WO2011121823A1 - Composition pharmaceutique particulaire pour administration orale - Google Patents

Composition pharmaceutique particulaire pour administration orale Download PDF

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Publication number
WO2011121823A1
WO2011121823A1 PCT/JP2010/067039 JP2010067039W WO2011121823A1 WO 2011121823 A1 WO2011121823 A1 WO 2011121823A1 JP 2010067039 W JP2010067039 W JP 2010067039W WO 2011121823 A1 WO2011121823 A1 WO 2011121823A1
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Prior art keywords
pharmaceutical composition
oral administration
particulate pharmaceutical
particulate
drug
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PCT/JP2010/067039
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English (en)
Japanese (ja)
Inventor
弘朗 田崎
卓也 石井
裕希 笠島
竜 小嶋
啓之 梅島
啓 近藤
聡一郎 中村
武史 矢野
佳之 早川
敦 上林
豊 高橋
和博 迫
俊典 渡辺
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アステラス製薬株式会社
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Priority to JP2012508015A priority Critical patent/JP5614445B2/ja
Publication of WO2011121823A1 publication Critical patent/WO2011121823A1/fr

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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—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 having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present invention relates to a particulate pharmaceutical composition for oral administration comprising atorvastatin.
  • the present invention relates to a particulate pharmaceutical composition for oral administration, wherein a core containing atorvastatin and sodium lauryl sulfate is coated with a coating material containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance, and
  • the present invention relates to an orally disintegrating tablet containing a particulate pharmaceutical composition for oral administration.
  • the present invention also relates to the use of polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance for producing a granular pharmaceutical composition for oral administration which is coated with atorvastatin-containing particles and reduces the change in dissolution rate after compression molding. Is. Furthermore, this invention relates to the manufacturing method of the granular pharmaceutical composition for oral administration which coat
  • HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A
  • atorvastatin calcium hydrate is sold as Lipitor®, which has the chemical name [R- (R *, R *)]-2- (4-fluorophenyl) - ⁇ , ⁇ -dihydroxy- 5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid calcium salt (2: 1) trihydrate and has the following formula:
  • Atorvastatin and its pharmaceutically acceptable salts are selective and competitive inhibitors of HMG-CoA reductase.
  • Atorvastatin calcium is a potent lipid-lowering compound and is therefore useful as a lipid-lowering agent and / or cholesterol-lowering agent, and at the same time useful for the treatment of osteoporosis, benign prostatic hypertrophy (BPH), and Alzheimer's disease. is there.
  • atorvastatin or a pharmaceutically acceptable salt thereof in a pure crystalline form so that a formulation containing atorvastatin or a pharmaceutically acceptable salt thereof can meet strict pharmaceutical requirements and standards There is a need. Furthermore, the process for producing atorvastatin or a pharmaceutically acceptable salt thereof is required to follow a large scale production. It is also desirable that the product be in a form that can be quickly filtered and easily dried. Ultimately, it is economically desirable for the product to be stable for long periods of time without requiring special storage conditions. So far, various crystal forms of atorvastatin or a pharmaceutically acceptable salt thereof have been disclosed (Patent Documents 1 and 2).
  • atorvastatin is a poorly soluble drug, its in-vitro dispersibility and dissolution properties are poor, resulting in a problem of reduced bioavailability.
  • a method of changing a crystal to an amorphous form there is a method of changing a crystal to an amorphous form.
  • atorvastatin and optionally excipients are dissolved in a non-hydroxyl solvent to form a solution, and the solvent is lyophilized to provide an amorphous
  • a method for producing amorphous atorvastatin (Patent Document 4), which comprises producing quality atorvastatin.
  • a solid pharmaceutical composition comprising a solid dispersion with a pharmaceutically acceptable excipient which is a larger optional ingredient, comprising amorphous atorvastatin or a pharmaceutically acceptable complex, salt,
  • a solid pharmaceutical composition comprising a solvate or hydrate and a melt processable polymer is disclosed (Patent Document 5).
  • Patent Document 6 a method of heat treatment at a specific temperature is disclosed.
  • atorvastatin or a pharmaceutically acceptable salt thereof is a drug having a strong bitter taste.
  • the drug or the composition comprising the drug may be treated with a coating that suppresses the drug release for a certain period of time in the oral cavity. is there. Since the coating generally uses a water-insoluble polymer or the like, there is a problem that the dispersibility / elution property of the drug is lowered.
  • oral particulate pharmaceutical compositions such as granules, fine granules, and powders are smaller in size than tablets and capsules, so that they are easy to take even for patients who have difficulty swallowing tablets and capsules.
  • the particulate pharmaceutical composition for oral administration is small in size, the specific surface area increases, so that the drug is rapidly released in the oral cavity after taking it, causing various problems. For example, if the drug has an unpleasant taste, the drug quickly released in the oral cavity may cause a strong discomfort to the patient and significantly reduce dosage compliance.
  • a saccharide having a low moldability is sprayed with a high moldability saccharide as a binder and coated and / or granulated, and when tablet strength is further required
  • Orally disintegrating tablet humidity-dried tablet
  • drug, diluent, and saccharide having a melting point relatively lower than that of the drug and diluent, and the saccharide having a low melting point is uniformly contained in the tablet
  • An orally disintegrating tablet (Patent Document 8) containing a drug and / or diluent particles, which is blended with a melt-solidified product of a saccharide having a low melting point, and a drug, the degree of gelatinization of 30% or more and 60% Processed starches which are the following, orally disintegrating tablets containing sugars (Patent Document 9) and the like are known.
  • a drug having a bitter taste when applied to these orally disintegrating tablets, for example, a drug solution is sprayed onto a core made of crystalline cellulose to prepare drug-containing particles, and then a polymer suitable for the particles is prepared.
  • a method of applying a film coating with a substance is employed.
  • the film tears and the drug leaks out so it is technically very difficult to suppress the bitter taste of the drug in the oral cavity.
  • tableting is performed at a low pressure in order to avoid breakage of the coated film due to tableting, there is a concern that tablet hardness suitable for handling in the production process and transportation process cannot be obtained.
  • an acrylic polymer As a method for suppressing an unpleasant taste, use of an acrylic polymer is known. Oral administration containing a drug-containing core, an intermediate layer containing two types of water-soluble components, an insolubilization accelerator and an insolubilizing substance, and a water infiltration control layer that controls the rate of water intrusion into the outermost layer A time-release particulate pharmaceutical composition for use is known, and an acrylic acid polymer is exemplified as a material used for a water infiltration control layer (Patent Document 10). However, depending on the drug or base selected, there is room for further improvement to reduce initial drug elution and to achieve subsequent rapid drug release.
  • Patent Document 11 An invention relating to a taste-masked pharmaceutical composition comprising a polymer mixture is known (Patent Document 11).
  • Patent Document 12 a film coating agent that conceals an unpleasant taste such as a bitter taste of a solid preparation by a film coat containing methyl cellulose and an acrylic acid-based polymer containing a methacrylic acid ester and / or an acrylic acid ester in a monomer unit, and having an excellent dissolution property.
  • Patent Document 12 neither of Patent Documents 11 and 12 describes an elution change when compression-molding the coated granule, and there is a concern about a change in elution rate due to compression molding.
