WO2014003454A1 - Oral dosage form product of clopidogrel hydrogen sulfate with improved stability - Google Patents

Oral dosage form product of clopidogrel hydrogen sulfate with improved stability Download PDF

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Publication number
WO2014003454A1
WO2014003454A1 PCT/KR2013/005695 KR2013005695W WO2014003454A1 WO 2014003454 A1 WO2014003454 A1 WO 2014003454A1 KR 2013005695 W KR2013005695 W KR 2013005695W WO 2014003454 A1 WO2014003454 A1 WO 2014003454A1
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Prior art keywords
hydrogen sulfate
dosage form
clopidogrel hydrogen
oral dosage
product
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PCT/KR2013/005695
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French (fr)
Inventor
Woo Sin Hwang
Geun Tae Kim
Seong Jae Park
Joo Yong Yoon
Jae Yoen JUNG
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Lg Life Sciences Ltd.
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Publication of WO2014003454A1 publication Critical patent/WO2014003454A1/en

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K31/47—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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to an oral dosage form product containing clopidogrel hydrogen sulfate with improved stability. More specifically, the present invention relates to an oral dosage form product of clopidogrel hydrogen sulfate which is a product in a package form wherein an oral dosage form of clopidogrel hydrogen sulfate is sealed together with an oxygen absorbent, and thus increases the stability to oxidation of clopidogrel hydrogen sulfate so that the generation and increase of related compounds can be suppressed during the storage of the product.
  • Clopidogrel is a dextro-rotary enantiomer of methyl alpha-5-(4,5,6,7-tetrahydro (3,2-c) thieno pyridyl)(2-chlorophenyl)-acetate. Clopidogrel acts as a blood-platelet aggregation inhibitor, and thus is useful as a medicinal drug for preventing and treating thrombotic events such as coronary artery disease, peripheral vascular disease and cerebrovascular disease.
  • Plavix ® which is a commercial product of clopidogrel currently on the market ⁇ is a tablet containing crystal Form II of clopidogrel hydrogen sulfate.
  • US Patent No. 6,429,210 discloses that crystal Form II is more compact and much less electrostatic than crystal Form I and thus is more suitable for formulation, and crystal Form II is thermodynamically stable and thus shows a low drug decomposition rate according to the elapse of time.
  • US Patent Publication No. 2003/0096837 discloses a technology of preparing a tablet by mixing clopidogrel hydrogen sulfate with a lubricant and a disintegrant, and tableting the mixture for improving the storage stability of clopidogrel hydrogen sulfate, wherein zinc stearate, stearic acid or stearyl fumarate is used as the lubricant; and crospovidone, croscarmellose sodium or sodium starch glycolate is used as the disintegrant.
  • Korean Patent Laid-open Publication No. 10-2007-0044323 discloses a tablet containing clopidogrel hydrogen sulfate together with a starch and a cellulose-based excipient for improving the storage stability.
  • selection and use of restricted disintegrant(s) or excipient(s) cannot be a fundamental solution for solving problems of all clopidogrel hydrogen sulfates having different properties.
  • US Patent Publication No. 2010/0086590 uses a hydrophilic polymer and further uses a chelating agent and an antioxidant for increasing the stability of clopidogrel oral dosage form.
  • chelating agents and antioxidants are known as materials that adversely affect the human body.
  • the present invention is intended to solve the problems involved in the prior arts as stated above.
  • the technical purpose of the present invention is to provide an oral dosage form product of clopidogrel hydrogen sulfate which increases the stability to oxidation of clopidogrel hydrogen sulfate so that the generation and increase of related compounds can be suppressed during the storage of the product, without the limitation of using a specific additive or excipient.
  • the present invention provides an oral dosage form product of clopidogrel hydrogen sulfate having a package form wherein an oral dosage form of clopidogrel hydrogen sulfate, which comprises clopidogrel hydrogen sulfate as an active ingredient and a pharmaceutically acceptable carrier, and an oxygen absorbent are sealed together in a single container.
