereof composition.
On the other hand, above-mentioned enteric coatings agent can be selected the group of free Lac, HPMCAS, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalic acid ester, cellulose acetate, polyvinyl alcohol phthalic acid ester, poly-(methacrylate-copolymerization-methyl methacrylate), poly-(acrylic acid methyl ester .-copolymerization-methyl methacrylate-copolymerization-methacrylic acid), poly-(methacrylate-copolymerization-ethyl acrylate) and composition thereof composition.
Wherein, poly-(methacrylate-copolymerization-methyl methacrylate) more preferably poly-(methacrylate-copolymerization-methyl methacrylate) 1:1 such as Eudragit L100, Eudragit L12.5, the Eudragit L100P of Evonik Degussa (Germany) or poly-(methacrylate-copolymerization-methyl methacrylate) 1:2 such as Eudragit S100, Eudragit S12.5, Eudragit S100P.
In addition poly-(acrylic acid methyl ester .-copolymerization-methyl methacrylate-copolymerization-methacrylic acid) more preferably poly-(acrylic acid methyl ester .-copolymerization-methyl methacrylate-copolymerization-methacrylic acid) 7:3:1 such as the Eudragit FS30D of Evonik Degussa (Germany).
Finally, poly-(methacrylate-copolymerization-ethyl acrylate) more preferably poly-(methacrylate-copolymerization-ethyl acrylate) 1:1 such as Eudragit L30D-55, the Eudragit L100-55 of Evonik Degussa (Germany).
In addition, in above-mentioned clopidogrel outer core, aspirin outer core, rapid release protective layer or enteric layer, can further comprise the additive in the group of selecting free diluent, lubricant, stabilizing agent, film coating agent and composition thereof composition.
Above-mentioned diluent can select the group of free calcium carbonate, calcium phosphate, cellulose, dextrin, dextrose, ethyl cellulose, fructose, glyceryl palmitostearate, maltose, sucrose, starch, microcrystalline Cellulose, lactose, glucose, mannitol, alginate, alkali earth metal salt, clay, Polyethylene Glycol, dicalcium phosphate and composition thereof composition.
Above-mentioned lubricant can select the group of free Talcum, stearic acid and its esters, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, Polyethylene Glycol and composition thereof composition.
Aforementioned stable agent can be selected the group of free dibenzylatiooluene (BHT), Butylated hydroxyanisole (BHA), ascorbic acid, tocopherol, ethylenediaminetetraacetic acid (EDTA) and composition thereof composition.
Above-mentioned film coating agent can select free gelatin, methylcellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, Polyethylene Glycol, Lac, ethyl cellulose, methyl hydroxyethylcellulose, hydroxyethyl-cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, the polymer of vinyl pyrrolidone and vinyl acetate, copolymer (for example for ethyl acrylate-methyl methacrylate-MethacryloyloxyethylTrimethyl Trimethyl Ammonium Chloride (trimethylammonium ethyl methacrylate chloride), trade name Eudragit RS or RL, Evonik Degussa), Eudragit NE30D (for example, trade name Eudragit NE30D, Evonik Degussa), the group of Pioloform, polyvinyl acetal dimethylamino acetas (polyvinyl acetyl dimethyl amino acetate) and composition thereof composition.
In compound formulation of the present invention; above-mentioned clopidogrel outer core, rapid release protective layer or clopidogrel outer core and rapid release protective layer can increase rate of release by further comprising rapid release thing, and above-mentioned rapid release thing can be selected from disintegrating agent, foaming agent, buffer agent and composition thereof.
Above-mentioned disintegrating agent can select starch or the modified starches such as free starch sodium starch glycollate, corn starch, potato starch or pregelatinized Starch; The clays such as bentonite, Montmorillonitum, Magnesiumaluminumsilicate (veegum); The cellulose families such as microcrystalline Cellulose, hydroxypropyl cellulose or carmellose; The Brown algae such as sodium alginate or alginic acid acids; The cross-linked cellulose classes such as cross-linked carboxymethyl cellulose (croscarmellose) sodium; The glue such as guar gum, xanthan gum class; And the group of crospolyvinylpyrrolidone (crospovidone) and composition thereof composition.
Above-mentioned foaming agent can comprise the inorganic matter and the organic acid that contain carbonic acid.