  • Patent Document 13 A method for regenerating the elution control function inside a compression molded product is disclosed (Patent Document 13). Furthermore, as a method of compressing together with an excipient that absorbs impact due to compression, a preparation is described in which a film-protecting agent having an average particle diameter of 20 ⁇ m or less is physically mixed with a drug-containing film particle and then compression-molded.
  • Patent Document 14 In order to provide a compression-molded preparation with reduced coating damage during compression molding of drug-containing coated particles, a substance containing drug-containing coated particles and having an average particle diameter of about 50 ⁇ m or more and an initial dissolution rate ratio of 4 or more An invention relating to a compression molding preparation containing fine particles as a film protective agent is disclosed (Patent Document 14).
  • Patent Documents 13 and 14 depending on the selected drug or base, even if the initial drug elution is reduced, subsequent rapid drug release is not achieved, and a special device capable of alcohol treatment is used. There is a problem that needs to be used.
  • Patent Document 15 an atorvastatin preparation containing a mixture containing atorvastatin and sodium lauryl sulfate is disclosed in Patent Document 15 (Example 3).
  • Patent document 15 makes it a subject to stabilize atorvastatin, and a technical idea differs from this invention.
  • a particulate pharmaceutical composition for oral administration that can reduce or reduce the change in drug elution rate even after compression molding while reducing the initial drug elution amount of atorvastatin and maintaining rapid drug release thereafter. That is, a particulate pharmaceutical composition for oral administration that achieves rapid dispersibility and dissolution in the digestive tract when concealing an unpleasant taste in the oral cavity (compliance compliance), and an oral cavity containing the composition Technology development regarding disintegrating tablets is necessary.
  • Japanese Patent No. 3296564 specification (I, II, IV type), Japanese Patent No. 3965155 (V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, and XIX types)
  • International Publication No. WO2006 / 046109 Pamphlet International Publication No. WO2004 / 110407 Pamphlet International Publication No. WO2006 / 059224 Pamphlet International Publication No. WO2007 / 034316 Pamphlet International Publication No. WO95 / 20380 (corresponding to US Pat. No. 5,576,014) International Publication No. WO02 / 92057 (corresponding US Pat. No.
  • the present invention relates to a particulate pharmaceutical composition for oral administration that can reduce or reduce a change in drug elution rate even after compression molding while reducing the initial drug elution amount of atorvastatin and maintaining rapid drug release thereafter. And an orally disintegrating tablet containing the composition.
  • the present invention also provides a particulate pharmaceutical composition for oral administration which achieves rapid dispersibility and dissolution in the digestive tract when atorvastatin is used to conceal an unpleasant taste in the mouth (compliance compliance), and An orally disintegrating tablet containing the composition is provided.
  • the present inventors can reduce or reduce the initial drug elution amount of atorvastatin, and suppress or reduce the change in drug elution rate even after compression molding while maintaining rapid drug release thereafter.
  • the particulate pharmaceutical composition for oral administration in which particles containing atorvastatin and sodium lauryl sulfate are coated with a coating material containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance, the desired effect of the present invention described in detail below
  • a drug based on the interaction between atorvastatin and a specific base The delayed elution induces a decrease in bioavailability, and the desired effect of the present invention is achieved by the selection and use of a specific polymer substance;
  • the pharmaceutical composition for oral administration described above By confirming that the or
  • the present invention [1] Particulate pharmaceutical for oral administration in which particles containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate are coated with a coating substance containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance Composition, [2]
  • the water-soluble polymer substance is selected from the group consisting of hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose, povidone, copolyvidone, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, and polyethylene oxide 1
  • the water-soluble polymer substance is selected from the group consisting of hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose, povidone, copolyvidone, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, and polyethylene oxide.
  • a method for producing a particulate pharmaceutical composition for oral administration according to [9], which is a species or two or more species [11] The method for producing a granular pharmaceutical composition for oral administration according to [9], wherein the water-soluble polymer substance is hypromellose.
  • the fluidizing agent is talc, kaolin, calcium silicate, magnesium silicate, light anhydrous silicic acid, magnesium stearate, calcium stearate, iron oxide, titanium oxide, calcium carbonate, calcium phosphate, gypsum, magnesium carbonate, hydroxide
  • atorvastatin it is possible to reduce the release of atorvastatin from the core of the particulate pharmaceutical composition after compression molding for a certain period of time during which particles are present in the oral cavity, and (2) atorvastatin is rapidly released after a certain period of time. (3) It is possible to express sufficient efficacy by being released in the upper part of the digestive tract. (3) About atorvastatin having an unpleasant taste, in the digestive tract when concealing an unpleasant taste in the oral cavity It is possible to achieve quick elution in the case of (4) taking compliance and preventing delay in absorption, and the like.
  • Example 3 water, Japanese Pharmacopoeia dissolution test 1st liquid (JP1), and Japanese Pharmacopoeia dissolution test 2nd liquid (JP2) were used as test solutions. It is the elution profile obtained in this way.
  • Example 5 water, Japanese Pharmacopoeia dissolution test 1st liquid (JP1), and Japanese Pharmacopoeia dissolution test 2nd liquid (JP2) were used as test solutions. It is the elution profile obtained in this way.
  • Example 2 is an elution profile obtained by conducting a liquid displacement elution test on the particulate pharmaceutical compositions (masking particles before tableting) prepared in Example 3 and Comparative Examples 2 to 4. It is a graph which shows the collection
  • SLS sodium lauryl sulfate
  • AEA polyvinyl acetal diethylaminoacetate
  • the term “particulate pharmaceutical composition” refers to a drug-containing particulate composition that is smaller than the following fixed value and is orally administered in various forms together with one or more pharmaceutical additives. means.
  • the size of the particulate pharmaceutical composition is defined as an average particle diameter of 2 mm or less.
  • the shape of the particulate pharmaceutical composition is a shape other than a sphere, the size of the particulate pharmaceutical composition is defined as having an average longest diameter of 2 mm or less.
  • the lower limit value is not particularly limited as long as it is a pharmaceutically acceptable range, and for example, 1 ⁇ m or more, another embodiment is 10 ⁇ m or more, and a further embodiment is 20 ⁇ m or more.
  • Examples of the method for measuring the particle diameter include the microscopy described in the Fifteenth Revised Japanese Pharmacopoeia General Test Method. Microscopy is a method of directly observing the appearance and shape of individual particles with the naked eye or micrographs using an optical microscope, and measuring their sizes. The major axis average diameter, the triaxial average diameter, and the biaxial average The diameter can be used as the particle diameter.
  • the “core” is not particularly limited as long as it can be a pharmaceutically acceptable grain. It is a group for constituting the particulate pharmaceutical composition of the present invention and for coating the intermediate layer and the coating material used in the present invention.
  • the core is composed of the drug itself or pharmaceutically acceptable additives. Particles [eg, crystalline cellulose (grains) (may be described as microcrystalline cellulose), lactose, starch, etc.] can also be used. It is also possible to use a drug alone or a mixture of a drug and a pharmaceutically acceptable additive. You may manufacture the particle
  • additives and sodium lauryl sulfate and a binder for example, water-soluble polymer: for example, hypromellose (also known as hydroxypropylmethylcellulose) (TC-5, Shin-Etsu Chemical), hydroxypropylcellulose ( Nisso HPC, Nippon Soda Co., Ltd.), methyl methacrylate / butyl methacrylate containing an acidic substance in an amount that neutralizes 10% or more of the basic group described in Japanese Patent No.
