WO2016076280A1 - 光に対して不安定な薬物を含有する多層錠剤 - Google Patents
光に対して不安定な薬物を含有する多層錠剤 Download PDFInfo
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- WO2016076280A1 WO2016076280A1 PCT/JP2015/081526 JP2015081526W WO2016076280A1 WO 2016076280 A1 WO2016076280 A1 WO 2016076280A1 JP 2015081526 W JP2015081526 W JP 2015081526W WO 2016076280 A1 WO2016076280 A1 WO 2016076280A1
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- oxide
- active ingredient
- light stabilizer
- weight
- multilayer tablet
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- 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
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2813—Inorganic compounds
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl]-(3R, 5S) as an active ingredient -3,5-dihydroxyhept-6-enoic acid or a pharmaceutically acceptable salt thereof (rosuvastatin or a salt thereof), especially a calcium salt of rosuvastatin (rosuvastatin calcium), a light stabilizer, and an inorganic salt or basic oxidation
- the present invention relates to a tablet that is stable against light, temperature and humidity, preferably an orally disintegrating tablet, by making a bilayer tablet, a trilayer tablet and a multilayer tablet containing the product.
- Rosuvastatin especially rosuvastatin calcium
- Rosuvastatin is decomposed under certain conditions, especially light, temperature and humidity. This makes it difficult to obtain a pharmaceutical composition having a product formulation and a good shelf life.
- Patent Document 1 discloses a pharmaceutical composition containing rosuvastatin and a tribasic phosphate as a stabilizer.
- Reference Document 2 contains amorphous rosuvastatin and magnesium hydroxide and / or calcium acetate as a stabilizer.
- Patent Document 3 describes a pharmaceutical composition in which hypromellose is coated on a plain tablet containing rosuvastatin and a stabilizer.
- a cored tablet containing a drug unstable to light and a coated tablet including an outer layer covering the same are disclosed (cited documents 4 to 6).
- the outer layer once to produce a tablet place the inner core tablet on the outer layer tablet, and then tablet again, the production method becomes very complicated. Further, due to a trouble with the tableting machine, the position of the inner core tablet may be shifted, and a plurality of inner core tablets may be included.
- the drugs When containing unstable drugs, the drugs may be contained in different layers to form multilayer tablets (Cited documents 7 to 9). However, it is not disclosed that the preparation can be applied to drugs unstable to light and temperature.
- the preparation containing the drug is covered with a light stabilizer, or the preparation is packaged with aluminum.
- the disintegration of the preparation is slowed by coating the preparation, and it is difficult to apply the preparation to a preparation having rapid disintegration, particularly an orally disintegrating tablet.
- the packaging cost is increased and the packaging process may be complicated.
- the present inventors As a result of intensive studies to develop an orally disintegrating tablet of rosuvastatin that is stable to light, temperature, and humidity and rapidly disintegrates in the oral cavity, the present inventors have found an optimal formulation, and It came to be completed. Specifically, it contains an active ingredient layer containing rosuvastatin or a salt thereof as an active ingredient, and a multilayer tablet having a two-layer structure consisting of an outer layer adjacent to the active ingredient layer, or rosuvastatin or a salt thereof as an active ingredient An active ingredient layer and an outer layer sandwiching the active ingredient layer.
- the present invention (1) (E) -7- [4- (4-Fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl]-(3R, 5S)-as an active ingredient Multilayer tablets containing 3,5-dihydroxyhept-6-enoic acid or a pharmaceutically acceptable salt thereof, a light stabilizer, and an inorganic salt or basic oxide; (2) The multilayer tablet according to the above (1), which has a two-layer structure comprising an active ingredient layer containing an active ingredient and an outer layer adjacent to the active ingredient layer, (3) The multilayer tablet according to the above (1), comprising an active ingredient layer containing an active ingredient, and an outer layer sandwiching the active ingredient layer, (4) The multilayer tablet according to the above (3), which has a three-layer structure, (5) The multilayer tablet according to any one of (2) to (4), wherein the active ingredient layer contains a light stabilizer.
- the active ingredient layer contains a light stabilizer and an inorganic salt or a basic oxide, and at least one outer layer contains a light stabilizer, according to any one of (2) to (4) above Multilayer tablets, (10) Any of (1) to (9) above, wherein the light stabilizer is one or more selected from the group consisting of edible tar dyes, edible lake tar dyes, edible natural dyes, iron oxides and titanium oxides Multilayer tablets as described in (11)
- the light stabilizer is food red 2, food red 3, food red 102, food red 104, food red 105, food red 106, food yellow 4, food yellow 5, food green
- Inorganic salt or basic oxide is magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium alumina hydroxide, aluminum hydroxide, aluminum hydroxide gel, aluminum hydroxide / sodium hydrogen carbonate copre
- the orally disintegrating tablet of the present invention (hereinafter referred to as “the present preparation”) is an orally disintegrating tablet that has high stability against light and temperature, high tablet hardness, and fast oral disintegration time.
- the active ingredient (drug) is (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl]-( 3R, 5S) -3,5-dihydroxyhept-6-enoic acid or a pharmaceutically acceptable salt thereof (hereinafter sometimes abbreviated as “rosuvastatin”), particularly (E) -7- [4- (4-Fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl]-(3R, 5S) -3,5-dihydroxyhept-6-enoic acid calcium salt ( Hereinafter, it may be abbreviated as “rosuvastatin calcium”. This compound is described in European Patent Application No. 0521471 and Bioorganic Medicinal Chemistry (1997).
- the content of the active ingredient (drug) in this preparation may be an amount that produces a medicinal effect. For example, it is 0.01 to 90% by weight, preferably 0.025 to 80% by weight, more preferably 0.05 to 70% by weight, based on the total amount of the preparation. If the content is higher than these, the disintegration of the tablet may be delayed. If the content is lower, the preparation itself may be enlarged or a large amount of tablets may be taken.
- the structure of the formulation in the present specification is preferably a multilayer tablet in order to improve the light stability of rosuvastatin or a pharmaceutically acceptable salt thereof.
- the multilayer tablet is a tablet having two or more layer components.
- As the structure of this preparation 1) a two-layer structure comprising an active ingredient layer containing rosuvastatin as an active ingredient or a pharmaceutically acceptable salt thereof and an outer layer adjacent to the active ingredient layer, or 2) an active ingredient It is a multilayer structure of three or more layers including an active ingredient layer containing rosuvastatin or a pharmaceutically acceptable salt thereof and an outer layer sandwiching the active ingredient layer.
- the multilayer structure is preferably a three-layer structure including an active ingredient layer containing rosuvastatin, which is an active ingredient, or a pharmaceutically acceptable salt thereof, and an outer layer sandwiching the active ingredient layer.
- the active ingredient layer and the outer layer may contain other active ingredients other than rosuvastatin.
- the content of the active ingredient layer is 20 to 80% by weight, preferably 30 to 70% by weight, more preferably 40 to 60% by weight, based on the total amount of the preparation.
