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WO2012042951A1 - Comprimé médicinal contenant de l'atorvastatine - Google Patents

Comprimé médicinal contenant de l'atorvastatine Download PDF

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Publication number
WO2012042951A1
WO2012042951A1 PCT/JP2011/058279 JP2011058279W WO2012042951A1 WO 2012042951 A1 WO2012042951 A1 WO 2012042951A1 JP 2011058279 W JP2011058279 W JP 2011058279W WO 2012042951 A1 WO2012042951 A1 WO 2012042951A1
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Prior art keywords
atorvastatin
weight
pharmaceutical
tablet
pharmaceutical tablet
Prior art date
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Ceased
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PCT/JP2011/058279
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English (en)
Japanese (ja)
Inventor
佳之 早川
聡一郎 中村
▲高▼石　勇希
正範 小林
敬康 豊田
敦 上林
高橋　豊
迫　和博
啓之 梅島
均 河合
高之 吉田
武史 矢野
弘朗 田崎
近藤　啓
渡辺　俊典
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Astellas Pharma Inc
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Astellas Pharma Inc
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Priority to JP2012536240A priority Critical patent/JP5807642B2/ja
Publication of WO2012042951A1 publication Critical patent/WO2012042951A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a pharmaceutical tablet containing atorvastatin or a pharmaceutically acceptable salt thereof, which reduces the bitter taste of atorvastatin and has rapid drug dissolution.
  • the present invention comprises atorvastatin or a pharmaceutically acceptable salt thereof and glycyrrhizic acid or a pharmaceutically acceptable salt thereof, which reduces the bitter taste of atorvastatin and allows rapid drug dispersion.
  • the present invention relates to an orally disintegrating tablet having solubility and dissolution properties.
  • HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A
  • atorvastatin calcium hydrate is sold as Lipitor®, which has the chemical name [R- (R *, R *)]-2- (4-fluorophenyl) - ⁇ , ⁇ -dihydroxy- 5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid calcium salt (2: 1) trihydrate and has the following formula:
  • Atorvastatin and its pharmaceutically acceptable salts are selective and competitive inhibitors of HMG-CoA reductase.
  • Atorvastatin calcium is a potent lipid-lowering compound and is therefore useful as a lipid-lowering agent and / or cholesterol-lowering agent, and at the same time useful for the treatment of osteoporosis, benign prostatic hypertrophy (BPH), and Alzheimer's disease. is there.
  • atorvastatin or a pharmaceutically acceptable salt thereof in a pure crystalline form so that a formulation containing atorvastatin or a pharmaceutically acceptable salt thereof can meet strict pharmaceutical requirements and standards There is a need. Furthermore, the method 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 the need for special storage conditions. So far, various crystal forms of atorvastatin or a pharmaceutically acceptable salt thereof have been disclosed (Patent Documents 1 and 2).
  • atorvastatin is a poorly soluble drug, its in-vitro dispersibility and dissolution properties are poor, resulting in a problem of reduced bioavailability.
  • a method of changing a crystal to an amorphous form there is a method of changing a crystal to an amorphous form.
  • atorvastatin and optionally excipients are dissolved in a non-hydroxyl solvent to form a solution, and the solvent is lyophilized to provide an amorphous
  • a method for producing amorphous atorvastatin (Patent Document 4), which comprises producing quality atorvastatin.
  • a solid pharmaceutical composition comprising a solid dispersion with a pharmaceutically acceptable excipient which is a larger optional ingredient, comprising amorphous atorvastatin or a pharmaceutically acceptable complex, salt,
  • a solid pharmaceutical composition comprising a solvate or hydrate and a melt processable polymer is disclosed (Patent Document 5).
  • Patent Document 6 a method of heat treatment at a specific temperature is disclosed.
  • atorvastatin or a pharmaceutically acceptable salt thereof is a drug having a strong bitter taste.
  • the drug or the composition comprising the drug may be subjected to a treatment such as 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. Therefore, there is room for studying alternative technologies for coating.
  • an average particle diameter comprising a drug having a bitter taste and / or a drug having poor fluidity and a preparation carrier, which is spray-dried
  • a technique relating to an orally disintegrating tablet characterized in that it contains drug-containing particles having an apparent specific gravity of about 0.5 to about 1.2 and about 50 to about 250 ⁇ m is known.
  • saccharides are also exemplified (Patent Document 7).
  • Patent Document 7 when atorvastatin is applied, there is room for further improvement from the viewpoint of drug dissolution.
  • glycyrrhizic acid also called glycyrrhizin
  • glycyrrhizin is a white to slightly yellow crystalline powder (salt) obtained by acidifying an aqueous solution of glycyrrhizic acid extracted from licorice rhizomes or roots. Because of its sweetness, it is used as a sweetener and a corrigent. It is also known that glycyrrhizic acid itself has an anti-inflammatory effect.
  • oral particulate pharmaceutical compositions such as granules, fine granules, powders, etc. are smaller in size than tablets and capsules, and thus are easy to take even for patients who have difficulty swallowing tablets and capsules. .
  • the particulate pharmaceutical composition for oral administration is small in size, the specific surface area increases, so that the drug is rapidly released in the oral cavity after taking it, causing various problems. For example, if the drug has an unpleasant taste, the drug quickly released in the oral cavity may cause a strong discomfort to the patient and significantly reduce dosage compliance.
