KR101675501B1 - Combination of Clopidogrel and Aspirin - Google Patents
Combination of Clopidogrel and Aspirin Download PDFInfo
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- KR101675501B1 KR101675501B1 KR1020110113131A KR20110113131A KR101675501B1 KR 101675501 B1 KR101675501 B1 KR 101675501B1 KR 1020110113131 A KR1020110113131 A KR 1020110113131A KR 20110113131 A KR20110113131 A KR 20110113131A KR 101675501 B1 KR101675501 B1 KR 101675501B1
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- A—HUMAN NECESSITIES
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- 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
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- 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
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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 combination preparation comprising clopidogrel and aspirin, which comprises granules coated with a clopidogrel layer as an immediate-release layer and aspirin granules coated with an enteric layer in an encapsulated capsule. The present invention relates to a pharmaceutical composition for preventing clopidogrel and aspirin from physically interfering with each other to prevent eutectic phenomenon from occurring and prevent changes in formulation content, dissolution characteristics and bioequivalence in the short term, In addition, it has an effect of preventing the gastric wall injury by coating the aspirin with the enteric layer.
Description
The present invention relates to a combination preparation comprising clopidogrel and aspirin. More specifically, the present invention relates to a stable, bioavailable composite preparation containing capsules containing granules coated with a clopidogrel layer as a core protecting layer and aspirin granules coated with an enteric layer as an enteric layer.
Clopidogrel, i.e., methyl (+) - (S) -? - (2-chlorophenyl) -6,7-dihydrothieno [3,2- c] pyridin-5 (4H) -acetate, , As well as for the treatment of coronary artery disease such as stroke, thrombosis, embolism and myocardial infarction. Clopidogrel inhibits ADP-induced platelet aggregation by direct inhibition of ADP binding to the adenosine diphosphate (ADP) receptor and by direct inhibition of subsequent ADP-mediated activation of the glycoprotein GPIIb / IIa complex. Clopidogrel also inhibits platelet aggregation induced by agonists other than ADP by blocking the amplification of platelet activation by released ADP.
The pharmacological action of clopidogrel is achieved by an active type body formed by metabolisation in the liver after oral administration of clopidogrel. This active form selectively and irreversibly blocks the binding of ADP to the ADP receptor by modifying the ADP receptor on the platelets. Therefore, the effect of clopidogrel is highly dependent on the enzyme that metabolizes clopidogrel in the liver.
The chemical name of clopidogrel bisulfate, a representative pharmaceutical ingredient of clopidogrel, is the chemical name of methyl (+) - (S) -a- (2- chlorophenyl) -6,7-dihydrothieno [3,2- c] pyridin- 4H) -acetate sulfate (1: 1). The empirical formula of clopidogrel bisulfate is C 16 H 16 ClNO 2 SH 2 SO 4 and its molecular weight is 419.9.
Clopidogrel bisulfate is a white to gray powder. It is insoluble in water at substantially neutral pH, but is highly soluble at pH 1.0. It is also freely soluble in methanol, which is slightly soluble in methylene chloride and substantially insoluble in ethyl ether.
Clopidogrel bisulfate is prescribed for the reduction of thrombotic events such as recent myocardial infarction (MI), acute stroke, or established arterial disease , The combined end point of the new ischemic stroke, the new MI, and other vascular deaths. For patients with acute coronary syndromes, clopidogrel bisulfate may be used for the treatment of cardiovascular death, MI, stroke, or refractory ischemia, as well as the rate of combined endpoints of cardiovascular death, MI, or stroke It has been found to reduce the speed of the combined endpoint.
Also known as acetylsalicylic acid, aspirin is often used as analgesics (for mild pain and pain), antipyretics (for fever), and anti-inflammatory agents. Aspirin also has an anticoagulant (blood thinning) effect and is used to prevent a heart attack with a low-dose of long-term.
CAS Number (Number): Aspirin, 50-78-2, is chemically known as 2-acetoxybenzoic acid. Aspirin has molecular formula C 9 H 8 O 4 and molecular weight of 180.16.
Aspirin is a colorless or white crystal or a white crystalline powder or granule. Aspirin is odorless or has a slight acid taste. Aspirin has a melting point of 136 占 폚 and a boiling point of 140 占 폚. Aspirin may be administered in combination with an effective amount of a compound selected from the group consisting of free acid, acetanilide, aminopyrine, phenazone, hexamine, iron salts, phenobarbital sodium, quinine salts, potassium and sodium iodide, and alkaline hydroxides, . Acetylsalicylic acid is stable in dry air, but is gradually hydrolyzed in contact with water to acetic acid and salicylic acid. In an alkaline solution, the hydrolysis proceeds quickly so that the formed clear solution can consist entirely of acetate and salicylate. Acetylsalicylic acid is rapidly degraded in ammonium acetate, or in an acetate, carbonate, citrate or hydroxide solution of an alkali metal.
