WO2011121824A1 - Orally disintegrating tablet - Google Patents

Abstract

Disclosed is an orally disintegrating tablet which contains grains and a carbonate or a hydrogen carbonate and has improved drug release properties. The grains are obtained by coating cores, which contain atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate, with a coating material that contains a methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer or a polyvinyl acetal diethylamino acetate and a water-soluble polymer material.

Description

Orally disintegrating tablets

The present invention relates to an orally disintegrating tablet having improved drug dissolution, comprising a granule coated with a core containing atorvastatin.
Specifically, 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”.

The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate is an early rate-limiting process in the biosynthetic pathway of cholesterol. This process is catalyzed by the enzyme HMG-CoA reductase. Statins inhibit HMG-CoA reductase from catalyzing this conversion. Statins are therefore generally potent lipid lowering agents.

Currently, atorvastatin calcium hydrate is sold as Lipitor®, which has the chemical name [R- (R *, R *)]-2- (4-fluorophenyl) -β, δ-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.

Manufacture 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).

On the other hand, since atorvastatin is a poorly soluble drug, its in-vitro dispersibility and dissolution properties are poor, resulting in a problem of reduced bioavailability. As a means for improving such a problem, there is a method of changing a crystal to an amorphous form.

For example, with the aim of providing an improved process for producing amorphous atorvastatin, 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 of forming amorphous atorvastatin including obtaining atorvastatin (Patent Document 3), or dissolving atorvastatin in a solution containing a hydroxyl group-containing solvent, and rapidly evaporating the hydroxyl group-containing solvent from the solution to produce amorphous Disclosed is a method for producing amorphous atorvastatin (Patent Document 4), which comprises producing quality atorvastatin.

In addition, for the purpose of obtaining a method for producing amorphous atorvastatin that does not involve the use of a volatile organic solvent and a stable pharmaceutical composition containing amorphous 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).

Furthermore, in order to stabilize amorphous atorvastatin, a method of heat treatment at a specific temperature is disclosed (Patent Document 6).

In addition, atorvastatin or a pharmaceutically acceptable salt thereof is a drug having a strong bitter taste. For the purpose of concealing the unpleasant taste of the drug and avoiding absorption in the oral cavity, 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.

On the other hand, 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. . However, since 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.

In order to avoid this problem, it is necessary to suppress or reduce drug release in the oral cavity for a certain period of time in the oral particulate pharmaceutical composition. For example, when the drug has an unpleasant taste, means for reducing the release of the drug for a certain period of time when the oral particulate pharmaceutical composition is present in the oral cavity can be employed.

On the other hand, in recent years, orally disintegrating tablets can be taken without water and are relatively easy to take even for patients who have difficulty swallowing. Has been.

As a technique relating to the orally disintegrating tablet, for example, 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) (Patent Document 7), 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.

For example, when a drug having a bitter taste is 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. Depending on the type of polymer substance to be coated and the pressure at the time of tableting, 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. Conversely, when 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.

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.

Also coated with a core comprising a drug and a mixture of at least 5 wt% hot film forming polymer and at least 5 wt% cold film forming polymer to prepare a chewable and taste masked formulation An invention relating to a taste-masked pharmaceutical composition comprising a polymer mixture is known (Patent Document 11).
In addition, 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).
However, 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.

On the other hand, the elution control function is lost when the particulate composition coated with methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer is compressed, but by treating with an alcohol solvent, 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 μm or less is physically mixed with a drug-containing film particle and then compression-molded. 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 μm 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).
However, in either of 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.

Under the above circumstances, drug dissolution that contains granules that can reduce the initial drug elution amount of atorvastatin and maintain or prevent subsequent drug release while suppressing or reducing changes in drug elution rate even after compression molding Orally disintegrating tablets, that is, drug elution containing granules that achieve quick dispersibility and dissolution in the digestive tract when unpleasant taste concealment (compliance compliance) is applied in the oral cavity There is a need for technological development related to orally disintegrating tablets with improved characteristics.

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. 6,872,405) International Publication No. WO2008 / 032767 Pamphlet International Publication No. WO2005 / 105045 (corresponding US Patent Application Publication No. USP20005 / 0287211) Japanese National Patent Publication No. 1-502589 JP 2001-192344 A JP 2006-45134 A JP-A-8-333242 International Publication No. WO2005 / 037254 Pamphlet

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.
In addition, 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. As a result of the examination of the grains, 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.
Under the circumstances described above, 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. As a result of intensive investigations into the creation of orally disintegrating tablets containing grains that achieve rapid dispersibility and dissolution in the digestive tract when concealing an unpleasant taste in the oral cavity (compliance compliance), The invention has been completed.