  • the present invention provides a method for improving the stability of a pharmaceutical dosage form by seal-packaging a pharmaceutical oral dosage form together with an oxygen absorbent in a single container.
  • the stability to oxidation and storage stability of a pharmaceutical dosage form can be improved even without restricting the excipient and/or the formulation form to specific types. Furthermore, since there is no need to restrict the excipient to specific types, the present invention has the advantage of preparing a stable oral dosage form product of an active ingredient (particularly, clopidogrel hydrogen sulfate) having various particle distribution, various flowability and various hygroscopicity.
  • clopidogrel hydrogen sulfate can be used as an active ingredient, and preferably clopidogrel hydrogen sulfate Form I is used.
  • the oral dosage form product there is no special limitation in the form of the oral dosage form product, and it can be properly selected from conventional oral dosage forms such as tablet, capsule, granule, fine granule or pellet according to concrete use of the product, and preferably it can be tablet. Furthermore, in case of tablet, it can be prepared through a wet, dry and/or direct mixing method, etc. conventionally used in the pharmaceutical field.
  • an oxygen absorbent is sealed in single container together with an oral dosage form of clopidogrel hydrogen sulfate, and plays the role of preventing the oxidation of clopidogrel hydrogen sulfate by absorbing oxygen present in the sealed container and reducing it.
  • the oxygen absorbent comprises a metallic reducing agent such as iron, copper, etc. and if necessary, it may further comprise one or more ingredients selected from electrolyte, water, and moisture donor.
  • the oxygen absorbent may not comprise water or moisture donor (moisture-dependent oxygen absorbent); and if the moisture level in the sealed container is low (i.e., if the moisture content of the dosage form which is sealed together is low), it is preferable that the oxygen absorbent comprises water and/or moisture donor (self-reactive oxygen absorbent). In a preferred embodiment of the present invention, a self-reactive oxygen absorbent is used.
  • the oxygen absorbent Although there is no special limitation in the form of the oxygen absorbent, its constitutional materials should not directly contact with the pharmaceutical dosage form which is sealed together. According to an embodiment of the present invention, it is preferable that the oxygen absorbent is in patch form where aforesaid ingredients are contained in air-permeable material (for example, non-woven fabric, etc.).
  • the amount of the oxygen absorbent incorporated in the container there is no special limitation in the amount of the oxygen absorbent incorporated in the container, and it can be selected properly in consideration of the concrete composition of the oxygen absorbent (in particular, the amount of metallic reducing agent), the amount and moisture content of the pharmaceutical dosage form incorporated together, the kind and amount of the active ingredient in the dosage form, etc.
  • the concrete composition of the oxygen absorbent in particular, the amount of metallic reducing agent
  • the amount and moisture content of the pharmaceutical dosage form incorporated together the kind and amount of the active ingredient in the dosage form, etc.
  • an oxygen absorbent in patch form having oxygen-absorbing capacity of 75 cc to 500 cc can be packaged together.
  • the package form and method of the product can be seal-packaged by a conventional method using a container such as bottle, aluminum pouch, etc.
  • a container such as bottle, aluminum pouch, etc.
  • a bottle package product it can be produced by incorporating an oral dosage form of clopidogrel hydrogen sulfate and an oxygen absorbent in a bottle and sealing the bottle.
  • an aluminum pouch package product it can be produced by incorporating an oral dosage form of clopidogrel hydrogen sulfate and an oxygen absorbent in an aluminum pouch and sealing the pouch.
  • a method of induction sealing, heat adhesion, etc. may be used.
  • the packaging container is a bottle
  • a bottle made of a synthetic resin material such as HDPE (high-density polyethylene), LDPE (low-density polyethylene), PP (polypropylene), PE (polyethylene), etc.
  • HDPE high-density polyethylene
