WO2011121824A1 - Comprimé à désintégration orale - Google Patents

Comprimé à désintégration orale Download PDF

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Publication number
WO2011121824A1
WO2011121824A1 PCT/JP2010/067040 JP2010067040W WO2011121824A1 WO 2011121824 A1 WO2011121824 A1 WO 2011121824A1 JP 2010067040 W JP2010067040 W JP 2010067040W WO 2011121824 A1 WO2011121824 A1 WO 2011121824A1
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Prior art keywords
orally disintegrating
drug
disintegrating tablet
carbonate
weight
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PCT/JP2010/067040
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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
均 河合
高之 吉田
俊典 渡辺
和博 迫
聡一郎 中村
武史 矢野
佳之 早川
敦 上林
豊 高橋
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アステラス製薬株式会社
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Priority to JP2012508016A priority Critical patent/JP5534004B2/ja
Publication of WO2011121824A1 publication Critical patent/WO2011121824A1/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
    • A61K9/14—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
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an orally disintegrating tablet having improved drug dissolution, comprising a granule coated with a core containing atorvastatin.
  • the present invention provides a nucleus containing atorvastatin and sodium lauryl sulfate, a methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer or polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance.
  • the present invention relates to an orally disintegrating tablet having improved drug dissolution, comprising a grain coated with a coating material containing, and “carbonate or bicarbonate”.
  • 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 discloses an orally disintegrating tablet containing a combination of mannitol and other sugars, and an inorganic excipient such as magnesium aluminate metasilicate, calcium carbonate, and talc. The technical idea is completely different from the present invention.
  • 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 reduces the initial drug elution amount of atorvastatin, and maintains a rapid drug release thereafter, and contains granules capable of suppressing or reducing the change in drug elution rate even after compression molding.
  • An improved orally disintegrating tablet is provided.
  • the present invention improves drug elution, comprising grains that achieve quick dispersibility and dissolution in the gastrointestinal tract when atorvastatin is used to mask unpleasant taste in the mouth (compliance compliance)
  • An orally disintegrating tablet is provided.
  • the present inventors coated a nucleus containing atvarstatin and sodium lauryl sulfate with a coating containing methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer or polyvinyl acetal diethylaminoacetate.
  • a rapid drug release was achieved after lag time formation in the pH neutral region, but a phenomenon in which the drug release was suppressed in the pH acidic region was observed.
  • 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 invention has been completed.
  • a nucleus containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate is water-soluble with methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer or polyvinyl acetal diethylaminoacetate
  • the carbonate or bicarbonate is one or more selected from the group consisting of calcium carbonate, sodium carbonate, ammonium carbonate, sodium bicarbonate, potassium bicarbonate, and magnesium carbonate.
  • Orally disintegrating tablets [3] An orally disintegrating tablet according to [1] or [2], containing carbonate or bicarbonate as an excipient, [4] An orally disintegrating tablet according to [3], which further contains a saccharide with low moldability as an excipient, [5] Carbonate or hydrogen carbonate is contained as a coating component of a grain coated with a coating substance or in a coating inside or outside the coating layer of a grain coated with a coating substance.
  • the present invention relates to the use of carbonate or hydrogen carbonate for producing an orally disintegrating tablet comprising granules coated with a coating material containing a functional polymer substance.
  • 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 The present invention provides an orally disintegrating tablet with improved drug elution that can achieve rapid dissolution in a drug, (4) can achieve compliance such as compliance and prevention of delayed absorption, etc. be able to.
  • Example 2 and Comparative Example 1 Obtained by conducting a liquid displacement dissolution test on orally disintegrating tablets (Example 2 and Comparative Example 1) containing drug-containing particles containing aminoalkyl methacrylate copolymer E (Eudragit E) and having mannitol replaced with calcium carbonate Elution profile.
  • Dissolution profiles obtained by conducting liquid displacement dissolution tests on orally disintegrating tablets (Example 1 and Comparative Example 2) containing drug-containing particles containing polyvinyl acetal diethylaminoacetate (AEA) and having mannitol replaced with calcium carbonate It is.
  • AEA polyvinyl acetal diethylaminoacetate
  • binders maltose, maltitol
  • liquid-displacement dissolution tests were conducted on orally disintegrating tablets containing drug-containing particles containing polyvinyl acetal diethylaminoacetate (AEA) and mannitol replaced with sodium bicarbonate. It is the elution profile obtained by implementation.