That is, the present invention
[1] 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 An orally disintegrating tablet with improved drug dissolution, comprising granules coated with a coating substance containing a functional polymer substance, and carbonate or bicarbonate
[2] 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. 1] or [2] orally disintegrating tablets,
[6] An orally disintegrating tablet according to [5], which further contains a saccharide having high moldability as a binder,
[7] 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 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.

According to the present invention, (1) 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.

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. It is an dissolution profile obtained by conducting a liquid displacement dissolution test on an orally disintegrating tablet containing drug-containing particles containing aminoalkyl methacrylate copolymer E (EudragitragE) and having mannitol replaced with calcium carbonate at various substitution rates. It is an dissolution profile obtained by conducting a liquid displacement dissolution test on orally disintegrating tablets containing drug-containing particles containing aminoalkyl methacrylate copolymer E (Eudragit E) and having mannitol substituted with a substance other than calcium carbonate. Obtained by conducting a liquid displacement dissolution test on orally disintegrating tablets (Example 13 and Comparative Example 1) containing drug-containing particles containing aminoalkyl methacrylate copolymer E (Eudragit E) and having mannitol replaced with sodium bicarbonate. Elution profile. Dissolution obtained by conducting a liquid displacement dissolution test on orally disintegrating tablets (Example 14 and Comparative Example 2) containing drug-containing particles containing polyvinyl acetal diethylaminoacetate (AEA) and having mannitol replaced with sodium bicarbonate It is a profile. This is an dissolution profile obtained by conducting a liquid displacement dissolution test on orally disintegrating tablets containing drug-containing particles containing aminoalkyl methacrylate copolymer E (Eudragit） E) and mannitol replaced with sodium bicarbonate at various substitution rates. . In order to evaluate the effect of binders (maltose, maltitol), liquid-dissolved dissolution of orally disintegrating tablets containing drug-containing particles containing aminoalkyl methacrylate copolymer E (Eudragit E) and mannitol substituted with sodium bicarbonate It is the elution profile obtained by implementing a test. In order to evaluate the effects of 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. 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. Is a dissolution profile obtained by conducting a liquid displacement dissolution test. It is the pharmacokinetic (PK) profile obtained by conducting a dog test about the orally disintegrating tablet which substituted all or a part of mannitol with the calcium carbonate.

Hereinafter, the orally disintegrating tablet of the present invention will be described.
As used herein, 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. When the shape of the particulate composition can approximate a sphere, the size of the particulate pharmaceutical composition is defined as an average particle diameter of 2 mm or less. Moreover, when 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 μm or more, another embodiment is 10 μm or more, and a further embodiment is 20 μm 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 | grains which consist of 1 type, or 2 or more types of additives using a well-known technique, and may use it. In addition, 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. 3356730 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. Furthermore, if desired, 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 μm or more and 1000 μm or less, other embodiments include 5 μm or more and 500 μm or less, and further embodiments include 10 μm or more and 200 μm or less.

In the present invention, “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”.

In the present specification, “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.
In the present specification, 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.
In the present specification, “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.
In the present specification, “insolubilization” means a phenomenon in which the solubility in water or the dissolution rate is lowered. In addition, “insolubilize”, “insolubilize”, and “promoting insolubilization” means that a dissolved substance is phase-separated from water, precipitated, precipitated, precipitated, or dissolved in water. Indicates blocking.
In the present specification, 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) -β, δ-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. As another embodiment, 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. Can be mentioned. As a further embodiment, 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. The crystalline forms of atorvastatin include, for example, types I, II, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, and XIX. As another embodiment, 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. For example, 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. Alternatively, 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. In another embodiment, 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. Generally, treatment is initiated with an amount lower than the optimum dose of the compound. Thereafter, the dosage is increased gradually until the optimum effect is reached according to the circumstances. If necessary, the total dose per day can be divided and administered several times a day.
In addition, 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. There is no particular limitation. For example, 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. For example, it 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, London).

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).

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. 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%.