Aspirin is an analgesic for the treatment of mild to moderate pain and is prescribed as an anti-inflammatory agent for the treatment of soft tissues and joint inflammation, and as a drug for an antipyretic. Aspirin is generally administered in an amount of 4 g per day in an amount of 300-1000 mg every 4 hours in adults with pain and fever. In the case of acute rheumatoid arthritis (acute polyarthritis rheumatica), the dose is generally given as 1 g per 6 times per day and up to 8 g per day. In the case of rheumatoid arthritis, administration is generally given in 0.5 g to 1 g six times per day and a maximum of 8 g per day is provided. For prevention of transient ischemic attack and prevention of arterial thrombosis, administration is generally administered 300 mg to 1200 mg per day in two or three administrations.
Aspirin can be used to reduce the likelihood of heart attacks, strokes, or other problems that can occur when blood vessels are blocked by blood clots. Aspirin prevents the production of dangerous blood clots.
Low-dose, long-term aspirin irreversibly blocks the production of thromboxane A2 in the platelets, producing an inhibitory effect on platelet aggregation, and this blood thinning characteristic is useful in reducing the incidence of heart attacks Do.
However, aspirin is known to activate enzymes that convert clopidogrel from the liver into an active metabolite. Therefore, although a lot of studies have been conducted on formulations for administering clopidogrel and aspirin together, eutectic phenomenon occurs when two drugs are in direct contact with each other. Above all, aspirin is a substance with low gastrointestinal uptake, so it is necessary to administer more than a certain amount, but the aspirin itself has a property to injure the gastrointestinal tract and its use is very limited. This problem becomes more serious in formulations in which aspirin first elutes for the metabolism of clopidogrel.
Disclosure of the Invention The present invention has been conceived in order to solve the above-mentioned problems, and it is an object of the present invention to provide a stable, bioavailable combination preparation containing a granule coated with a clopidogrel layer and a granule coated with an aspirin layer, The purpose is to provide.
In order to achieve the above-mentioned object,
(A) an inner core comprising an excipient,
A clopidogrel outer nucleus adjacent to the outer core of the inner core and comprising clopidogrel, an isomer thereof or a pharmaceutically acceptable salt thereof and a first binding agent as pharmacologically active ingredients, and
A second protective layer disposed adjacent the outer core of the outer core and comprising a second binder and a first plasticizer,
Clopidogrel < / RTI > granules,
(B) an inner core comprising an excipient,
An aspirin outer nucleus adjacent to the outer core of the inner core and comprising aspirin or a pharmaceutically acceptable salt thereof and a third binding agent as the pharmacologically active ingredient,
And an enteric coating layer adjacent to the outside of the outer core and comprising an enteric coating agent and a second plasticizer,
Aspirin granules,
(C) a capsule containing the clopidogrel granule and the aspirin granule
And a control unit.
In addition, the clopidogrel outer core may further comprise a third plasticizer.
In addition, the aspirin outer core may further comprise a fourth plasticizer.
In addition, the excipient may be selected from the group consisting of sugar, starch, microcrystalline cellulose, lactose. Mannitol, mannitol, mannitol, tartaric acid, xylitol, and mixtures thereof.
In addition, the pharmaceutically acceptable salt of clopidogrel may be selected from the group consisting of clopidogrel hydrogen peroxide, resinate, camsylate, besylate, napadicylate monohydrate, hydrochloride and mixtures thereof.
The first binder, the second binder and the third binder may be independently selected from the group consisting of substituted or unsubstituted alkylcellulose or salts thereof, polyvinyl derivatives, polyalkylene glycols, polymethacrylic acid, and mixtures thereof. .
The substituted or unsubstituted alkylcellulose or its salt may be dissolved or dispersed in a solvent such as methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and mixtures thereof Can be selected from the group consisting of.
The polyvinyl derivative may be selected from the group consisting of polyvinyl pyrrolidone, polyvinyl alcohol, and mixtures thereof.
In addition, the polyalkylene glycol may be selected from the group consisting of polyethylene glycol, polypropylene glycol, and mixtures thereof.
In addition, the polymethacrylic acid may be selected from the group consisting of poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate), poly (ethyl acrylate, methyl methacrylate) Acid, trimethylaminoethyl methacrylic acid chloride), and mixtures thereof.