The above-mentioned inorganic matter that contains carbonic acid can select the group of free sodium bicarbonate, sodium carbonate, calcium carbonate, potassium carbonate, magnesium carbonate, calcium bicarbonate, potassium bicarbonate and composition thereof composition.
Above-mentioned organic acid can select the group of free citric acid, hydrochloric acid, lactic acid, propanoic acid, sulphuric acid, tartaric acid, fumaric acid, malic acid and composition thereof composition.
Above-mentioned buffer agent can select the group of free calcium carbonate, sodium dihydrogen phosphate, disodium-hydrogen, paddy ammonia acid Na, potassium citrate, sodium bicarbonate, sodium citrate, sodium hydride, calcium phosphate, calcium hydrogen phosphate or various salt and composition thereof composition.
In addition, with respect to above-mentioned clopidogrel 100 weight portions, aspirin can be 10 to 1000 weight portions, and above-mentioned capsule can be hard capsules.
Below, embodiments of the invention are described.
Embodiment
comparative example: eutectic validation test
Respectively for bisulfate clopidogrel (Korea S United pharmacy, Korea S) 2mg, aspirin (Rhodia, Thailand) the 1:1 mixture 2mg of 2mg and above-mentioned two kinds of materials, utilize differential scanning calorimetry (DSC) (TA Instrument, the U.S.), observe fusing point.Temperature range is 50 to 250 DEG C, and programming rate is 10 DEG C/min.
Fig. 2 is the differential scanning calorimetry (DSC) figure about clopidogrel, and Fig. 3 is the figure about aspirin, and in addition, Fig. 4 is the figure about the mixture of two kinds of materials.According to Fig. 2 to Fig. 4, the fusing point of bisulfate clopidogrel is 178.50 DEG C, and the fusing point of aspirin is 142.83 DEG C, but for its mixture, because of the merged melting point depression to 128.41 DEG C in peak.Can confirm thus two kinds of pharmacological active substance generation eutectic, a kind of dosage form that can block direct contact of known needs.
embodiment: compound formulation
In the mixed solvent of dichloromethane 1000g and ethanol 500g, dissolve bisulfate clopidogrel ((Korea S United pharmacy, Korea S) 97.875g and hydroxypropyl emthylcellulose (SHIN-ETSU HANTOTAI, Japan) after 40g, utilize fluidized-bed coating machine (Glatt GmbH Process Technology, fluidized bed coating process, Germany), be the spherical white sugar (IPS of 600 to 710 μ m to the mean diameter that is equivalent to kernel, Italy) granule 92.125g, spraying said mixture, forms clopidogrel outer core.Then; in the mixed solvent of dichloromethane 300g and ethanol 300g; dissolve hydroxypropyl emthylcellulose (SHIN-ETSU HANTOTAI; Japan) (Sanyo changes into industry for 9.5g and Polyethylene Glycol; Japan) after 0.5g; to above-mentioned clopidogrel outer core spraying, form rapid release protective layer, thereby manufacture clopidogrel granule.
Therewith separately, in the mixed solvent of dichloromethane 600g and ethanol 300g, dissolve aspirin (Rhodia, Thailand) 100g and hydroxypropyl emthylcellulose (SHIN-ETSU HANTOTAI, Japan) after 5.0g, utilize fluidized-bed coating machine (Glatt GmbH Process Technology, Germany), be the spherical white sugar (IPS of 600 to 710 μ m to the mean diameter that is equivalent to kernel, Italy) granule 30g, spraying said mixture, forms aspirin outer core.Then, in the mixed solvent of dichloromethane 250g and ethanol 250g, dissolve hydroxypropylmethyl cellulose phthalate (SHIN-ETSU HANTOTAI, Japan) 9.5g and triethyl citrate (Morimura Bros., Inc., Japan) after 0.5g, to above-mentioned aspirin outer core spraying, form enteric layer, thereby manufacture aspirin granule.