- the content of the outer layer is the remaining content obtained by subtracting the content of the active ingredient layer from the total amount of the preparation.
- This formulation contains a photostabilizer to improve the photostability of rosuvastatin or a pharmaceutically acceptable salt thereof.
- the light stabilizer may be blended in any layer in a multilayered preparation, but is preferably blended in an active ingredient layer containing an active ingredient.
- rosuvastatin particularly rosuvastatin calcium
- Japanese Pharmacopoeia Japanese Pharmacopoeia Pharmaceutical Standards, Pharmaceutical Additive Standards
- those listed in the Food Additives Official Document can be used.
- examples thereof include edible tar dyes, edible rake tar dyes, edible natural dyes, iron oxide, and titanium oxide.
- Copper Chlorophyllin Sodium Copper Examples include chlorophyll, bengara, iron sesquioxide, yellow iron sesquioxide, black iron oxide, yellow iron oxide, and titanium oxide. More preferred are iron sesquioxide, yellow ferric oxide, black iron oxide, yellow iron oxide, and titanium oxide, and particularly preferred is yellow ferric oxide.
- the content of the light stabilizer in this specification may be an amount that rosuvastatin, particularly rosuvastatin calcium, is stabilized against light.
- it is 0.01 to 80% by weight, preferably 0.025 to 70% by weight, more preferably 0.05 to 50% by weight, based on the total amount of the preparation. If the content is higher than these, the preparation may not be produced, and if it is less, the light stabilization may be insufficient.
- This preparation contains an inorganic salt or a basic oxide in order to improve the temperature / humidity stability of rosuvastatin or a pharmaceutically acceptable salt thereof.
- An inorganic salt is a salt or an inorganic substance formed by replacing hydrogen of an inorganic acid with a metal.
- a basic oxide is an oxide of a metal element that reacts with water to produce a base or reacts with an acid to produce a salt.
- the inorganic salt or the basic oxide may be blended in any layer in the preparation having a multilayer structure, but is preferably blended in the active ingredient layer containing the active ingredient.
- the inorganic salt or basic oxide may be any additive that stabilizes rosuvastatin, particularly rosuvastatin calcium, and includes Japanese Pharmacopoeia, Japanese Pharmacopoeia Standards for Pharmaceuticals, Pharmaceutical Additives Standards, and Food Additives. Those listed in the official document can be used.
- it is magnesium oxide.
- the content of the inorganic salt or basic oxide in the present specification may be an amount that can stabilize rosuvastatin, particularly rosuvastatin calcium, against temperature and moisture (humidity). For example, it is 0.01 to 80% by weight, preferably 0.025 to 70% by weight, more preferably 0.05 to 50% by weight, based on the total amount of the preparation. If it is more than these contents, there is a possibility that the preparation cannot be produced, and if it is less, there is a possibility that it cannot be stabilized, particularly under high temperature and high humidity.
- the light stabilizer and the inorganic salt or basic oxide can be used in combination.
- the light stabilizer is yellow ferric oxide and / or titanium oxide
- the inorganic salt or basic oxide is magnesium oxide.
- a preferred combination and the content thereof are determined when the light stabilizer is yellow ferric oxide and the inorganic salt or basic oxide is magnesium oxide.
- Yellow iron sesquioxide is 0.01 to 80% by weight
- magnesium oxide is 0.01 to 80% by weight, preferably 0.025 to 70% by weight of yellow iron sesquioxide
- magnesium oxide is 0.1% by weight based on the total amount. 025 to 70% by weight, more preferably 0.05 to 50% by weight of yellow ferric oxide and 0.05 to 50% by weight of magnesium oxide.
- the titanium oxide is 0.01 to 80% by weight
- the magnesium oxide is 0.01 to 80% by weight
- titanium oxide is 0.025 to 70% by weight
- magnesium oxide is 0.025 to 70% by weight, more preferably 0.05 to 50% by weight of titanium oxide, and 0.05 to 50% by weight of magnesium oxide. It is.
- the light stabilizer is yellow ferric oxide and titanium oxide
- the inorganic salt or basic oxide is magnesium oxide
- 0.01 to 80% by weight of yellow ferric oxide and titanium oxide is oxidized relative to the total amount of the formulation.
- Magnesium oxide is 0.05 to 50% by weight.
- This preparation may contain disintegrants, and use disintegrants listed in Japanese Pharmacopoeia, Japanese Pharmacopoeia Standards for Pharmaceuticals, Standards for Pharmaceutical Additives, and Food Additives Standards. Can do. Examples thereof include carmellose, crospovidone, croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropylcellulose, and the like. Carmellose is preferable.
- the content of the disintegrant is, for example, 1 to 30% by weight, preferably 5 to 25% by weight, more preferably 7.5 to 20% by weight, based on the total amount of the preparation. If the content is higher than these, the hardness of the tablet may be lowered, and if it is less, the disintegration time of the tablet may be prolonged.
- This preparation may contain excipients and uses the excipients listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Standards for Drugs, the Standards for Pharmaceutical Additives, and the Food Additives Standards can do.
- the content of the excipient is, for example, 1 to 95% by weight, preferably 2.5 to 92.5% by weight, more preferably 5 to 90% by weight, based on the total amount of the preparation. If the content is higher than these, the preparation itself may be increased in size or a large amount of tablets may need to be taken.
- This preparation may contain sweeteners, and use the sweeteners listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Standards for Drugs, the Standards for Pharmaceutical Additives, and the Food Additives Standards. Can do.
- aspartame aminoacetic acid, fructose, reduced maltose syrup, licorice, licorice extract, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, dimonoammonium glycyrrhizinate, saccharin, saccharin sodium, thaumatin, glucose, powdered reduced maltose syrup
- sweeteners listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Standards for Drugs, the Standards for Pharmaceutical Additives, and the Food Additives Standards.
- can do for example, aspartame, aminoacetic acid, fructose, reduced maltose syrup, licorice, lic
- the content of the sweetener is, for example, 10% by weight or less, preferably 0.01 to 10% by weight, more preferably 0.1 to 7.5% by weight, based on the total amount of the preparation. If the content is higher than these, tablets may not be produced, and if the content is lower, sweetness may not be sufficiently produced.
- This preparation may contain a fluidizing agent, and uses the fluidizing agent listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Standards for Drugs, the Standards for Pharmaceutical Additives and the Food Additives Standards. can do.
- fluidizing agents include hydrous silicon dioxide, light anhydrous silicic acid, heavy anhydrous silicic acid, titanium oxide, synthetic aluminum silicate, talc, etc., preferably hydrous silicon dioxide and light anhydrous silicic acid. .
- the content of the fluidizing agent is, for example, 0.01 to 15% by weight, preferably 0.05 to 10% by weight, more preferably 0.1 to 7.5% by weight, based on the total amount of the preparation. If the content is higher than these, the preparation itself may be increased in size or a large amount of tablets may need to be taken.
- This preparation may contain a lubricant and use the lubricants listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Standards for Drugs, the Standards for Pharmaceutical Additives, and the Food Additives Standards. can do.