  • water-soluble polymer for example, hypromellose (also known as hydroxypropylmethylcellulose) (TC-5, Shin-Etsu Chemical), hydroxypropylcellulose ( Nisso HPC, Nippon Soda Co., Ltd.), methyl methacrylate / butyl methacrylate containing an acidic substance in an amount that neutralizes 10% or more of the basic group described in Japanese Patent No.
  • dimethylaminoethyl methacrylate copolymer [aminoalkyl methacrylate copolymer E (trade name; Eudragit E100, Evonik Degussa GmbH)], povidone (Collidon, BASF), methylcellulose (METOLOSE, Shin-Etsu Chemical) etc.)
  • the dispersed liquid may be sprayed.
  • the core can be coated with sodium lauryl sulfate and a water-soluble polymer.
  • Examples of the size of the nucleus include, for example, 1 ⁇ m or more and 1000 ⁇ m or less, other embodiments include 5 ⁇ m or more and 500 ⁇ m or less, and further embodiments include 10 ⁇ m or more and 200 ⁇ m or less.
  • “rapid dispersibility / dissolution” means that when a test is performed using 900 mL of Japanese Pharmacopoeia Dissolution Test Solution 1 (JP1) according to the 15th revised Japanese Pharmacopoeia Dissolution Test Method 2, It means that the elution rate at 15 minutes is 50% or more. In another embodiment, it means that the dissolution rate in 15 minutes is 60% or more.
  • “suppressing drug release for a certain period of time” or “suppressing initial drug dissolution” means that the dissolution rate of a drug is suppressed to 0 to 3% in a dissolution test assuming the oral cavity.
  • the “lag time” means the “time when the drug dissolution rate is suppressed to 0 to 3%”.
  • the “lag time” is used for the purpose of shielding the unpleasant taste of the drug in the oral cavity, and the characteristics and purpose of the drug / formulation (for example, the type and degree of the unpleasant taste of the drug, the duration of the taste, the oral cavity of the formulation It is appropriately set in consideration of the internal residence time, etc., but is defined as, for example, 2 minutes or more, for example, “lag time” is, for example, “intermediate layer” component in the composition, its blending ratio / coating amount, water It can be arbitrarily adjusted by designing such as appropriately increasing / decreasing the components of the infiltration amount control layer and the blending ratio / coating amount thereof.
  • unpleasant taste means a taste that causes unpleasant feeling when taken, and specifically includes bitterness, astringency, gummy taste, acidity, pungent taste, astringent taste, and the like.
  • insolubilization means a phenomenon in which the solubility in water or the dissolution rate is lowered.
  • insolubilize”, “insolubilize”, and “promoting insolubilization” means that a dissolved substance is phase-separated from water, precipitated, precipitated, precipitated, or dissolved in water. Indicates blocking.
  • the “test solution assuming the oral cavity” means a pH 6.8 phosphate buffer solution (the 15th revised Japanese Pharmacopoeia dissolution test method second solution).
  • the particulate pharmaceutical composition for oral administration according to the present invention is such that particles containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate are coated with a coating substance containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance. It is a particulate pharmaceutical composition for oral administration.
  • the orally disintegrating tablet of the present invention is an orally disintegrating tablet comprising the particulate pharmaceutical composition for oral administration of the present invention.
  • Atorvastatin or a pharmaceutically acceptable salt thereof used in the present invention is atorvastatin calcium hydrate, chemical name [R- (R *, R *)] disclosed in US Pat. No. 5,273,995. -2- (4-Fluorophenyl) - ⁇ , ⁇ -dihydroxy-5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid calcium salt 2: 1) Trihydrate is included. Atorvastatin calcium hydrate has the following formula: Currently marketed as Lipitor®. Atorvastatin or a pharmaceutically acceptable salt thereof is a selective and competitive inhibitor of HMG-CoA reductase.
  • Examples of pharmaceutically acceptable salts include metal salts such as alkali metals and alkaline earth metals, or amine salts such as organic amines.
  • a salt with sodium, potassium, lithium, calcium, magnesium, aluminum, iron, zinc, calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, magnesium aluminum hydroxide is used.
  • a salt with calcium can be mentioned.
  • Atorvastatin calcium is a potent lipid-lowering compound and is therefore useful as a lipid-lowering agent and / or cholesterol-lowering agent, and at the same time useful for the treatment of osteoporosis, benign prostatic hypertrophy (BPH), and Alzheimer's disease. is there.
  • atorvastatin examples include, for example, types I, II, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, and XIX.
  • type I may be mentioned.
  • "Type I crystal” is crystalline Form I atorvastatin hydrate disclosed in Japanese Patent No. 3,296,564.
  • the amount of atorvastatin or a pharmaceutically acceptable salt thereof is not particularly limited as long as it is a pharmaceutically preventive or therapeutically effective amount.
  • it is about 2.5 mg to about 80 mg per day. It is about 5 mg or more and about 500 mg or less, and as a further aspect, it is about 2.5 mg or more and about 80 mg or less.
  • it is administered to a patient at an adult dosage level of about 0.1 mg to about 8.0 mg / kg body weight per day.
  • the daily dose is in the range of about 0.1 mg / kg to about 2.0 mg / kg.
  • the blending amount can be changed or adjusted to 5 mg or more and 80 mg or less, and in another embodiment, 5 mg or more and 100 mg or less depending on efficacy or application.
  • the dosage is increased gradually until the optimum effect is reached according to the circumstances.
  • the total dose per day can be divided and administered several times a day.
  • the proportion of the drug is usually appropriately selected according to the type, use (indication), and age (or body weight) of the drug, as long as it is a therapeutically effective amount or a prophylactically effective amount.
  • it is 0.5 wt% or more and 90 wt% or less per "particulate pharmaceutical composition" or pharmaceutical preparation of the present invention, and in another embodiment, 0.5 wt% or more and 80 wt% or less. As 0.5 to 70% by weight.
  • the sodium lauryl sulfate used in the present invention is not particularly limited as long as it has a function of improving dispersibility of atorvastatin or a pharmaceutically acceptable salt thereof. Moreover, sodium lauryl sulfate will not be specifically limited if it has a function which improves the solubility of polyvinyl acetal diethylamino acetate. Examples of sodium lauryl sulfate include trade names NIKKOL SLS (Nikko Chemicals), Emar 0 (Kao), TEXAPON K12 P PH (Cognis Japan), and TEXAPON K12 G PH (Cognis Japan).
  • the amount of sodium lauryl sulfate is not particularly limited as long as it is pharmaceutically acceptable and improves the dispersibility of atorvastatin or a pharmaceutically acceptable salt thereof. , Atorvastatin or a pharmaceutically acceptable salt thereof, 30 wt% or more and 200 wt% or less, in another embodiment, 40 wt% or more and 100 wt% or less, and in another embodiment, atorvastatin or a pharmaceutical product thereof It can be 60 wt% or more and 100 wt% or less based on the amount of salt allowed.
  • the amount of sodium lauryl sulfate is not particularly limited as long as it is an amount that improves the solubility of polyvinyl acetal diethylaminoacetate.
  • the aspect is 50% by weight to 200% by weight with respect to polyvinyl acetal diethylaminoacetate.
  • the aspect may be 100% by weight or more and 200% by weight or less, still another aspect may be 120% by weight or more and 200% by weight or less, and still another aspect may be 130% by weight or more and 200% by weight or less.
