WO2011121823A1 - Particulate pharmaceutical composition for oral administration - Google Patents

Abstract

Disclosed is a particulate pharmaceutical composition for oral administration, which is obtained by coating particles, which contain atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate, with a coating material that contains a polyvinyl acetal diethylamino acetate and a water-soluble polymer material.

Description

Particulate pharmaceutical composition for oral administration

The present invention relates to a particulate pharmaceutical composition for oral administration comprising atorvastatin.
Specifically, the present invention relates to a particulate pharmaceutical composition for oral administration, wherein a core containing atorvastatin and sodium lauryl sulfate is coated with a coating material containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance, and The present invention relates to an orally disintegrating tablet containing a particulate pharmaceutical composition for oral administration.
The present invention also relates to the use of polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance for producing a granular pharmaceutical composition for oral administration which is coated with atorvastatin-containing particles and reduces the change in dissolution rate after compression molding. Is.
Furthermore, this invention relates to the manufacturing method of the granular pharmaceutical composition for oral administration which coat | covers atorvastatin containing particle | grains and reduces the change of an elution rate after compression molding.

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.

In addition, an atorvastatin preparation containing a mixture containing atorvastatin and sodium lauryl sulfate is disclosed in Patent Document 15 (Example 3). Patent document 15 makes it a subject to stabilize atorvastatin, and a technical idea differs from this invention.

Under the above circumstances, a particulate pharmaceutical composition for oral administration that can reduce or reduce the change in drug elution rate even after compression molding while reducing the initial drug elution amount of atorvastatin and maintaining rapid drug release thereafter. That is, a particulate pharmaceutical composition for oral administration that achieves rapid dispersibility and dissolution in the digestive tract when concealing an unpleasant taste in the oral cavity (compliance compliance), and an oral cavity containing the composition Technology development regarding disintegrating tablets is necessary.

Japanese Patent No. 3296564 specification (I, II, IV type), Japanese Patent No. 3965155 (V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, and XIX types) International Publication No. WO2006 / 046109 Pamphlet International Publication No. WO2004 / 110407 Pamphlet International Publication No. WO2006 / 059224 Pamphlet International Publication No. WO2007 / 034316 Pamphlet International Publication No. WO95 / 20380 (corresponding to US Pat. No. 5,576,014) International Publication No. WO02 / 92057 (corresponding US Pat. No. 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 JP 2005-522444 A

The present invention relates to a particulate pharmaceutical composition for oral administration that can reduce or reduce a change in drug elution rate even after compression molding while reducing the initial drug elution amount of atorvastatin and maintaining rapid drug release thereafter. And an orally disintegrating tablet containing the composition.
The present invention also provides a particulate pharmaceutical composition for oral administration which achieves rapid dispersibility and dissolution in the digestive tract when atorvastatin is used to conceal an unpleasant taste in the mouth (compliance compliance), and An orally disintegrating tablet containing the composition is provided.

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 a granular pharmaceutical composition for oral administration that achieves rapid dispersibility and dissolution in the digestive tract when concealing an unpleasant taste in the mouth (compliance compliance), (1) The particulate pharmaceutical composition for oral administration, in which particles containing atorvastatin and sodium lauryl sulfate are coated with a coating material containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance, the desired effect of the present invention described in detail below (2) a drug based on the interaction between atorvastatin and a specific base The delayed elution induces a decrease in bioavailability, and the desired effect of the present invention is achieved by the selection and use of a specific polymer substance; (3) the pharmaceutical composition for oral administration described above; By confirming that the orally disintegrating tablet contained has the desired effects of the present invention, the present invention has been completed.