The clopidogrel granule 240mg of above-mentioned manufacturing and aspirin granule 145mg are packed in hard capsules, manufacture compound formulation of the present invention.
test example 1: estimation of stability
For the compound formulation of the present invention of manufacturing by above-described embodiment, carry out the accelerated test (temperature is 40 ± 2 DEG C, and relative humidity is 75 ± 5%) of 6 months, evaluate stability, evaluation result is shown in to Fig. 5 to Figure 11.Fig. 5 and Fig. 6 are the results of respectively changes of contents of clopidogrel and aspirin being observed with 2 months intervals, can confirm, even after 6 months, changes of contents maintains in 1%.
Fig. 7 is the result that the dissolution rate of clopidogrel is changed to observe with 2 months intervals, Fig. 8 changes the result of observing to the dissolution rate of aspirin in 0.1N HCl solution, and Fig. 9 changes the result of observing to the dissolution rate of aspirin in the time of pH6.8, even after 6 months, do not observe significant dissolution rate yet and change.
Figure 10 is the result of the analog changes of contents of clopidogrel being observed with 2 months intervals, and Figure 11 is the result that the analog changes of contents of aspirin is observed, similarly, even after 6 months, also fail to observe significant changes of contents.
The approaching of stability result of above-mentioned Fig. 5 to Figure 11, confirms compound formulation of the present invention and meets desired stability criterion, and this reason can be judged as, and blocking-up is in the past because of clopidogrel and the direct eutectic phenomenon causing that contacts of aspirin.
CPCS001, the CPCS002 recording in the figure of Fig. 5 to Figure 11 and CPCS003 are the Mission Numbers of testing with independent batch (batch) respectively, the result of 3 batches of experiments shown in each figure.
test example 2: relatively dissolution test
Utilize dissolution test machine (Labfine Instrument, Korea S) and ultraviolet rays detector (Shimadzu, Japan), according to dissolution test method the second method oar method in great Han pharmacopeia ordinary test method, compare dissolution test.In embodiment, with regard to clopidogrel granule, pH1.2 (Figure 12), 4.0 (Figure 13), 6.8 (Figure 14), water (Figure 15) are tested, now, the volume of dissolution fluid is each 900ml, slurry rotary speed is 50rpm, and ultraviolet wavelength is 240nm.In comparative example for above-mentioned clopidogrel, use Plavix tablet (Sanofi-aventis Korea, Korea S).
In addition, with regard to aspirin granule, pH1.2 (Figure 16), 6.0 (Figure 17), 6.8 (Figure 18) are tested, now, the volume of dissolution fluid is each 900ml, and slurry rotary speed is 50rpm, and ultraviolet wavelength is 265nm.In comparative example for above-mentioned aspirin, use Astrix capsule (BORYUNG pharmacy, Korea S).
Can confirm from above-mentioned Figure 12 to Figure 18, compound formulation of the present invention demonstrates and is equal in the dissolution characteristic of unitary agent in the past.
test example 3: clinical trial
In the embodiment of compound formulation of the present invention, in comparative example for clopidogrel granule (bisulfate clopidogrel 97.875mg, clopidogrel 75mg), use Plavix tablet (Sanofi-aventis Korea, Korea S), and in the comparative example for aspirin granule (aspirin 100mg), use (the BORYUNG pharmacy of Astrix capsule, Korea S), measure blood level.
Specifically, select each 33 of embodiment group and comparative example group, take 1 time at first day, each 2 capsules (or tablet), after cycle blood sampling in accordance with regulations, change embodiment group and comparative example group, after the withdrawal time of 14 days, at the 15 day, again take 1 time, each 2 capsules (or tablet), average (in initial 66 personnel, 61 except 5 of the persons of dropping by the wayside being averaged) to the result of the cycle blood sampling by identical.
Figure 19 illustrates the blood level figure of clopidogrel, and Figure 20 illustrates the blood level figure of aspirin, and Figure 21 illustrates the salicylic blood level figure as the metabolite of aspirin.
Specifically, the experimental result of Figure 19 to Figure 21 can be summarized as follows.
figure 19
Embodiment: after compound formulation administration of the present invention, measure the blood level of clopidogrel
Comparative example: after the administration of Plavix tablet, measure the blood level of clopidogrel
figure 20
Embodiment: after compound formulation administration of the present invention, measure the blood level of aspirin
Comparative example: after the administration of Astrix capsule, measure the blood level of aspirin
figure 21
Embodiment: after compound formulation administration of the present invention, measure salicylic blood level
Comparative example: after the administration of Astrix capsule, measure salicylic blood level
In above-mentioned Figure 19 to Figure 21, compound formulation of the present invention illustrate and clopidogrel or aspirin unitary agent almost similarly blood level change, show thus, it shows aforesaid effect of the present invention completely.