In the particulate pharmaceutical composition used in the present invention, only one of 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. In addition, 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. There is no particular limitation as long as it has a function of reducing drug elution.
Examples of the polymer substance 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. Propylcellulose, hypromellose, Chill cellulose, hydroxyethyl cellulose, povidone, copolyvidone, polyvinyl alcohol - polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, polyethylene oxide, and the like. Further embodiments include hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose and the like. Still other embodiments include hydroxypropylcellulose, hypromellose, hydroxyethylcellulose and the like. Examples of hypromellose 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.

As a 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, In general, 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. For example, 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. When 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.
In addition, if desired, 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.

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. For example, when producing 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. Examples of the fluidizing agent 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.

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 | blended uniformly is mentioned. As an aspect, for example, (1) 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 embodiments may be combined as appropriate, an appropriate amount.

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.

About the pharmaceutical formulation of this invention, the particle | grains of an intermediate body other than an orally disintegrating tablet can be mix | blended, and it can be set as various pharmaceutical formulations. Examples of pharmaceutical preparations other than orally disintegrating tablets include powders, fine granules, dry syrups, tablets and the like.
Hereinafter, the orally disintegrating tablet of the present invention will be described, but the pharmaceutical preparation of the present invention is not limited thereto.

In the present invention, 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. For example, 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. 2,807,346 (U.S. Pat. No. 5,466,464), No. 5-2171054 (European Patent No. 553777), Japanese Patent Application Laid-Open No. 10-182436 (U.S. Patent No. 5958543), Patent No. 3412694 (U.S. Patent No. 5223264), Of the known orally disintegrating tablets described in the International Publication WO98 / 02185 pamphlet (US Patent No. 6287596) and International Publication No. WO2008 / 032767 pamphlet (US Patent Application Publication No. 2008/0085309) Applying the particulate pharmaceutical composition as a drug The orally disintegrating tablet base described in the publication can be used to make an orally disintegrating tablet according to the method described in the publication. 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. Thus, for example, the particulate pharmaceutical composition used in the present invention, 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. .

In the case of a normal tableting type, International Publication No. WO95 / 20380 pamphlet (US corresponding patent No. 5576014 specification), International Publication No. WO2002 / 92057 pamphlet (US corresponding patent application No. 2003/099701 specification), Japanese Patent Application Laid-Open No. 10-182436 (US Patent No. 5958543), Japanese Patent Application Laid-Open No. 9-48726, Japanese Patent Application Laid-Open No. 8-19589 (US Patent No. 5672364), Patent 2919771, Patent No. 3069458 As disclosed in US Pat. No. 5,018,861 (corresponding to US Pat. No. 5,018,974, US Pat. No. 5,720,974), WO 2008/032767 pamphlet (US-patent published application No. 2008/0085309). It is prepared through a normal tableting process. In order to prepare 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 As disclosed in the specification, 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. After granulation using this, 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. In order to prepare a normal tablet type orally disintegrating tablet as shown in International Publication No. WO99 / 47124 Pamphlet (US Patent No. 6658554), for example, 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. Furthermore, in order to prepare 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. Furthermore, in order to prepare a normal tablet type orally disintegrating tablet as disclosed in International Publication No. WO2008 / 032767 (US Patent Application Publication No. 2008/0085309), for example, the present invention 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%.

As the excipient used in the orally disintegrating tablet of the present invention, 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. 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. In addition to typical excipients, high melting point saccharides can be used. In the orally disintegrating tablet of the present invention, carbonate or bicarbonate can be contained as an excipient.

Here, “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. In addition, 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.
In the orally disintegrating tablet of the present invention, 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.

In addition, 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. Examples of 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.

When a water-soluble polymer is used instead of a highly moldable saccharide, for example, hydroxypropylcellulose, hypromellose, povidone, polyvinyl alcohol, gum arabic powder, gelatin, pullulan and the like are suitable.

In addition, “α-ized” means that when physical treatment is applied to starch, water enters between the molecules and swells (gelatinizes). Become. Examples of the 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 description of the patent document of the orally disintegrating tablet is cited as the description of the present specification for the types of other optional additives, their blending and blending amounts, and the like.

In addition, when 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. Preferably, 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.

In the particulate pharmaceutical composition for oral administration to be used in the present invention, various pharmaceutical excipients are appropriately used as necessary, and formulated. Such a pharmaceutical excipient is not particularly limited as long as it is pharmaceutically acceptable and pharmacologically acceptable. For example, binders, disintegrants, acidulants, foaming agents, artificial sweeteners, fragrances, lubricants, colorants, stabilizers, buffers, antioxidants, surfactants, and the like are used.