  • LDPE low-density polyethylene
  • PP polypropylene
  • PE polyethylene
  • the thickness of aluminum may be determined variously.
  • an oxygen absorbent is sealed in a single container together with an oral dosage form of clopidogrel hydrogen sulfate, absorbs oxygen present in the container and removes it during the storage after sealing, and thus prevents the oxidation of clopidogrel hydrogen sulfate.
  • the generation and increase of related compounds can be suppressed during the storage and thus the stability of the product can be improved remarkably.
  • Such a technical idea can be applied to all pharmaceutical dosage form products, not just the dosage form product of clopidogrel hydrogen sulfate.
  • a method for improving the stability of a pharmaceutical dosage form by seal-packaging a pharmaceutical oral dosage form together with an oxygen absorbent in a single container is provided.
  • the method for improving the stability of a pharmaceutical dosage form of the present invention can be usefully applied to a dosage form of an active ingredient having low oxidation stability in particular.
  • Clopidogrel hydrogen sulfate, microcrystalline cellulose, light anhydrous silicic acid, crospovidone, low-substituted hydroxypropylcellulose and talc were put in a speed mixer, and mixed, dried and granulated.
  • Crospovidone, light anhydrous silicic acid, hardened oil, sodium stearyl fumarate and talc were added to the granulated product, and mixed and tableted. The resulting tablets were put in a Highcoater and coated by using Opadry solution.
  • the coated tablets were put in an HDPE bottle (30 tablets/bottle) and one patch-type oxygen absorbent (300 cc, H60 ® , Lipmen Company Ltd.) was incorporated therein, and the bottle was closed with a cap having an induction-sealing foil and sealed by induction.
  • one patch-type oxygen absorbent 300 cc, H60 ® , Lipmen Company Ltd.
  • Clopidogrel hydrogen sulfate, microcrystalline cellulose, sodium stearyl fumarate, crospovidone, low-substituted hydroxypropylcellulose and talc were mixed and compact-granulated by using a roller compactor.
  • Crospovidone, gelatinized starch and sodium stearyl fumarate were added to the compact-granulated product, and mixed and tableted.
  • the resulting tablets were put in a Highcoater and coated by using Opadry solution.
  • the coated tablets were put in an HDPE bottle (30 tablets/bottle) and one patch-type oxygen absorbent (300 cc, H60 ® , Lipmen Company Ltd.) was incorporated therein, and the bottle was closed with a cap having an induction-sealing foil and sealed by induction.
  • one patch-type oxygen absorbent 300 cc, H60 ® , Lipmen Company Ltd.
  • Clopidogrel hydrogen sulfate, light anhydrous silicic acid, Prosolv SMCC ® (Silicified Microcrystalline Cellulose), low-substituted hydroxypropylcellulose, D-mannitol, crospovidone, talc and hardened oil were mixed and tableted.
  • the resulting tablets were put in a Highcoater and coated by using Opadry solution.
  • the coated tablets were put in an HDPE bottle (30 tablets/bottle) and one patch-type oxygen absorbent (300 cc, H60 ® , Lipmen Company Ltd.) was incorporated therein, and the bottle was closed with a cap having an induction-sealing foil and sealed by induction.
  • Clopidogrel hydrogen sulfate, microcrystalline cellulose, crospovidone, talc and sodium stearyl fumarate were mixed and filled in capsules by using a capsule filler.
  • the filled capsules were put in an HDPE bottle (30 capsules/bottle) and one patch-type oxygen absorbent (300 cc, H60 ® , Lipmen Company Ltd.) was incorporated therein, and the bottle was closed with a cap having an induction-sealing foil and sealed by induction.
  • Clopidogrel hydrogen sulfate, D-mannitol and sodium stearyl fumarate were mixed, and the given amount of the mixture was put in an HDPE bottle and one patch-type oxygen absorbent (300 cc, H60 ® , Lipmen Company Ltd.) was incorporated therein, and the bottle was closed with a cap having an induction-sealing foil and sealed by induction.
  • one patch-type oxygen absorbent 300 cc, H60 ® , Lipmen Company Ltd.
  • Oral tablets were prepared in the same manner as that of Example 1 and put in an HDPE bottle (30 tablets/bottle), and silica gel was incorporated therein and the bottle was sealed.
  • Capsules were prepared in the same manner as that of Example 4 and put in an HDPE bottle (30 capsules/bottle), and silica gel was incorporated therein and the bottle was sealed.