The first plasticizer, the second plasticizer, the third plasticizer and the fourth plasticizer may be independently selected from the group consisting of a glycol, an ester, an oil, a glycerin, a glycerin derivative and a mixture thereof.
In addition, the glycol may be selected from the group consisting of propylene glycol, polyethylene glycol, and mixtures thereof.
In addition, the ester may be selected from the group consisting of diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triacetin, and mixtures thereof.
In addition, the oil may be selected from the group consisting of castor oil, coconut oil, and mixtures thereof.
The glycerin and glycerin derivatives may be selected from the group consisting of glycerin, monostearin glycerin, and mixtures thereof.
The enteric coating agent may be selected from the group consisting of shellac, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate, polyvinyl alcohol phthalate, poly (methacrylic acid, methylmethacrylic acid), poly (Methacrylic acid, methyl methacrylic acid, methacrylic acid), poly (methacrylic acid, ethyl acrylic acid), and mixtures thereof.
In addition, the clopidogrel outer core, aspirin outer core, inner protective layer or intestinal layer may further include additives selected from the group consisting of diluents, lubricants, stabilizers, film coating agents and mixtures thereof.
The aspirin may be 10 to 1000 parts by weight based on 100 parts by weight of the clopidogrel.
In addition, the capsule may be a hard capsule.
The combined preparation of the present invention is characterized in that clopidogrel and aspirin are designed so as not to come into direct physical contact with each other, thereby fundamentally blocking eutectic phenomenon of the two components. By preventing the eutectic phenomenon as described above and preventing the change in the physicochemical properties of each component, it is possible to prevent the change of the content of the preparation, the elution property and the bioequivalence in the short term, and the stability of the preparation in the long term.
In addition, the combination preparation of the present invention was coated with aspirin as an enteric layer so that the aspirin could dissolve only in the intestine and not dissolve in the upper part in order to prevent the problem that the aspirin stimulates the gastric wall and causes damage. Accordingly, when the combination preparation of the present invention is orally administered, clopidogrel elutes first from the top, and aspirin elutes later from the intestines to prevent gastric wall damage.
Although aspirin promotes the production of clopidogrel-activating metabolites in the liver, the production of such activated metabolites is not always desirable due to the presence of individual differences, which may cause unexpected variations in drug plasma concentrations. Specifically, the cytochrome P450 2C19 (CYP450 2C19) metabolizing enzyme activated by the pre-released aspirin has an individual difference in the degree of production of the activated metabolite, and this individual difference inevitably causes a deviation in the drug blood concentration of the above- . And this deviation is undesirable because it can not be controlled and can have an unpredictable effect on the patient.
Finally, the combination preparation of the present invention can increase the convenience and compliance of taking the clopidogrel and the aspirin both at the same time or at different time intervals. Of course, because of the complementary pharmacological actions of the two drugs, The same results can be obtained even with a small capacity, and there is an advantage in that side effects and manufacturing costs can be reduced by pharmacological components.
1 is a schematic view of the structure of the combination preparation of the present invention.
2 is a differential scanning calorimetry graph of clopidogrel hydrogen sulphate.
3 is a differential scanning calorimetry graph of aspirin.
Figure 4 is a graph of differential scanning calorimetry of a mixture of clopidogrel hydrogen sulphate and aspirin.
FIG. 5 is a graph showing the content of clopidogrel in a 6-month accelerated test.
Fig. 6 is a graph showing changes in the content of aspirin in the 6-month accelerated test.
Fig. 7 is a graph showing the dissolution rate of clopidogrel in the 6-month accelerated test.
FIG. 8 is a graph showing the dissolution rate of aspirin in 0.1 N HCl in the 6-month accelerated test. FIG.
FIG. 9 is a graph showing the dissolution rate of aspirin in pH 6.8 in the 6-month accelerated test. FIG.
FIG. 10 is a graph showing the change in the total content of clopidogrel in a 6-month accelerated test. FIG.
11 is a graph showing the change in the total content of aspirin in the 6-month accelerated test.
Figure 12 is a comparison graph of the dissolution in pH 1.2 for clopidogrel granules and Plavix ® tablet.
Figure 13 is a comparison graph of the dissolution in pH 4.0 for clopidogrel granules and Plavix ® tablet.
Figure 14 is a comparison graph of the dissolution in pH 6.8 for clopidogrel granules and Plavix ® tablet.
Figure 15 is a comparison graph of the dissolution in water of the clopidogrel granules and Plavix ® tablet.
Figure 16 is a comparison graph of the elution at pH 1.2 of the aspirin granule and ahseuteurikseu ® capsules.