  • a saccharide having a low moldability is sprayed with a high moldability saccharide as a binder and coated and / or granulated, and when tablet strength is further required
  • Orally disintegrating tablets humidity-dried tablet
  • drug, diluent, and saccharide having a melting point relatively lower than that of the drug and the diluent are examples of orally disintegrating tablets.
  • Patent Document 10 An orally disintegrating tablet (Patent Document 10) 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%
  • Patent Document 11 An orally disintegrating tablet containing patented processed starches and saccharides
  • a drug having a bitter taste when applied to these orally disintegrating tablets, for example, a drug solution is sprayed onto a core made of crystalline cellulose to prepare drug-containing particles, and then a polymer suitable for the particles is prepared.
  • a method of applying a film coating with a substance is employed.
  • the film tears and the drug leaks out so it is technically very difficult to suppress the bitter taste of the drug in the oral cavity.
  • tableting is performed at a low pressure in order to avoid breakage of the coated film due to tableting, there is a concern that tablet hardness suitable for handling in the production process and transportation process cannot be obtained.
  • an acrylic polymer As a method for suppressing an unpleasant taste, use of an acrylic polymer is known. Oral administration containing a drug-containing core, an intermediate layer containing two types of water-soluble components, an insolubilization accelerator and an insolubilizing substance, and a water infiltration control layer that controls the rate of water intrusion into the outermost layer A time-release particulate pharmaceutical composition for use is known, and an acrylic acid polymer is exemplified as a material used for a water infiltration control layer (Patent Document 12). 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.
  • the present invention provides a pharmaceutical tablet, particularly an orally disintegrating tablet, which reduces the bitter taste of atorvastatin and has rapid drug dispersibility and dissolution.
  • the present invention provides a pharmaceutical tablet, particularly an orally disintegrating tablet, which has improved dosage compliance by reducing the unpleasant taste of atorvastatin in the oral cavity and has rapid dispersibility and dissolution of the drug in the digestive tract. To do.
  • the present inventors prepared a spray-dried product of atorvastatin and a saccharide as a pharmaceutical carrier for the purpose of concealing the bitter taste of atorvastatin, and produced a pharmaceutical tablet.
  • the elution of atorvastatin from the tablet is currently sold. I knew that there was room for further improvement in order to judge that it was equivalent to the tablet.
  • the present inventors have unexpectedly found that dipotassium glycyrrhizinate contained in pharmaceutical additives as a sweetener or a corrigent has been Knowing that the dispersibility and dissolution of atorvastatin are also improved, the present invention has been completed.
  • a pharmaceutical tablet comprising atorvastatin or a pharmaceutically acceptable salt thereof, and glycyrrhizic acid or a pharmaceutically acceptable salt thereof
  • Glycyrrhizic acid or a pharmaceutically acceptable salt thereof is di (di) potassium glycyrrhizinate, monosodium glycyrrhizinate, di (di) sodium glycyrrhizinate, tri (tri) sodium glycyrrhizinate, monoammonium glycyrrhizinate 1 or 2 or more pharmaceutical tablets selected from the group consisting of di (di) ammonium glycyrrhizinate, [3]
  • the amount of glycyrrhizic acid or a pharmaceutically acceptable salt thereof is 0.001 part by weight or more and 4 parts by weight or less based on 1 part by weight of atorvastatin, or 0.0005 weight / weight% or more
  • the carbonate or bicarbonate is one or more selected from the group consisting of calcium carbonate, sodium carbonate, ammonium carbonate, sodium bicarbonate, potassium bicarbonate, and magnesium carbonate.
  • the bitter taste of atorvastatin in the oral cavity can be reduced.
  • atorvastatin having an unpleasant taste is concealed with an unpleasant taste in the oral cavity.
  • an orally disintegrating tablet can be provided.
  • FIG. 2 is an dissolution profile obtained by conducting a liquid displacement dissolution test on an orally disintegrating tablet containing dipotassium glycyrrhizinate (Examples 1 to 3) and an orally disintegrating tablet not containing (Comparative Example 1).
  • 2 is an dissolution profile obtained by conducting a liquid displacement dissolution test on an orally disintegrating tablet (Examples 4 to 7) containing dipotassium glycyrrhizinate and an orally disintegrating tablet (Comparative Example 2) not containing it.
  • Example 6 is a graph showing the results of measuring the solubility when atorvastatin calcium trihydrate (Comparative Example 6) and glycyrrhizic acid or a pharmaceutically acceptable salt thereof (Examples 12 to 21) were added to JP1 solution. .
  • rapid dispersibility / dissolution means the fifteenth revised Japanese Pharmacopoeia General Test Method Dissolution Test Method Paddle Method Dissolution Test 1st Solution (JP1) 300mL was used to start the paddle method (50rpm) At the time of 30 minutes, JP1 was used in the liquid displacement dissolution test in which 600 mL of 5 times concentrated solution of the 15th revised Japanese Pharmacopoeia General Test Method Dissolution Test Method Paddle Method Dissolution Test Second Solution (JP2) was added. It is defined that the drug elution rate (JP1: D5min) after 5 minutes after the start of the test exceeds 30% (in another embodiment, 40% or more).
  • “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.
  • the “test solution assuming the oral cavity” means a pH 6.8 phosphate buffer solution (first fifth revised Japanese Pharmacopoeia, General Test Method, Dissolution Test Method, Paddle Method, Dissolution Test Solution 2 (JP2)). To do.