  • Polyvinyl acetal diethylaminoacetate (hereinafter sometimes abbreviated as AEA) used in the present invention is an acetal obtained by dehydration condensation of polyvinyl alcohol and acetaldehyde, and a part of the remaining hydroxyl groups and diethylaminoacetic acid It is an ester bond and is not particularly limited as long as it is pharmaceutically acceptable. Specific examples include those commercially available under the trade name “AEA (registered trademark)” (for example, average molecular weight 65000) as gastric coating agents (Pharmaceutical Additive Standards, pp. 634-635, 2003, Yakuji Nipposha).
  • AEA registered trademark
  • the blending amount of polyvinyl acetal diethylaminoacetate is, for example, 1% by weight or more and 500% by weight or less with respect to the drug-containing particles, and in another aspect, 5% by weight or more and 300% by weight or less, and in another aspect, 10% by weight. % Or more and 150% by weight or less.
  • it is 1% by weight or more and 300% by weight or less with respect to the intermediate layer-coated particles.
  • it is 5% by weight or more and 200% by weight or less, and in another embodiment, it is 5% by weight or more and 150% by weight or less. be able to.
  • the ratio of the coating amount in the particulate pharmaceutical composition is, for example, 1% by weight or more and 200% by weight or less, and in another embodiment, 5% by weight or more and 100% by weight or less, and in another embodiment, 5% by weight or more and 50% by weight or less. It can be up to wt%.
  • the “water-soluble polymer substance” used in the present invention is not particularly limited as long as it is pharmaceutically acceptable.
  • the polymer substance constitutes a coating component together with polyvinyl acetal diethylaminoacetate, and the “particulate pharmaceutical composition” is coated with the coating substance, so that the drug substance from the “particulate pharmaceutical composition” is compressed after compression molding.
  • polymer substance examples include gum arabic, sodium alginate, pregelatinized starch, casein sodium, carrageenan, carboxyvinyl polymer, sodium carboxymethyl starch, carmellose sodium, xanthan gum, dextran, dextrin, hydroxypropylcellulose, hypromellose, methylcellulose. , Hydroxyethyl cellulose, pullulan, povidone, copolyvidone, polyoxyethylene-polyoxypropylene glycol, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, and polyethylene oxide.
  • Further embodiments include hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose and the like.
  • Still other embodiments include hydroxypropylcellulose, hypromellose, hydroxyethylcellulose and the like.
  • hypromellose examples include a high-molecular substance (indicated viscosity of 3 mPa ⁇ s to 15 mPa ⁇ s) marketed under the trade name of the 15th revised Japanese Pharmacopoeia Hypromellose (Shin-Etsu Chemical). These water-soluble polymer substances can be used alone or in combination of two or more.
  • composition ratio (mixing ratio) of polyvinyl acetal diethylaminoacetate and water-soluble polymer substance used in the present invention, usually depending on purposes such as physical properties of the drug, stability, absorption site, type and use of dosage form, An appropriate blending amount is appropriately selected.
  • the amount of the water-soluble polymer substance is, for example, from 1% by weight to 30% by weight with respect to polyvinyl acetal diethylaminoacetate. In another embodiment, the amount is from 5% by weight to 20% by weight, and in a further embodiment, from 5% by weight to 15%. % By weight or less.
  • an appropriate ratio is appropriately selected for the coating amount of the coating material containing the polyvinyl acetal diethylaminoacetate and the water-soluble polymer material in the present invention.
  • the content is 1% by weight or more and 500% by weight or less with respect to the core containing the drug. In another embodiment, it is 5 wt% or more and 300 wt% or less, and in a further embodiment, it is 10 wt% or more and 150 wt% or less.
  • the coating amount is lower than 1% by weight, the surface of the particulate pharmaceutical composition is not uniformly coated and the coating layer is extremely thin, so that the drug elution from the particulate pharmaceutical composition by compression molding There is concern about an increase in speed.
  • intermediate layer coated particles when the particles containing drug-containing particles are coated with an intermediate layer (which will be described later and may be abbreviated as “intermediate layer” coated particles hereinafter), 1 wt% or more and 500 wt% or less. In another embodiment, it is 5% by weight or more and 200% by weight or less, and in a further embodiment, it is 10% by weight or more and 150% by weight or less.
  • the ratio of the coating amount in the particulate pharmaceutical composition is, for example, 1% by weight or more and 200% by weight or less. In another embodiment, it is 5% by weight or more and 100% by weight or less, and in another embodiment, it is 5% by weight or more and 50% by weight or less.
  • the particulate pharmaceutical composition of the present invention can employ an embodiment in which a “fluidizing agent” is blended as desired.
  • a “fluidizing agent” is blended as desired.
  • the blending of the fluidizing agent is not particularly limited during a specific production method.
  • the “particulate pharmaceutical composition” of the present invention is produced by a fluidized bed granulation method, mixing of the components and particles As the material dries, static electricity is generated, which may hinder fluidization.
  • the fluidizing agent has a function of neutralizing generated static electricity and the like, and is not particularly limited as long as it improves fluidization during coating.
  • the fluidizing agent examples include metal silicates, silicon dioxides, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, metal hydroxides, and other embodiments include talc, kaolin, Calcium silicate, magnesium silicate, light anhydrous silicic acid, magnesium stearate, calcium stearate, iron oxide, titanium oxide, calcium carbonate, calcium phosphate, gypsum, magnesium carbonate, aluminum hydroxide, hydrous silicon dioxide, crystalline cellulose, synthetic silicic acid Aluminum, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, corn starch, magnesium aluminate metasilicate, calcium hydrogen phosphate granulate, and glyceryl monostearate, further embodiments include talc, Kaolin, silicate Siumu, magnesium silicate, light anhydrous silicic acid, magnesium stearate, and glyceryl monostearate.
  • One or more fluidizing agents can be added in appropriate combination.
  • the blending amount of the fluidizing agent is, for example, 1% by weight to 500% by weight with respect to the drug-containing particles. In another embodiment, it is 1% by weight or more and 200% by weight or less, and in a further embodiment, it is 5% by weight or more and 100% by weight or less. With respect to polyvinyl acetal diethylaminoacetate, it is, for example, 1% by weight or more and 200% by weight or less, and in another aspect, it is 5% by weight or more and 100% by weight or less, and in a further aspect, it is 20% by weight or more and 60% by weight or less.
  • grains of an intermediate body other than an orally disintegrating tablet can be mix
  • pharmaceutical preparations other than orally disintegrating tablets include powders, fine granules, dry syrups, tablets and the like.
  • the orally disintegrating tablet of the present invention will be described, but the pharmaceutical preparation of the present invention is not limited thereto.
  • the “orally disintegrating tablet” means that when taking a tablet without ingesting water, the oral cavity is substantially within 2 minutes only by saliva, as another aspect within 1 minute, as a further aspect It means tablets that disintegrate within 45 seconds and other preparations similar to tablets.
  • the particulate pharmaceutical composition of the present invention can be contained in such an orally disintegrating tablet.
  • International Publication No. WO95 / 20380 US Patent No. 5576014
  • International Publication No. WO2002 / 92057 Pamphlet U.S. Patent Application Publication No. 2003/099701
  • U.S. Pat. No. 4,305,502 U.S. Pat. No. 4,371,516, U.S. Pat. No.