- a lubricant for example, sodium stearyl fumarate, sucrose fatty acid ester, stearic acid, magnesium stearate, calcium stearate, talc, hydrous silicon dioxide and the like can be mentioned, preferably magnesium stearate.
- the content of the lubricant is, for example, 0.001 to 2% by weight, preferably 0.001 to 1% by weight, more preferably 0.001 to 0.8% by weight, based on the total amount of the preparation. If it is more than these contents, tablet hardness and disintegration may be lowered, and if it is less, there is a possibility that tablets cannot be produced.
- this preparation may contain additives other than those mentioned above.
- Additives listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Pharmaceutical Standards, the Pharmaceutical Additives Standard, and the Food Additives Official Standard Can be used.
- the content of these additives may be an arbitrary ratio.
- additives other than those described above include fragrances, binders, colorants, corrigents, and coating agents.
- the fragrance includes what is called a flavoring agent, such as sugar flavor, banana flavor, sunfix banana, orange essence, orange oil, caramel, camphor, cinnamon oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, Spruce oil, pine oil, mint oil, vanilla flavor, bitter essence, fruit flavor, peppermint essence, mixed flavor, mint flavor, menthol, lemon powder, lemon oil, rose oil, and the like, preferably sugar flavor.
- a flavoring agent such as sugar flavor, banana flavor, sunfix banana, orange essence, orange oil, caramel, camphor, cinnamon oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, Spruce oil, pine oil, mint oil, vanilla flavor, bitter essence, fruit flavor, peppermint essence, mixed flavor, mint flavor, menthol, lemon powder, lemon oil, rose oil, and the like, preferably sugar flavor.
- binders include hydroxypropylcellulose, corn starch, pregelatinized starch, partially pregelatinized starch, gum arabic, gum arabic powder, gelatin, agar, dextrin, pullulan, povidone, polyvinyl alcohol, crystalline cellulose, methylcellulose, ethylcellulose, carboxy Examples thereof include methyl ethyl cellulose, carmellose, carmellose sodium, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hypromellose and the like.
- colorants include yellow sesquioxide, sesquioxide, edible red No. 3, edible yellow No. 5, edible blue No.
- ascorbic acid and its salt aspartame, sucralose, glycine, sodium chloride, magnesium chloride, hydrochloric acid, dilute hydrochloric acid, citric acid and its salt (sodium citrate), anhydrous citric acid, L-glutamic acid and its salt, Succinic acid and its salt, acetic acid, tartaric acid and its salt, sodium hydrogencarbonate, fumaric acid and its salt, malic acid and its salt, glacial acetic acid, disodium inosinate, honey and the like.
- a coating agent for example, polyvinyl alcohol, ethyl cellulose, carboxymethyl ethyl cellulose, carmellose, carmellose sodium, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, PVA copolymer, ethyl acrylate / methyl methacrylate copolymer dispersion, Aminoalkyl methacrylate copolymer, Opadry, carnauba wax, carboxyvinyl polymer, dry methacrylic acid copolymer, dimethylaminoethyl methacrylate / methyl methacrylate copolymer, stearyl alcohol, shellac, cetanol, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose Sufutareto, fumaric acid, stearic acid Polyvinyl acetal diethylamino acetate hydroxypropy
- the dosage form of this preparation is a tablet prescribed in the Japanese Pharmacopoeia General Rules for Preparation.
- the preparation method of this preparation is as follows: 1) A method in which a drug and an additive are mixed, and the mixture is compressed into tablets (direct powder compression method). 2) A drug and an additive are mixed and granulated. There are a method of tableting and manufacturing a product (granular compression method), 3) a method of mixing an additive with granulation, and then mixing with a drug and then tableting and manufacturing.
- the method is preferably a method in which a drug and an additive are mixed and the mixture is tableted.
- the granulated product may be produced by a granulation method usually used pharmaceutically. For example, dry granulation method, extrusion granulation method, stirring granulation method, fluidized bed granulation method, rolling granulation method and the like.
- the granulated product may be covered with a coating agent.
- compression molding is performed using a single tableting machine, a rotary tableting machine, or the like.
- the lubricant can be added using a normal tableting method (internal mixing method) or an external lubricant method in which the lubricant is attached to the mortar of a tableting machine.
- An apparatus for performing the external lubrication method includes ELSP1-type III manufactured by Kikusui Seisakusho Co., Ltd. You may compression-mold using the external lubrication method together with the mixed powder manufactured by the internal mixing method.
- Any shape can be adopted for the molding of the preparation, and for example, a round shape, an oval shape, a spherical shape, a rod shape, a donut shape, and the like can be used, and further, a coating can be formed by coating. .
- marks for improving the identification, characters, etc., or a dividing line may be added.
- the diameter of this preparation may be any size that can be taken by the patient, but is usually 3 to 20 mm, preferably 4 to 15 mm, more preferably 5 to 10 mm.
- the thickness of the preparation may be any size that can be taken by the patient, but is usually 1 to 9 mm, preferably 1.5 to 7 mm, more preferably 1.75 to 5 mm.
- the thickness of the active ingredient layer and the outer layer of this preparation may be any thickness as long as the active ingredient is stable, but the thickness of the active ingredient layer is usually 2.5 to 90%, preferably 5 to 85%, more preferably 10 to 80%, and the total thickness of the outer layer is usually 10 to 97.5%, preferably 15 to 95%, more preferably 20 to 90% with respect to the total thickness. .
- the present preparation has a multilayer structure and can contain an active ingredient, a light stabilizer, and an inorganic salt or basic oxide for each outer layer and active ingredient layer.
- Preferred active ingredients, light stabilizers, inorganic salts or basic oxides are blended as follows: 1) Light stabilizers in the outer layer, active ingredients in the active ingredient layer, light stabilizers, and inorganic salts or basic oxides 2) The active ingredient layer is blended with the active ingredient, light stabilizer, and inorganic salt or basic oxide. 3) The outer layer is light stabilizer, and the inorganic salt or basic oxide, active ingredient layer.
- the content of each of the total amount of the preparation is, for example, 0.01 to 90% by weight of the active ingredient, 0.01 to 80% by weight of the light stabilizer, inorganic salt or basic 0.01 to 80% by weight of oxide, preferably 0.025 to 80% by weight of active ingredient, 0.025 to 70% by weight of light stabilizer, 0.025 to 70 of inorganic salt or basic oxide More preferably, the active ingredient is 0.05 to 70% by weight, the light stabilizer is 0.05 to 50% by weight, and the inorganic salt or basic oxide is 0.05 to 50% by weight.