Examples of the binder include hypromellose and gum arabic.
Examples of the disintegrant include corn starch, potato starch, carmellose calcium, and carmellose sodium.
Examples of the sour agent include citric acid, tartaric acid, malic acid and the like.
Examples of the foaming agent include baking soda.
Examples of the artificial sweetener include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia and thaumatin.
Examples of the 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.
Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.
Examples of the surfactant include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like. As the pharmaceutical excipient, one or a combination of two or more can be added as appropriate.
The compounding amount of these various pharmaceutical excipients is, for example, 1% by weight or more and 100% by weight or less with respect to the drug-containing particles, and in another aspect, 5% by weight or more and 80% by weight or less, and 10% as a further aspect. % By weight to 50% by weight.

In the particulate pharmaceutical composition for oral administration of the present invention, 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. As the drug-containing nucleus, particles made of only a drug can be used. In addition, using a known technique, particles comprising a drug and one or more additives may be produced and used. For the production of particles composed of a drug and an additive, for example, the drug and a suitable excipient (for example, microcrystalline cellulose, lactose, corn starch, etc.) are mixed, and 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. 3356730 Methyl methacrylate / Butyl methacrylate / Dimethylaminoethyl methacrylate copolymer [aminoalkyl methacrylate copolymer E (trade name; Eudragit E100, Evonik Degussa GmbH) ], Povidone (Kollidon, BASF), methylcellulose (METOLOSE, Shin-Etsu Chemical), etc.) The grains may be dried. Further, 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. These particles can be further coated with a coating material containing sodium lauryl sulfate and a water-soluble polymer.

In the particulate pharmaceutical composition for oral administration used in the present invention, 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 | cover after coat | covering two or more layers. In the orally disintegrating tablet of the present invention, a carbonate or bicarbonate can be contained as a coating component of the coating substance. In the case of coating after coating one layer or two or more layers, for example, between the coating material containing copolymer E or polyvinyl acetal diethylaminoacetate and a water-soluble polymer material and the core containing the drug, 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. In addition, 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. Specifically, for example, “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”.

More specifically, 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. Potassium dihydrogen, potassium bicarbonate, sodium bicarbonate, ammonium carbonate, sodium polyphosphate, sodium pyrophosphate, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium sulfate, sodium sulfite, sodium hydrogen sulfite, sodium hydroxide, citric acid Sodium acetate, disodium citrate, sodium glutamate, arginine glutamate, disodium succinate, calcium acetate, glycine, alanine, sorbitol, xylitol, inositol, sucrose, glucose, fructose or it Such as hydrates, and the like. Other 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”.

More specifically, 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. . Other embodiments include 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 And 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. Specifically, for example, 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. Specifically, for example, the content is 1% by weight or more and 500% by weight or less with respect to the core particles containing the drug. In another embodiment, it is 1% by weight or more and 300% by weight or less. In still another embodiment, 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. When 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. In addition, 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.

In the particulate pharmaceutical composition used in the present invention, 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. . Examples of 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. In the orally disintegrating tablet of the present invention, 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.

Although the manufacturing method of the particulate pharmaceutical composition used by this invention is demonstrated below, these do not limit this invention.
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.
In order to obtain the particulate pharmaceutical composition used in the present invention, the core material containing the drug is coated with the coating substance in the present invention. As the drug-containing nucleus, particles made of only a drug can be used. In addition, using a known technique, particles comprising a drug and one or more additives may be produced and used. For the production of particles consisting of a drug and an additive, for example, the drug and an appropriate excipient (for example, crystalline cellulose, lactose, corn starch, etc.) are mixed, and a binder (for example, hydroxypropyl cellulose) is added as necessary. Then, it may be granulated, sized and dried. In addition, 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. The dispersed liquid may be sprayed.

As a method of coating the coating substance in the present invention on the outer side of the drug-containing core, it is possible to coat 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. For example, in 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.
Alternatively, 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.

As a method for coating the intermediate layer on the core particles containing the drug, it is produced by a method known per se. For example, 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. For example, in a fluidized bed side spray type coating apparatus, 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. For example, 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 μm or less. In another embodiment, the average particle diameter is 1 μm or more and 350 μm or less, and in a further embodiment, it is 20 μm or more and 350 μm or less.

As 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, Examples of 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.
Examples of the tableting device include a rotary tableting machine and a single-shot tableting machine. However, the tableting device is not particularly limited as long as it is a method for producing a compression-molded product (preferably a tablet) pharmaceutically. .