  • AEA polyvinyl acetal diethylaminoacetate
  • An orally disintegrating tablet (Comparative Example 1) containing drug-containing particles coated with a coating material containing aminoalkyl methacrylate copolymer E (Eudragit E) and talc, and an oral cavity containing drug-containing particles in which the talc is replaced with calcium carbonate
  • An orally disintegrating tablet (Example 16), an orally disintegrating tablet (Example 18) comprising drug-containing particles coated with sodium bicarbonate on the outside of a coating film containing the aminoalkyl methacrylate copolymer E (Eudragit E) and talc.
  • PK pharmacokinetic
  • 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 used in the present invention and covering the intermediate layer and the coating substance 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 the paddle method (50 rpm) was started using 300 mL of the 15th revision Japanese Pharmacopoeia Dissolution Test 1st liquid (JP1), and at 30 minutes, JP1: D10 min (drug elution rate after 10 minutes) is 30% or more (40% or more as another aspect) in a liquid displacement dissolution test in which 600 mL of a 5-fold concentrated solution of the second solution of pharmacopoeia (JP2) is added. And JP2 (after liquid replacement): D45min (drug elution rate after 45 minutes) means 60% or more (70% or more as another embodiment). Further, when D10min is 30% or more (40% or more as another embodiment) and D45min is 60% or more (70% or more as another embodiment), it is defined as “dissolution is improved”.
  • “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 orally disintegrating tablet of the present invention comprises a core containing atorvastatin or a pharmaceutically acceptable salt thereof, and sodium lauryl sulfate, a methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer or It is an orally disintegrating tablet with improved drug dissolution, comprising granules coated with a coating material containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance, and carbonate or bicarbonate.
  • 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.
  • 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.
  • “Methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer” used in the present invention [hereinafter, aminoalkyl methacrylate copolymer E, copolymer E, Eudragit (registered trademark) E (Evonik Degussa GmbH) And may be described as methyl methacrylate butyl methacrylate (2-dimethylaminoethyl) methacrylate copolymer, etc.] means Eudragit (registered trademark) E100 or Eudragit (registered trademark) EPO (both from Evonik Degussa GmbH) It is a high-molecular substance marketed under the trade name, and has an average molecular weight of 150,000 (Pharmaceutical Additive Standard, P76-77, 1998, Yakuji Nipposha; Handbook Pharmaceutical Ecipients second edition p362-366, 1994, American Pharmaceutical Association, Washington and The Pharmac eutical Press
  • the blending amount of methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer is, for example, from 1% by weight to 500% by weight with respect to the drug-containing particles, and in another embodiment, 5% by weight. It is 300 wt% or less, and in another embodiment, it can be 10 wt% or more and 150 wt% or less. For example, it is 1% by weight or more and 300% by weight or less with respect to the intermediate layer-coated particles. In another embodiment, 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%.
  • 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%.
  • methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer (copolymer E) or polyvinyl acetal diethylaminoacetate may be blended. It is possible to mix both at the same time.
  • 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 the copolymer E or polyvinyl acetal diethylaminoacetate, and the “particulate pharmaceutical composition” is coated with the coating substance, so that the “particulate pharmaceutical composition” after compression molding.
  • the “particulate pharmaceutical composition” 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 methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer (copolymer E) or polyvinyl acetal diethylaminoacetate and water-soluble polymer substance used in the present invention
  • an appropriate blending amount is selected according to purposes such as physical properties, stability, absorption site, type and use of dosage form.
  • the amount of the water-soluble polymer substance is, for example, 1% by weight or more and 30% by weight or less with respect to the copolymer E or polyvinyl acetal diethylaminoacetate. In another embodiment, the amount is 5% by weight or more and 20% by weight or less. % To 15% by weight.
  • an appropriate ratio is appropriately selected for the coating amount of the coating material containing the copolymer E or 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.
  • a “fluidizing agent” in the particulate pharmaceutical composition used in the present invention, an embodiment in which a “fluidizing agent” is blended may be employed as desired.
  • the formulation of the fluidizing agent is not particularly limited during a specific production method.
  • a “particulate pharmaceutical composition” used in the present invention by a fluidized bed granulation method, As the particles dry, 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. For example, 1% by weight or more and 200% by weight or less with respect to the copolymer E or polyvinyl acetal diethylaminoacetate, and in another embodiment, 5% by weight or more and 100% by weight or less, and in a further aspect, 20% by weight or more and 60% by weight or less. It is.