- Preferred active ingredients, light stabilizers, inorganic salts or basic oxides are blended as follows: 1) Yellow ferric oxide as a light stabilizer in the outer layer, rosuvastatin calcium as an active ingredient in the active ingredient layer, as a light stabilizer Contains yellow iron sesquioxide and magnesium oxide as inorganic salt or basic oxide 2) Rosuvastatin calcium as active ingredient in the active ingredient layer, yellow iron sesquioxide as light stabilizer and magnesium oxide as inorganic salt or basic oxide 3) Yellow ferric oxide as light stabilizer in outer layer, magnesium oxide as inorganic salt or basic oxide, rosuvastatin calcium as active ingredient in active ingredient layer, yellow ferric oxide and inorganic salt as light stabilizer Or contains magnesium oxide as basic oxide 4) Inorganic salt or basic oxidation in outer layer Magnesium oxide, rosuvastatin calcium as active ingredient in the active ingredient layer, if containing magnesium oxide as a light stabilizer as a yellow ferric oxide and inorganic salt or a basic oxide as rosuvastatin calcium, which
- the respective contents with respect to the total amount of the preparation are, for example, 0.01 to 90% by weight of rosuvastatin calcium, 0.01 to 80% by weight of yellow ferric oxide, and 0.1% of magnesium oxide.
- 01 to 80% by weight preferably 0.025 to 80% by weight of rosuvastatin calcium, 0.025 to 70% by weight of yellow ferric oxide, 0.025 to 70% by weight of magnesium oxide, more preferably 0 to rosuvastatin calcium 0.05 to 70% by weight
- yellow ferric oxide is 0.05 to 50% by weight
- magnesium oxide is 0.05 to 50% by weight.
- Preferred active ingredients, light stabilizers, inorganic salts or basic oxides are blended as follows: 1) Titanium oxide as the light stabilizer in the outer layer, Rosuvastatin calcium as the active ingredient in the active ingredient layer, Titanium oxide as the light stabilizer And magnesium oxide as the inorganic salt or basic oxide, 2) rosuvastatin calcium as the active ingredient in the active ingredient layer, titanium oxide as the light stabilizer and magnesium oxide as the inorganic salt or basic oxide, 3) outer layer Contains titanium oxide as light stabilizer, magnesium oxide as inorganic salt or basic oxide, rosuvastatin calcium as active ingredient in active ingredient layer, titanium oxide as light stabilizer and magnesium oxide as inorganic salt or basic oxide 4) Magnesium oxide as inorganic salt or basic oxide in outer layer Arm, rosuvastatin calcium as active ingredient in the active ingredient layer, if containing magnesium oxide as a titanium oxide and an inorganic salt or a basic oxide as a light stabilizer, rosuvastatin calcium, which is an active ingredient is stabilized.
- the respective contents with respect to the total preparation amount are, for example, 0.01 to 90% by weight of rosuvastatin calcium, 0.01 to 80% by weight of titanium oxide, and 0.01 to 90% of magnesium oxide.
- 80% by weight preferably 0.025 to 80% by weight of rosuvastatin calcium, 0.025 to 70% by weight of titanium oxide, 0.025 to 70% by weight of magnesium oxide, more preferably 0.05 to 70% of rosuvastatin calcium %
- Preferred active ingredients, light stabilizers, inorganic salts or basic oxides are blended as follows: 1) Yellow ferric oxide as a light stabilizer in the outer layer, rosuvastatin calcium as an active ingredient in the active ingredient layer, as a light stabilizer Contains titanium oxide and magnesium oxide as inorganic salt or basic oxide, 2) yellow iron sesquioxide as light stabilizer in outer layer, magnesium oxide as inorganic salt or basic oxide, rosuvastatin calcium as active ingredient in active ingredient layer Contains titanium oxide and inorganic salt or magnesium oxide as light stabilizer, 3) titanium oxide as light stabilizer in outer layer, rosuvastatin calcium as active ingredient in active ingredient layer, yellow as light stabilizer Contains iron oxide and magnesium oxide as an inorganic salt or basic oxide.
- the content of each of the total preparation amount is, for example, 0.01 to 90% by weight of rosuvastatin calcium, 0.01 to 80% by weight of titanium oxide and yellow ferric oxide, magnesium oxide 0.01 to 80% by weight, preferably 0.025 to 80% by weight of rosuvastatin calcium, 0.025 to 70% by weight of titanium oxide and yellow iron sesquioxide, 0.025 to 70% by weight of magnesium oxide, and more
- rosuvastatin calcium is 0.05 to 70% by weight
- titanium oxide and yellow ferric oxide are 0.05 to 50% by weight
- magnesium oxide is 0.05 to 50% by weight.
- Preferred active ingredients, light stabilizers, inorganic salts or basic oxides are blended as follows: 1) Yellow ferric oxide and titanium oxide as the light stabilizer in the outer layer, Rosuvastatin calcium as the active ingredient in the active ingredient layer, light stability Contains yellow ferric oxide and titanium oxide as agent, magnesium oxide as inorganic salt or basic oxide 2) Yellow ferric oxide and titanium oxide as light stabilizer in outer layer, rosuvastatin calcium as active ingredient in active ingredient layer , Containing yellow ferric oxide as light stabilizer and magnesium oxide as inorganic salt or basic oxide, 3) yellow ferric oxide and titanium oxide as light stabilizer in outer layer, rosuvastatin calcium as active ingredient in active ingredient layer , Titanium oxide as light stabilizer and magnesium oxide as inorganic salt or basic oxide 4) Yellow ferric oxide and titanium oxide as light stabilizer in outer layer, magnesium oxide as inorganic salt or basic oxide, rosuvastatin calcium as active ingredient in active ingredient layer, yellow sesquioxide as light stabilizer Iron and titanium oxide, containing magnesium oxide as inorganic
- the content of each of the total preparation amount is, for example, 0.01 to 90% by weight of rosuvastatin calcium, 0.01 to 80% by weight of titanium oxide and yellow ferric oxide, magnesium oxide 0.01 to 80% by weight, preferably 0.025 to 80% by weight of rosuvastatin calcium, 0.025 to 70% by weight of titanium oxide and yellow iron sesquioxide, 0.025 to 70% by weight of magnesium oxide, and more
- rosuvastatin calcium is 0.05 to 70% by weight
- titanium oxide and yellow ferric oxide are 0.05 to 50% by weight
- magnesium oxide is 0.05 to 50% by weight.
- Preferred active ingredients, light stabilizers, inorganic salts or basic oxides and disintegrators are blended with yellow ferric oxide as the light stabilizer in the outer layer and carmellose as the disintegrant, and rosuvastatin calcium as the active ingredient in the active ingredient layer.
- Rosuvastatin calcium as an active ingredient is stabilized and has high hardness and short disintegration time if it contains yellow ferric oxide as a light stabilizer, magnesium oxide as an inorganic salt or basic oxide, and carmellose as a disintegrant
- Orally disintegrating tablets can be produced.
- the respective contents with respect to the total amount of the preparation are, for example, 0.01 to 90% by weight of rosuvastatin calcium, 0.01 to 80% by weight of yellow ferric oxide, and 0.1% of magnesium oxide.