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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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Abstract

The present invention relates to an oral dosage form product containing clopidogrel hydrogen sulfate with improved stability. More specifically, the present invention relates to an oral dosage form product of clopidogrel hydrogen sulfate which is a product in a package form wherein an oral dosage form of clopidogrel hydrogen sulfate is sealed together with an oxygen absorbent, and thus increases the stability to oxidation of clopidogrel hydrogen sulfate so that the generation and increase of related compounds can be suppressed during the storage of the product.

Description

ORAL DOSAGE FORM PRODUCT OF CLOPIDOGREL HYDROGEN SULFATE WITH IMPROVED STABILITY
The present invention relates to an oral dosage form product containing clopidogrel hydrogen sulfate with improved stability. More specifically, the present invention relates to an oral dosage form product of clopidogrel hydrogen sulfate which is a product in a package form wherein an oral dosage form of clopidogrel hydrogen sulfate is sealed together with an oxygen absorbent, and thus increases the stability to oxidation of clopidogrel hydrogen sulfate so that the generation and increase of related compounds can be suppressed during the storage of the product.
Clopidogrel is a dextro-rotary enantiomer of methyl alpha-5-(4,5,6,7-tetrahydro (3,2-c) thieno pyridyl)(2-chlorophenyl)-acetate. Clopidogrel acts as a blood-platelet aggregation inhibitor, and thus is useful as a medicinal drug for preventing and treating thrombotic events such as coronary artery disease, peripheral vascular disease and cerebrovascular disease.
Plavix®―which is a commercial product of clopidogrel currently on the market―is a tablet containing crystal Form II of clopidogrel hydrogen sulfate. US Patent No. 6,429,210 discloses that crystal Form II is more compact and much less electrostatic than crystal Form I and thus is more suitable for formulation, and crystal Form II is thermodynamically stable and thus shows a low drug decomposition rate according to the elapse of time.
US Patent Publication No. 2003/0096837 discloses a technology of preparing a tablet by mixing clopidogrel hydrogen sulfate with a lubricant and a disintegrant, and tableting the mixture for improving the storage stability of clopidogrel hydrogen sulfate, wherein zinc stearate, stearic acid or stearyl fumarate is used as the lubricant; and crospovidone, croscarmellose sodium or sodium starch glycolate is used as the disintegrant. However, by the use of the restricted lubricant and disintegrant alone, it is difficult to solve sticking, which is a problem mainly generated during the tableting process due to the difference in raw material properties of clopidogrel hydrogen sulfate form I, and it is also difficult to solve the increase of related materials.
Korean Patent Laid-open Publication No. 10-2007-0044323 discloses a tablet containing clopidogrel hydrogen sulfate together with a starch and a cellulose-based excipient for improving the storage stability. However, selection and use of restricted disintegrant(s) or excipient(s) cannot be a fundamental solution for solving problems of all clopidogrel hydrogen sulfates having different properties.
US Patent Publication No. 2010/0086590 uses a hydrophilic polymer and further uses a chelating agent and an antioxidant for increasing the stability of clopidogrel oral dosage form. However, chelating agents and antioxidants are known as materials that adversely affect the human body.
Accordingly, there are requests for development of a technology applicable in commercializing all raw materials of clopidogrel hydrogen sulfate, which can improve the stability and tableting property of clopidogrel hydrogen sulfate dosage form even without restricting the excipient, lubricant and disintegrant as above.
The present invention is intended to solve the problems involved in the prior arts as stated above. The technical purpose of the present invention is to provide an oral dosage form product of clopidogrel hydrogen sulfate which increases the stability to oxidation of clopidogrel hydrogen sulfate so that the generation and increase of related compounds can be suppressed during the storage of the product, without the limitation of using a specific additive or excipient.
To achieve the purpose as explained above, the present invention provides an oral dosage form product of clopidogrel hydrogen sulfate having a package form wherein an oral dosage form of clopidogrel hydrogen sulfate, which comprises clopidogrel hydrogen sulfate as an active ingredient and a pharmaceutically acceptable carrier, and an oxygen absorbent are sealed together in a single container.
In another aspect, the present invention provides a method for improving the stability of a pharmaceutical dosage form by seal-packaging a pharmaceutical oral dosage form together with an oxygen absorbent in a single container.
According to the present invention, the stability to oxidation and storage stability of a pharmaceutical dosage form (particularly, a dosage form of clopidogrel hydrogen sulfate) can be improved even without restricting the excipient and/or the formulation form to specific types. Furthermore, since there is no need to restrict the excipient to specific types, the present invention has the advantage of preparing a stable oral dosage form product of an active ingredient (particularly, clopidogrel hydrogen sulfate) having various particle distribution, various flowability and various hygroscopicity.