  • the pharmaceutical tablet (especially orally disintegrating tablet) of the present invention comprises atorvastatin or a pharmaceutically acceptable salt thereof, and glycyrrhizic acid or a pharmaceutically acceptable salt thereof, and has rapid drug dispersibility.
  • -It is a preparation with dissolution properties.
  • Atorvastatin or a pharmaceutically acceptable salt thereof used in the present invention is atorvastatin calcium hydrate, chemical name [R- (R *, R *)] disclosed in US Pat. No. 5,273,995. -2- (4-Fluorophenyl) - ⁇ , ⁇ -dihydroxy-5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid calcium salt 2: 1) Trihydrate is included. Atorvastatin calcium hydrate has the following formula: Currently marketed as Lipitor®. Atorvastatin or a pharmaceutically acceptable salt thereof is a selective and competitive inhibitor of HMG-CoA reductase.
  • Examples of pharmaceutically acceptable salts include metal salts such as alkali metals and alkaline earth metals, or amine salts such as organic amines.
  • a salt with sodium, potassium, lithium, calcium, magnesium, aluminum, iron, zinc, calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, magnesium aluminum hydroxide is used.
  • a salt with calcium can be mentioned.
  • Atorvastatin calcium is a potent lipid-lowering compound and is therefore useful as a lipid-lowering agent and / or cholesterol-lowering agent, and at the same time useful for the treatment of osteoporosis, benign prostatic hypertrophy (BPH), and Alzheimer's disease. is there.
  • atorvastatin examples include, for example, types I, II, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, and XIX.
  • type I may be mentioned.
  • "Type I crystal” is crystalline Form I atorvastatin hydrate disclosed in Japanese Patent No. 3,296,564.
  • the amount of atorvastatin or a pharmaceutically acceptable salt thereof is not particularly limited as long as it is a pharmaceutically preventive or therapeutically effective amount.
  • it is about 2.5 mg to about 80 mg per day. It is about 5 mg or more and about 500 mg or less, and as a further aspect, it is about 2.5 mg or more and about 80 mg or less.
  • it is administered to a patient at an adult dosage level of about 0.1 mg to about 8.0 mg / kg body weight per day.
  • the daily dose is in the range of about 0.1 mg / kg to about 2.0 mg / kg.
  • the blending amount can be changed or adjusted to 5 mg or more and 80 mg or less, and in another embodiment, 5 mg or more and 100 mg or less depending on efficacy or application.
  • 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.
  • 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.
  • it is 0.5 wt / wt% or more and 90 wt / wt% or less per “pharmaceutical tablet” or pharmaceutical preparation of the present invention, and in another embodiment, 0.5 wt / wt% or more and 80 wt / wt% or less. In a further embodiment, it is 0.5% by weight or more and 70% by weight or less.
  • a pharmaceutical preparation (formulation) is used, including an embodiment in which the composition includes atorvastatin and a pharmaceutical carrier.
  • the preparation carrier include saccharides such as maltose (preferably candy powder (containing maltose 83% or more): pharmaceutical additive standard 1998), glucose, maltitol, sorbitol, trehalose and the like. Another embodiment is maltose.
  • the composition can be produced, for example, by spray drying, coating and / or granulation.
  • examples of the spray drying method include a method of spray-drying a solution or suspension of atorvastatin and a saccharide.
  • atorvastatin or atorvastatin and a pharmaceutical carrier are dissolved or suspended in another additive (eg, excipient) and / or granulated.
  • another additive eg, excipient
  • the preparation method is explained in full detail about the preparation process of a melt
  • any method can be used as long as it is a method for preparing a solution or suspension for spray drying by dissolving or suspending atorvastatin and a pharmaceutical carrier in a pharmaceutically acceptable solvent.
  • the preparation carrier may be dissolved or suspended in a pharmaceutically acceptable solvent, and atorvastatin may be suspended therein to prepare a solution or suspension for spray drying.
  • the solvent used here is not particularly limited as long as it is a pharmaceutically acceptable solvent. Examples of such a solvent include water and organic solvents.
  • organic solvent examples include alcohols (eg, methanol, ethanol, propanol, isopropanol, etc.), halogenated alkanes (eg, dichloromethane, chloroform, chloroethane, trichloroethane, carbon tetrachloride, etc.), ketones (eg, acetone, methyl ethyl ketone). Etc.), nitriles (eg acetonitrile), hydrocarbons (eg n-hexane, cyclohexane etc.) and the like. These organic solvents may be used singly or as a mixture of two or more at an appropriate ratio, or a mixed liquid with an appropriate ratio with water may be used.
  • alcohols eg, methanol, ethanol, propanol, isopropanol, etc.
  • halogenated alkanes eg, dichloromethane, chloroform, chloroethane, trichloroethane
  • the dissolution or suspension can be prepared by a method known per se. Examples of such a method include a method using a mixer such as a propeller-type stirrer or a turbine-type stirrer, a colloid mill method, a homogenizer method, and an ultrasonic irradiation method.
  • the solid concentration of the dissolved or suspended liquid is within a range that can be sprayed and dried in a spray dryer, that is, from about 30 to about 70% by weight, and in another embodiment from about 40 to about 70% by weight.
  • the spray liquid may be spray-dried in the transfer tube. Have difficulty.
  • Other additives can be appropriately added to the pharmaceutical carrier used in the present invention.