- 5 to 25% by weight of carmellose more preferably 0.05 to 70% by weight of rosuvastatin calcium, 0.05 to 50% by weight of titanium oxide and yellow ferric oxide, 0.05 to 50% by weight of magnesium oxide and Carmellose is 7.5 to 20% by weight.
- the outer layer is yellow ferric oxide as a light stabilizer, carmellose as a disintegrant, and as an excipient.
- Anhydrous calcium hydrogen phosphate and crystalline cellulose, rosuvastatin calcium as active ingredient in active ingredient layer, yellow ferric oxide as light stabilizer, magnesium oxide as inorganic salt or basic oxide, carmellose as disintegrant, and excipient When anhydrous calcium hydrogen phosphate and crystalline cellulose are contained, rosuvastatin calcium which is an active ingredient is stabilized, and an orally disintegrating tablet having a high hardness and a short disintegration time can be produced.
- the respective contents with respect to the total amount of the preparation are, for example, 0.01 to 90% by weight of rosuvastatin calcium, 0.01 to 80% by weight of yellow ferric oxide, and 0.1% of magnesium oxide.
- Preferred active ingredients, light stabilizers, inorganic salts or basic oxides, disintegrants, excipients and sweeteners are blended with yellow ferric oxide as the light stabilizer in the outer layer, carmellose as the disintegrant, and shaping Anhydrous calcium hydrogen phosphate and crystalline cellulose as agent, sucralose and acesulfame potassium as sweetener, rosuvastatin calcium as active ingredient in active ingredient layer, yellow ferric oxide as light stabilizer, magnesium oxide as inorganic salt or basic oxide , Carmellose as a disintegrant, anhydrous calcium hydrogen phosphate and crystalline cellulose as excipients, and sucralose and acesulfame potassium as sweeteners, rosuvastatin calcium, which is an active ingredient, stabilizes and has high hardness, disintegration time Short orally disintegrating tablets It is possible to elephants.
- the respective contents with respect to the total amount of the preparation are, for example, 0.01 to 90% by weight of rosuvastatin calcium, 0.01 to 80% by weight of yellow ferric oxide, and 0.1% of magnesium oxide.
- the outer layer is yellow ferric oxide as a light stabilizer, as a disintegrant.
- Rosbastachi is an active ingredient Calcium stabilized, and high hardness can disintegration time producing short orally disintegrating tablets.
- the respective contents with respect to the total amount of the preparation are, for example, 0.01 to 90% by weight of rosuvastatin calcium, 0.01 to 80% by weight of yellow ferric oxide, and 0.1% of magnesium oxide.
- Preferred active ingredients, light stabilizers, inorganic salts or basic oxides, disintegrants, excipients, sweeteners, fluidizing agents and lubricants are blended with yellow ferric oxide as a light stabilizer in the outer layer.
- the respective contents with respect to the total amount of the preparation are, for example, 0.01 to 90% by weight of rosuvastatin calcium, 0.01 to 80% by weight of yellow ferric oxide, and 0.1% of magnesium oxide.
- This preparation is useful as an orally disintegrating tablet, and is rapidly disintegrated in the oral cavity by saliva and can be taken smoothly without leaving roughness.
- the disintegration time of this preparation is usually about 1 to 60 seconds, preferably 1 to 40 seconds, and more preferably about 1 to 30 seconds.
- the hardness (measured by a tablet hardness meter) of this preparation is usually a value with no problem if it is about 30 to 70 N, but the orally disintegrating tablet of the present invention is 10 to 200 N, preferably It is about 30 to 150N.
- this preparation can be taken without being disintegrated in the oral cavity or taken with water.
- Table 1 shows the tablet formulation per tablet.
- rosuvastatin calcium manufactured by AstraZeneca
- yellow ferric oxide manufactured by Kasei Chemical
- magnesium hydroxide manufactured by Kyowa Chemical Industries
- magnesium oxide manufactured by ICL industrial products
- calcium triphosphate Innophos Inc
- crystalline cellulose made by Asahi Kasei Chemicals
- anhydrous calcium hydrogen phosphate made by Kyowa Chemical Industry
- carmellose made by Gotoku Pharmaceutical
- sucralose made by Saneigen FFI
- acesulfame potassium Korean Chemical Company
- Foods thaumatin (manufactured by Saneigen FFI), light anhydrous silicic acid (manufactured by CABOT), peppermint oil (manufactured by Ogi Pharmaceutical), orange oil (manufactured by Ogawa Fragrance) and magnesium stearate (manufactured by Marinckrod) was used.
- a powder for tablets was prepared by mixing light anhydrous silicic acid and l-menthol or orange oil as a fragrance.
- the pestle and mortar coated with magnesium stearate and the powder for tablets were tableted with a compression tester ABM100S type static compressor (manufactured by JT Toshi) for tableting into tablets.
- the comparative example 2 was manufactured as a formulation which does not contain an inorganic salt or a basic oxide. At this time, the shape of the ridge was round and the diameter was 6.5 mm.
- Hardness test Measured using a tablet hardness tester (manufactured by ERWEKA International AG). The test is performed with 2 tablets, and the average value is shown.
- Table 4 shows the amounts of lactones as the main analogs and Table 3 shows the amounts of other analogs after 4, 8, and 12 weeks storage at 40 ° C and 75% relative humidity. .
- Results of hardness and disintegration time of monolayer tablet Table 4 shows the hardness and disintegration time of the tablets of Reference Examples 1, 2, 3, and Comparative Example 1. As a result, the hardness of any tablet was 30 N or more, and the tablet disintegrated within 30 seconds.
- Method for producing monolayer tablet containing light stabilizer Table 5 shows the formulation of tablets per tablet.
- rosuvastatin calcium manufactured by AstraZeneca
- yellow ferric oxide manufactured by Kasei Kasei
- magnesium hydroxide manufactured by Kyowa Chemical Industry Co., Ltd.
- crystalline cellulose made by Asahi Kasei Chemicals
- anhydrous calcium hydrogen phosphate made by Kyowa Chemical Industry
- carmellose made by Gotoku Pharmaceutical
- sucralose made by Saneigen FFI
- acesulfame potassium Karlin Kyowa
- Foods thaumatin (manufactured by Saneigen FFI), talc (manufactured by Fuji Talc), light anhydrous silicic acid (manufactured by CABOT), sugar flavor (manufactured by Ogawa Fragrance) and magnesium stearate (manufactured by Marinck Rod) Using.
- rosuvastatin calcium, yellow iron sesquioxide, magnesium hydroxide, crystalline cellulose, anhydrous calcium hydrogen phosphate, carmellose, sucralose, acesulfame potassium, thaumatin, talc, light anhydrous silicic acid and sugar flavor are mixed for tablets.
- a powder was produced.
- the pestle and mortar coated with magnesium stearate and the tablet powder were tableted with a compression tester ABM100S type static compressor (manufactured by JT Toshi) for formulation experiment to obtain tablets.
- the comparative example 3 was manufactured as a formulation which does not contain the yellow ferric oxide which is a light stabilizer. At this time, the shape of the ridge was round and the diameter was 6.5 mm.