Hereinafter, the present invention will be described concretely.
In the oral dosage form product according to the present invention, all known types of clopidogrel hydrogen sulfate can be used as an active ingredient, and preferably clopidogrel hydrogen sulfate Form I is used.
In the present invention, there is no special limitation in the form of the oral dosage form product, and it can be properly selected from conventional oral dosage forms such as tablet, capsule, granule, fine granule or pellet according to concrete use of the product, and preferably it can be tablet. Furthermore, in case of tablet, it can be prepared through a wet, dry and/or direct mixing method, etc. conventionally used in the pharmaceutical field.
In the present invention, an oxygen absorbent is sealed in single container together with an oral dosage form of clopidogrel hydrogen sulfate, and plays the role of preventing the oxidation of clopidogrel hydrogen sulfate by absorbing oxygen present in the sealed container and reducing it. Concretely, the oxygen absorbent comprises a metallic reducing agent such as iron, copper, etc. and if necessary, it may further comprise one or more ingredients selected from electrolyte, water, and moisture donor. If the environment in the sealed container can provide sufficient moisture, the oxygen absorbent may not comprise water or moisture donor (moisture-dependent oxygen absorbent); and if the moisture level in the sealed container is low (i.e., if the moisture content of the dosage form which is sealed together is low), it is preferable that the oxygen absorbent comprises water and/or moisture donor (self-reactive oxygen absorbent). In a preferred embodiment of the present invention, a self-reactive oxygen absorbent is used.
Although there is no special limitation in the form of the oxygen absorbent, its constitutional materials should not directly contact with the pharmaceutical dosage form which is sealed together. According to an embodiment of the present invention, it is preferable that the oxygen absorbent is in patch form where aforesaid ingredients are contained in air-permeable material (for example, non-woven fabric, etc.).
In the oral dosage form product according to the present invention, there is no special limitation in the amount of the oxygen absorbent incorporated in the container, and it can be selected properly in consideration of the concrete composition of the oxygen absorbent (in particular, the amount of metallic reducing agent), the amount and moisture content of the pharmaceutical dosage form incorporated together, the kind and amount of the active ingredient in the dosage form, etc. According to an embodiment of the present invention, if 10 to 500 tablets, each of which has 97.875 mg of clopidogrel hydrogen sulfate Form I (unit weight: 100 mg to 400 mg), are incorporated in the container, an oxygen absorbent in patch form having oxygen-absorbing capacity of 75 cc to 500 cc can be packaged together.
There is no special limitation in the package form and method of the product; for example, it can be seal-packaged by a conventional method using a container such as bottle, aluminum pouch, etc. For example, in case of a bottle package product, it can be produced by incorporating an oral dosage form of clopidogrel hydrogen sulfate and an oxygen absorbent in a bottle and sealing the bottle. In case of an aluminum pouch package product, it can be produced by incorporating an oral dosage form of clopidogrel hydrogen sulfate and an oxygen absorbent in an aluminum pouch and sealing the pouch. For the sealing, a method of induction sealing, heat adhesion, etc. may be used.
If the packaging container is a bottle, a bottle made of a synthetic resin material such as HDPE (high-density polyethylene), LDPE (low-density polyethylene), PP (polypropylene), PE (polyethylene), etc. may be used. Preferably, HDPE is used. If the packaging container is an aluminum pouch, the thickness of aluminum may be determined variously.
In the oral dosage form product according to the present invention, an oxygen absorbent is sealed in a single container together with an oral dosage form of clopidogrel hydrogen sulfate, absorbs oxygen present in the container and removes it during the storage after sealing, and thus prevents the oxidation of clopidogrel hydrogen sulfate. As a result, the generation and increase of related compounds can be suppressed during the storage and thus the stability of the product can be improved remarkably. Such a technical idea can be applied to all pharmaceutical dosage form products, not just the dosage form product of clopidogrel hydrogen sulfate.
Therefore, according to another aspect of the present invention, a method for improving the stability of a pharmaceutical dosage form by seal-packaging a pharmaceutical oral dosage form together with an oxygen absorbent in a single container is provided.
The method for improving the stability of a pharmaceutical dosage form of the present invention can be usefully applied to a dosage form of an active ingredient having low oxidation stability in particular.
The present invention is explained in more detail by the following Examples and Comparative Examples. However, the scope of the present invention is not limited to the Examples.
[EXAMPLES]
[Examples 1 to 3: Tablet preparation]
The ingredients and their amounts used in the preparation of tablets containing clopidogrel hydrogen sulfate in Examples 1 to 3 are shown in the following Table 1.