  • the dissolution or suspension obtained in the above preparation step is sprayed into the drying chamber of the spray dryer using a nozzle, and the water or organic solvent in the atomized droplets is volatilized in a very short time.
  • the drug substance SD (spray dry) product is obtained.
  • the nozzle include a two-fluid nozzle type, a multi-fluid nozzle type, a pressure nozzle type, and a rotating disk type. Of these, the rotating disk type is preferable.
  • Such conditions are not particularly limited as long as the dissolution or suspension prepared as described above is sprayed. Such conditions can be appropriately selected according to the individual drug particle formulation and the spray dryer used.
  • the intake air temperature is appropriately adjusted depending on the solvent used, but in the case of an aqueous system, it is usually 70 to 200 ° C., preferably about 80 to 150 ° C.
  • the amount of spray liquid is appropriately adjusted depending on the scale of the apparatus. For example, at the laboratory scale (chamber diameter 0.8 m) level, it is usually 10 to 50 g / min, preferably 20 to 40 g / min. At the scale (chamber diameter of 3.2 m) level, it is usually 0.5 to 2 kg / min, preferably 0.6 to 1.2 kg / min.
  • the rotational speed of a rotating disk type disk is particularly important in relation to the solid concentration.
  • the rotation speed of such a rotating disk type is usually about 5000 to about 15000 rpm, preferably about 6000 to about 12000 rpm, although it depends on the particle diameter of the drug substance SD product to be prepared.
  • the drug substance SD product can be heated if necessary, and the moisture or solvent in the drug substance SD product can be completely removed under reduced pressure.
  • the average particle size of the drug substance SD product is not particularly limited as long as the roughness in the mouth is reduced, but it is usually about 50 to about 250 ⁇ m as the average particle size, preferably about 50 to About 150 ⁇ m.
  • the amount of the pharmaceutical carrier used in the present invention can be adjusted as appropriate depending on the bitterness of atorvastatin as a whole preparation (including an aspect including a sweetener) or the fluidity, but usually atorvastatin or
  • the amount of the pharmaceutically acceptable salt is 0.05 to 3 parts by weight ( ⁇ : means “above” or “below”. The same shall apply hereinafter). 1 to 1 part by weight, and in a further embodiment 0.2 to 1 part by weight.
  • glycyrrhizic acid or a pharmaceutically acceptable salt thereof used in the present invention examples include glycyrrhizic acid, di (potassium) glycyrrhizinate, monosodium glycyrrhizinate, disodium (di) sodium glycyrrhizinate, and triglyceryl citrate ( Tri) alkali metal salts such as sodium, ammonium salts such as monoammonium glycyrrhizinate and di (di) ammonium glycyrrhizinate.
  • alkali metal salts such as di (di) potassium glycyrrhizinate, monosodium glycyrrhizinate, di (di) sodium glycyrrhizinate, and tri (tri) sodium glycyrrhizinate, monoammonium glycyrrhizinate, di (diethyl glycyrrhizinate) ) Ammonium salts such as ammonium. These can be used alone or in combination of two or more.
  • the blending amount is not particularly limited as long as it improves the dispersibility / dissolution property of atorvastatin and achieves rapid dispersibility / dissolution property of the drug. Specifically, for example, 0.001 to 4 parts by weight with respect to 1 part by weight of atorvastatin, and in another aspect, 0.0005 to 20% by weight in the total amount of the preparation Is mentioned.
  • atorvastatin or a pharmaceutically acceptable salt thereof is mixed with glycyrrhizic acid or a pharmaceutically acceptable salt thereof in a single preparation, that is, in a tablet (including an orally disintegrating tablet). If it is the aspect made, it will not restrict
  • the pharmaceutical tablet of the present invention is not particularly limited as long as it is a formulation that is usually prescribed as a pharmaceutical product.
  • a tablet and an orally disintegrating tablet are mentioned.
  • the method for producing the pharmaceutical tablet of the present invention is not particularly limited as long as it is a method for obtaining a tablet, and may be a normal method.
  • a method prescribed in a pharmacopoeia for example, Japanese pharmacopoeia, US pharmacopoeia, European pharmacopoeia is adopted.
  • each component (atorvastatin, for example, a pharmaceutical carrier such as sugar, glycyrrhizic acid or a pharmaceutically acceptable salt thereof, and optionally, an excipient, a binder, a sweetener, (2) (i) Atorvastatin and a saccharide as a pharmaceutical carrier are dissolved in a solvent, for example, or mixed with a tableting agent such as a corrigent, a disintegrant, a dispersant, a stabilizer, and a lubricant.
  • a pharmaceutical carrier such as sugar, glycyrrhizic acid or a pharmaceutically acceptable salt thereof, and optionally, an excipient, a binder, a sweetener
  • Atorvastatin and a saccharide as a pharmaceutical carrier are dissolved in a solvent, for example, or mixed with a tableting agent such as a corrigent, a disintegrant, a dispersant, a stabilizer, and a lubricant.
  • Atorvastatin is coated and / or granulated with a saccharide as a pharmaceutical carrier to obtain a powder, and then the remaining components And the like.
  • the orally disintegrating tablet of the present invention is not particularly limited as long as it is a tablet comprising a component capable of obtaining a tablet (orally disintegrating tablet) that disintegrates and dissolves in the oral cavity without taking water.