  • the “carbonate or bicarbonate” used in the present invention is pharmaceutically acceptable, reduces the initial drug elution amount of atorvastatin, maintains the rapid drug release thereafter, and dissolves the drug even after compression molding. It is not particularly limited as long as it is a substance that can suppress or reduce the change in speed, or can achieve quick dispersibility and dissolution in the digestive tract when concealing unpleasant taste (compliance compliance) of atorvastatin in the oral cavity. . Specific examples include calcium carbonate, sodium carbonate, ammonium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and magnesium carbonate. These carbonates or bicarbonates can be used singly or in appropriate combination of two or more.
  • carbonate or bicarbonate When “or carbonate or bicarbonate” is administered orally, it is administered as a separate formulation at the same time or after a certain period of time, or as a single formulation administered in the orally disintegrating tablet. There is no particular limitation as long as it is an embodiment.
  • the aspect in which “carbonate or bicarbonate” is contained in the orally disintegrating tablet as a single preparation is not particularly limited as long as “carbonate or bicarbonate” is pharmaceutically included in the preparation. For example, the uneven distribution aspect or the aspect mix
  • an aspect contained in a drug-containing particle (2) when the drug layer is coated on the nucleus, the drug layer is simultaneously and / or inside and / or outside the drug layer Aspects included, (3) When a coating material containing “methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer” or “polyvinyl acetal diethylaminoacetate” and a water-soluble polymer is coated , Embodiments included simultaneously in the coating layer, and / or embodiments included inside and / or outside the coating layer, (4) when “intermediate layer” is coated, embodiments included simultaneously in the intermediate layer, and And / or an aspect included inside and / or outside of the intermediate layer, (5) when a “water intrusion control layer” is coated, a state of being simultaneously included in the water intrusion control layer , And / or inner and / or aspects included on the outside of the water penetration amount control layer, or the one or more
  • Examples of the amount of the carbonate or bicarbonate include 1% by weight or more and 100% by weight or less based on the weight of the entire preparation.
  • the amount of the carbonate or bicarbonate can be contained in an amount of 9% or more and 100% or less with respect to the weight of the excipient, for example, “sugar with low moldability” described below (particularly mannitol). . Further, it can be contained in an amount of 10% or more and 100% or less as a substitution rate with respect to the usual use amount of an excipient such as a “low-moldable saccharide” (particularly mannitol) described later.
  • 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 used in 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 used in the present invention can be contained in these orally disintegrating tablets.
  • Orally disintegrating tablets are generally roughly classified into a mold type, a moist type, and a normal tableting type, and the particulate pharmaceutical composition used in 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 used in the present invention is, for example, a particulate pharmaceutical composition used in the present invention, an excipient such as a saccharide, and a solution of a binder such as gelatin or agar or After the suspension is filled in the PTP pocket, 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). After tableting under low pressure, the product is dried.
  • excipients such as saccharides can be wetted with a small amount of water or a mixture of water and alcohol, and the wet mixture can be molded at low pressure and then dried to produce. .
  • WO 2008/032767 pamphlet US-patent published application No. 2008/0085309. It is prepared through a normal tableting process.
  • a normal tablet type orally disintegrating tablet containing the particulate pharmaceutical composition used in the present invention for example, International Publication No. WO95 / 20380 (US Patent No. 5576014), Patent No. 2919771
  • a particulate pharmaceutical composition used in the present invention and an excipient such as a saccharide having low moldability are mixed with a solution or suspension of a saccharide or water-soluble polymer having high moldability.
  • the granulated product can be compression-molded to obtain a compressed molded product, or the compressed molded product can be further humidified and dried to produce an orally disintegrating tablet.
  • a particulate medicine used in the present invention is used.
  • the composition, an excipient such as crystalline saccharide, and amorphous saccharide can be used for compression molding, followed by humidification and drying to produce an orally disintegrating tablet.
  • a normal tablet type orally disintegrating tablet as disclosed in International Publication No.
  • WO2002 / 92057 pamphlet (US Patent Application Publication No. 2003/099701), for example, in the present invention, A mixture of the particulate pharmaceutical composition to be used, an excipient, and a saccharide having a melting point lower than that of the excipient is compression-molded and heated to melt and solidify the saccharide having a lower melting point to form a crosslink.
  • 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 used in 1) 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.
  • carbonate or bicarbonate can be contained as an excipient.
  • 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.
  • all or part of the “low moldability saccharide” in the embodiment using a combination of “low moldability saccharide” and “high moldability saccharide” as an excipient. Can be substituted to contain a carbonate or bicarbonate.
  • “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, lactitol and the like, and these saccharides may be used alone or in combination as appropriate. It is also possible to use in combination.