That is, the present invention
[1] Particulate pharmaceutical for oral administration in which particles containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate are coated with a coating substance containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance Composition,
[2] The water-soluble polymer substance is selected from the group consisting of hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose, povidone, copolyvidone, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, and polyethylene oxide 1 A particulate pharmaceutical composition for oral administration according to [1], which is a species or two or more species,
[3] The particulate pharmaceutical composition for oral administration according to [1], wherein the water-soluble polymer substance is hypromellose,
[4] A particulate pharmaceutical composition for oral administration according to any one of [1] to [3], further comprising a fluidizing agent in the coating substance,
[5] One or two fluidizing agents selected from the group consisting of metal silicates, silicon dioxides, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, and metal hydroxides The above-mentioned particulate pharmaceutical composition for oral administration according to [4],
[6] The fluidizing agent is talc, kaolin, calcium silicate, magnesium silicate, light anhydrous silicic acid, magnesium stearate, calcium stearate, iron oxide, titanium oxide, calcium carbonate, calcium phosphate, gypsum, magnesium carbonate, hydroxide Aluminum, hydrous silicon dioxide, crystalline cellulose, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, corn starch, magnesium aluminate metasilicate, calcium hydrogen phosphate granules, and glyceryl monostearate [1] a particulate pharmaceutical composition for oral administration, which is one or more selected from the group consisting of:
[7] The particulate pharmaceutical composition for oral administration according to [4], wherein the fluidizing agent is talc,
[8] An orally disintegrating tablet comprising the particulate pharmaceutical composition for oral administration according to any one of [1] to [7],
[9] A granular pharmaceutical composition for oral administration, in which particles containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate are coated with a coating substance containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance. Manufacturing method,
[10] The water-soluble polymer substance is selected from the group consisting of hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose, povidone, copolyvidone, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, and polyethylene oxide. A method for producing a particulate pharmaceutical composition for oral administration according to [9], which is a species or two or more species,
[11] The method for producing a granular pharmaceutical composition for oral administration according to [9], wherein the water-soluble polymer substance is hypromellose.
[12] The method for producing a granular pharmaceutical composition for oral administration according to any one of [9] to [11], further comprising a fluidizing agent in the coating substance,
[13] One or two fluidizing agents selected from the group consisting of metal silicates, silicon dioxides, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, and metal hydroxides [12] The method for producing a particulate pharmaceutical composition for oral administration according to the above,
[14] The fluidizing agent is talc, kaolin, calcium silicate, magnesium silicate, light anhydrous silicic acid, magnesium stearate, calcium stearate, iron oxide, titanium oxide, calcium carbonate, calcium phosphate, gypsum, magnesium carbonate, hydroxide Aluminum, hydrous silicon dioxide, crystalline cellulose, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, corn starch, magnesium aluminate metasilicate, calcium hydrogen phosphate granules, and glyceryl monostearate [12] A method for producing a particulate pharmaceutical composition for oral administration according to [12], which is one or more selected from the group consisting of
[15] The method for producing a granular pharmaceutical composition for oral administration according to [12], wherein the fluidizing agent is talc,
[16] Polyvinyl acetal diethylamino for producing a granular pharmaceutical composition for oral administration which is coated with particles containing atorvastatin or a pharmaceutically acceptable salt thereof and reduces the change in release rate even after compression molding The use of acetate and water-soluble polymeric substances.

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 It is possible to achieve quick elution in the case of (4) taking compliance and preventing delay in absorption, and the like.

It is an elution profile obtained with the particulate pharmaceutical composition (masking particles before tableting) prepared in Example 1 and an orally disintegrating tablet (after tableting) containing the same. It is an elution profile obtained with the particulate pharmaceutical composition (masking particles before tableting) prepared in Example 2 and an orally disintegrating tablet (after tableting) containing the same. It is an elution profile obtained with the particulate pharmaceutical composition (masking particles before tableting) prepared in Example 3 and the orally disintegrating tablet (after tableting) containing the same. It is the dissolution profile obtained with the particulate pharmaceutical composition (masking particles before tableting) prepared in Example 4 and the orally disintegrating tablet (after tableting) containing the same. It is the dissolution profile obtained by the particulate pharmaceutical composition (masking particle before tableting) prepared in Comparative Example 1 and the orally disintegrating tablet (after tableting) containing it. Regarding the particulate pharmaceutical composition (masking particles before tableting) prepared in Comparative Example 2, water, Japanese Pharmacopoeia dissolution test 1st liquid (JP1), and Japanese Pharmacopoeia dissolution test 2nd liquid (JP2) were used as test solutions. It is the elution profile obtained in this way. For the particulate pharmaceutical composition (masking particles before tableting) prepared in Comparative Example 3, water, Japanese Pharmacopoeia Dissolution Test 1st Liquid (JP1), and Japanese Pharmacopoeia Dissolution Test 2nd Liquid (JP2) were used as test solutions. It is the elution profile obtained in this way. For the particulate pharmaceutical composition (masking particles before tableting) prepared in Comparative Example 4, water, Japanese Pharmacopoeia Dissolution Test 1st Liquid (JP1), and Japanese Pharmacopoeia Dissolution Test 2nd Liquid (JP2) were used as test liquids. It is the elution profile obtained in this way. Regarding the particulate pharmaceutical composition (masking particles before tableting) prepared in Example 3, water, Japanese Pharmacopoeia dissolution test 1st liquid (JP1), and Japanese Pharmacopoeia dissolution test 2nd liquid (JP2) were used as test solutions. It is the elution profile obtained in this way. Regarding the particulate pharmaceutical composition (masking particles before tableting) prepared in Example 5, water, Japanese Pharmacopoeia dissolution test 1st liquid (JP1), and Japanese Pharmacopoeia dissolution test 2nd liquid (JP2) were used as test solutions. It is the elution profile obtained in this way. 2 is an elution profile obtained by conducting a liquid displacement elution test on the particulate pharmaceutical compositions (masking particles before tableting) prepared in Example 3 and Comparative Examples 2 to 4. It is a graph which shows the collection | recovery rate of the precipitation fraction collect | recovered by mixing after mixing sodium lauryl sulfate (SLS) and polyvinyl acetal diethylaminoacetate "(AEA) under acidic conditions, shaking for 30 minutes.