  • orally disintegrating tablets containing the particulate pharmaceutical composition As such orally disintegrating tablets containing the particulate pharmaceutical composition, the orally disintegrating tablets described in Japanese Patent No. 3412694 (US Patent No. 5223264) and Japanese Patent Application Laid-Open No. 2003-55197 are disclosed.
  • the particulate pharmaceutical composition of the present invention can be contained in these orally disintegrating tablets.
  • Orally disintegrating tablets are generally classified into a mold type, a moist type, and a normal tableting type, and the particulate pharmaceutical composition of the present invention may be contained in any type of orally disintegrating tablet.
  • the mold-type orally disintegrating tablet is prepared by filling a mold with a solution or suspension such as an excipient as disclosed in, for example, Japanese Patent No. 2807346 (US Pat. No. 5,466,464). It is made by drying.
  • the mold-type orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention is, for example, a solution or suspension of the particulate pharmaceutical composition of the present invention, excipients such as sugars, and binders such as gelatin and agar.
  • the PTP pocket After filling the PTP pocket with the liquid, it can be produced by removing moisture by a method such as freeze drying, drying under reduced pressure, or low temperature drying.
  • Wet type orally disintegrating tablets are moistened with excipients such as saccharides as shown in Patent No. 3069458 (U.S. Pat. No. 5,018,618, U.S. Pat. No. 5,720,974).
  • the product After tableting under low pressure, the product is dried. Therefore, for example, the particulate pharmaceutical composition of the present invention, an excipient such as a saccharide can be wetted with a small amount of water or a mixture of water and alcohol, and the wet mixture can be molded at a low pressure and dried.
  • the granulated product can be compression-molded to form a compressed molded product, or the compressed molded product can be humidified and dried to produce an orally disintegrating tablet.
  • a normal tablet type orally disintegrating tablet as shown in International Publication No. WO99 / 47124 Pamphlet (US Patent No. 6658554)
  • the particulate pharmaceutical composition of the present invention is used.
  • An orally disintegrating tablet can be produced by compression molding using an amorphous sugar and an excipient such as a product and a crystalline saccharide, followed by humidification and drying.
  • a normal tablet type orally disintegrating tablet as disclosed in International Publication No.
  • WO2002 / 92057 pamphlet (US Patent Application Publication No. 2003/099701 specification), for example, A mixture of a particulate pharmaceutical composition, an excipient, and a saccharide having a melting point lower than that of the excipient is compression-molded and heated to form a crosslink by melting and solidifying the saccharide having a lower melting point.
  • Orally disintegrating tablets can be prepared. By such humidification drying or heat treatment, the tablet strength of the orally disintegrating tablet can be improved.
  • Orally disintegrating tablets can be prepared by compression-molding a mixture of the particulate pharmaceutical composition and excipients and processed starches having a pregelatinization degree of 30% to 60%.
  • a general excipient can be used, but it is particularly preferable to use a pharmaceutically acceptable saccharide, and a technique utilizing the moldability of the saccharide.
  • a pharmaceutically acceptable saccharide In the case of using saccharides with low moldability, crystalline / amorphous saccharides, and tablet strength improvement technology by humidification drying, it is common to use cross-linking technology with crystalline saccharides and saccharide melt-solidified products.
  • high melting point saccharides can be used.
  • the saccharide having low moldability means, for example, when tableting 150 mg of saccharide with a punch having a diameter of 8 mm at a tableting pressure of 10 kg / cm 2 or more and 50 kg / cm 2 or less, the hardness of the tablet is 0 kp or more and 2 kp or less.
  • the term “highly moldable saccharide” means that the hardness by the same method is 2 kp or more.
  • Saccharides with low moldability are pharmaceutically acceptable, and examples thereof include lactose, mannitol, glucose, sucrose, xylitol, and erythritol. One or two or more of these may be used in appropriate combination.
  • Highly moldable saccharides are pharmaceutically acceptable, and examples thereof include maltose, maltitol, sorbitol, trehalose, lactitol and the like. These saccharides can also be used alone or in combination of two or more.
  • “Crystalline saccharide” is pharmaceutically acceptable, and examples thereof include mannitol, maltitol, erythritol, xylitol and the like. These may be used alone or in combination of two or more. “Amorphous saccharides” are pharmaceutically acceptable and include, for example, lactose, sucrose, glucose, sorbitol, maltose, trehalose, etc., and these saccharides may be used alone or in combination of two or more. It is also possible to use it.
  • the “saccharide having a high melting point” is pharmaceutically acceptable, and examples thereof include xylitol, trehalose, maltose, sorbitol, erythritol, glucose, sucrose, maltitol, mannitol and the like. One or two or more of these may be used in appropriate combination.
  • the “sugar having a low melting point” is pharmaceutically acceptable, and examples thereof include xylitol, trehalose, maltose, sorbitol, erythritol, glucose, sucrose, maltitol, mannitol and the like. These saccharides can also be used alone or in combination of two or more.
  • binders for orally disintegrating tablets include maltitol and copolyvidone. Also about this binder, it is also possible to use 1 type or in combination of 2 or more types as appropriate.
  • a water-soluble polymer for example, hydroxypropylcellulose, hypromellose, povidone, polyvinyl alcohol, gum arabic powder, gelatin, pullulan and the like are suitable.
  • ⁇ -ized means that when physical treatment is applied to starch, water enters between the molecules and swells (gelatinizes). Become.
  • processed starch include corn starch, wheat starch, potato starch, rice starch, tapioca starch and the like.
  • the blending amount of the excipient used for the orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention, or the total amount of the excipient in the whole preparation is the blending amount of the particulate pharmaceutical composition of the present invention and / or Or it is suitably adjusted according to the size of the tablet and the like, but usually 20 mg or more and 1000 mg or less per tablet is preferable, 50 mg or more and 900 mg or less is preferable as another aspect, and 50 mg or more and 800 mg or less is preferable as a further aspect.
  • the blending amount of highly moldable saccharides, water-soluble polymers, amorphous saccharides, and saccharides with a low melting point is 0.5 wt. % Or more and 50% by weight or less is preferable, and in another embodiment, it is 1% by weight or more and 40% by weight or less, and in a further embodiment, it is 2% by weight or more and 30% by weight or less, or 1% by weight or more and 20% by weight or less % Or less is preferred.
  • the orally disintegrating tablet contains the particulate pharmaceutical composition of the present invention
  • a particulate pharmaceutical composition equivalent to 0.5% by weight or more and 90% by weight or less of the whole orally disintegrating tablet can be contained.
  • it is 0.5 wt% or more and 80 wt% or less, and in another embodiment, it corresponds to 1 wt% or more and 60 wt% or less.
  • various pharmaceutical excipients are appropriately used as necessary, and formulated.
  • a pharmaceutical excipient is not particularly limited as long as it is pharmaceutically acceptable and pharmacologically acceptable.
  • binders, disintegrants, acidulants, foaming agents, artificial sweeteners, fragrances, lubricants, colorants, stabilizers, buffers, antioxidants, surfactants, and the like are used.
  • binder examples include hypromellose and gum arabic.
  • disintegrant examples include corn starch, potato starch, carmellose calcium, and carmellose sodium.
  • sour agent examples include citric acid, tartaric acid, malic acid and the like.
  • foaming agent examples include baking soda.
  • artificial sweetener examples include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia and thaumatin.
  • fragrances include lemon, lemon lime, orange and menthol.
  • the lubricant examples include magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.