  • water-soluble substances include sugars (eg, sugar (eg, lactose, glucose, sucrose, maltose (preferably candy powder (containing maltose 83% or more)), trehalose, lactose fructose), sugar alcohols (eg, mannitol, Xylitol, maltitol, sorbitol, erythritol)), carbonate (eg, sodium carbonate, potassium carbonate), bicarbonate (eg, sodium bicarbonate, potassium bicarbonate), water-soluble polymer (eg, hydroxypropylmethylcellulose, hydro And cyclopropylcellulose, polyvinylpyrrolidone, methylcellulose).
  • sugars eg, sugar (eg, lactose, glucose, sucrose, mal
  • a water-soluble substance can be used 1 type or in combination of 2 or more types.
  • blending saccharides it is classified into the categories of “low formability saccharides” and “high formability saccharides” defined in International Publication No. WO95 / 20380 pamphlet (US Patent No. 5576014).
  • a composition containing a “low moldability saccharide” is used as a granulated product obtained by spraying and coating and / or granulating a “high moldability saccharide” as a binder solution. can do.
  • “formability” means the ability to maintain the shape when compression molded.
  • the hardness of the tablet similarly indicates 2 kp or more.
  • the “sugar having low moldability” is not particularly limited as long as it is pharmaceutically acceptable and has low moldability but dissolves rapidly in the oral cavity.
  • saccharides include lactose, mannitol, glucose, sucrose, xylitol, erythritol, and the like. In other embodiments, lactose or mannitol is used. Such saccharides can be used alone or in combination of two or more.
  • the blending amount of the saccharide is not particularly limited as long as the orally disintegrating tablet of the present invention rapidly disintegrates and dissolves in the oral cavity. The blending amount is appropriately adjusted depending on the dose of the drug or the size of the tablet, but is usually 30 to 95% by weight / weight%, and in another embodiment, 50 to 90% by weight / weight%.
  • the “highly moldable saccharide” is not particularly limited as long as it is pharmaceutically acceptable and has an ability to maintain its shape when the orally disintegrating tablet of the present invention is used.
  • examples of such saccharides include maltose, maltitol, sorbitol, trehalose, lactose fructose and the like, and maltose or maltitol is another aspect. Saccharides can be used alone or in combination of two or more.
  • the amount of the saccharide is usually 1 to 25% by weight / weight% with respect to the “low-moldable saccharide”, and in another embodiment, 2 to 20% by weight / weight%, or 2 to 20% by weight of the whole preparation. / Wt%.
  • the “carbonate or bicarbonate” used in the present invention is pharmaceutically acceptable, reduces the initial drug elution amount of atorvastatin, maintains the rapid drug release thereafter, and dissolves the drug even after compression molding. Any substance that can suppress or reduce the change in speed or can achieve quick dispersibility and dissolution in the gastrointestinal tract when improving compliance by concealing the unpleasant taste of atorvastatin in the mouth Not.
  • Specific examples include calcium carbonate, sodium carbonate, ammonium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and magnesium carbonate. Another embodiment includes calcium carbonate. These carbonates or bicarbonates can be used singly or in appropriate combination of two or more.
  • Carbonate or bicarbonate when administered orally, is administered as a separate pharmaceutical preparation at the same time or at a certain time, or as a single preparation, as a pharmaceutical tablet or orally disintegrating If it is an aspect contained as an aspect contained in a tablet, it will not restrict
  • the compounding amount of “carbonate or bicarbonate” may be 1 wt / wt% or more and 100 wt / wt% or less with respect to the weight of the whole preparation.
  • the blending amount of “carbonate or bicarbonate” is 9% or more and 100% or less with respect to the weight of the excipient, for example, the aforementioned “low moldability saccharide” (particularly mannitol). It can be included. Further, it can be contained in an amount of 10% or more and 100% or less as a substitution rate with respect to the usual use amount of the excipient, for example, the aforementioned “low moldability saccharide” (particularly mannitol).
  • the pharmaceutical preparation of the present invention can be made into various pharmaceutical preparations by blending intermediate particles in addition to orally disintegrating tablets.
  • Examples of pharmaceutical preparations other than orally disintegrating tablets include powders, fine granules, dry syrups, tablets and the like.
  • 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 orally disintegrating tablet of the present invention include, for example, International Publication No. WO95 / 20380 pamphlet (US corresponding patent No. 5576014), International Publication No. WO2002 / 92057 pamphlet (US corresponding patent application No. 2003/099701). Description), U.S. Pat. No. 4,305,502, U.S. Pat. No. 4,371,516, U.S. Pat. No. 2,807,346 (U.S. Pat.
  • additives that are pharmaceutically acceptable and used as additives may be blended.
  • additives include excipients (diluents or extenders), disintegrants, binders, acidulants, foaming agents, sweeteners, fragrances, lubricants, colorants, stabilizers, and the like.
  • excipients include sugars such as lactose, glucose, sucrose, maltose (preferably candy powder (containing maltose 83% or more)), trehalose, lactose fructose, etc., such as mannitol, xylitol, maltitol, sorbitol, erythritol, etc. Sugar alcohol, crystalline cellulose and the like.
  • disintegrant include starches such as corn starch, carmellose calcium, partially pregelatinized starch, crospovidone, and low-substituted hydroxypropylcellulose.
  • binder examples include polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, gum arabic powder, gelatin, pullulan and the like.