Hereinafter, the particulate pharmaceutical composition for oral administration 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 of the present invention and for coating the intermediate layer and the coating material used in the present invention. The core is composed of the drug itself or pharmaceutically acceptable additives. Particles [eg, crystalline cellulose (grains) (may be described as microcrystalline cellulose), lactose, starch, etc.] can also be used. It is also possible to use a drug alone or a mixture of a drug and a pharmaceutically acceptable additive. You may manufacture the particle | 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 this specification, regarding “change in release rate after compression molding”, the time when 10% of atorvastatin is eluted from the masking particles before tableting is made as “T _10% (before tableting)” at 2-3 kN. When the time for 10% dissolution of atorvastatin from the orally disintegrating tablet containing masking particles is “T _10% (after tableting)”, T _10% (after tableting) / T _10% (before tableting) When the rate of change with respect to the defined T of _10% is 30 to 100%, a further embodiment is 50 to 100%, and a further embodiment is 70 to 100%, it is defined that the dissolution enhancement by tableting is reduced.

In the present invention, “rapid dispersibility / dissolution” means that when a test is performed using 900 mL of Japanese Pharmacopoeia Dissolution Test Solution 1 (JP1) according to the 15th revised Japanese Pharmacopoeia Dissolution Test Method 2, It means that the elution rate at 15 minutes is 50% or more. In another embodiment, it means that the dissolution rate in 15 minutes is 60% or more.

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 particulate pharmaceutical composition for oral administration according to the present invention is such that particles containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate are coated with a coating substance containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance. It is a particulate pharmaceutical composition for oral administration.
The orally disintegrating tablet of the present invention is an orally disintegrating tablet comprising the particulate pharmaceutical composition for oral administration of the present invention.

Atorvastatin or a pharmaceutically acceptable salt thereof used in the present invention is atorvastatin calcium hydrate, chemical name [R- (R *, R *)] disclosed in US Pat. No. 5,273,995. -2- (4-Fluorophenyl) -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. Moreover, sodium lauryl sulfate will not be specifically limited if it has a function which improves the solubility of polyvinyl acetal diethylamino acetate. Examples of sodium lauryl sulfate include trade names NIKKOL SLS (Nikko Chemicals), Emar 0 (Kao), TEXAPON K12 P PH (Cognis Japan), and TEXAPON K12 G PH (Cognis Japan).

The amount of sodium lauryl sulfate is not particularly limited as long as it is pharmaceutically acceptable and improves the dispersibility of atorvastatin or a pharmaceutically acceptable salt thereof. , Atorvastatin or a pharmaceutically acceptable salt thereof, 30 wt% or more and 200 wt% or less, in another embodiment, 40 wt% or more and 100 wt% or less, and in another embodiment, atorvastatin or a pharmaceutical product thereof It can be 60 wt% or more and 100 wt% or less based on the amount of salt allowed.
The amount of sodium lauryl sulfate is not particularly limited as long as it is an amount that improves the solubility of polyvinyl acetal diethylaminoacetate. 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.

“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%.

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 polyvinyl acetal diethylaminoacetate, and the “particulate pharmaceutical composition” is coated with the coating substance, so that the drug substance from the “particulate pharmaceutical composition” is compressed after compression molding. There is no particular limitation as long as it has a function of reducing 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 polyvinyl acetal diethylaminoacetate and water-soluble polymer substance used in the present invention, usually depending on purposes such as physical properties of the drug, stability, absorption site, type and use of dosage form, An appropriate blending amount is appropriately selected. The amount of the water-soluble polymer substance is, for example, from 1% by weight to 30% by weight with respect to polyvinyl acetal diethylaminoacetate. In another embodiment, the amount is from 5% by weight to 20% by weight, and in a further embodiment, from 5% by weight to 15%. % By weight or less.

An appropriate ratio is appropriately selected for the coating amount of the coating material containing the polyvinyl acetal diethylaminoacetate and the water-soluble polymer material in the present invention. 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.

The particulate pharmaceutical composition of the present invention can employ an embodiment in which a “fluidizing agent” is blended as desired. The blending of the fluidizing agent is not particularly limited during a specific production method. For example, when the “particulate pharmaceutical composition” of the present invention is produced by a fluidized bed granulation method, mixing of the components and particles As the material dries, static electricity is generated, which may hinder fluidization. The fluidizing agent has a function of neutralizing generated static electricity and the like, and is not particularly limited as long as it improves fluidization during coating. 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. With respect to polyvinyl acetal diethylaminoacetate, it is, for example, 1% by weight or more and 200% by weight or less, and in another aspect, it is 5% by weight or more and 100% by weight or less, and in a further aspect, it is 20% by weight or more and 60% by weight or less.