In the use of the carbonate or hydrogen carbonate of the present invention, a nucleus containing atorvastatin and sodium lauryl sulfate is a water-soluble copolymer of methyl methacrylate, butyl methacrylate, dimethylaminoethyl methacrylate, or polyvinyl acetal diethylaminoacetate. For the production of an orally disintegrating tablet comprising particles coated with a coating material containing a functional polymer substance. For a detailed description of the invention, the description of the orally disintegrating tablet of the present invention is given below. Quote.

The method for producing the orally disintegrating tablet of the present invention containing the particulate pharmaceutical composition will be described below.
As an example, in the case of an orally disintegrating tablet described in International Publication No. WO95 / 20380 (U.S. Pat. No. 5,576,014), 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. Furthermore, in order to increase the hardness of the prepared molded 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. For example, 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. For example, the drying temperature condition can be set to 10 ° C. or more and 100 ° C. or less, and in another embodiment, 20 ° C. or more and 60 ° C. or less can be set. 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.

In addition, as an example, in the case of an orally disintegrating tablet described in International Publication No. WO2002 / 92057 pamphlet (U.S. Patent Application Publication No. 2003/099701 specification), 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. . When combining an excipient with a high melting point and a saccharide with a low melting point, 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.

Hereinafter, the present invention will be specifically described by way of examples, but these do not limit the scope of the present invention. Each layer is numbered, but this number does not limit the present invention.

Reference example:
As atorvastatin calcium trihydrate, crystalline Form I atorvastatin produced according to the example of Japanese Patent No. 3296564 (WO97 / 03959) was used.

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. 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.

(2) Preparation of the second layer For 7.80 kg of particles coated with the first layer, 1.33 kg of sodium lauryl sulfate and 1.17 kg of methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., product name METALOSE SM-4, the same shall apply hereinafter) 33.21 purified water The liquid dissolved in kg was sprayed using a fluidized bed granulator to prepare particles covering the second layer.

(3) Preparation of the third layer For 10.3 kg of particles coated with the second layer, a solution obtained by dissolving 0.52 kg of methylcellulose in 12.48 kg of purified water is sprayed using a fluidized bed granulator to cover the third layer. Particles were prepared.

(4) Preparation of the fourth layer 65.82 kg of methanol was added to and mixed with 0.29 kg of hypromellose dissolved in 16.45 kg of purified water to prepare a hypromellose solution (water / alcohol mixture). To this hypromellose solution, 2.57 kg of polyvinyl acetal diethylaminoacetate (manufactured by Meguro Chemical Co., product name AEA, the same below) is added and dissolved, and 1.47 kg of talc (manufactured by Matsumura Sangyo Co., Ltd., product name high filler, same hereinafter) is added. Added and dispersed. This dispersion was sprayed onto 10.82 kg of the particles coated with the third layer using a fluidized bed granulator to prepare particles coated with the fourth layer.

(5) Preparation of the fifth layer For 15.15 kg of particles coated with the fourth layer, fluidized bed granulation of 0.76 kg of mannitol (ROQUETTE, product name PEARLITOL 50C, hereinafter the same) dissolved in 6.84 kg of purified water The particles coated with the fifth layer were prepared by spraying using the apparatus.

(Preparation of orally disintegrating tablets)
1326.2 g of atorvastatin-containing particles, precipitated calcium carbonate (manufactured by Kosuge Pharmaceutical, the same shall apply hereinafter) 4486.8 g, maltose (manufactured by Sanwa Starch Co., Ltd., product name San Marto S, the same shall apply hereinafter) 66.0 g aspartame (Ajinomoto Healthy Supply, the same shall apply hereinafter) 50.0 g Using a fluidized bed granulator (Glatt, product name GPCG5 / 15), a mixture of 110.0g of flavor preparation (Astellas, same below) is granulated with 2112.0g of maltose aqueous solution (including 528.0g of maltose). 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.

(2) Preparation of the second layer A solution obtained by dissolving 1.33 kg of sodium citrate hydrate (manufactured by Wako Pure Chemicals, the same shall apply hereinafter) and 1.17 kg of methylcellulose in 30.96 kg of purified water with respect to 7.80 kg of particles coated with the first layer. Were sprayed using a fluidized bed granulator to prepare particles coated with the second layer.