Figure 17 is a comparison graph of the dissolution in pH 6.0 for aspirin granules and ahseuteurikseu ® capsules.
Figure 18 is a comparison graph of the elution at pH 6.8 of the aspirin granule and ahseuteurikseu ® capsules.
19 is a graph showing the blood concentration of clopidogrel.
20 is a graph of blood concentration of aspirin.
21 is a graph showing the blood concentration of salicylic acid.
Hereinafter, preferred embodiments of the present invention will be described in detail. In the following description, numerous specific details, such as specific elements, are set forth in order to provide a thorough understanding of the present invention, and it is to be understood that the present invention may be practiced without these specific details, It will be obvious to those who have knowledge of. In the following description of the present invention, a detailed description of known functions and configurations incorporated herein will be omitted when it may make the subject matter of the present invention rather unclear.
As shown in FIG. 1, the combination preparation of the present invention comprises clopidogrel granules and aspirin granules in a capsule, wherein the clopidogrel granule is composed of an inner core comprising an excipient, an outer core adjacent to the inner core and a clopidogrel, A clopidogrel outer nucleus comprising an isomer thereof or a pharmaceutically acceptable salt thereof and a first binding agent and a contraceptive protective layer adjacent to the outside of the outer nucleus and comprising a second binder and a first plasticizer. And wherein the aspirin granules comprise an inner core comprising an excipient, an aspirin outer nucleus adjacent to the outside of the inner core, comprising aspirin or a pharmaceutically acceptable salt thereof and a third binding agent as a pharmacologically active ingredient, And an enteric layer comprising an enteric coating agent and a second plasticizer.
Such a combination preparation of the present invention first elutes the clopidogrel granules from above, and the aspirin granules elute later from the intestines. Thus, it is possible to exhibit complementary pharmacological effects of clopidogrel and aspirin, while preventing aspirin-induced gastric wall damage. Furthermore, blocking the direct contact between clopidogrel and aspirin prevents the eutectic phenomenon, thereby preventing changes in the content or dissolution characteristics and enhancing the stability of the drug.
In the combination preparation of the present invention, the clopidogrel outer core may further comprise a third plasticizer, and the aspirin outer core may further comprise a fourth plasticizer. Such a plasticizer improves the processability by imparting plasticity to a rigid polymer and assists the flexibility of the coating film when the tablet and granule are coated.
The excipient may be selected from the group consisting of sugar, starch, microcrystalline cellulose, lactose, cannauba lead, mannitol, tartaric acid, xylitol, and mixtures thereof.
The pharmaceutically acceptable salt of clopidogrel may be selected from the group consisting of clopidogrel hydrogen peroxide, resinate, camsylate, besylate, napadicylate monohydrate, hydrochloride and mixtures thereof, The acid salts and the besylate are preferable.
The first binder, the second binder and the third binder may be independently selected from the group consisting of substituted or unsubstituted alkylcellulose or salts thereof, polyvinyl derivatives, polyalkylene glycols, polymethacrylic acid, and mixtures thereof. The substituted or unsubstituted alkylcellulose or its salt may be selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium , A salt thereof, and a mixture thereof, and hydroxypropylmethylcellulose is particularly preferable.
The polyvinyl derivative may be selected from the group consisting of polyvinyl pyrrolidone, polyvinyl alcohol and mixtures thereof, and the polyalkylene glycol may be selected from the group consisting of polyethylene glycol, polypropylene glycol, and mixtures thereof have.
In addition, the polymethacrylic acid may be selected from the group consisting of poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate), poly (ethyl acrylate, methyl methacrylate) Acid, trimethylaminoethyl methacrylic acid chloride), and mixtures thereof.
Poly (butylmethacrylic acid, (2-dimethylaminoethyl) methacrylic acid, methylmethacrylic acid) among the above polymethacrylic acids can be obtained from
The poly (ethyl acrylate, methyl methacrylate) is more preferably poly (ethyl acrylate, methyl methacrylate) 2: 1 such as Eudragit NE 30D, Eudragit NE 40D and Eudragit NM 30D from Evonik Degussa (Germany) .
The poly (ethyl acrylate, methyl methacrylate, trimethylaminoethyl methacrylate chloride) is preferably a poly (ethyl acrylate) such as
The first plasticizer, the second plasticizer, the third plasticizer and the fourth plasticizer may be independently selected from the group consisting of glycol, ester, oil, glycerin, glycerin derivatives, and mixtures thereof. Glycols, polyethylene glycols and mixtures thereof, and the esters may be selected from the group consisting of diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triacetin And mixtures thereof.