  • acidulant examples include citric acid, tartaric acid, malic acid and the like.
  • foaming agent examples include baking soda.
  • sweetening agent examples include saccharin sodium, aspartame, stevia, thaumatin and the like.
  • fragrance flavor, lemon, lemon lime, orange, menthol, etc. are mentioned, for example.
  • the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.
  • the colorant examples include edible pigments such as edible yellow No. 5, edible red No. 2, and edible blue No. 2, edible lake pigments, and bengara.
  • the stabilizer a substance that stabilizes atorvastatin is selected after various studies.
  • the pharmaceutical additive can be used in an appropriate amount as appropriate by combining one kind or two or more kinds.
  • the method for producing an orally disintegrating tablet is not particularly limited as long as it is a method capable of obtaining a tablet (orally disintegrating tablet) that disintegrates and dissolves in the oral cavity without taking water.
  • a powder comprising atorvastatin or atorvastatin and a pharmaceutical carrier such as saccharide is mixed with glycyrrhizic acid or a pharmaceutically acceptable salt thereof, and if desired, a saccharide with low moldability may be added.
  • Blend Such a blend can be prepared by spraying “highly moldable saccharide” as a binder, coating and / or granulating, and compression molding the granulated product.
  • a step of humidifying and drying can be employed.
  • the tablet hardness is increased by changing the amorphized saccharide in the spraying process from the amorphous state to the crystalline state in the drying step.
  • “Humidification” is determined by the apparent critical relative humidity of the contained component, but humidifies more than the critical relative humidity of the normal component.
  • 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 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 minute or more and 72 hours or less, and in another embodiment, it is 1 hour or more and 36 hours or less, and in another embodiment, it is 12 hours or more and 24 hours or less.
  • “Dry” is not particularly limited as long as it is a step of removing moisture absorbed by humidification.
  • the temperature at the time of drying can be set to 10 ° C. or more and 100 ° C. or less, 20 to 60 ° C. or less can be set as another aspect, and 25 to 40 ° C. can be set as a further aspect.
  • the treatment time can be set as 0.5 hours or more and 6 hours or less, and as another aspect, it can be set as 1 hour or more and 4 hours or less.
  • dissolution test liquid displacement dissolution test
  • the following method was set as a dissolution test method capable of predicting pharmacokinetics (PK) in humans, assuming that the orally disintegrating tablet is taken without water.
  • the test conditions were as follows. Using the 15th revised Japanese Pharmacopoeia General Test Method Dissolution Test Method Paddle Method Dissolution Test 1st Solution (JP1), the test solution volume was 300 mL and the paddle rotation speed was 50 rpm. When the minute passed, 600 mL of a 5-fold concentrated solution of the second dissolution test solution (JP2) was added.
  • the criterion was defined as “having rapid dispersibility and dissolution” when the drug dissolution rate (D5min) after 5 minutes exceeds 30% after the start of the test using JP1.
  • Example 1 271 g of atorvastatin calcium trihydrate (manufactured by Pfizer, the same applies hereinafter), 3704 g of calcium carbonate, 50 g of maltose, 250 g of sucralose, and 150 g of a flavor preparation are fluidized bed granulator (GPCG-5 / 15 manufactured by Glatt, the same applies hereinafter). It was granulated with 1600 g of an aqueous maltose solution (including 400 g of maltose) to prepare a granulated product for orally disintegrating tablets.
  • aqueous maltose solution including 400 g of maltose
  • Example 2 Granulate 325.2 g of atorvastatin calcium trihydrate, 4384.8 g of calcium carbonate, 60 g of maltose, 300 g of sucralose, 180 g of flavor preparation with 1920 g of maltose aqueous solution (including maltose 480 g) using a fluidized bed granulator A granulated product for disintegrating tablets was prepared.
  • Example 3 Spray-dried 3200 g of water suspension containing 600 g of atorvastatin calcium trihydrate and 600 g of maltose using a spray dryer (spray dryer CBD-12, manufactured by Okawahara Chemical Co., Ltd.) to obtain a drug substance SD (spray dry) product. .
  • a spray dryer spray dryer CBD-12, manufactured by Okawahara Chemical Co., Ltd.
  • Comparative Example 1 Granulate 325.2 g of atorvastatin calcium trihydrate, 4444.8 g of calcium carbonate, 60 g of maltose, 300 g of sucralose, 180 g of flavored product with 1920 g of maltose aqueous solution (including 480 g of maltose) using a fluidized bed granulator.
  • a granulated product for disintegrating tablets was prepared. This granulated product (1351g) and magnesium stearate (14g) are mixed, compressed into tablets using a rotary tableting machine, and humidified and dried (25-30 ° C / 40-62% RH / 18 hours). Tablets (orally disintegrating tablets) were produced.
  • Experimental example 1 According to the evaluation method described above, the in vitro test was performed on the pharmaceutical tablet (orally disintegrating tablet) of the present invention prepared in Examples 1 to 3 and the comparative pharmaceutical tablet (orally disintegrating tablet) prepared in Comparative Example 1. A dissolution test (liquid displacement dissolution test) was performed. Moreover, the canine test which is an in vivo test was implemented regarding the pharmaceutical tablet (orally disintegrating tablet) of Example 1 of the present invention and the comparative pharmaceutical tablet (orally disintegrating tablet) of Comparative Example 1.