(3) Preparation of third layer 62.67 kg of methanol was added to and mixed with 0.28 kg of hypromellose dissolved in 15.67 kg of purified water to prepare a hypromellose solution (water / alcohol mixture). Subsequently, 2.45 kg of aminoalkyl methacrylate copolymer E (manufactured by Evonik Degussa Japan, product name Eudragit E100, hereinafter the same) was added to this hypromellose solution and dissolved, and 1.40 kg of talc was added and dispersed. This dispersion was sprayed onto 10.3 kg of particles coated with the third layer using a fluidized bed granulator to prepare particles coated with the fourth layer.

(4) Preparation of the fourth layer The 14.3 kg of the particles coated with the third layer was sprayed with a fluid obtained by dissolving 0.72 kg of mannitol in 6.48 kg of purified water using a fluidized bed granulator to coat the fourth layer. Particles were prepared.

(Preparation of orally disintegrating tablets)
A mixture of 1262.8 g atorvastatin-containing particles, 3977.2 g precipitated calcium carbonate, 60.0 g maltose, 50.0 g aspartame, and 110.0 g flavor preparation using a fluidized bed granulator (Glatt, product name GPCG5 / 15), maltose aqueous solution Granulated with 1920.0 g (including maltose 480.0 g) to prepare a granulated product for orally disintegrating tablets. 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. 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. 213.2 mg of this mannitol granulated product, 23.7 mg of precipitated calcium carbonate granulated product, and 63.1 mg of atorvastatin-containing particles prepared in Example 2 were mixed and beaten using an autograph (Shimadzu Corporation, AGS-20KNG, the same applies hereinafter). The tablet was made into an orally disintegrating tablet of the present invention.

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.

(2) Preparation of third layer For 300.0 g of particles coated with the second layer, a solution obtained by dissolving 15.0 g of methylcellulose in 360.0 g of purified water was used as a fluidized bed granulator (product name: GPCG-1). Were sprayed to prepare particles coated with the third layer.

(3) Preparation of the fourth layer To a solution obtained by dissolving 8.1 g of hypromellose in 456.0 g of purified water, 1824.0 g of methanol was added and mixed to prepare a hypromellose solution (water / alcohol mixture). Subsequently, 71.2 g of polyvinyl acetal diethylaminoacetate was added and dissolved in this hypromellose solution, and 40.7 g of talc was added and dispersed. This dispersion was sprayed onto 300.0 g of particles coated with the third layer using a fluidized bed granulator (Glatt; product name GPCG-1) to prepare particles coated with the fourth layer.

(Preparation of orally disintegrating tablets)
Using a fluidized bed granulator (Glatt; product name GPCG-1) 99.5 g of atorvastatin-containing particles, 284.0 g of mannitol, 50.1 g of sodium bicarbonate, 5.0 g of maltose, 3.8 g of aspartame, and 8.3 g of a flavor preparation, Granulated with 198.0 g of maltose aqueous solution (including 39.6 g of maltose) to prepare a granulated product for orally disintegrating tablets. 326.7mg of this granulated product and 3.3mg of magnesium stearate (Merck, the same applies below) are mixed, tableted using an autograph, and humidified and dried (25-30 ° C / 40-62% RH / 18 hours) And the orally disintegrating tablet of the present invention was produced.

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. 233.9 mg of this granulated product, 63.1 mg of atorvastatin-containing particles prepared in Example 2 and 3 mg of magnesium stearate 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.

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.

(2) Preparation of the second layer A solution obtained by dissolving 1.33 kg of sodium citrate hydrate and 1.17 kg of methylcellulose in 30.96 kg of purified water is used in a fluidized bed granulator for 7.80 kg of particles coated with the first layer. And sprayed to prepare particles coated with the second layer.

(3) Preparation of third layer 1824.0 kg of methanol was added to and mixed with a solution of 8.1 g of hypromellose in 4560 g of purified water to prepare a hypromellose solution (water / alcohol mixture). Subsequently, 71.2 g of aminoalkyl methacrylate copolymer E was added and dissolved in this hypromellose solution, and 40.7 g of calcium carbonate was added and dispersed. This dispersion was sprayed onto 300.0 g of particles coated with the third layer using a fluidized bed granulator (Glatt; product name GPCG-1) to prepare particles coated with the fourth layer. .

(Preparation of orally disintegrating tablets)
239.9 mg of the mannitol granulated product prepared in Example 4 and 60.1 mg of atorvastatin-containing particles of the present invention were mixed and tableted using an autograph to produce an orally disintegrating tablet of the present invention.

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.

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.