The oil may be selected from the group consisting of castor oil, coconut oil and mixtures thereof, and glycerin and glycerin derivatives may be selected from the group consisting of glycerin, monostearin glycerin and mixtures thereof.
On the other hand, the enteric coating agent is selected from the group consisting of shellac, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate, polyvinyl alcohol phthalate, poly (methacrylic acid, methylmethacrylic acid) (Methacrylic acid, methyl methacrylic acid, methacrylic acid), poly (methacrylic acid, ethyl acrylic acid), and mixtures thereof.
Of these, poly (methacrylic acid, methyl methacrylic acid) is a poly (methacrylic acid, methyl methacrylic acid) 1: 1 such as
Poly (methyl acrylic acid, methyl methacrylic acid, methacrylic acid) 7: 3: 1 such as Eudragit FS 30D of Evonik Degussa (Germany) is more preferable as poly (methyl acrylic acid, methyl methacrylic acid, methacrylic acid) Do.
Finally, poly (methacrylic acid, ethyl acrylate) is more preferably 1: 1 poly (methacrylic acid, ethyl acrylate) such as Eudragit L 30 D-55 and Eudragit L 100-55 from Evonik Degussa (Germany).
In addition, the clopidogrel outer core, aspirin outer core, inner protective layer or intestinal layer may further include additives selected from the group consisting of diluents, lubricants, stabilizers, film coating agents and mixtures thereof.
The diluent may be selected from the group consisting of calcium carbonate, calcium phosphate, cellulose, dextrin, dextrose, ethylcellulose, fructose, glyceryl palmitostearate, maltose, sucrose, starch, microcrystalline cellulose, lactose, glucose, mannitol, Alkaline earth metal salts, clay, polyethylene glycol, dicalcium phosphate, and mixtures thereof.
The lubricant may be selected from the group consisting of talc, stearic acid and its salts, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, polyethylene glycol and mixtures thereof.
The stabilizer may be selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid, tocopherol, edetic acid (EDTA), and mixtures thereof.
Wherein the film coating agent is selected from the group consisting of gelatin, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, shellac, ethylcellulose, methylhydroxyethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, polyvinylalcohol, Polyvinyl pyrrolidone, a polymer of vinylpyrrolidone and vinyl acetate, ethyl acrylate / methyl methacrylate / methacrylic acid / trimethylammonium ethyl copolymer (for example, trade name: Eudragit RS or RL, Degussa) , Methyl methacrylate / ethyl acrylate copolymer (e.g., trade name: Eudragit NE30D, Degussa), polyvinylacetyl dimethylanaminoacetate, and mixtures thereof.
In the combined preparation of the present invention, the clopidogrel outer core, the immediate-release protective layer or the clopidogrel outer core and the immediate-release layer may further comprise a release-releasing material to increase the release rate and the release-releasing material may be a disintegrant, a foaming agent, ≪ / RTI >
The disintegrant may be selected from the group consisting of starch or modified starch such as starch glycolic acid sodium, corn starch, potato starch or pregelatinized starch, clay such as bentonite, montmorillonite, veegum, microcrystalline cellulose, hydroxypropylcellulose or Cellulose derivatives such as carboxymethyl cellulose, alginates such as sodium alginate or alginic acid, cross-linked cellulose such as croscarmellose sodium, gums such as guar gum and xanthan gum, and crosslinked polyvinylpyrrolidone crospovidone, and mixtures thereof.
The blowing agent may include a carbonate-containing inorganic substance and an organic acid.
The carbonic acid-containing inorganic material may be selected from the group consisting of sodium hydrogen carbonate, sodium carbonate, calcium carbonate, potassium carbonate, magnesium carbonate, calcium hydrogen carbonate, potassium hydrogen carbonate, and mixtures thereof.
The organic acid may be selected from the group consisting of citric acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, fumaric acid, malic acid and mixtures thereof.
The buffer may be selected from the group consisting of calcium carbonate, sodium dihydrogenphosphate, sodium monohydrogenphosphate, sodium glutamate, potassium citrate, sodium hydrogencarbonate, sodium citrate, sodium hydroxide, calcium phosphate, calcium hydrogenphosphate or various salts and mixtures thereof .
The aspirin may be 10 to 1000 parts by weight based on 100 parts by weight of the clopidogrel, and the capsule may be a hard capsule.
Hereinafter, embodiments of the present invention will be described.