Above, although preferred embodiments of the present invention have been disclosed for illustrative, the present invention is not limited to above-mentioned specific embodiment, needless to say, as long as having and conventionally know the knowledgeable in described technical field,, in the case of not departing from the main idea of the present application, can implement various distortion.Therefore, scope of the present invention should not be construed as limited to the above embodiments, should determine by described claims and with the equivalent of claims.
Claims (17)
1. a compound formulation, comprises:
(A) clopidogrel granule, (B) aspirin granule and (C) hold the capsule of described clopidogrel granule and aspirin granule,
Described (A) clopidogrel granule comprises:
The kernel that contains excipient;
Clopidogrel outer core, the outside of itself and described kernel is adjacent, and contains clopidogrel, its isomer or its pharmaceutically useful salt and the first bonding agent as pharmacologically active principles; And
Rapid release protective layer, the outside of itself and described outer core is adjacent, and contains the second bonding agent and the first plasticizer,
Described (B) aspirin granule comprises:
The kernel that contains excipient;
Aspirin outer core, the outside of itself and described kernel is adjacent, and contains aspirin or its pharmaceutically useful salt and the 3rd bonding agent as pharmacologically active principles; And
Enteric layer, the outside of itself and described outer core is adjacent, and contains enteric coatings agent and the second plasticizer.
2. compound formulation according to claim 1, is characterized in that, described clopidogrel outer core further comprises the 3rd plasticizer.
3. compound formulation according to claim 1, is characterized in that, described aspirin outer core further comprises the 4th plasticizer.
4. according to the compound formulation described in any one in claims 1 to 3, it is characterized in that the freely group of sugar, starch, microcrystalline Cellulose, lactose, Brazil wax, mannitol, tartaric acid, xylitol and composition thereof composition of described excipient choosing.
5. according to the compound formulation described in any one in claims 1 to 3, it is characterized in that, the pharmaceutically useful salt of described clopidogrel selects the group of disulfate, resinate, camsilate, benzene sulfonate, napadisilate monohydrate, hydrochlorate of free clopidogrel and composition thereof composition.
6. according to the compound formulation described in any one in claims 1 to 3, it is characterized in that, described the first bonding agent, the second bonding agent and the 3rd bonding agent select independently of one another and freely replace or the group of unsubstituted alkylcellulose or its salt, polythene derivative, poly alkylene glycol, polymethylacrylic acid and composition thereof composition.
7. compound formulation according to claim 6, it is characterized in that, described replacement or unsubstituted alkylcellulose or its salt select the group of free methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, methyl hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose and composition thereof composition.
8. compound formulation according to claim 6, is characterized in that, described polythene derivative selects the group of free polyvinylpyrrolidone, polyvinyl alcohol and composition thereof composition.
9. compound formulation according to claim 6, is characterized in that, described poly alkylene glycol is selected the group of free Polyethylene Glycol, polypropylene glycol and composition thereof composition.
10. compound formulation according to claim 6, it is characterized in that, described polymethylacrylic acid choosing freely gathers the group of (butyl methacrylate-copolymerization-(2-dimethyl aminoethyl) methacrylate-copolymerization-methyl methacrylate), poly-(ethyl acrylate-copolymerization-methyl methacrylate), poly-(ethyl acrylate-copolymerization-methyl methacrylate-copolymerization-methacrylic acid chlorination trimethylamine groups ethyl ester) and composition thereof composition.
11. according to the compound formulation described in any one in claims 1 to 3, it is characterized in that, described the first plasticizer, the second plasticizer, the 3rd plasticizer and the 4th plasticizer select the group of free glycol, ester, oil, glycerol, glycerol derivatives and composition thereof composition independently of one another.
12. compound formulations according to claim 11, is characterized in that, described glycol selects the group of free propylene glycol, Polyethylene Glycol and composition thereof composition.
13. compound formulations according to claim 11; it is characterized in that, described ester selects the group of free diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, glyceryl triacetate and composition thereof composition.