(Preparation of orally disintegrating tablets)
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. 243.8 mg of this granulated product and 86.2 mg of atorvastatin-containing particles are mixed, tableted using an autograph, and humidified and dried (25-30 ° C / 40-62% RH / 18 hours). An orally disintegrating tablet was made.

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.

(2) Preparation of 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). Subsequently, 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.

(3) Preparation of the third layer To a solution obtained by dissolving 5.2 g of methylcellulose in 99.4 g of purified water, a solution obtained by dissolving 52.3 g of sodium hydrogen carbonate (manufactured by Tosoh Corporation, sodium bicarbonate, the same shall apply hereinafter) in 994.2 g of purified water is added. Mixed. This mixed solution was sprayed on 270.0 g of the particles coated with the second layer using a fluidized bed granulator to prepare particles coated with the third layer.

(4) Preparation of the fourth layer A solution obtained by dissolving 150 g of methylcellulose in 2850.0 g of purified water was sprayed onto the 300.0 g of particles coated with the third layer using a fluidized bed granulator to coat the fourth layer. Particles were prepared.
(Preparation of orally disintegrating tablets)
204.53 mg of the mannitol granulated product prepared in Example 4 and 95.47 mg of atorvastatin-containing particles of the present invention were mixed and tableted using an autograph to produce the orally disintegrating tablet of the present invention.

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.

(2) Preparation of the third layer 2430.2 g of methanol was added to and mixed with 10.8 g of hypromellose dissolved in 607.6 g of purified water to prepare a hypromellose solution (water / alcohol mixture). Subsequently, 94.9 g of polyvinyl acetal diethylaminoacetate was added and dissolved in this hypromellose solution, and 54.2 g of talc was added and dispersed. This dispersion was sprayed onto 400.0 g of particles coated with the second layer using a fluidized bed granulator to prepare particles coated with the third layer.

(3) Preparation of the fourth layer A solution obtained by dissolving 20.0 g of mannitol in 180.0 g of purified water is sprayed onto the 400.0 g of particles coated with the third layer using a fluidized bed granulator to cover the fourth layer. Particles were prepared.

(Preparation of orally disintegrating tablets)
229.65 mg of the mannitol granule prepared in Example 4 and 70.35 mg of atorvastatin-containing particles of the present invention were mixed and tableted using an autograph to produce the orally disintegrating tablet of the present invention.

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. 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.

Experimental Example 1: Usefulness of calcium carbonate (liquid displacement dissolution test)
In the liquid displacement dissolution test carried out in the following experimental examples, the following conditions were set as a dissolution test method capable of predicting pharmacokinetics (PK) in humans, assuming oral use of orally disintegrating tablets without water. That is, the paddle method (50 rpm) was started using 300 mL of the Japanese Pharmacopoeia Dissolution Test 1st liquid (JP1), and at 30 minutes, 600 mL of 5 times concentrated solution of the Japanese Pharmacopoeia Dissolution 2nd liquid (JP2) was added. Added.
In this experimental example, 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) In any of Examples 2), it was found that drug elution was suppressed. In all cases, aggregation was observed in JP1 (0 to 30 min), and this aggregation was considered to be the cause. 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)
In this experimental example, 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)
In 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. In addition to calcium carbonate, 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 4: Usefulness of sodium bicarbonate (liquid displacement elution test)
In this experimental example, in order to confirm the effect of sodium bicarbonate, orally disintegrating tablets containing drug-containing particles containing Eudragit E (comparison of Example 2 and Comparative Example 1; the results are shown in FIG. 5), AEA A liquid displacement dissolution test was carried out on the orally disintegrating tablets containing the contained drug-containing particles (comparison of Example 14 and Comparative Example 2; the results are shown in FIG. 6).
Orally disintegrating tablet containing Eudragit E-coated granules containing atorvastatin and sodium lauryl sulfate (Comparative Example 1 in FIG. 5), or orally disintegrating tablet containing AEA-coated grains of the same nucleus (Comparison of FIG. 6) In any of Examples 2), drug elution was suppressed. In all cases, aggregation was observed in JP1 (0 to 30 min), and this aggregation was considered to be the cause. By substituting sodium bicarbonate for a portion of the excipient of the orally disintegrating tablet with sodium bicarbonate, it was found that the granules do not aggregate, dispersibility is improved, and drug dissolution is improved (Example of FIG. 5). 13, Example 14 of FIG.