  • Examples of the colorant include yellow ferric oxide, red ferric oxide, edible yellow No. 4, No. 5, edible red No. 3, No. 102, and edible blue No. 3.
  • Buffers include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid Boric acid or a salt thereof.
  • Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.
  • surfactant examples include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.
  • the pharmaceutical excipient one or a combination of two or more can be added as appropriate.
  • the compounding amount of these various pharmaceutical excipients is, for example, 1% by weight or more and 100% by weight or less with respect to the drug-containing particles, and in another aspect, 5% by weight or more and 80% by weight or less, and 10% as a further aspect. % By weight to 50% by weight.
  • the core containing the drug and sodium lauryl sulfate may be coated with a coating material containing atorvastatin, sodium lauryl sulfate, and a water-soluble polymer. it can.
  • a coating material containing atorvastatin, sodium lauryl sulfate, and a water-soluble polymer it can.
  • the drug-containing nucleus particles made of only a drug can be used.
  • particles comprising a drug and one or more additives may be produced and used.
  • the drug and a suitable excipient for example, microcrystalline cellulose, lactose, corn starch, etc.
  • a binder for example, a water-soluble polymer: For example, hydroxypropyl methylcellulose (also known as hypromellose) (TC-5, Shin-Etsu Chemical), hydroxypropyl cellulose (Nisso HPC, Nippon Soda Co., Ltd.), 10% or more of the basic group described in Japanese Patent No.
  • a solution in which a drug and a binder are dissolved or dispersed may be sprayed on additive particles [for example, crystalline cellulose (grains), purified white sucrose spherical granules, white sucrose / starch spherical granules, etc.] serving as an appropriate core.
  • additive particles for example, crystalline cellulose (grains), purified white sucrose spherical granules, white sucrose / starch spherical granules, etc.
  • These particles can be further coated with a coating material containing sodium lauryl sulfate and a water-soluble polymer.
  • the coating substance containing polyvinyl acetal diethylaminoacetate and the water-soluble polymer substance may be directly coated on the core containing the drug, or one layer or two or more layers. It may be coated after coating.
  • an “intermediate layer” is formed between a coating substance containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance and a nucleus containing a drug. It may be arranged.
  • the “intermediate layer” means a coating layer containing one or more water-soluble insolubilizers and one or more water-soluble insolubilizers.
  • the intermediate layer can be directly coated on the core containing the drug. Further, the intermediate layer may be coated after the drug-containing core is coated in advance as a coating layer of one layer or two or more components that do not prevent the formation of lag time and subsequent rapid drug release.
  • the intermediate layer contains two or more kinds of essential components (insolubilization accelerator and insolubilizing substance), and these plural essential components can be contained in one layer and covered. May be uniform or unevenly distributed.
  • the intermediate layer can cover two or more essential components (insolubilization accelerator and insolubilizing substance) by dividing them into two or more layers, and in that case, how to divide the components Any arrangement may be used. Even in the case of a plurality of layers, the coating layers containing a plurality of essential components are collectively referred to as an intermediate layer.
  • the “insolubilization accelerator” used in the “intermediate layer” is not particularly limited as long as it is a pharmaceutically acceptable water-soluble substance and has a property to promote insolubilization of the “insolubilized substance” described later.
  • “insolubilization accelerator” is “extremely soluble”, “easily soluble” in the definition / measurement method of “solubility” described in the general rules of the 15th revision Japanese Pharmacopoeia, It is a substance with solubility that is “slightly soluble”, “slightly difficult to dissolve”, and “hardly soluble”.
  • examples of the “insolubilization accelerator” include sodium carbonate, potassium carbonate, sodium dihydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, sodium metaphosphate, trisodium phosphate, and phosphoric acid.
  • Embodiments include sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium metaphosphate, trisodium phosphate, potassium bicarbonate, sodium bicarbonate, sodium polyphosphate, sodium pyrophosphate, sodium chloride, chloride Potassium, sodium sulfate, sodium sulfite, sodium citrate, disodium citrate, sodium glutamate, disodium succinate, glycine, alanine, sorbitol, xylitol, inositol, sucrose, glucose, or fructose or their hydrates
  • further Embodiments include sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium citrate, disodium citrate or hydrates thereof.
  • One or two or more insolubilizers can be used in appropriate combination.
  • the “insolubilizing substance” used in the “intermediate layer” is not particularly limited as long as it is a pharmaceutically acceptable water-soluble substance and insolubilized by the “insolubilization accelerator”. Specifically, for example, in the provisions and measurement methods for “solubility” described in the 15th revised Japanese Pharmacopoeia General Rules, “very soluble”, “easy to dissolve”, “slightly soluble”, “ It is a substance with solubility that is said to be “slightly insoluble” or “hard to dissolve”.
  • examples of the “insolubilizing substance” include hypromellose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, carboxyvinyl polymer, polyvinyl alcohol, polyethylene oxide, povidone, copolyvidone, polyoxyethylene cured Castor oil, N-isopropylacrylamide, and polymers containing a hydrophobic group introduced at the N-position of acrylamide, polyoxyethylene-polyoxypropylene glycol, macrogol (molecular weight 6000 or more), hydroxyethyl cellulose, etc. .
  • hypromellose hydroxypropylcellulose, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, carboxyvinyl polymer, polyvinyl alcohol, polyethylene oxide, povidone, copolyvidone, polyoxyethylene hydrogenated castor oil, N-isopropylacrylamide and acrylamide
  • a polymer or a polyoxyethylene-polyoxypropylene glycol containing a derivative having a hydrophobic group introduced at the N-position thereof and as further embodiments, hypromellose, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, N-isopropylacrylamide
  • a polymer containing a derivative having a hydrophobic group introduced at the N-position of acrylamide One or more insolubilizing substances can be used in appropriate combination.
  • the ratio of the insolubilization accelerator to the weight of the intermediate layer is not particularly limited as long as it is a ratio suitable for achieving the object of the present invention.
  • the content is 20% by weight or more and less than 95% by weight, as another aspect, 30% by weight or more and less than 90% by weight, and as another aspect, 40% by weight or more and less than 80% by weight.
  • the coating amount of the intermediate layer is not particularly limited as long as it is an amount suitable for achieving the object of the present invention.
  • the content is 1% by weight or more and 500% by weight or less with respect to the core particles containing the drug.
  • it is 1% by weight or more and 300% by weight or less.
  • it is 20% by weight or more and 200% by weight or less, and in another embodiment, it is 30% by weight or more and 100% by weight or less.
  • the coating amount is lower than 1% by weight, there is a concern that a sufficiently long lag time cannot be formed. Considering the efficiency in production, if the coating amount is too large, the production time is long and inefficient.
  • the ratio of the intermediate layer to the total weight of the particulate composition is not particularly limited as long as it is a ratio suitable for achieving the object of the present invention. Specifically, for example, 0.1 wt% or more and 95 wt% or less, as another embodiment, 1 wt% or more and 85 wt% or less, and as another embodiment, 3 wt% or more and 80 wt% or less, 5 wt% More than 70% by weight, and still another embodiment is 10% by weight to 60% by weight.
  • an embodiment in which the above-mentioned pharmaceutical excipient is further coated on the outside of the coating layer containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance can be employed.
  • coating additives include amino acids such as glycine and alanine, sweeteners such as glycyrrhizic acid, sugars such as sucrose, fructose, maltose, glucose, and cyclodextrin, and sugar alcohols such as mannitol, xylitol, maltitol, and sorbitol. Is mentioned.