  • the “sugar having a high melting point” is pharmaceutically acceptable, and examples thereof include xylitol, trehalose, maltose, sorbitol, erythritol, glucose, sucrose, maltitol, mannitol, and lactitol. 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 in the orally disintegrating tablet containing the particulate pharmaceutical composition used in the present invention, or the total amount of the excipient in the whole preparation is the blending amount of the particulate pharmaceutical composition used in the present invention. And / or is appropriately adjusted according to the size of the tablet, etc., but usually 20 mg or more and 1000 mg or less per tablet is preferable. In another embodiment, 50 mg or more and 900 mg or less is preferable, and as a further embodiment, 50 mg or more and 800 mg or less are preferable. is there.
  • 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 used in the present invention
  • a particulate pharmaceutical composition corresponding 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.
  • 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.
  • Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, magnesium magnesium metasilicate, 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 its salts, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or its salts, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid Boric acid or a salt thereof.
  • antioxidant examples include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.
  • surfactant examples include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.
  • 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 the copolymer E or polyvinyl acetal diethylaminoacetate and the water-soluble polymer substance may be directly coated on the core containing the drug, or one layer or You may coat
  • a carbonate or bicarbonate can be contained as a coating component of the coating substance.
  • An “intermediate layer” may be disposed.
  • 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 outer side of the coating layer containing copolymer E or 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.
  • a carbonate or bicarbonate is contained in this coating that can be provided on the outside of the coating layer containing the copolymer E or polyvinyl acetal diethylaminoacetate and the water-soluble polymer substance. Can do.
  • 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 used in the present invention can be produced by a method known per se, such as coating, drying, heat treatment, tableting and the like.
  • the core material containing the drug is coated with the coating substance in 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 outside of the nucleus containing the drug, or the particulate pharmaceutical composition used in the present invention may be further coated with a pharmaceutical excipient and then coated with the coating substance in 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. .
  • a nucleus containing atorvastatin and sodium lauryl sulfate is a water-soluble copolymer of methyl methacrylate, butyl methacrylate, dimethylaminoethyl methacrylate, or polyvinyl acetal diethylaminoacetate.
  • the method for producing the orally disintegrating tablet of the present invention containing the particulate pharmaceutical composition will be described below.
  • a particulate pharmaceutical composition used in the present invention and a saccharide with low moldability are used. It is possible to employ a step of mixing, spraying the mixture with a highly moldable saccharide as a binder, coating and / or granulating, and compression molding the granulated product.
  • 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.
  • a particulate pharmaceutical composition used in the present invention An excipient having a high melting point and a saccharide having a low melting point can be mixed, and the mixture can be 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.
  • Example 1 (Preparation of atorvastatin-containing particles) (1) Preparation of the first layer 3.25 kg of sodium lauryl sulfate (manufactured by Nikko Chemicals, product name NIKKOL SLS, the same below) and 2.17 kg of hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd., product name TC-5E, same hereinafter) purified water To a solution dissolved in 43.36 kg, 5.42 kg of atorvastatin calcium trihydrate (manufactured by Pfizer, the same applies hereinafter) was added with stirring to prepare a dispersion.
  • sodium lauryl sulfate manufactured by Nikko Chemicals, product name NIKKOL SLS, the same below
  • hypromellose manufactured by Shin-Etsu Chemical Co., Ltd., product name TC-5E, same hereinafter
  • Crystalline cellulose (granule) (product name CP-, manufactured by Asahi Kasei Chemicals Co., Ltd.) using the prepared dispersion using a fluidized bed granulator (Glatt, product name WCG-15 / 30, unless otherwise specified). 102Y (the same applies hereinafter) was sprayed onto 5.42 kg to prepare particles coated with the first layer.
  • a granulated product for an orally disintegrating tablet was prepared.
  • This granulated product is mixed with 33.0 g of sucrose fatty acid ester (Daiichi Kogyo Seiyaku, DK Ester F-20W, the same applies hereinafter), and this mixture is mixed with a rotary tableting machine (product name: HT-X20, manufactured by Hata Iron Works). 1 tablet 330 mg using the same), and humidified and dried (25-30 ° C./40-62% RH / 18 hours) to produce an orally disintegrating tablet of the present invention.
  • Example 2 (Preparation of atorvastatin-containing particles) (1) Preparation of the first layer A dispersion was prepared by adding 5.42 kg of atorvastatin calcium trihydrate with stirring to a solution of 3.25 kg of sodium lauryl sulfate and 2.17 kg of hypromellose in 43.36 kg of purified water. The prepared dispersion was sprayed onto 5.42 g of crystalline cellulose (grains) using a fluidized bed granulator to prepare particles covering the first layer.