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 of 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. Publication No. 5-271054 (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), International Drugs of known orally disintegrating tablets described in published WO98 / 02185 pamphlet (US patent 6287596) and international published WO2008 / 032767 pamphlet (US published patent application 2008/0085309) The particulate pharmaceutical composition is applied as An orally disintegrating tablet base described in the report 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 of the present invention can be contained in these orally disintegrating tablets.

Orally disintegrating tablets are generally classified into a mold type, a moist type, and a normal tableting type, and the particulate pharmaceutical composition of the present invention may be contained in any type of orally disintegrating tablet. The mold-type orally disintegrating tablet is prepared by filling a mold with a solution or suspension such as an excipient as disclosed in, for example, Japanese Patent No. 2807346 (US Pat. No. 5,466,464). It is made by drying. The mold-type orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention is, for example, a solution or suspension of the particulate pharmaceutical composition of the present invention, excipients such as sugars, and binders such as gelatin and agar. After filling the PTP pocket with the liquid, it can be produced by removing moisture by a method such as freeze drying, drying under reduced pressure, or low temperature drying. Wet type orally disintegrating tablets are moistened with excipients such as saccharides as shown in Patent No. 3069458 (U.S. Pat. No. 5,018,618, U.S. Pat. No. 5,720,974). After tableting under low pressure, the product is dried. Therefore, for example, the particulate pharmaceutical composition of the present invention, an excipient such as a saccharide can be wetted with a small amount of water or a mixture of water and alcohol, and the wet mixture can be molded at a low pressure and dried.

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 of the present invention, for example, International Publication No. WO95 / 20380 (US Patent No. 5576014), Patent No. 2919771 As described in the document, the particulate pharmaceutical composition of the present invention and an excipient such as a saccharide having a low moldability are mixed with a solution or suspension of a saccharide or a water-soluble polymer having a high moldability. After granulation, the granulated product can be compression-molded to form a compressed molded product, or the compressed molded product can be humidified and dried to produce an orally disintegrating tablet. 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, the particulate pharmaceutical composition of the present invention is used. An orally disintegrating tablet can be produced by compression molding using an amorphous sugar and an excipient such as a product and a crystalline saccharide, followed by humidification and drying. 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 specification), for example, A mixture of a particulate pharmaceutical composition, an excipient, and a saccharide having a melting point lower than that of the excipient is compression-molded and heated to form a crosslink by melting and solidifying the saccharide having a lower melting point. Orally disintegrating tablets can be prepared. By such humidification drying or heat treatment, the tablet strength of the orally disintegrating tablet can be improved. 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 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.

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.

“Crystalline saccharide” is pharmaceutically acceptable, and examples thereof include mannitol, maltitol, erythritol, xylitol and the like. These may be used alone or in combination of two or more. “Amorphous saccharides” are pharmaceutically acceptable and include, for example, lactose, sucrose, glucose, sorbitol, maltose, trehalose, etc., and these saccharides may be used alone or in combination of two or more. It is also possible to use it.

In addition, the “saccharide having a high melting point” is pharmaceutically acceptable, and examples thereof include xylitol, trehalose, maltose, sorbitol, erythritol, glucose, sucrose, maltitol, mannitol and the like. One or two or more of these may be used in appropriate combination. The “sugar having a low melting point” is pharmaceutically acceptable, and examples thereof include xylitol, trehalose, maltose, sorbitol, erythritol, glucose, sucrose, maltitol, mannitol and the like. These saccharides can also be used alone or in combination of two or more. 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 for the orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention, or the total amount of the excipient in the whole preparation is the blending amount of the particulate pharmaceutical composition of the present invention and / or Or it is suitably adjusted according to the size of the tablet and the like, but usually 20 mg or more and 1000 mg or less per tablet is preferable, 50 mg or more and 900 mg or less is preferable as another aspect, and 50 mg or more and 800 mg or less is preferable as a further aspect.

The blending amount of highly moldable saccharides, water-soluble polymers, amorphous saccharides, and saccharides with a low melting point is 0.5 wt. % Or more and 50% by weight or less is preferable, and in another embodiment, it is 1% by weight or more and 40% by weight or less, and in a further embodiment, it is 2% by weight or more and 30% by weight or less, or 1% by weight or more and 20% by weight or less % Or less is preferred.