Example
Comparative Example : Eutectic confirmation test
Using a differential scanning calorimeter (TA Instrument, USA), 2 mg of clopidogrel hydrogen sulphate (Korea United Pharmaceutical Co., Ltd.), 2 mg of aspirin (Rhodia, Thailand) or 2 mg of a mixture of 1: Respectively. The temperature range was 50 to 250 占 폚, and the rate of temperature increase was 10 占 폚 / min. Figure 2 is a graph of differential scanning calorimetry for clopidogrel, Figure 3 is a graph for aspirin, and Figure 4 is a graph for a mixture of two materials. 2 to 4, the melting point of clopidogrel hydrogen sulphate was 178.50 ° C and the melting point of aspirin was 142.83 ° C, but the melting point of the mixture was decreased to 128.41 ° C with the addition of peaks. Therefore, it can be confirmed that the two pharmacologically active substances are eutectic, and that a formulation capable of blocking direct contact is required.
Example : Compound preparation
97.875 g of clopidogrel hydrogen sulfate (Korea United Pharmaceutical Co., Ltd.) and 40 g of hydroxypropylmethylcellulose (Shin-Etsu, Japan) were dissolved in a mixed solvent of 1000 g of methylene chloride and 500 g of ethanol and then an average particle diameter of 600 to 710 μm (IPS, Italy) granules of 92.125 g were sprayed with a fluid bed coater (Glatt GmbH Process Technology, Germany) to form clopidogrel outer nuclei. Subsequently, 9.5 g of hydroxypropyl methylcellulose (Shin-Etsu, Japan) and 0.5 g of polyethylene glycol (Sanyo chemical industry, Japan) were dissolved in a mixed solvent of 300 g of methylene chloride and 300 g of ethanol and sprayed onto the clopidogrel outer core To form the immediate-release protective layer, thereby producing clopidogrel granules.
Separately, 100 g of aspirin (Rhodia, Thailand) and 5.0 g of hydroxypropyl methylcellulose (Shin-Etsu, Japan) were dissolved in a mixed solvent of 600 g of methylene chloride and 300 g of ethanol, 30 g of spherical white sugar (IPS, Italy) granules were sprayed with a fluid bed coater (Glatt GmbH Process Technology, Germany) to form the aspirin outer core. Subsequently, 9.5 g of hydroxypropyl methylcellulose phthalate (Shin-Etsu, Japan) and 0.5 g of triethyl citrate (Morimurabros INC, Japan) were dissolved in a mixed solvent of 250 g of methylene chloride and 250 g of ethanol, Aspirin granules were prepared by spraying on the outer core to form enteric layers.
The prepared clopidogrel granules (240 mg) and aspirin granules (145 mg) were placed in hard capsules to prepare the combined preparation of the present invention.
Test Example 1: Stability evaluation
The stability of the combination preparation of the present invention produced by the above example was evaluated by performing an accelerated test (
FIG. 7 shows the results of observation of the dissolution rate of clopidogrel at intervals of 2 months, FIG. 8 shows the results of observation of the dissolution rate of aspirin at 0.1N HCl solution and FIG. 9 shows the dissolution rate of aspirin at pH 6.8, No change was observed.
FIG. 10 shows the change in the content of clopidogrel in two months intervals, and FIG. 11 shows the change in the content of asparagine in the asparagine. Similarly, no significant change in content was observed after 6 months.
As a result of the stability studies of FIGS. 5 to 11, it was confirmed that the combination preparation of the present invention meets the required stability standard, which is considered to be caused by blocking the eutectic phenomenon by direct contact between clopidogrel and aspirin.
Test Example 2: Comparative dissolution test
A comparative dissolution test was conducted according to the dissolution test method (Labfine Instrument, Korea) and the ultraviolet ray measuring device (Shimadzu, Japan) according to the dissolution test method second method paddle method in the Korean Pharmacopoeia general test method. The clopidogrel granules in the examples were tested for pH 1.2 (Figure 12), 4.0 (Figure 13), 6.8 (Figure 14) and water (Figure 15), where the volume of the effluent was 900 ml each, rpm, and the ultraviolet wavelength was 240 nm. A comparative example of the above clopidogrel was Plavix ( R ) (Sanofi-aventis Korea, Korea).
Aspirin granules were tested for pH 1.2 (FIG. 16), 6.0 (FIG. 17) and 6.8 (FIG. 18), where the volume of the eluate was 900 ml, the paddle rotation rate was 50 rpm, the ultraviolet wavelength was 265 nm . Comparative Examples for the aspirin was ahseuteurikseu ® capsule (Boryung, South Korea).
12 to 18, it can be confirmed that the combination preparation of the present invention exhibits dissolution characteristics comparable to those of the conventional single preparation.