Table 1
Figure PCTKR2013005695-appb-T000001
Example 1
Clopidogrel hydrogen sulfate, microcrystalline cellulose, light anhydrous silicic acid, crospovidone, low-substituted hydroxypropylcellulose and talc were put in a speed mixer, and mixed, dried and granulated. Crospovidone, light anhydrous silicic acid, hardened oil, sodium stearyl fumarate and talc were added to the granulated product, and mixed and tableted. The resulting tablets were put in a Highcoater and coated by using Opadry solution. The coated tablets were put in an HDPE bottle (30 tablets/bottle) and one patch-type oxygen absorbent (300 cc, H60®, Lipmen Company Ltd.) was incorporated therein, and the bottle was closed with a cap having an induction-sealing foil and sealed by induction.
Example 2
Clopidogrel hydrogen sulfate, microcrystalline cellulose, sodium stearyl fumarate, crospovidone, low-substituted hydroxypropylcellulose and talc were mixed and compact-granulated by using a roller compactor. Crospovidone, gelatinized starch and sodium stearyl fumarate were added to the compact-granulated product, and mixed and tableted. The resulting tablets were put in a Highcoater and coated by using Opadry solution. The coated tablets were put in an HDPE bottle (30 tablets/bottle) and one patch-type oxygen absorbent (300 cc, H60®, Lipmen Company Ltd.) was incorporated therein, and the bottle was closed with a cap having an induction-sealing foil and sealed by induction.
Example 3
Clopidogrel hydrogen sulfate, light anhydrous silicic acid, Prosolv SMCC® (Silicified Microcrystalline Cellulose), low-substituted hydroxypropylcellulose, D-mannitol, crospovidone, talc and hardened oil were mixed and tableted. The resulting tablets were put in a Highcoater and coated by using Opadry solution. The coated tablets were put in an HDPE bottle (30 tablets/bottle) and one patch-type oxygen absorbent (300 cc, H60®, Lipmen Company Ltd.) was incorporated therein, and the bottle was closed with a cap having an induction-sealing foil and sealed by induction.
[Example 4: Capsule preparation]
The ingredients and their amounts used in the preparation of capsules containing clopidogrel hydrogen sulfate in Example 4 are shown in the following Table 2.
Table 2
Figure PCTKR2013005695-appb-T000002
Clopidogrel hydrogen sulfate, microcrystalline cellulose, crospovidone, talc and sodium stearyl fumarate were mixed and filled in capsules by using a capsule filler. The filled capsules were put in an HDPE bottle (30 capsules/bottle) and one patch-type oxygen absorbent (300 cc, H60®, Lipmen Company Ltd.) was incorporated therein, and the bottle was closed with a cap having an induction-sealing foil and sealed by induction.
[Example 5: Fine granule preparation]
The ingredients and their amounts used in the preparation of fine granules containing clopidogrel hydrogen sulfate in Example 5 are shown in the following Table 3.
Table 3
Figure PCTKR2013005695-appb-T000003
Clopidogrel hydrogen sulfate, D-mannitol and sodium stearyl fumarate were mixed, and the given amount of the mixture was put in an HDPE bottle and one patch-type oxygen absorbent (300 cc, H60®, Lipmen Company Ltd.) was incorporated therein, and the bottle was closed with a cap having an induction-sealing foil and sealed by induction.
[Comparative Examples 1 and 2: Preparation of product not comprising oxygen absorbent]
Comparative Example 1
Oral tablets were prepared in the same manner as that of Example 1 and put in an HDPE bottle (30 tablets/bottle), and silica gel was incorporated therein and the bottle was sealed.
Comparative Example 2
Capsules were prepared in the same manner as that of Example 4 and put in an HDPE bottle (30 capsules/bottle), and silica gel was incorporated therein and the bottle was sealed.
[Experimental Example 1: Test for effect of suppressing increase of related compounds in stress test]
On the products prepared in Examples 1 and 4 and Comparative Example 1, a stress test at 80℃ was conducted for 3 days with checking the amount change of related compounds. The analysis was conducted according to the analysis method for related compounds of clopidogrel tablet of USP 32nd edition. The test results are shown in the following Table 4.
Column: Capcell pack C18 (150mm× 4.6mm, 5μm particle size)
Mobile phase: Phosphate Buffer and Acetonitril (75:25, v/v)
Absorbance: 220nm
Flow rate: 1.0 ml/min
Table 4
Figure PCTKR2013005695-appb-T000004
As can be seen from the results of the above Table 4, after the stress test the products of Examples 1 and 4 comprising an oxygen absorbent were stable at the high temperature of 80℃, whereas the product of Comparative Example 1 showed about a 5-fold increase of the amount of related compounds after 3 days.
[Experimental Example 2: Test for effect of suppressing increase of related compounds in accelerated test]
On the products prepared in Examples 1 and 4 and Comparative Example 1, the amount change of related compounds was checked at 40℃/75%RH for 4 months. The analysis was conducted under the same HPLC condition as that of Experimental Example 1. The test results are shown in the following Table 5.
Table 5
Figure PCTKR2013005695-appb-T000005
As can be seen from the results of the above Table 5, after the long-term storage test the products of Examples 1 and 4 comprising an oxygen absorbent showed no increase of related compounds, whereas the product of Comparative Example 1 showed a rapid increase of the amount of related compounds.