The 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 of the present invention, a particulate pharmaceutical composition equivalent to 0.5% by weight or more and 90% by weight or less of the whole orally disintegrating tablet can be contained. 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 of 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, polyethylene glycol, talc, stearic acid and the like.
Examples of the colorant include yellow ferric oxide, red ferric oxide, edible yellow No. 4, No. 5, edible red No. 3, No. 102, and edible blue No. 3.
Buffers include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid Boric acid or a salt thereof.
Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.
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 according to the present invention, the coating substance containing polyvinyl acetal diethylaminoacetate and the water-soluble polymer substance may be directly coated on the core containing the drug, or one layer or two or more layers. It may be coated after coating. In the case of coating after coating one layer or two or more layers, for example, an “intermediate layer” is formed between a coating substance containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance and a nucleus containing a drug. It may be arranged. The “intermediate layer” means a coating layer containing one or more water-soluble insolubilizers and one or more water-soluble insolubilizers. The intermediate layer can be directly coated on the core containing the drug. Further, the intermediate layer may be coated after the drug-containing core is coated in advance as a coating layer of one layer or two or more components that do not prevent the formation of lag time and subsequent rapid drug release. The intermediate layer contains two or more kinds of essential components (insolubilization accelerator and insolubilizing substance), and these plural essential components can be contained in one layer and covered. May be uniform or unevenly distributed. 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 of the present invention, an embodiment in which the above-mentioned pharmaceutical excipient is further coated on the outside of the coating layer containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance can be employed. 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. 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 of this invention is demonstrated below, these do not limit this invention.
The particulate pharmaceutical composition of the present invention can be produced by a method known per se, such as coating, drying, heat treatment, tableting and the like.
In order to obtain the particulate pharmaceutical composition of the present invention, the core containing the drug is coated with the coating substance of 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 outer side of the core containing the drug, or the particulate pharmaceutical composition of the present invention may be further coated with a pharmaceutical excipient and then coated with the coating substance of the present invention.

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. .

As the use of the polyvinyl acetal diethylaminoacetate and the water-soluble polymer substance of the present invention, a granular pharmaceutical composition for oral administration is produced in which drug-containing particles having a bitter taste are coated and the change in release rate is reduced even after compression molding. The use of polyvinyl acetal diethylaminoacetate and a water-soluble polymeric substance for the purpose of this invention is referred to the description of the particulate pharmaceutical composition of the present invention for a detailed description of the invention.

The manufacturing method of the orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention will be described below.
As an example, in the case of an orally disintegrating tablet described in the pamphlet of International Publication No. WO95 / 20380 (US Patent No. 5576014), the particulate pharmaceutical composition of the present invention and a saccharide having low moldability are mixed. Then, it is possible to employ a step of compressing and molding the granulated product by spraying the mixture with a highly moldable saccharide as a binder and coating and / or granulating the mixture. 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 (US patent application publication No. 2003/099701 specification), the particulate pharmaceutical composition of the present invention, melting point A high-excipient excipient and a saccharide with a low melting point are mixed, and the mixture is sprayed with a binder for orally disintegrating tablets to coat and / or granulate, and the granulated product can be compression-molded. 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:

(1) Preparation of the first layer Sodium lauryl sulfate (product of Nikko Chemicals, product name Nikkor SLS, hereinafter the same) 3.25 kg and hypromellose (HPMC) (product of Shin-Etsu Chemical Co., product name TC-5E, unless otherwise specified) The same) 5.42 kg of atorvastatin calcium trihydrate (manufactured by Pfizer Inc., the same hereinafter) was added to a solution obtained by dissolving 2.17 kg in 43.36 kg of purified water to prepare a dispersion. Using a fluidized bed granulator, the prepared dispersion is sprayed onto 5.42 kg of crystalline cellulose (grain) (Asahi Kasei Chemicals, product name CP-102Y, the same shall apply hereinafter) to prepare particles covering the first layer. did.

(2) Preparation of the second layer For 7.8 kg of particles coated with the first layer, 1.33 kg of sodium citrate dihydrate (manufactured by Wako Pure Chemical Industries, the same shall apply hereinafter) and methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., product name) A solution in which 1.17 kg of SM-4 (same below) was dissolved in 30.96 kg of purified water was sprayed using a fluidized bed granulator to prepare particles coated with the second layer.

(3) Preparation of third layer For 600.0 g of particles coated with the second layer, a solution obtained by dissolving 30.0 g of methylcellulose in 720.0 g of purified water is sprayed using a fluidized bed granulator, and the third layer is sprayed. Coated particles were prepared.

(4) Preparation of Fourth Layer 1368.0 g of methanol was added to and mixed with a solution of 7.5 g of hypromellose in 342.0 g of purified water to prepare a hypromellose solution (water / alcohol mixture). To this hypromellose solution, 52.5 g of polyvinyl acetal diethylaminoacetate (AEA) (Mitsubishi Chemical Foods, product name AEA, the same below) is added and dissolved, and talc (Matsumura Sangyo Co., Ltd., product name High Filler, same below) is dissolved. 30.0 g was added and dispersed. This dispersion was sprayed onto 300.0 g of particles coated with the third layer using a fluidized bed granulator to produce a particulate pharmaceutical composition (masking particles) of the present invention.