  • This granulated product is mixed with 30.0 g of sucrose fatty acid ester, and this mixture is tableted with 300 mg of one tablet using a rotary tableting machine and humidified and dried (25-30 ° C / 40-62% RH / 18 hours) ) To produce an orally disintegrating tablet of the present invention.
  • Example 3 A mixture of 1262.8 g of atorvastatin-containing particles prepared in Example 2, 2982.8 g of mannitol, 994.4 g of precipitated calcium carbonate, 60.0 g of maltose, 50.0 g of aspartame, and 110.0 g of a flavor preparation was obtained in a fluidized bed granulator (product name, manufactured by Glatt). Using GPCG5 / 15), granulation was performed with 1920.0 g of an aqueous maltose solution (including 480.0 g of maltose) to prepare a granulated product for an orally disintegrating tablet.
  • a fluidized bed granulator product name, manufactured by Glatt
  • This granulated product is mixed with 120.0 g of sodium stearyl fumarate, and this mixture is tableted with 1 tablet 300 mg using a rotary tableting machine and humidified and dried (25-30 ° C / 40-62% RH / 18 hours). ) To produce an orally disintegrating tablet of the present invention.
  • Example 4 545.5g of mannitol was granulated with 181.7g of maltose aqueous solution (including 54.5g of maltose) using a fluidized bed granulator (Glatt; product name GPCG-1). Prepared. Similarly, 646.5 g of precipitated calcium carbonate was granulated with 215 g of an aqueous maltose solution (including 64.5 g of maltose) to prepare a granulated product for an orally disintegrating tablet.
  • Example 5 201.4 mg of the mannitol granulated product prepared in Example 4, 35.5 mg of precipitated calcium carbonate granulated product, and 63.1 mg of atorvastatin-containing particles prepared in Example 2 were mixed, and tableted using an autograph. An orally disintegrating tablet was made.
  • Example 6 The mannitol granule 177.8 mg and the precipitated calcium carbonate granule 59.1 mg prepared in Example 4 and the atorvastatin-containing particles 63.1 mg prepared in Example 2 were mixed and compressed using an autograph to obtain the present invention. An orally disintegrating tablet was made.
  • Example 7 118.5 mg of the mannitol granule prepared in Example 4 and 118.4 mg of the precipitated calcium carbonate granulated product and 63.1 mg of atorvastatin-containing particles prepared in Example 2 were mixed, and tableted using an autograph. An orally disintegrating tablet was made.
  • Example 8 236.9 mg of the precipitated calcium carbonate granulated product prepared in Example 4 and 63.1 mg of atorvastatin-containing particles prepared in Example 2 were mixed and tableted using an autograph to produce the orally disintegrating tablet of the present invention. .
  • Example 9 165.8 mg of mannitol granules prepared in Example 4, 71.1 mg of sodium bicarbonate (manufactured by Kanto Chemical Co., Ltd., the same shall apply hereinafter), and 63.1 mg of atorvastatin-containing particles prepared in Example 2 were mixed and compressed using an autograph. Thus, an orally disintegrating tablet of the present invention was produced.
  • Example 10 165.8 mg of mannitol granules prepared in Example 4, 71.1 mg of potassium hydrogen carbonate (manufactured by Kanto Chemical Co., Inc.), and 63.1 mg of atorvastatin-containing particles prepared in Example 2 were mixed, and tableted using an autograph. An orally disintegrating tablet of the invention was made.
  • Example 11 165.8 mg of mannitol granulate prepared in Example 4 and 71.1 mg of magnesium carbonate (manufactured by Wako Pure Chemical Industries, Ltd., product name: basic magnesium carbonate) and 63.1 mg of atorvastatin-containing particles prepared in Example 2 are mixed, and an autograph is used. And tableting was carried out to produce the orally disintegrating tablet of the present invention.
  • Example 12 Oral disintegration according to the present invention was prepared by mixing 213.2 mg of mannitol granule prepared in Example 4, 23.7 mg of sodium bicarbonate, and 63.1 mg of atorvastatin-containing particles prepared in Example 2, and tableting using an autograph. Made tablets.
  • Example 13 201.4 mg of granulated mannitol prepared in Example 4, 35.5 mg of sodium bicarbonate, and 63.1 mg of atorvastatin-containing particles prepared in Example 2 were mixed and tableted using an autograph, and the oral disintegration of the present invention Made tablets.
  • Example 14 (Preparation of atorvastatin-containing particles) (1) Preparation of second layer Fluidized bed granulation of a solution obtained by dissolving 51.3 g of sodium lauryl sulfate and 45.1 g of methylcellulose in 688.6 g of purified water with respect to 300.0 g of particles coated with the first layer prepared in Example 1 Spraying was performed using an apparatus (Glatt, product name GPCG-1) to prepare particles coated with the second layer.