Experimental example 5: Usefulness of sodium hydrogencarbonate 10% or more (liquid displacement elution test)
In this experimental example, 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 Using each orally disintegrating tablet of% (Example 9), a liquid displacement dissolution test was performed.
The results are shown in FIG. As a result of substituting a part of mannitol, which is an excipient for orally disintegrating tablets, with sodium bicarbonate, it was found that the drug dissolution was improved by substituting 10% or more of sodium bicarbonate.

Experimental Example 6: Usefulness of the binding agent maltitol (tablet hardness test)
Orally disintegrating tablets containing core Eudragit E-coated granules containing atorvastatin and sodium lauryl sulfate (Example 13) and orally disintegrating tablets containing AEA-coated grains (Example 14), and a combination of maltose binders The tablet hardness of the orally disintegrating tablets (Examples 15 and 17) substituted with tall was measured by a hardness measuring device (Model 6D, manufactured by PHARMATRON). The tablet hardness of the orally disintegrating tablets of Examples 13 and 14 (maltose) (not humidified and dried) was 53N and 50N, and the orally disintegrating tablets of Examples 15 and 17 (maltitol) (humidified and dried) The tablet hardness was 37N and 34N. As a result of substituting maltose as a binder for orally disintegrating tablets with maltitol, an increase in hardness due to humidification drying was observed as in the case of maltose.

(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.

Experimental Example 7: Usefulness of calcium carbonate membrane and sodium bicarbonate membrane (liquid displacement elution test)
In orally disintegrating tablets containing core Eudragit E-coated granules containing atorvastatin and sodium lauryl sulfate (the third layer of coated particles consists of Eudragit E, talc, and hypromellose), the third layer of talc is replaced with calcium carbonate Orally disintegrating tablet (Example 16) and orally disintegrating tablet comprising drug-containing particles coated with sodium bicarbonate on the outside of a coating film containing aminoalkyl methacrylate copolymer E (Eudragit E) and talc (Example 18) A liquid displacement elution test was conducted.
The results are shown in FIG. When the talc (plasticizer) of Eudragit E membrane was replaced with calcium carbonate, elution was improved. Also, elution was improved when sodium bicarbonate was coated on the outside. From this, it was confirmed that, when blended as an excipient and used as a fine particle coating component, the desired effects of the present invention were obtained.

Experimental Example 8: Usefulness of calcium carbonate (in vivo)
(Dog test)
In order to evaluate the usefulness of calcium carbonate in vivo, a dog test was conducted in which a small amount of water (5 mL) was administered assuming that the orally disintegrating tablet was taken without water. A healthy person was assumed, and evaluation was performed with an acidic dog in the stomach.
Comparative Example 1 (Eudragit E coating) containing mannitol as an excipient, Example 2 (Eudragit E coating) and Example 1 (AEA coating) in which all mannitol was replaced with calcium carbonate, part of mannitol (25%) An experiment was conducted on Example 3 (Eudragit E coating) in which is replaced with calcium carbonate.

The results are shown in Table 1 and FIG. “AUC” means AUC _0-8h . In the formulation (Example 2) in which the mannitol part of the excipient of the orally disintegrating tablet was replaced with calcium carbonate and the formulation (Example 3) in which a part was replaced with calcium carbonate, 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.
As mentioned above, although this invention was demonstrated along the specific aspect, the deformation | transformation and improvement obvious to those skilled in the art are included in the scope of the present invention.

Claims (7)

1. A core containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate is a methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer or polyvinyl acetal diethylaminoacetate and a water-soluble polymer. An orally disintegrating tablet with improved drug dissolution, comprising granules coated with a coating material containing a substance, and carbonate or bicarbonate.
2. The oral cavity according to claim 1, wherein the carbonate or bicarbonate is one or more selected from the group consisting of calcium carbonate, sodium carbonate, ammonium carbonate, sodium bicarbonate, potassium bicarbonate, magnesium carbonate. Inner disintegrating tablet.
3. The orally disintegrating tablet according to claim 1 or 2, comprising carbonate or bicarbonate as an excipient.
4. The orally disintegrating tablet according to claim 3, further comprising a saccharide having low moldability as an excipient.
5. The 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 orally disintegrating tablet according to 2.
6. The orally disintegrating tablet according to claim 5, further comprising a highly moldable saccharide as a binder.
7. A core containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate is a methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer or polyvinyl acetal diethylaminoacetate and a water-soluble polymer. Use of carbonate or hydrogen carbonate for producing an orally disintegrating tablet comprising granules coated with a coating substance containing a substance.

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