(5) Preparation of orally disintegrating tablets Maltose using a fluidized bed granulator, a mixture of 557.8 g of mannitol (ROQUETTE, product name PEARLITOL 50C) and 6.5 g of maltose (product name: San Malto S, product of Hayashibara Shoji) Granulation was performed with 258 g of an aqueous solution (including 51.6 g of maltose) to prepare a granulated product for orally disintegrating tablets. After mixing this granulated material 234.56 mg and the particulate pharmaceutical composition (masking particles) 58.6 mg of the present invention, and filling this mixture into a 9.5 mm diameter mortar, Autograph (manufactured by Shimadzu Corporation, AGS-20KNG, The same applies hereinafter) and tableting was carried out at various pressures (2.0 kN and 3.0 kN) to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention.

Example 2:

(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 The particles coated with the second layer were prepared by spraying using the apparatus.

(2) Preparation of the 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 is sprayed using a fluidized bed granulator to cover the third layer. Particles were prepared.

(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 to produce a particulate pharmaceutical composition (masking particles) of the present invention.

(4) Preparation of orally disintegrating tablet The granulated product 252.6 mg for the orally disintegrating tablet prepared in Example 1 and 63.2 mg of the granular pharmaceutical composition (masking particle) of the present invention were mixed, and the mixture was mixed with a diameter. After filling a 9.5 mm mortar, the tablet was tableted with various pressures (2.0 kN and 3.0 kN) using an autograph to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention.

Example 3:

(1) Preparation of the third layer 1824.0 g of methanol was added to and mixed with a solution obtained by dissolving 8.1 g of hypromellose in 456.0 g of purified water 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 second layer prepared in Example 1 using a fluidized bed granulator to produce the particulate pharmaceutical composition (masking particles) of the present invention. .

(2) Preparation of Orally Disintegrating Tablets 240.6 mg of the granulated product for orally disintegrating tablets prepared in Example 1 and 60.2 mg of the granular pharmaceutical composition (masking particles) of the present invention were mixed, and this mixture was mixed with a diameter. After filling a 9.5 mm mortar, the tablet was tableted with various pressures (2.0 kN and 3.0 kN) using an autograph to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention.

Example 4:

(1) Preparation of fourth layer 2964.0 g of methanol was added to and mixed with a solution obtained by dissolving 13.1 g of hypromellose in 741.0 g of purified water to prepare a hypromellose solution (water / alcohol mixed solution). Subsequently, 141.5 g of polyvinyl acetal diethylaminoacetate was added and dissolved in this hypromellose solution, and 40.4 g of talc was added and dispersed. This dispersion was sprayed onto 300.0 g of particles coated with the third layer prepared in Example 2 using a fluidized bed granulator to produce particles coated with the fourth layer.

(2) Preparation of the fifth layer 15.5 g of mannitol was dissolved in 139.5 g of purified water. This mannitol solution was sprayed onto 310.0 g of the particles coated with the fourth layer using a fluidized bed granulator to produce the particulate pharmaceutical composition (masking particles) of the present invention.

(3) Preparation of Orally Disintegrating Tablets 251.0 mg of the granulated product for orally disintegrating tablets prepared in Example 1 and 62.8 mg of the granular pharmaceutical composition (masking particles) of the present invention were mixed, and this mixture was mixed with a diameter. After filling a 9.5 mm mortar, the tablet was tableted with various pressures (2.0 kN and 3.0 kN) using an autograph to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention.

Example 5:

(1) Preparation of the first layer 300.0 g of atorvastatin calcium trihydrate was added with stirring to 300.0 g of sodium lauryl sulfate and 120.0 g of hypromellose in 2880.0 g of purified water to prepare a dispersion. The prepared dispersion was sprayed onto 300.0 g of crystalline cellulose (grains) using a fluidized bed granulator to prepare particles covering the first layer.

(2) Preparation of the second layer To 300.0 g of particles coated with the first layer, a solution obtained by dissolving 64.3 g of sodium lauryl sulfate and 25.7 g of methylcellulose in 1195.7 g of purified water is sprayed using a fluidized bed granulator. Then, particles coated with the second layer were prepared.

(3) 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 is sprayed using a fluidized bed granulator, and the third layer is sprayed. Coated particles were prepared.

(4) Preparation of the fourth layer 1824.0 g of methanol was added to and mixed with 8.1 g of hypromellose dissolved in 456.0 g of purified water 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 to produce a particulate pharmaceutical composition (masking particles) of the present invention.

(5) Preparation of orally disintegrating tablet 229.6 mg of the granulated product for orally disintegrating tablet prepared in Example 1 and 70.4 mg of the granular pharmaceutical composition (masking particle) of the present invention were mixed, and the mixture was mixed with a diameter. After filling a 9.5 mm mortar, the tablet is tableted at various pressures (2.0 kN and 3.0 kN) using an autograph to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of the present invention.

Comparative Example 1:

(1) Preparation of Fourth Layer 57.3 g of polyvinyl acetal diethylaminoacetate was dissolved in a mixed solution of 342.0 g of purified water and 1368.0 g of methanol, and 32.7 g of talc was added and dispersed. This dispersion is sprayed onto 300.0 g of particles coated with the third layer prepared in Example 1 using a fluidized bed granulator to produce a particulate pharmaceutical composition (masking particles) of Comparative Example 1. did.