Test Example 3: Clinical trials
Comparative examples of clopidogrel granules Comparative example for the (clopidogrel hydrogen sulphate 97.875 mg, clopidogrel 75 mg) is Plavix ® tablets (Sanofi Aventis Korea, South Korea), and aspirin granules (
Specifically, each of 33 patients in the group of the Example and Comparative Example was selected, and 2 capsules (or tablets) were taken once each day on the first day. After collecting blood according to a predetermined cycle, On the 15th day, the average of the results obtained by taking two capsules (or tablets) once per day and taking the blood samples in the same cycle was averaged (average of 61 out of the initial 66 persons excluding five dropouts).
FIG. 19 shows a blood concentration graph of clopidogrel, FIG. 20 shows a blood concentration graph of aspirin, and FIG. 21 shows a blood concentration graph of salicylic acid as a metabolism of aspirin.
19 to 21 show that the combination agent of the present invention exhibits a blood concentration change almost similar to that of a clopidogrel or aspirin single agent, thus fully manifesting the effect of the present invention described above.
While the present invention has been described in connection with what is presently considered to be practical exemplary embodiments, it is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, Of course it is possible. Accordingly, the scope of the present invention should not be construed as being limited to the above-described embodiments, but should be determined by equivalents to the appended claims, as well as the following claims.
Claims (17)
A clopidogrel outer nucleus adjacent to the outer core of the inner core and comprising clopidogrel, an isomer thereof or a pharmaceutically acceptable salt thereof and a first binding agent as pharmacologically active ingredients, and
A second protective layer disposed adjacent the outer core of the outer core and comprising a second binder and a first plasticizer,
Clopidogrel < / RTI > granules,
(B) an inner core comprising an excipient,
An aspirin outer nucleus adjacent to the outer core of the inner core and comprising aspirin or a pharmaceutically acceptable salt thereof and a third binding agent as the pharmacologically active ingredient,
And an enteric coating layer adjacent to the outside of the outer core and comprising an enteric coating agent and a second plasticizer,
Aspirin granules,
(C) a capsule containing the clopidogrel granule and the aspirin granule
/ RTI >
Wherein the first binder, the second binder and the third binder are each independently selected from the group consisting of substituted or unsubstituted alkylcellulose or salts thereof, polyvinyl derivatives, polyalkylene glycols, polymethacrylic acid, and mixtures thereof,
Wherein the first plasticizer and the second plasticizer are each independently selected from the group consisting of glycol, ester, oil, glycerin, monostearin glycerin, and mixtures thereof,
Wherein the polyvinyl derivative is selected from the group consisting of polyvinyl pyrrolidone, polyvinyl alcohol, and mixtures thereof,
Wherein the glycol is selected from the group consisting of propylene glycol, polyethylene glycol and mixtures thereof,
Wherein the ester is selected from the group consisting of diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triacetin and mixtures thereof,
Wherein the oil is selected from the group consisting of castor oil, coconut oil, and mixtures thereof.
Wherein the clopidogrel outer core further comprises a third plasticizer,
Wherein the third plasticizer is selected from the group consisting of glycols, esters, oils, glycerin, monostearin glycerin, and mixtures thereof,
Wherein the glycol is selected from the group consisting of propylene glycol, polyethylene glycol and mixtures thereof,
Wherein the ester is selected from the group consisting of diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triacetin and mixtures thereof,
Wherein the oil is selected from the group consisting of castor oil, coconut oil, and mixtures thereof.
Wherein the aspirin outer core further comprises a fourth plasticizer,
Wherein the fourth plasticizer is selected from the group consisting of glycols, esters, oils, glycerin, monostearin glycerin, and mixtures thereof,
Wherein the glycol is selected from the group consisting of propylene glycol, polyethylene glycol and mixtures thereof,
Wherein the ester is selected from the group consisting of diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triacetin and mixtures thereof,
Wherein the oil is selected from the group consisting of castor oil, coconut oil, and mixtures thereof.
Wherein the excipient is selected from the group consisting of sugar, starch, microcrystalline cellulose, lactose, cannauba wax, mannitol, tartaric acid, xylitol, and mixtures thereof.
Wherein the pharmaceutically acceptable salt of clopidogrel is selected from the group consisting of clopidogrel hydrogen peroxide, resinate, camsylate, besylate, napadicylate monohydrate, hydrochloride and mixtures thereof.
The substituted or unsubstituted alkylcellulose or a salt thereof is preferably a cellulose derivative such as methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium and mixtures thereof ≪ / RTI >
Wherein the polyalkylene glycol is selected from the group consisting of polyethylene glycol, polypropylene glycol, and mixtures thereof.