  • D5mim, D15mim, D30mim, and D45mim shown in Table 2 are drug elution rates 5 minutes, 15 minutes, 30 minutes, and 45 minutes after the start of the dissolution test, respectively.
  • 60 mL of a 5-fold concentrated solution of JP2 was added.
  • the addition of the JP2 concentrated solution was performed after measuring D30mim.
  • dipotassium glycyrrhizinate significantly improved dissolution (liquid replacement method, 5-minute value). Also in the absorption evaluation experiment in dogs, the value of Cmax (ng / mL) increased and absorption improvement was achieved. This result suggests that the addition of dipotassium glycyrrhizinate improved the solubility (initial dissolution) due to the improvement in wettability and dispersibility of atorvastatin itself and contributed to the improvement in absorption.
  • Table 3 shows the prescription and Table 4 shows the amount charged.
  • Glycyrrhizic acid or dipotassium glycyrrhizinate was weighed and placed in a mortar (other than Comparative Example 2). After adding 0.4 mL of pure water to the mortar and mixing well, 0.3252 g of atorvastatin calcium trihydrate was weighed and put in the mortar and mixed well.
  • the calcium carbonate granulated product was weighed and put in a mortar and mixed well. This was dried for 1 hour or more under the condition of 40 ° C./30% RH. After the dried product was pulverized with a pestle, magnesium stearate was added and mixed. 200 mg of this mixture is weighed and compressed into tablets with a diameter of 7.5 mm using an autograph (Shimadzu Corporation, AGS-20KNG, the same shall apply hereinafter) and humidified (25-30 ° C / 40-62% RH / 18) Time) to produce a pharmaceutical tablet of the present invention (orally disintegrating tablet) and a comparative pharmaceutical tablet (orally disintegrating tablet).
  • Experimental example 2 According to the evaluation method described above, the in vitro test was performed on the pharmaceutical tablet (orally disintegrating tablet) of the present invention prepared in Examples 4 to 7 and the comparative pharmaceutical tablet (orally disintegrating tablet) prepared in Comparative Example 2. A dissolution test (liquid displacement dissolution test) was performed.
  • FIG. D5mim, D15mim, D30mim, and D45mim shown in Table 5 are drug elution rates 5 minutes, 15 minutes, 30 minutes, and 45 minutes after the start of the dissolution test, respectively.
  • 60 mL of a 5-fold concentrated solution of JP2 was added.
  • the addition of the JP2 concentrated solution was performed after measuring D30mim.
  • dipotassium glycyrrhizinate significantly improved dissolution (liquid replacement method, 5-minute value). This result suggests that the addition of dipotassium glycyrrhizinate improved the solubility (initial dissolution) due to the improvement in wettability and dispersibility of atorvastatin itself and contributed to the improvement in absorption.
  • Example 8 Comparative Example 3: Table 6 shows the prescription and Table 7 shows the amount charged. Atorvastatin calcium trihydrate, monoammonium glycyrrhizinate, a granulated calcium carbonate product (same as that produced in Examples 4 to 7) and magnesium stearate were weighed and placed in a plastic bottle and mixed well for 1 minute or more. 200 mg of this mixed product was weighed, compressed into tablets with a diameter of 7.5 mm using an autograph, humidified and dried (25 to 30 ° C./40 to 62% RH / 18 hours), and the pharmaceutical tablet of the present invention ( Orally disintegrating tablets) and comparative pharmaceutical tablets (orally disintegrating tablets) were prepared.
  • Orally disintegrating tablets Orally disintegrating tablets
  • comparative pharmaceutical tablets orally disintegrating tablets
  • This mixed product is tableted with a 9 mm diameter punch using an autograph, humidified and dried (25-30 ° C / 40-62% RH / 18 hours), and the pharmaceutical tablet of the present invention (orally disintegrating tablet) ) And comparative pharmaceutical tablets (orally disintegrating tablets).
  • Experimental Example 4 According to the evaluation method described above, the in vitro test was performed on the pharmaceutical tablet (orally disintegrating tablet) of the present invention prepared in Examples 9 to 10 and the comparative pharmaceutical tablet (orally disintegrating tablet) prepared in Comparative Example 4. A dissolution test (liquid displacement dissolution test) was performed.
  • Example 11 Comparative Example 5: Table 11 shows the prescription. Weigh the prescribed amount of atorvastatin calcium trihydrate and dipotassium glycyrrhizinate into a volumetric flask, add 50 mL of JP1 solution and stir for 30 minutes, then stir again, then laser diffraction particle size distribution analyzer SALD The particle size was measured using -2000A (Shimadzu).
  • Example 11 The result of particle size distribution measurement is shown in FIG.
  • the median diameters of Example 11 and Comparative Example 5 were 7.716 ⁇ m and 35.35 ⁇ m, respectively. Further, when the solution was allowed to stand for several minutes after stirring, Example 11 was uniformly clouded, whereas Comparative Example 5 was clouded and particles were precipitated. This result suggests that the addition of dipotassium glycyrrhizinate improved the dispersibility of atorvastatin itself. It can be considered that this contributes to the improvement of dissolution.
  • Table 12 shows the prescription and the charged amount. Weigh the prescribed amounts of atorvastatin calcium trihydrate, glycyrrhizic acid, dipotassium glycyrrhizinate and monoammonium glycyrrhizinate into a 10 mL Spitz tube, add 10 mL of JP1 solution, stir for 1 hour, filter the supernatant (GE Healthcare GD / X The concentration of the solution filtered with a syringe filter (PVDF), 25 mm) was measured.