  • Example 15 Fluidized bed granulator (Glatt; product: 253.5 g of mannitol, 44.7 g of sodium bicarbonate, 4.5 g of maltitol (product name: Sweet Pearl P200, the same applies hereinafter) 4.5 g, aspartame 3.8 g, flavor preparation 8.3 g Using the name GPCG-1), granulation was performed with 180.0 g of an aqueous maltitol solution (including 36.0 g of maltitol) to prepare a granulated product for an orally disintegrating tablet.
  • aqueous maltitol solution including 36.0 g of maltitol
  • Example 16 (Preparation of atorvastatin-containing particles) (1) Preparation of the first layer A dispersion was prepared by adding 5.42 kg of atorvastatin calcium trihydrate with stirring to a solution of 3.25 kg of sodium lauryl sulfate and 2.17 kg of hypromellose in 43.36 kg of purified water. The prepared dispersion was sprayed onto 5.42 g of crystalline cellulose (grains) using a fluidized bed granulator to prepare particles covering the first layer.
  • Example 17 Using a fluidized bed granulator (Glatt; product name GPCG-1), 253.5 g of mannitol, 44.7 g of sodium hydrogen carbonate, 4.5 g of maltitol, 3.8 g of aspartame, and 8.3 g of the flavor preparation were used. Granulated at 180.0 g (including 36.0 g of tall) to prepare granules for orally disintegrating tablets. 233.9 mg of this granulated product and 66.3 mg of atorvastatin-containing particles prepared in Example 14 were mixed, tableted using an autograph, and humidified and dried (25-30 ° C / 40-62% RH / 18 hours). Then, the orally disintegrating tablet of the present invention was produced.
  • Gelatt fluidized bed granulator
  • Example 18 (Preparation of atorvastatin-containing particles) A solution obtained by dissolving 60 g of mannitol and 60 g of sodium hydrogen carbonate in 1080 g of purified water with respect to 300.0 g of the particles coated with the third layer prepared in Example 1 is a fluidized bed granulator (manufactured by Glatt; product name GPCG-1 ) To prepare particles coated with the fourth layer.
  • a fluidized bed granulator manufactured by Glatt; product name GPCG-1
  • Fluidized bed granulator (Glatt; product name: GPCG-1) 253.5 g of mannitol, 44.7 g of sodium bicarbonate, 4.5 g of lactitol (manufactured by Danisco Japan, product name Lactitol MC), 3.8 g of aspartame, and 8.3 g of flavor preparation was then granulated with 180.0 g of an aqueous lactitol solution (including 36.0 g of lactitol) to prepare a granulated product for orally disintegrating tablets.
  • aqueous lactitol solution including 36.0 g of lactitol
  • Example 19 (Preparation of atorvastatin-containing particles) (1) Preparation of first layer To a solution obtained by dissolving 5.42 kg of sodium lauryl sulfate and 2.17 kg of hypromellose (HPMC) in 43.36 kg of purified water, 5.42 kg of atorvastatin calcium trihydrate was added with stirring to prepare a dispersion. . The prepared dispersion was sprayed onto 5.42 kg of crystalline cellulose (grains) using a fluidized bed granulator to prepare particles covering the first layer.
  • HPMC hypromellose
  • Second layer 2233.0 g of methanol was added to and mixed with 9.9 g of hypromellose dissolved in 558.2 g of purified water to prepare a hypromellose solution (water / alcohol mixture).
  • a hypromellose solution water / alcohol mixture
  • 87.1 g of polyvinyl acetal diethylaminoacetate was added and dissolved in this hypromellose solution, and 49.8 g of talc was added and dispersed.
  • This dispersion was sprayed onto 300.0 g of particles coated with the first layer using a fluidized bed granulator to prepare particles coated with the second layer.
  • Example 20 (Preparation of atorvastatin-containing particles) (1) Preparation of second layer A solution prepared by dissolving 108.5 g of sodium hydrogen carbonate in 2061.9 g of purified water was added to and mixed with 10.9 g of methyl cellulose dissolved in 206.2 g of purified water. This mixed solution was sprayed to 400.0 g of the particles coated with the first layer prepared in Example 19 using a fluidized bed granulator to prepare particles coated with the second layer.
  • Comparative Example 1 A mixture of 6314.0 g of atorvastatin-containing particles prepared in Example 2, 1988. g of mannitol, 300.0 g of maltose, 250.0 g of aspartame, and 550.0 g of a flavor preparation was used using a fluidized bed granulator (product name: GPCG5 / 15, manufactured by Glatt). Then, it was granulated with 12000.0 g of an aqueous maltose solution (including 2400.0 g of maltose) to prepare a granulated product for orally disintegrating tablets.