  • An appropriate amount of one or more kinds of pharmaceutical excipients can be appropriately added to the coating layer (outer layer) made of the pharmaceutical excipient.
  • the coating amount of the outer layer is, for example, 1% by weight or more and 200% by weight or less with respect to the drug-containing particles, in another aspect, 1% by weight or more and 100% by weight or less, and in a further aspect, 5% by weight or more and 40% by weight or less. is there.
  • the ratio of the outer layer to the total weight of the particulate composition is, for example, 1% by weight or more and 50% by weight or less, in another embodiment 1% by weight or more and 25% by weight or less, and in a further embodiment 5% by weight or more and 10% by weight or less. It is as follows.
  • the particulate pharmaceutical composition of the present invention can be produced by a method known per se, such as coating, drying, heat treatment, tableting and the like.
  • the core containing the drug is coated with the coating substance of the present invention.
  • the drug-containing nucleus particles made of only a drug can be used.
  • particles comprising a drug and one or more additives may be produced and used.
  • the drug and an appropriate excipient for example, crystalline cellulose, lactose, corn starch, etc.
  • a binder for example, hydroxypropyl cellulose
  • the drug and the binder are dissolved in additive particles (for example, crystalline cellulose (granule) (may be described as microcrystalline cellulose), purified white sucrose spherical granules, white sucrose / starch spherical granules, etc.) that serve as an appropriate core.
  • additive particles for example, crystalline cellulose (granule) (may be described as microcrystalline cellulose), purified white sucrose spherical granules, white sucrose / starch spherical granules, etc.
  • the dispersed liquid may be sprayed.
  • a particulate pharmaceutical composition such as a fluidized bed coating apparatus, a rolling coating apparatus, or a centrifugal rolling coating apparatus. Any method may be used.
  • a fluidized bed side spray type coating apparatus a necessary amount of liquid containing a coating component may be sprayed with a spray gun while a core containing a drug is flowed with warm air.
  • the liquid containing the coating component is prepared by dissolving or dispersing essential components in a solvent such as water, ethanol, methanol or the like. Further, these solvents can be appropriately mixed and used.
  • the intermediate layer may be coated on the outer side of the core containing the drug, or the particulate pharmaceutical composition of the present invention may be further coated with a pharmaceutical excipient and then coated with the coating substance of the present invention.
  • a method for coating the intermediate layer on the core particles containing the drug it is produced by a method known per se.
  • any method capable of coating the particulate pharmaceutical composition such as a fluidized bed coating apparatus, a rolling coating apparatus, or a centrifugal rolling coating apparatus, may be used.
  • a necessary amount of a liquid containing a coating component may be sprayed with a spray gun while flowing the core particles containing the drug with warm air.
  • the liquid containing the coating component is prepared by dissolving or dispersing essential components in a solvent such as water, ethanol, methanol or the like. Further, these solvents can be appropriately mixed and used.
  • the preferred spraying speed of the coating varies depending on the production method or the scale to be produced, but when produced on a 1 kg scale by the fluidized bed granulation method, it is 2 g / min or more and 8 g / min or less, and in another embodiment, 5 g / min or more. 7 g / min or less.
  • a preferable product temperature when the intermediate layer or the water infiltration control layer is coated on the drug-containing core is 15 ° C. or more and 60 ° C. or less, and in another embodiment, 15 ° C. or more and 45 ° C. or less.
  • the particulate pharmaceutical composition coated with the drug-containing particles may be subjected to drying, heat treatment and the like.
  • This coating film can also be processed by adjusting the temperature and humidity.
  • the temperature can be 40 to 80 ° C. and the humidity can be 10 to 60 RH%.
  • the particle size of the particulate pharmaceutical composition in the present invention is not particularly limited as long as the longest diameter is 2 mm or less.
  • the case where it is contained in the orally disintegrating tablet is not particularly limited as long as it does not give an unpleasant feeling of roughness such as sand when taken, but the average particle diameter is preferably adjusted to 350 ⁇ m or less.
  • the average particle diameter is 1 ⁇ m or more and 350 ⁇ m or less, and in a further embodiment, it is 20 ⁇ m or more and 350 ⁇ m or less.
  • a tableting method a direct tableting method in which a tablet is obtained by mixing a drug-containing particle and an appropriate additive and then compression-molded, a wet granulation in which a binder liquid is sprayed and granulated after mixing the drug-containing particle and the additive
  • the method include tableting after melt granulation in which drug-containing particles and an appropriate low-melting substance are mixed and then heated and granulated.
  • the tableting device include a rotary tableting machine and a single-shot tableting machine.
  • the tableting device is not particularly limited as long as it is a method for producing a compression-molded product (preferably a tablet) pharmaceutically. .
  • polyvinyl acetal diethylaminoacetate and the water-soluble polymer substance of the present invention a granular pharmaceutical composition for oral administration is produced in which drug-containing particles having a bitter taste are coated and the change in release rate is reduced even after compression molding.
  • the use of polyvinyl acetal diethylaminoacetate and a water-soluble polymeric substance for the purpose of this invention is referred to the description of the particulate pharmaceutical composition of the present invention for a detailed description of the invention.
  • the manufacturing method of the orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention will be described below.
  • the particulate pharmaceutical composition of the present invention and a saccharide having low moldability are mixed.
  • humidification and drying processes can be employed.
  • “Humidification” is determined by the apparent critical relative humidity of the saccharides contained, but usually humidifies above its critical relative humidity.
  • the humidity is 30 RH% or more and 100 RH% or less, and in another aspect, it is 50 RH% or more and 90 RH% or less.
  • the temperature at this time is preferably 15 ° C. or more and 50 ° C. or less, and in another embodiment, it is 20 ° C. or more and 40 ° C. or less.
  • the treatment time is 1 hour or more and 36 hours or less, and in another aspect, it is 12 hours or more and 24 hours or less.
  • “Drying” is not particularly limited as long as it is a step of removing moisture absorbed by humidification.
  • the drying temperature condition can be set to 10 ° C.
  • the treatment time can be 0.5 hours or more and 6 hours or less, and in another aspect, it can be 1 hour or more and 4 hours or less.
  • the particulate pharmaceutical composition of the present invention melting point A high-excipient excipient and a saccharide with a low melting point are mixed, and the mixture is sprayed with a binder for orally disintegrating tablets to coat and / or granulate, and the granulated product can be compression-molded.
  • a heating step can be employed to increase the hardness of the prepared molded product.
  • Heating is determined by the melting point of the saccharide having a low melting point, and is usually heated to a temperature not lower than the melting point of the low saccharide and lower than the melting point of the high excipient.
  • the treatment time can be 0.5 minutes or more and 120 minutes or less, and in another aspect, it can be 1 minute or more and 60 minutes or less.
  • the prepared dispersion is sprayed onto 5.42 kg of crystalline cellulose (grain) (Asahi Kasei Chemicals, product name CP-102Y, the same shall apply hereinafter) to prepare particles covering the first layer. did.
  • atorvastatin calcium trihydrate was added with stirring to 300.0 g of sodium lauryl sulfate and 120.0 g of hypromellose in 2880.0 g of purified water to prepare a dispersion.
  • the prepared dispersion was sprayed onto 300.0 g of crystalline cellulose (grains) using a fluidized bed granulator to prepare particles covering the first layer.