- Light stability test Place the specimen in a large light stability tester (manufactured by Nagano Kagaku Kikai Seisakusho Co., Ltd.), irradiate it with light of 3570 lux at 25 ° C for 336 hours (D65 lamp, integrated illuminance 600,000 lux / hour), and use HPLC. The amount of analog was measured.
- Results of light stability test Table 6 shows the total amount of analogs after light irradiation. As a result, compared to the preparation of Comparative Example 2 that did not contain yellow ferric oxide, the amount of the analog was decreased in the preparation of Reference Example 4 that was contained, but the amount was about 5%.
- Table 7 shows the hardness and disintegration time of the tablets of Comparative Example 2 and Reference Example 4. As a result, the hardness of any tablet was 30 N or more, and the tablet disintegrated within 30 seconds.
- Manufacturing method of multilayer tablet containing light stabilizer Tables 8 and 9 show the formulation of tablets per tablet.
- rosuvastatin calcium manufactured by AstraZeneca
- yellow iron sesquioxide manufactured by Kasei Kasei
- titanium oxide manufactured by Toho Titanium
- magnesium oxide manufactured by ICL industrial products
- crystalline cellulose made by Asahi Kasei Chemicals
- anhydrous calcium hydrogen phosphate made by Kyowa Chemical Industry
- carmellose made by Gotoku Pharmaceutical
- sucralose made by Saneigen FFI
- acesulfame potassium Karlin Kyowa
- Foods thaumatin (manufactured by Saneigen FFI), light anhydrous silicic acid (manufactured by CABOT), sugar flavor (manufactured by Ogawa Fragrance), and magnesium stearate (manufactured by Taihei Chemical Sangyo) were used.
- the production method includes rosuvastatin calcium, yellow ferric oxide, titanium oxide, magnesium oxide, crystalline cellulose, anhydrous calcium hydrogen phosphate, carmellose, sucralose, acesulfame potassium, thaumatin, light anhydrous silicic acid, and sugar flavor as an active ingredient.
- a mixed powder for the layer was produced. Yellow iron sesquioxide, crystalline cellulose, anhydrous calcium hydrogen phosphate, carmellose, sucralose, acesulfame potassium, thaumatin, light anhydrous silicic acid and sugar flavor were mixed to produce a mixed powder for the outer layer.
- the outer powder, powder for the active ingredient layer, and powder for the outer layer are filled in the order with the magnesium stearate coated pestle and mortar, and by the ABM100S type static compression machine (made by JT Toshi) Tableted into tablets.
- the shape of the ridge was round, the diameters of Examples 1 to 3 were 6.5 mm, and the diameters of Examples 4 to 6 were 8 mm.
- Table 11 shows the hardness and disintegration time of the tablets of Examples 1 to 6. As a result, the hardness of any tablet was 30 N or more, and the tablet disintegrated within 30 seconds.
- Tables 12 and 13 show the tablet formulation per tablet.
- rosuvastatin calcium manufactured by AstraZeneca
- yellow ferric oxide manufactured by Kasei Chemical
- magnesium oxide manufactured by Tomita Pharmaceutical
- Other additives include crystalline cellulose (made by Asahi Kasei Chemicals), anhydrous calcium hydrogen phosphate (made by Kyowa Chemical Industry), carmellose (made by Gotoku Pharmaceutical), sucralose (made by Saneigen FFI), and acesulfame potassium (Kirin Kyowa).
- thaumatin manufactured by Saneigen FFI
- light anhydrous silicic acid manufactured by CABOT
- sugar flavor manufactured by Ogawa Fragrance
- magnesium stearate manufactured by Taihei Chemical Sangyo
- rosuvastatin calcium, yellow iron sesquioxide, magnesium oxide, crystalline cellulose, anhydrous calcium hydrogen phosphate, carmellose, sucralose, acesulfame potassium, thaumatin, light anhydrous silicic acid and sugar flavor are mixed for an active ingredient layer.
- a mixed powder was produced.
- Yellow iron sesquioxide, crystalline cellulose, anhydrous calcium hydrogen phosphate, carmellose, sucralose, acesulfame potassium, thaumatin, light anhydrous silicic acid and sugar flavor were mixed to produce a mixed powder for the outer layer.
- the outer powder, powder for the active ingredient layer, and powder for the outer layer are filled in the order with the magnesium stearate coated pestle and mortar, and by the ABM100S type static compression machine (made by JT Toshi) Tableted into tablets. At this time, the shape of the ridge was round, and the diameters of the ridges of Examples 7 to 9 and Comparative Example 3 were 6.5 mm.
- Results of light stability test Table 14 shows the total amount of analogs after light irradiation. As a result, the amount of analogs of Examples 7 to 9 containing 0.08 w / w% or more of yellow ferric oxide could be significantly reduced compared to Comparative Example 3 containing no yellow ferric oxide. It was also found that the greater the amount of yellow ferric oxide blended, the less the amount of analog produced.
- An orally disintegrating tablet containing rosuvastatin or a salt thereof is stable to light, temperature and humidity, and can provide a practical level tablet. Furthermore, an orally disintegrating tablet comprising rosuvastatin or a salt thereof and another pharmaceutical product can be produced.