14. according to the compound formulation described in any one in claims 1 to 3, it is characterized in that, free Lac is selected in described enteric coatings agent, HPMCAS, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalic acid ester, cellulose acetate, polyvinyl alcohol phthalic acid ester, poly-(methacrylate-copolymerization-methyl methacrylate), poly-(acrylic acid methyl ester .-copolymerization-methyl methacrylate-copolymerization-methacrylic acid), the group of poly-(methacrylate-copolymerization-ethyl acrylate) and composition thereof composition.
15. according to the compound formulation described in any one in claims 1 to 3; it is characterized in that, described clopidogrel outer core, aspirin outer core, rapid release protective layer or enteric layer further comprise the additive in the group of selecting free diluent, lubricant, stabilizing agent, film coating agent and composition thereof composition.
16. according to the compound formulation described in any one in claims 1 to 3, it is characterized in that, with respect to described clopidogrel 100 weight portions, aspirin is 10 to 1000 weight portions.
17. according to the compound formulation described in any one in claims 1 to 3, it is characterized in that, described capsule is hard capsules.
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| KR10-2011-0113131 | 2011-11-02 | ||
| KR1020110113131A KR101675501B1 (en) | 2011-11-02 | 2011-11-02 | Combination of Clopidogrel and Aspirin |
| PCT/KR2012/006316 WO2013065936A1 (en) | 2011-11-02 | 2012-08-08 | Complex agent containing clopidogrel and aspirin |
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Cited By (6)
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| CN107260700A (en) * | 2016-04-09 | 2017-10-20 | 厦门恩成制药有限公司 | A kind of preparation method of ticagrelor compound oral solid pharmaceutical preparation |
| CN107669690A (en) * | 2017-10-23 | 2018-02-09 | 罗铭炽 | A kind of tablet containing aspirin and clopidogrel |
| CN107693524A (en) * | 2017-10-23 | 2018-02-16 | 罗铭炽 | A kind of preparation method containing aspirin and clopidogrel |
| CN109069436A (en) * | 2016-03-16 | 2018-12-21 | 韩国联合制药株式会社 | Compound formulation containing clopidogrel and aspirin |
| US20230059869A1 (en) * | 2021-08-03 | 2023-02-23 | Liqmeds Worldwide Limited | Oral pharmaceutical solution of clopidogrel |
| EP4110301A4 (en) * | 2020-02-27 | 2023-11-15 | HK inno.N Corporation | Pharmaceutical composition for oral administration |
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| WO2015015062A1 (en) * | 2013-08-02 | 2015-02-05 | Sanofi | Pharmaceutical tablet comprising acetylsalicylic acid and clopidogrel |
| KR101764785B1 (en) * | 2015-05-29 | 2017-08-07 | 한국유나이티드제약 주식회사 | Pharmaceutical combination preparation |
| KR101843396B1 (en) | 2016-04-04 | 2018-03-29 | 가톨릭대학교 산학협력단 | Formulation composition of once-daily fixed-dose combination bilayer tablets of cilostazol and clopidogrel and manufacturing method thereof |
| CN114209675B (en) * | 2022-01-20 | 2023-06-02 | 北京微智瑞医药科技有限公司 | Clopidogrel hydrogen sulfate aspirin microchip capsule and preparation method thereof |
| CN115770229A (en) * | 2022-12-13 | 2023-03-10 | 山东诺明康药物研究院有限公司 | Clopidogrel sulfate aspirin tablet and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109069436A (en) * | 2016-03-16 | 2018-12-21 | 韩国联合制药株式会社 | Compound formulation containing clopidogrel and aspirin |
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| CN107669690A (en) * | 2017-10-23 | 2018-02-09 | 罗铭炽 | A kind of tablet containing aspirin and clopidogrel |
| CN107693524A (en) * | 2017-10-23 | 2018-02-16 | 罗铭炽 | A kind of preparation method containing aspirin and clopidogrel |
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| US20230059869A1 (en) * | 2021-08-03 | 2023-02-23 | Liqmeds Worldwide Limited | Oral pharmaceutical solution of clopidogrel |
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| WO2013065936A1 (en) | 2013-05-10 |
| KR20130048335A (en) | 2013-05-10 |
| KR101675501B1 (en) | 2016-11-14 |
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