  • orally disintegrating tablet 229.6 mg of the granulated product for orally disintegrating tablet prepared in Example 1 and 70.4 mg of the granular pharmaceutical composition (masking particle) of the present invention were mixed, and the mixture was mixed with a diameter. After filling a 9.5 mm mortar, the tablet is tableted at various pressures (2.0 kN and 3.0 kN) using an autograph to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention.
  • T 10% of the oral disintegrating tablet calculated from the elution profile, and the rate of change with respect to T 10% of the particulate pharmaceutical composition of the tableting shown in Tables 9 to 13.
  • T 10% represents the time to elution rate of 10%, and the change rate with respect to T 10% was calculated from the following equation.
  • T 10% change rate (%) T 10% (after tableting) / T 10% (before tableting)
  • Experimental Example 2 Dissolution test of particulate pharmaceutical composition Japanese Pharmacopoeia dissolution of particulate pharmaceutical compositions of Comparative Examples 2 to 4 and Examples 3 and 5 (masking particles before tableting) using an automatic 6-series dissolution tester The dissolution test was performed according to Test Method No. 2. The drug content was 10 mg, and 900 mL each of water, Japanese Pharmacopoeia dissolution test 1st liquid (JP1), and Japanese Pharmacopoeia dissolution test 2nd liquid (JP2) were used (paddle rotation speed: 100 rotations / minute). The elution profiles obtained as a result of the test are shown in FIGS.
  • Example 3 masking particles provided with a third film made of polyvinyl acetal diethylaminoacetate, talc, and hypromellose (TC-5E)
  • TC-5E hypromellose
  • Example 3 Liquid Displacement Dissolution Test of Particulate Pharmaceutical Composition Dissolution of Example 3 or Comparative Examples 2 to 4 (masking particles before tableting) reflecting vivo using an automatic 6-series dissolution tester The test was conducted. 30 minutes after adding a particulate pharmaceutical composition containing 10 mg of drug to JP1 300 mL, 600 mL of 5-fold concentrated JP2 was added thereto, and dissolution of the drug from the preparation was measured (paddle rotation speed: 50 rotations / Min). In addition, the drug dissolution rate from the preparation after 45 minutes obtained in this test correlates with Cmax and AUC in the dog oral administration test. The obtained elution profile is shown in FIG.
  • the particulate pharmaceutical composition coated with polyvinyl acetal diethylaminoacetate (Example 3) has a higher D45min (drug elution rate after 45 minutes) than the particulate pharmaceutical composition coated with a film comprising other components in the liquid replacement test. showed that.
  • the particulate pharmaceutical composition of the present invention has a drug dispersibility and dissolution property equal to or higher than that of a solid preparation containing atorvastatin or a pharmaceutically acceptable salt thereof currently provided in the medical field. It is useful as a pharmaceutical composition that can achieve rapid dispersibility and dissolution in the digestive tract even when an unpleasant taste is masked in the oral cavity.
  • atorvastatin or a pharmaceutically acceptable salt thereof currently provided in the medical field.

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  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Obesity (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Diabetes (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique particulaire pour administration orale, qui peut être obtenue par enrobage de particules contenant de l'atorvastatine ou son sel pharmaceutiquement acceptable et du sulfate sodique de lauryle avec un matériau d'enrobage contenant un diéthylaminoacétate d'acétal polyvinylique et un matériau polymère hydrosoluble.
PCT/JP2010/067039 2010-03-29 2010-09-30 Composition pharmaceutique particulaire pour administration orale WO2011121823A1 (fr)

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
WO2013125497A1 (fr) * 2012-02-20 2013-08-29 ニプロ株式会社 Procédé de fabrication d'un comprimé à désintégration par voie orale
JP2013231011A (ja) * 2012-05-01 2013-11-14 Sawai Pharmaceutical Co Ltd アトルバスタチン含有医薬組成物およびそれを用いた口腔内崩壊錠
WO2014207162A1 (fr) * 2013-06-27 2014-12-31 Assistance Publique - Hopitaux De Paris Composition pharmaceutique sous forme de granules pour le traitement de desordres metaboliques chez l'enfant
JP2015040206A (ja) * 2013-08-23 2015-03-02 高田製薬株式会社 刺激性（収斂性、酸味、苦み）のある薬物を含有する口腔内速崩壊錠およびその製造方法
GB2624171A (en) * 2022-11-08 2024-05-15 Novumgen Ltd An orally disintegrating tablet containing atorvastatin and process of preparing the same

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WO2001076565A1 (fr) * 2000-04-12 2001-10-18 Banyu Pharmaceutical Co., Ltd. Compositions et preparations se desintegrant dans la cavite buccale
JP2005522444A (ja) * 2002-02-14 2005-07-28 ランバクシー ラボラトリーズ リミテッド アルカリ金属の添加により安定化させたアトーバスタチン製剤
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WO2005105045A1 (fr) * 2004-04-30 2005-11-10 Astellas Pharma Inc. Composition pharmaceutique granulaire du type à libération limitée dans le temps en vue d'une administration orale et comprimé à désintégration rapide intra orale contenant la composition
JP2008531681A (ja) * 2005-03-02 2008-08-14 アクタヴィス・グループ・エイチエフ 炭酸マグネシウムヘビーを含む速崩壊型製剤
JP2006327943A (ja) * 2005-05-23 2006-12-07 Towa Yakuhin Kk 経時的溶出遅延を抑制したテイストマスク錠剤
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JP2008044870A (ja) * 2006-08-11 2008-02-28 Elmed Eisai Kk 医薬組成物及びその製造方法
WO2008081891A1 (fr) * 2006-12-28 2008-07-10 Takeda Pharmaceutical Company Limited Préparation solide se désintégrant oralement
JP2009114113A (ja) * 2007-11-06 2009-05-28 Nipro Corp 口腔内崩壊錠及びその製造方法
WO2010038688A1 (fr) * 2008-09-30 2010-04-08 アステラス製薬株式会社 Composition pharmaceutique particulaire pour une administration orale d’atorvastatine
WO2010038691A1 (fr) * 2008-09-30 2010-04-08 アステラス製薬株式会社 Composition pharmaceutique particulaire destinée à être administrée oralement
JP2010083886A (ja) * 2008-09-30 2010-04-15 Astellas Pharma Inc 経口投与用粒子状医薬組成物

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013125497A1 (fr) * 2012-02-20 2013-08-29 ニプロ株式会社 Procédé de fabrication d'un comprimé à désintégration par voie orale
JPWO2013125497A1 (ja) * 2012-02-20 2015-07-30 ニプロ株式会社 口腔内崩壊錠の製造方法
JP2013231011A (ja) * 2012-05-01 2013-11-14 Sawai Pharmaceutical Co Ltd アトルバスタチン含有医薬組成物およびそれを用いた口腔内崩壊錠
WO2014207162A1 (fr) * 2013-06-27 2014-12-31 Assistance Publique - Hopitaux De Paris Composition pharmaceutique sous forme de granules pour le traitement de desordres metaboliques chez l'enfant
JP2015040206A (ja) * 2013-08-23 2015-03-02 高田製薬株式会社 刺激性（収斂性、酸味、苦み）のある薬物を含有する口腔内速崩壊錠およびその製造方法
GB2624171A (en) * 2022-11-08 2024-05-15 Novumgen Ltd An orally disintegrating tablet containing atorvastatin and process of preparing the same

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