(2) Preparation of orally disintegrating tablet 234.6 mg of granulated product for orally disintegrating tablet prepared in Example 1 and 58.6 mg of particulate pharmaceutical composition (masking particle) of Comparative Example 1 were mixed. After filling a 9.5 mm diameter mortar, the tablet was tableted with various pressures (2.0 kN and 3.0 kN) using an autograph to produce an orally disintegrating tablet containing the particulate pharmaceutical composition of Comparative Example 1.

Comparative Example 2:

(1) Preparation of third layer A solution obtained by dissolving 2.3 g of polysorbate 80 (Tween 80) (product of Merck; product name Tween 80) in 138.0 g of purified water was used as an aminoalkyl methacrylate copolymer aqueous dispersion (Evonik Degussa GmbH, Product name Eudragit RS30D) was added to 173.0 g to prepare Eudragit RS solution. A hypromellose solution prepared by dissolving 5.8 g of hypromellose in 880.9 g of purified water was added to the Eudragit RS solution prepared above to prepare a coating solution. Using a fluidized bed granulator, the particles coated with 300.0 g of the second layer prepared in Example 1 were sprayed to produce the particulate pharmaceutical composition (masking particles) of Comparative Example 2.

Comparative Example 3:

76.4 g of hypromellose acetate succinate (manufactured by Shin-Etsu Chemical Co., Ltd., product name HPMC-AS HF) was dissolved in a mixed solution consisting of 570.0 g of purified water and 2280.0 g of ethanol, and 43.6 g of talc was added and dispersed. This dispersion is sprayed onto 300.0 g of particles coated with the second layer prepared in Example 1 using a fluidized bed granulator to produce a particulate pharmaceutical composition (masking particles) of Comparative Example 3. did.

Comparative Example 4:

Hydroxylcellulose (manufactured by Nippon Soda Co., Ltd., product name HPC-SL) 84.0 g and ethylcellulose (Dow Chemical Co., Ltd., Etocel STD10) 36 g were dissolved in methanol 1080.0 g to prepare a coating solution. This coating solution is sprayed onto 300.0 g of particles coated with the second layer prepared in Example 1 using a fluidized bed granulator to produce a particulate pharmaceutical composition (masking particles) of Comparative Example 4. did.

Experimental Example 1: Dissolution test of particulate pharmaceutical composition and orally disintegrating tablet Particulate pharmaceutical composition prepared in Examples 1 to 4 or Comparative Example 1 (masking particles before tableting (described as “0 kN” in the table)) And orally disintegrating tablets containing them (after tableting, described as “2 kN” and “3 kN” in the table), using an automatic 6-dissolution tester, perform dissolution test according to Japanese Pharmacopoeia Dissolution Test Method 2 went. The drug content was 10 mg, and 900 mL of Japanese Pharmacopoeia dissolution test second liquid (JP2) was used as the test solution (paddle rotation speed: 100 rotations / minute).
The elution profiles obtained as a result of the test are shown in FIGS. Further, T _10% of the oral disintegrating tablet calculated from the elution profile, and the rate of change with respect to T _10% of the particulate pharmaceutical composition of the tableting shown in Tables 9 to 13. T _10% represents the time to elution rate of 10%, and the change rate with respect to T _10% was calculated from the following equation.
T _10% change rate (%) = T _10% (after tableting) / T _10% (before tableting)

Experimental Example 2: Dissolution test of particulate pharmaceutical composition Japanese Pharmacopoeia dissolution of particulate pharmaceutical compositions of Comparative Examples 2 to 4 and Examples 3 and 5 (masking particles before tableting) using an automatic 6-series dissolution tester The dissolution test was performed according to Test Method No. 2. The drug content was 10 mg, and 900 mL each of water, Japanese Pharmacopoeia dissolution test 1st liquid (JP1), and Japanese Pharmacopoeia dissolution test 2nd liquid (JP2) were used (paddle rotation speed: 100 rotations / minute). The elution profiles obtained as a result of the test are shown in FIGS.

In Comparative Example 2 (masking particles coated with a third film comprising aminoalkyl methacrylate copolymer RS, hypromellose (TC-5E), polysorbate 80), elution with JP1 was insufficient (FIG. 6).
In Comparative Example 3 (masking particles coated with a third membrane composed of hypromellose acetate succinate and talc), elution with JP1 was insufficient and the length of lag time was also insufficient (FIG. 7). .
In Comparative Example 4 (masking particles coated with a third film composed of ethyl cellulose and hydroxypropyl cellulose), although lag time was formed, elution with JP1 was insufficient (FIG. 8).
In Example 3 (masking particles provided with a third film made of polyvinyl acetal diethylaminoacetate, talc, and hypromellose (TC-5E)), sufficient lag time and high elution with JP1 were achieved (FIG. 9).
In Example 5 (sodium lauryl sulfate / polyvinyl acetal diethylaminoacetate = 1.57), higher elution with JP1 was achieved compared to Example 3 (sodium lauryl sulfate / polyvinyl acetal diethylaminoacetate = 0.63) (FIG. 10).