  • a fluidized bed granulator product name: GPCG5 / 15, manufactured by Glatt
  • This granulated product is mixed with 300.0 g of magnesium stearate, and this mixture is compressed into tablets at 300 mg using a rotary tableting machine, and then humidified and dried (25-30 ° C / 40-62% RH / 18 hours). And the orally disintegrating tablet of the present invention was produced.
  • Comparative Example 2 263.7 mg of the mannitol granulate prepared in Example 4 and 66.3 mg of atorvastatin-containing particles prepared in Example 1 were mixed, compressed into tablets using an autograph, and humidified and dried (25-30 ° C./40-62% RH / 18 hours) to produce an orally disintegrating tablet of the present invention.
  • Comparative Example 3 225.1 mg of mannitol granules prepared in Example 4, 11.8 mg of precipitated calcium carbonate granules and 63.1 mg of atorvastatin-containing particles prepared in Example 2 were mixed, compressed into tablets using an autograph, and humidified and dried ( 25-30 ° C./40-62% RH / 18 hours) to produce an orally disintegrating tablet of the present invention.
  • Comparative Example 4 225.1 mg of mannitol granules prepared in Example 4, 11.8 mg of sodium bicarbonate, and 63.1 mg of atorvastatin-containing particles prepared in Example 2 were mixed, compressed into tablets using an autograph, and humidified and dried (25-30). At 40 ° C./40% to 62% RH / 18 hours) to produce an orally disintegrating tablet of the present invention.
  • Comparative Example 5 165.8 mg of mannitol granulated product prepared in Example 4, 71.1 mg of magnesium oxide (manufactured by Wako Pure Chemical Industries, Ltd.) and 63.1 mg of atorvastatin-containing particles prepared in Example 2 were mixed, tableted using an autograph, and humidified and dried. Treatment (25-30 ° C / 40-62% RH / 18 hours) was carried out to produce an orally disintegrating tablet of the present invention.
  • Comparative Example 6 165.8 mg of mannitol granules prepared in Example 4, 71.1 mg of fructose (manufactured by Wako Pure Chemical Industries), and 63.1 mg of atorvastatin-containing particles prepared in Example 2 were mixed, compressed into tablets using an autograph, and humidified and dried. (25-30 ° C./40-62% RH / 18 hours) was performed to produce an orally disintegrating tablet of the present invention.
  • Comparative Example 7 165.8 mg of mannitol granules prepared in Example 4, 71.1 mg of potassium hydrogen phosphate (manufactured by Kanto Chemical Co., Inc.), and 63.1 mg of atorvastatin-containing particles prepared in Example 2 were mixed, compressed into tablets using an autograph, and humidified. Drying treatment (25 to 30 ° C./40 to 62% RH / 18 hours) was performed to produce an orally disintegrating tablet of the present invention.
  • Comparative Example 8 165.8 mg of mannitol granulated product prepared in Example 4, 71.1 mg of polyethylene glycol 400 (manufactured by Sanyo Kasei) and 63.1 mg of atorvastatin-containing particles prepared in Example 2 were mixed, tableted using an autograph, and dried by humidification. Treatment (25-30 ° C / 40-62% RH / 18 hours) was carried out to produce an orally disintegrating tablet of the present invention.
  • Comparative Example 9 165.8 mg of mannitol granules prepared in Example 4, 71.1 mg of sucrose (manufactured by Wako Pure Chemical Industries), and 63.1 mg of atorvastatin-containing particles prepared in Example 2 are mixed, compressed into tablets using an autograph, and humidified and dried. (25-30 ° C./40-62% RH / 18 hours) was performed to produce an orally disintegrating tablet of the present invention.
  • an orally disintegrating tablet containing drug-containing particles containing aminoalkyl methacrylate copolymer E (Eudragit E) (comparison between Example 2 and Comparative Example 1; the results are shown in FIG. 1)
  • polyvinyl acetal diethylaminoacetate (AEA) was orally disintegrating tablets containing drug-containing particles (comparison of Example 1 and Comparative Example 2; the results are shown in FIG. 2) were subjected to a liquid displacement dissolution test.