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Abstract
Description
(1)有効成分としての(E)-7-[4-(4-フルオロフェニル)-6-イソプロピル-2-[メチル(メチルスルホニル)アミノ]ピリミジン-5-イル]-(3R,5S)-3,5-ジヒドロキシヘプト-6-エン酸または薬学的に認容できるその塩、光安定化剤、および無機塩または塩基性酸化物を含有する多層錠剤、
(2)有効成分を含有する有効成分層、および有効成分層と隣接する外層からなる二層構造である上記(1)記載の多層錠剤、
(3)有効成分を含有する有効成分層、および有効成分層を挟む外層を含む上記(1)記載の多層錠剤、
(4)三層構造である上記(3)記載の多層錠剤、
(5)有効成分層に光安定化剤を含有する上記(2)から(4)のいずれかに記載の多層錠剤、
(6)有効成分層に無機塩または塩基性酸化物を含有する上記(2)から(4)のいずれかに記載の多層錠剤、
(7)有効成分層に光安定化剤、および無機塩または塩基性酸化物を含有する上記(2)から(4)のいずれかに記載の多層錠剤、
(8)少なくとも1つの外層に光安定化剤を含有する上記(2)から(4)のいずれかに記載の多層錠剤、
(9)有効成分層に光安定化剤、および無機塩または塩基性酸化物を含有し、少なくとも1つの外層に光安定化剤を含有する上記(2)から(4)のいずれかに記載の多層錠剤、
(10)光安定化剤が食用タール色素、食用レーキ化したタール色素、食用天然色素、酸化鉄および酸化チタンからなる群から選択される1以上である上記(1)から(9)のいずれかに記載の多層錠剤、
(11)光安定化剤が食用赤色2号、食用赤色3号、食用赤色102号、食用赤色104号、食用赤色105号、食用赤色106号、食用黄色4号、食用黄色5号、食用緑色3号、食用青色1号、食用青色2号、食用赤色3号アルミニウムレーキ、食用黄色4号アルミニウムレーキ、食用黄色5号アルミニウムレーキ、食用青色1号アルミニウムレーキ、食用青色2号アルミニウムレーキ、カルミン、銅クロロフィリンナトリウム、銅クロロフィル、ベンガラ、三二酸化鉄、黄色三二酸化鉄、黒酸化鉄、黄酸化鉄および酸化チタンからなる群から選択される1以上である上記(10)記載の多層錠剤、
(12)光安定化剤が三二酸化鉄、黄色三二酸化鉄、黒酸化鉄、黄酸化鉄および酸化チタンからなる群から選択される1以上である上記(10)記載の多層錠剤、
(13)光安定化剤が黄色三二酸化鉄である上記(10)記載の多層錠剤、
(14)無機塩または塩基性酸化物が酸化マグネシウム、水酸化マグネシウム、炭酸マグネシウム、水酸化アルミナマグネシウム、水酸化アルミニウム、水酸化アルミニウムゲル、水酸化アルミニウム・炭酸水素ナトリウム共沈物、水酸化ナトリウム、ケイ酸カルシウム、第三リン酸カルシウム、酢酸カルシウム、グルコン酸カルシウム、グリセロリン酸カルシウム、炭酸カルシウム、無水炭酸ナトリウム、炭酸ナトリウム水和物およびクエン酸ナトリウム水和物からなる群から選択される1以上である上記(1)から(10)のいずれかに記載の多層錠剤、
(15)無機塩または塩基性酸化物が酸化マグネシウムである上記(14)記載の多層錠剤、
(16)光安定化剤が黄色三二酸化鉄であり、無機塩または塩基性酸化物が酸化マグネシウムである上記(1)から(15)のいずれかに記載の多層錠剤、
(17)有効成分が(E)-7-[4-(4-フルオロフェニル)-6-イソプロピル-2-[メチル(メチルスルホニル)アミノ]ピリミジン-5-イル]-(3R,5S)-3,5-ジヒドロキシヘプト-6-エン酸のカルシウム塩である上記(1)から(16)のいずれかに記載の多層錠剤、
(18)口腔内崩壊錠剤である上記(1)から(17)のいずれかに記載の多層錠剤、
に関する。
香料とは、着香剤といわれるものを含み、例えば、シュガーフレーバー、バナナフレーバー、サンフィックスバナナ、オレンジエッセンス、オレンジ油、カラメル、カンフル、ケイヒ油、スペアミント油、ストロベリーエッセンス、チョコレートエッセンス、チェリーフレーバー、トウヒ油、パインオイル、ハッカ油、バニラフレーバー、ビターエッセンス、フルーツフレーバー、ペパーミントエッセンス、ミックスフレーバー、ミントフレーバー、メントール、レモンパウダー、レモン油、ローズ油等が挙げられ、好ましくはシュガーフレーバーである。
結合剤として、例えば、ヒドロキシプロピルセルロース、トウモロコシデンプン、アルファー化デンプン、部分アルファー化デンプン、アラビアゴム、アラビアゴム末、ゼラチン、カンテン、デキストリン、プルラン、ポビドン、ポリビニルアルコール、結晶セルロース、メチルセルロース、エチルセルロース、カルボキシメチルエチルセルロース、カルメロース、カルメロースナトリウム、ヒドロキシエチルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルセルロース、ヒプロメロース等が挙げられる。
着色剤として、例えば、黄色三二酸化鉄、三二酸化鉄、食用赤色3号、食用黄色5号、食用青色1号などの食用色素、褐色酸化鉄、黒酸化鉄、銅クロロフィル、銅クロロフィリンナトリウム、リボフラビン、リボフラビン酪酸エステル、抹茶末等が挙げられる。
矯味剤として、例えば、アスコルビン酸およびその塩、アスパルテーム、スクラロース、グリシン、塩化ナトリウム、塩化マグネシウム、塩酸、希塩酸、クエン酸およびその塩(クエン酸ナトリウム)、無水クエン酸、L-グルタミン酸およびその塩、コハク酸およびその塩、酢酸、酒石酸およびその塩、炭酸水素ナトリウム、フマル酸およびその塩、リンゴ酸およびその塩、氷酢酸、イノシン酸二ナトリウム、ハチミツ等が挙げられる。
コーティング剤として、例えば、ポリビニルアルコール、エチルセルロース、カルボキシメチルエチルセルロース、カルメロース、カルメロースナトリウム、ヒドロキシエチルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、PVAコポリマー、アクリル酸エチル・メタクリル酸メチルコポリマー分散液、アミノアルキルメタクリレートコポリマー、オパドライ、カルナバロウ、カルボキシビニルポリマー、乾燥メタクリル酸コポリマー、ジメチルアミノエチルメタアクリレート・メチルメタアクリレートコポリマー、ステアリルアルコール、セラック、セタノール、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート、フマル酸・ステアリン酸・ポリビニルアセタールジエチルアミノアセテート・ヒドロキシプロピルメチルセルロース混合物、ポリビニルアセタールジエチルアミノアセテート、ポリビニルアルコール、メタクリル酸コポリマー、2-メチル-5-ビニルピリジンメチルアクリレート・メタクリル酸コポリマー等が挙げられる。
表1に1錠あたりの錠剤の処方を示す。薬物としては、ロスバスタチンカルシウム(アストラゼネカ製)を用いた。また、光安定化剤として黄色三二酸化鉄(癸巳化成製)、無機塩または塩基性酸化物として水酸化マグネシウム(協和化学工業製)、酸化マグネシウム(ICL industrial products製)および第三リン酸カルシウム(Innophos Inc.製)を用いた。その他の添加剤として、結晶セルロース(旭化成ケミカルズ製)、無水リン酸水素カルシウム(協和化学工業製)、カルメロース(五徳薬品製)、スクラロース(三栄源エフ・エフ・アイ製)、アセスルファムカリウム(キリン協和フーズ製)、タウマチン(三栄源エフ・エフ・アイ製)、軽質無水ケイ酸(CABOT製)、ハッカ油(小城製薬製)、オレンジ油(小川香料製)およびステアリン酸マグネシウム(マリンクロッド製)を用いた。