  • PVDF syringe filter
  • Solubility was measured for the suspensions prepared in Examples 12-21 and the suspension prepared in Comparative Example 6. The solubility results are shown in Table 13 and FIG. This result suggests that solubility (initial dissolution) has improved and contributed to improved absorption.
  • a pharmaceutical tablet particularly an orally disintegrating tablet, which improves the compliance of medication by reducing the unpleasant taste of atorvastatin in the oral cavity and has rapid dispersibility and dissolution in the digestive tract. Can do.
  • this invention was demonstrated along the specific aspect, the deformation

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Abstract

L'invention concerne un comprimé médicinal, en particulier un comprimé se dissolvant dans la bouche, qui réduit le goût désagréable de l'atorvastatine dans la cavité buccale (acceptation du médicament) et qui peut être dispersé ou dilué dans le tube digestif. Ledit comprimé médicinal contient de l'atorvastatine ou un sel pharmaceutiquement acceptable de l'atorvastatine et de l'acide glycyrrhétinique ou un sel pharmaceutiquement acceptable dudit acide.
PCT/JP2011/058279 2010-09-30 2011-03-31 Comprimé médicinal contenant de l'atorvastatine Ceased WO2012042951A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016074957A1 (fr) * 2014-11-10 2016-05-19 Aleksander Vladimirovich Dikovskiy Combinaison
CN107744507A (zh) * 2017-09-29 2018-03-02 西藏九瑞健康股份有限公司 一种阿托伐他汀钙药物组合物及其制备方法
JP2019218339A (ja) * 2018-06-13 2019-12-26 大原薬品工業株式会社 矯味剤含有顆粒を内在する、服用性が改善された口腔内崩壊錠

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06298668A (ja) * 1993-02-18 1994-10-25 Takeda Chem Ind Ltd 経口用医薬組成物
JPH08505640A (ja) * 1993-01-19 1996-06-18 ワーナー−ランバート・コンパニー 安定な経口用のｃｉ−９８１製剤およびその製法
JPH1025255A (ja) * 1996-07-11 1998-01-27 Taisho Pharmaceut Co Ltd 溶解性の改善された難溶性薬剤
JP2003128544A (ja) * 2001-09-04 2003-05-08 Pfizer Inc バイオモジュレーションされた多粒子製剤
US20060024335A1 (en) * 2004-07-29 2006-02-02 Roger Stier E Oral compositions which mask the bitter taste of a bitter-tasting agent
CN1911209A (zh) * 2006-08-25 2007-02-14 石家庄欧意药业有限公司 可快速崩解的阿托伐他汀钙片剂及其制备方法
JP2008106048A (ja) * 2006-09-25 2008-05-08 Aska Pharmaceutical Co Ltd 苦味が抑制された経口製剤
WO2010038688A1 (fr) * 2008-09-30 2010-04-08 アステラス製薬株式会社 Composition pharmaceutique particulaire pour une administration orale d’atorvastatine

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08505640A (ja) * 1993-01-19 1996-06-18 ワーナー−ランバート・コンパニー 安定な経口用のｃｉ−９８１製剤およびその製法
JPH06298668A (ja) * 1993-02-18 1994-10-25 Takeda Chem Ind Ltd 経口用医薬組成物
JPH1025255A (ja) * 1996-07-11 1998-01-27 Taisho Pharmaceut Co Ltd 溶解性の改善された難溶性薬剤
JP2003128544A (ja) * 2001-09-04 2003-05-08 Pfizer Inc バイオモジュレーションされた多粒子製剤
US20060024335A1 (en) * 2004-07-29 2006-02-02 Roger Stier E Oral compositions which mask the bitter taste of a bitter-tasting agent
CN1911209A (zh) * 2006-08-25 2007-02-14 石家庄欧意药业有限公司 可快速崩解的阿托伐他汀钙片剂及其制备方法
JP2008106048A (ja) * 2006-09-25 2008-05-08 Aska Pharmaceutical Co Ltd 苦味が抑制された経口製剤
WO2010038688A1 (fr) * 2008-09-30 2010-04-08 アステラス製薬株式会社 Composition pharmaceutique particulaire pour une administration orale d’atorvastatine

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016074957A1 (fr) * 2014-11-10 2016-05-19 Aleksander Vladimirovich Dikovskiy Combinaison
US20170304336A1 (en) * 2014-11-10 2017-10-26 Aleksander Vladimirovich Dikovskiy Combination
JP2017534687A (ja) * 2014-11-10 2017-11-24 ヴラヂミロヴィッヒ ディコヴスキィ，アレクサンダー 配合剤
CN107666909A (zh) * 2014-11-10 2018-02-06 亚历山大·弗拉基米罗维奇·季科夫斯基 组合物
CN107744507A (zh) * 2017-09-29 2018-03-02 西藏九瑞健康股份有限公司 一种阿托伐他汀钙药物组合物及其制备方法
CN107744507B (zh) * 2017-09-29 2019-11-15 西藏九瑞健康股份有限公司 一种阿托伐他汀钙药物组合物及其制备方法
JP2019218339A (ja) * 2018-06-13 2019-12-26 大原薬品工業株式会社 矯味剤含有顆粒を内在する、服用性が改善された口腔内崩壊錠

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