Claims (10)

  1. An oral dosage form product of clopidogrel hydrogen sulfate having a package form wherein an oral dosage form of clopidogrel hydrogen sulfate, which comprises clopidogrel hydrogen sulfate as an active ingredient and a pharmaceutically acceptable carrier, and an oxygen absorbent are sealed together in a single container.
  2. The oral dosage form product of clopidogrel hydrogen sulfate according to claim 1, wherein the clopidogrel hydrogen sulfate is clopidogrel hydrogen sulfate Form I.
  3. The oral dosage form product of clopidogrel hydrogen sulfate according to claim 1, wherein the oral dosage form of clopidogrel hydrogen sulfate is tablet, capsule or fine granule.
  4. The oral dosage form product of clopidogrel hydrogen sulfate according to claim 3, wherein the oral dosage form of clopidogrel hydrogen sulfate is tablet.
  5. The oral dosage form product of clopidogrel hydrogen sulfate according to claim 1, wherein the oxygen absorbent comprises a metallic reducing agent.
  6. The oral dosage form product of clopidogrel hydrogen sulfate according to claim 1, wherein the oxygen absorbent is in patch form.
  7. The oral dosage form product of clopidogrel hydrogen sulfate according to claim 1, wherein the container is a bottle or aluminum pouch.
  8. The oral dosage form product of clopidogrel hydrogen sulfate according to claim 7, wherein the container is a bottle.
  9. A method for improving the stability of a pharmaceutical dosage form by seal-packaging a pharmaceutical oral dosage form together with an oxygen absorbent in a single container.
  10. The method according to claim 9, wherein the pharmaceutical oral dosage form contains clopidogrel hydrogen sulfate.
PCT/KR2013/005695 2012-06-28 2013-06-27 Oral dosage form product of clopidogrel hydrogen sulfate with improved stability WO2014003454A1 (en)

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CN103877056A (en) * 2014-03-13 2014-06-25 武汉晟辉生物医药科技有限公司 Clopidogrel tablet and preparation method thereof
CN105078919A (en) * 2015-08-27 2015-11-25 青岛海之源智能技术有限公司 Clopidogrel hydrogen sulfate oral patch and method for manufacturing same
CN108888605A (en) * 2018-08-03 2018-11-27 安徽省金楠医疗科技有限公司 A kind of clopidogrel bisulfate tablet and preparation method thereof

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US20090281136A1 (en) * 2008-05-08 2009-11-12 Sandeep Mhetre Prasugrel pharmaceutical formulations
KR20100016295A (en) * 2007-04-09 2010-02-12 유에스브이 리미티드 Novel stable pharmaceutical compositions of clopidogrel bisulfate and process of preparation thereof
JP2013010751A (en) * 2011-05-31 2013-01-17 Sawai Pharmaceutical Co Ltd Clopidogrel-containing tablet and method for producing the same

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WO2008088030A1 (en) * 2007-01-17 2008-07-24 Mochida Pharmaceutical Co., Ltd. Composition for prevention or treatment of disease associated with thrombus or embolus
KR20100016295A (en) * 2007-04-09 2010-02-12 유에스브이 리미티드 Novel stable pharmaceutical compositions of clopidogrel bisulfate and process of preparation thereof
KR20080098964A (en) * 2007-05-08 2008-11-12 경동제약 주식회사 Pharmaceutical composition containing clopidogrel hydrogen sulfate and preparing method thereof
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CN103877056A (en) * 2014-03-13 2014-06-25 武汉晟辉生物医药科技有限公司 Clopidogrel tablet and preparation method thereof
CN103877056B (en) * 2014-03-13 2016-04-20 武汉晟辉生物医药科技有限公司 A kind of clopidogrel sheet and preparation method thereof
CN105078919A (en) * 2015-08-27 2015-11-25 青岛海之源智能技术有限公司 Clopidogrel hydrogen sulfate oral patch and method for manufacturing same
CN108888605A (en) * 2018-08-03 2018-11-27 安徽省金楠医疗科技有限公司 A kind of clopidogrel bisulfate tablet and preparation method thereof

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