(Methacrylic acid), poly (ethyl acrylate, methyl methacrylate), poly (ethyl acrylate, methyl methacrylate, methyl methacrylate, Trimethylaminoethylmethacrylic acid chloride), and a mixture thereof.
Wherein the enteric coating agent is selected from the group consisting of shellac, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate, polyvinyl alcohol phthalate, poly (methacrylic acid, methylmethacrylic acid) , Methyl methacrylic acid, methacrylic acid), poly (methacrylic acid, ethyl acrylic acid), and mixtures thereof.
The clopidogrel outer core, aspirin outer core, inner protective layer or enteric layer may further comprise additives selected from the group consisting of diluents, lubricants, stabilizers, film coatings and mixtures thereof,
Wherein the stabilizer is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid, tocopherol, edetic acid (EDTA), and mixtures thereof. Formulation.
Wherein aspirin is contained in an amount of 10 to 1000 parts by weight based on 100 parts by weight of the clopidogrel.
Wherein the capsule is a hard capsule.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
| CN201280053817.4A CN103957895A (en) | 2011-11-02 | 2012-08-08 | Complex agent containing clopidogrel and aspirin |
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| Application Number | Priority Date | Filing Date | Title |
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| KR1020110113131A KR101675501B1 (en) | 2011-11-02 | 2011-11-02 | Combination of Clopidogrel and Aspirin |
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| KR101675501B1 true KR101675501B1 (en) | 2016-11-14 |
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| KR (1) | KR101675501B1 (en) |
| CN (1) | CN103957895A (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP5905165B2 (en) * | 2013-08-02 | 2016-04-20 | サノフイ | Pharmaceutical tablets containing acetylsalicylic acid and clopidogrel |
| KR101764785B1 (en) * | 2015-05-29 | 2017-08-07 | 한국유나이티드제약 주식회사 | Pharmaceutical combination preparation |
| KR102024699B1 (en) * | 2016-03-16 | 2019-09-26 | 한국유나이티드제약 주식회사 | Complex formulation comprising clopidogrel and asprin |
| 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 |
| 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 |
| CN107693524A (en) * | 2017-10-23 | 2018-02-16 | 罗铭炽 | A kind of preparation method containing aspirin and clopidogrel |
| CN107669690A (en) * | 2017-10-23 | 2018-02-09 | 罗铭炽 | A kind of tablet containing aspirin and clopidogrel |
| UY39094A (en) * | 2020-02-27 | 2021-07-30 | Hk Inno N Corp | PHARMACEUTICAL COMPOSITION INCLUDING BENZIMIDAZOLE DERIVATIVE COMPOUND |
| US20230059869A1 (en) * | 2021-08-03 | 2023-02-23 | Liqmeds Worldwide Limited | Oral pharmaceutical solution of clopidogrel |
| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100295345B1 (en) | 1996-02-19 | 2001-08-07 | 디. 꼬쉬 | New associations of active principles containing clopidogrel and an antithrombotic agent |
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| FR2792836B3 (en) | 1999-04-30 | 2001-07-27 | Sanofi Sa | PHARMACEUTICAL COMPOSITION IN UNIT FORM CONTAINING ASPIRIN AND CLOPIDOGREL HYDROGENOSULFATE |
| JP2008543843A (en) * | 2005-06-13 | 2008-12-04 | エラン ファーマ インターナショナル リミテッド | Combination preparation of nanoparticulate clopidogrel and aspirin |
| KR100762847B1 (en) * | 2006-01-27 | 2007-10-04 | 씨제이 주식회사 | Multiple unit type sustained release oral formulation and process for the preparation thereof |
| EP2255797A4 (en) | 2008-02-22 | 2011-09-07 | Hanall Biopharma Co Ltd | Composite preparation |
| KR20090114190A (en) * | 2008-04-29 | 2009-11-03 | 한올제약주식회사 | Controlled release complex composition comprising hmg-coa reductase inhibitors and angiotensin-ii-receptor blockers |
| CN101584680A (en) * | 2008-05-23 | 2009-11-25 | 黑龙江福和华星制药集团股份有限公司 | Tablet capsule containing clopidogrel hydrogen sulfate salt tablets and acetylsalicylic acid tablets |
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- 2012-08-08 WO PCT/KR2012/006316 patent/WO2013065936A1/en active Application Filing
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100295345B1 (en) | 1996-02-19 | 2001-08-07 | 디. 꼬쉬 | New associations of active principles containing clopidogrel and an antithrombotic agent |
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| WO2013065936A1 (en) | 2013-05-10 |
| CN103957895A (en) | 2014-07-30 |
| KR20130048335A (en) | 2013-05-10 |
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