  • Orally disintegrating tablet containing core Eudragit E-coated granules containing atorvastatin and sodium lauryl sulfate (Comparative Example 1 in FIG. 1) or orally disintegrating tablet containing homonuclear AEA-coated grains (comparison of FIG. 2)
  • calcium carbonate (CaCO 3 ) By substituting a part of mannitol, which is an excipient for orally disintegrating tablets, with calcium carbonate (CaCO 3 ), it was found that the grains do not aggregate, dispersibility is improved, and drug dissolution is improved (FIG. 1).
  • Example 2 of FIG. 2 Example 1 of FIG.
  • Experimental example 2 Usefulness of 10% or more calcium carbonate (liquid displacement dissolution test)
  • the rate of substitution of the excipient of the orally disintegrating tablet with mannitol for calcium carbonate was 0% (Comparative Example 1), 5% (Comparative Example 3), 10% (Example 4), 15% (Example 5), 25% (Example 6, Example 3), 50% (Example 7), 100% (Example 8), using the orally disintegrating tablets, the same conditions as in Experimental Example 1
  • a liquid displacement elution test was conducted. The results are shown in FIG. As a result of substituting a part of mannitol, which is an excipient for orally disintegrating tablets, with calcium carbonate, it was found that the drug dissolution was improved by substituting 10% or more of calcium carbonate.
  • Experimental example 3 Usefulness of substances other than calcium carbonate (liquid displacement elution test)
  • this experimental example it was examined whether or not the same effect can be obtained by substances other than calcium carbonate.
  • the results are shown in FIG.
  • sodium hydrogen carbonate (Example 9), potassium hydrogen carbonate (Example 10), and magnesium carbonate (Example 11) showed the same effect (dissolution improvement by improving dispersibility).
  • Experimental example 5 Usefulness of sodium hydrogencarbonate 10% or more (liquid displacement elution test)
  • the substitution rate of mannitol in the orally disintegrating tablet excipient with sodium bicarbonate was 5% (Comparative Example 1), 10% (Example 12), 15% (Example 13), 30
  • a liquid displacement dissolution test was performed. The results are shown in FIG.
  • the tablet hardness of the orally disintegrating tablets of Examples 13 and 14 (maltose) (not humidified and dried) was 53N and 50N
  • the orally disintegrating tablets of Examples 15 and 17 (maltitol) (humidified and dried) The tablet hardness was 37N and 34N.
  • Liquid displacement dissolution test A liquid displacement dissolution test of orally disintegrating tablets (Examples 13 and 15) containing Eudragit E-coated granules containing atorvastatin and sodium lauryl sulfate with tablet hardness measured was performed. The results are shown in FIG. The liquid replacement test also showed a good profile and was confirmed to have the same performance as maltose.
  • Liquid displacement dissolution test A liquid displacement dissolution test of orally disintegrating tablets (Examples 14 and 17) containing core AEA-coated granules containing atorvastatin and sodium lauryl sulfate whose tablet hardness was measured was performed. The results are shown in FIG. The liquid replacement test also showed a good profile and was confirmed to have the same performance as maltose.
  • AUC means AUC 0-8h .
  • the formulation of mannitol (Comparative Example 1) It was confirmed that the bioavailability was significantly improved compared to The usefulness of calcium carbonate was also demonstrated in AEA coating (Example 1). From this, it was confirmed that the desired effect of the present invention was obtained also in vivo (dog).
  • 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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Abstract

La présente invention concerne un comprimé à désintégration orale qui contient des particules et un carbonate ou un hydrogénocarbonate et possède des propriétés de libération de médicament améliorées. Lesdites particules sont obtenues par enrobage de noyaux, qui contiennent de l'atorvastatine ou son sel pharmaceutiquement acceptable et du sulfate sodique de lauryle, avec un matériau d'enrobage contenant un copolymère de méthacrylate de méthyle-méthacrylate de butyle-méthacrylate de diméthylaminoéthyle ou un diéthylaminoacétate d'acétal polyvinylique et un matériau polymère hydrosoluble.
PCT/JP2010/067040 2010-03-29 2010-09-30 Comprimé à désintégration orale WO2011121824A1 (fr)

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WO2015045604A1 (fr) * 2013-09-30 2015-04-02 富士フイルム株式会社 Comprimé orodispersible
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JP2015530384A (ja) * 2012-08-31 2015-10-15 ハンミ ファーム． シーオー．， エルティーディー． アトルバスタチン、イルベサルタンおよび炭酸マグネシウムを含有する二層複合錠製剤
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JP2016501231A (ja) * 2012-11-30 2016-01-18 アキュラ・ファーマシューティカルズ・インコーポレーテッド 活性医薬成分の自己制御放出
JP2016506394A (ja) * 2012-12-17 2016-03-03 エティファーム 圧縮成形によって得られる口腔分散性錠剤
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