Experimental Example 3: Liquid Displacement Dissolution Test of Particulate Pharmaceutical Composition Dissolution of Example 3 or Comparative Examples 2 to 4 (masking particles before tableting) reflecting vivo using an automatic 6-series dissolution tester The test was conducted. 30 minutes after adding a particulate pharmaceutical composition containing 10 mg of drug to JP1 300 mL, 600 mL of 5-fold concentrated JP2 was added thereto, and dissolution of the drug from the preparation was measured (paddle rotation speed: 50 rotations / Min).
In addition, the drug dissolution rate from the preparation after 45 minutes obtained in this test correlates with Cmax and AUC in the dog oral administration test.
The obtained elution profile is shown in FIG. The particulate pharmaceutical composition coated with polyvinyl acetal diethylaminoacetate (Example 3) has a higher D45min (drug elution rate after 45 minutes) than the particulate pharmaceutical composition coated with a film comprising other components in the liquid replacement test. showed that.

Experimental Example 4:
10 mg of polyvinyl acetal diethylaminoacetate (AEA) was dissolved in 30 mL of 0.1N and 0.01N hydrochloric acid, and sodium lauryl sulfate (SLS) was added to the container so that the weight ratio with respect to polyvinyl acetal diethylaminoacetate was 0.01 to 2, and the container was sealed. After shaking for 30 minutes, the precipitated fraction was separated by centrifuging at 3000 rpm for 15 minutes, dried and then weighed.
The results are shown in FIG. In the range where the SLS / AEA ratio was small, precipitates thought to be due to the ion complex were observed, but when the SLS / AEA ratio was increased, polyvinyl acetal diethylaminoacetate was dissolved.

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 (16)

1. A particulate pharmaceutical composition for oral administration, wherein particles containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate are coated with a coating substance containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance.
2. The water-soluble polymer substance is one or two selected from the group consisting of hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose, povidone, copolyvidone, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, and polyethylene oxide The particulate pharmaceutical composition for oral administration according to claim 1, which is a species or more.
3. The particulate pharmaceutical composition for oral administration according to claim 1, wherein the water-soluble polymer substance is hypromellose.
4. The particulate pharmaceutical composition for oral administration according to any one of claims 1 to 3, further comprising a fluidizing agent in the coating substance.
5. The fluidizing agent is one or more selected from the group consisting of metal silicates, silicon dioxide, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, and metal hydroxides. The particulate pharmaceutical composition for oral administration according to claim 4.
6. Fluidizers 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, water content Group consisting of silicon dioxide, crystalline cellulose, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, corn starch, magnesium aluminate metasilicate, calcium hydrogen phosphate granule, and glyceryl monostearate The particulate pharmaceutical composition for oral administration according to claim 4, which is one or more selected from the above.
7. The particulate pharmaceutical composition for oral administration according to claim 4, wherein the fluidizing agent is talc.
8. An orally disintegrating tablet comprising the particulate pharmaceutical composition for oral administration according to any one of claims 1 to 7.
9. A method for producing a granular pharmaceutical composition for oral administration, comprising coating particles containing atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate with a coating material containing polyvinyl acetal diethylaminoacetate and a water-soluble polymer substance. .
10. The water-soluble polymer substance is one or two selected from the group consisting of hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose, povidone, copolyvidone, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, and polyethylene oxide The manufacturing method of the particulate-form pharmaceutical composition for oral administration of Claim 9 which is a seed | species or more.
11. The method for producing a granular pharmaceutical composition for oral administration according to claim 9, wherein the water-soluble polymer substance is hypromellose.
12. The method for producing a granular pharmaceutical composition for oral administration according to any one of claims 9 to 11, further comprising a fluidizing agent in the coating substance.
13. The fluidizing agent is one or more selected from the group consisting of metal silicates, silicon dioxide, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, and metal hydroxides. The manufacturing method of the particulate-form pharmaceutical composition for oral administration of Claim 12.
14. Fluidizers 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, water content Group consisting of silicon dioxide, crystalline cellulose, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, corn starch, magnesium aluminate metasilicate, calcium hydrogen phosphate granule, and glyceryl monostearate The manufacturing method of the granular pharmaceutical composition for oral administration of Claim 12 which is 1 type, or 2 or more types selected from more.
15. The method for producing a granular pharmaceutical composition for oral administration according to claim 12, wherein the fluidizing agent is talc.
16. Polyvinyl acetal diethylaminoacetate and aqueous solution for producing a granular pharmaceutical composition for oral administration that coats particles containing atorvastatin or a pharmaceutically acceptable salt thereof and reduces the change in release rate even after compression molding Use of functional polymer substances.

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