製造方法としては、ロスバスタチンカルシウム、無機塩または塩基性酸化物として、水酸化マグネシウム、酸化マグネシウム、第三リン酸カルシウムのいずれかを、結晶セルロース、無水リン酸水素カルシウム、カルメロース、スクラロース、アセスルファムカリウム、タウマチン、軽質無水ケイ酸および香料としてl-メントールまたはオレンジ油を混合して錠剤用粉末を作製した。ステアリン酸マグネシウムを塗布した杵及び臼と、この錠剤用粉末を製剤実験用圧縮試験機ABM100S型静的圧縮機(JTトーシ製)によって打錠し、錠剤とした。なお、無機塩または塩基性酸化物を含有しない製剤として、比較例2を製造した。このときの杵の形状は丸型、直径は6.5mmを用いた。
検体を恒温恒湿槽(ナガノサイエンス製)に入れ、40℃、75%相対湿度下に4、8、12週間保存した。その後、HPLCを用いて、ラクトン体およびその他類縁体量を測定した。
錠剤硬度計(ERWEKA International AG製)を用いて測定した。試験は2錠で行い、その平均値を示す。
第16改正日本薬局方崩壊試験法(補助盤なし、試験液:精製水)に従って崩壊試験機を用いて2錠の崩壊時間を測定した。表中には崩壊時間の最大値を示す。
40℃、75%相対湿度下に4、8、12週間保存後において、主要な類縁体であるラクトン体の量を表2に、その他類縁体の量を表3に示す。
その結果、無機塩または塩基性酸化物として水酸化マグネシウム(参考例1)、酸化マグネシウム(参考例2)、第三リン酸カルシウム(参考例3)を用いた製剤は、無機塩または塩基性酸化物を含有しない製剤(比較例1)と比較し、ラクトン体、その他の類縁体量は明らかに低い値となった。また、参考例1および2と、参考例3の製剤のラクトン体、その他の類縁体量を比べると、参考例1および2で低い値となった。
参考例1、2、3、比較例1の錠剤の硬度および崩壊時間を表4に示す。その結果、いずれの錠剤の硬度も30N以上であり、30秒以内に錠剤が崩壊した。
表5に1錠あたりの錠剤の処方を示す。薬物としては、ロスバスタチンカルシウム(アストラゼネカ社製)を用いた。また、光安定化剤として黄色三二酸化鉄(癸巳化成製)、無機塩または塩基性酸化物として水酸化マグネシウム(協和化学工業製)を用いた。その他の添加剤として、結晶セルロース(旭化成ケミカルズ製)、無水リン酸水素カルシウム(協和化学工業製)、カルメロース(五徳薬品製)、スクラロース(三栄源エフ・エフ・アイ製)、アセスルファムカリウム(キリン協和フーズ製)、タウマチン(三栄源エフ・エフ・アイ製)タルク(富士タルク工業製)、軽質無水ケイ酸(CABOT製)、シュガーフレーバー(小川香料製)およびステアリン酸マグネシウム(マリンクロッド製)を用いた。
製造方法としては、ロスバスタチンカルシウム、黄色三二酸化鉄、水酸化マグネシウム、結晶セルロース、無水リン酸水素カルシウム、カルメロース、スクラロース、アセスルファムカリウム、タウマチン、タルク、軽質無水ケイ酸およびシュガーフレーバーを混合して錠剤用粉末を製造した。ステアリン酸マグネシウムを塗布した杵及び臼とこの錠剤用粉末を製剤実験用圧縮試験機ABM100S型静的圧縮機(JTトーシ製)によって打錠し、錠剤とした。なお、光安定化剤である黄色三二酸化鉄を含有しない製剤として、比較例3を製造した。このときの杵の形状は丸型、直径は6.5mmを用いた。
検体を大型光安定性試験装置(ナガノ科学機械製作所製)に入れ、25℃3570ルクスの光を336時間(D65ランプ、積算照度60万ルクス・時間)照射し、HPLCを用いて類縁体量を測定した。
光照射後の類縁体量の合計を表6に示す。その結果、黄色三二酸化鉄を含有しない比較例2の製剤に比べ、含有する参考例4の製剤の方が類縁体の量は低下したが、その量は約5%であった。
比較例2、参考例4の錠剤の硬度および崩壊時間を表7に示す。その結果、いずれの錠剤の硬度も30N以上であり、30秒以内に錠剤が崩壊した。
表8、9に1錠あたりの錠剤の処方を示す。薬物としては、ロスバスタチンカルシウム(アストラゼネカ製)を用いた。また、光安定化剤として黄色三二酸化鉄(癸巳化成製)、酸化チタン(東邦チタニウム製)、無機塩または塩基性酸化物として酸化マグネシウム(ICL industrial products製)を用いた。その他の添加剤として、結晶セルロース(旭化成ケミカルズ製)、無水リン酸水素カルシウム(協和化学工業製)、カルメロース(五徳薬品製)、スクラロース(三栄源エフ・エフ・アイ製)、アセスルファムカリウム(キリン協和フーズ製)、タウマチン(三栄源エフ・エフ・アイ製)、軽質無水ケイ酸(CABOT製)、シュガーフレーバー(小川香料製)およびステアリン酸マグネシウム(太平化学産業製)を用いた。
製造方法としては、ロスバスタチンカルシウム、黄色三二酸化鉄、酸化チタン、酸化マグネシウム、結晶セルロース、無水リン酸水素カルシウム、カルメロース、スクラロース、アセスルファムカリウム、タウマチン、軽質無水ケイ酸およびシュガーフレーバーを混合して有効成分層用の混合末を製造した。黄色三二酸化鉄、結晶セルロース、無水リン酸水素カルシウム、カルメロース、スクラロース、アセスルファムカリウム、タウマチン、軽質無水ケイ酸およびシュガーフレーバーを混合して外層用の混合末を製造した。外層用混合末、有効成分層用混合末、外層用混合末の順に、ステアリン酸マグネシウムを塗布した杵及び臼に充填し、製剤実験用圧縮試験機ABM100S型静的圧縮機(JTトーシ製)によって打錠し、錠剤とした。このときの杵の形状は丸型、実施例1~3の直径は6.5mm、実施例4~6の直径は8mmを用いた。
検体を大型光安定性試験装置(ナガノ科学機械製作所製)に入れ、25℃3570ルクスの光を168時間(D65ランプ、積算照度60万ルクス・時間)照射し、HPLCを用いて類縁体量を測定した。
光照射後の類縁体量の合計を表10に示す。その結果、単層錠剤である参考例4の黄色三二酸化鉄の量は、0.27w/w%に対し、多層錠剤である実施例1~6の黄色三二酸化鉄の合計量は、0.24w/w%であり、実施例のほうが黄色三二酸化鉄の量が少ないにもかかわらず、類縁体の量は著しく低減することができた。さらに、酸化チタンを含有する製剤であれば、類縁体量はさらに低減することが明らかとなったが、服用すると舌や口腔内がやや白くなった。
実施例1~6の錠剤の硬度および崩壊時間を表11に示す。その結果、いずれの錠剤の硬度も30N以上であり、30秒以内に錠剤が崩壊した。
表12、13に1錠あたりの錠剤の処方を示す。薬物としては、ロスバスタチンカルシウム(アストラゼネカ製)を用いた。また、光安定化剤として黄色三二酸化鉄(癸巳化成製)、無機塩または塩基性酸化物として酸化マグネシウム(富田製薬製)を用いた。その他の添加剤として、結晶セルロース(旭化成ケミカルズ製)、無水リン酸水素カルシウム(協和化学工業製)、カルメロース(五徳薬品製)、スクラロース(三栄源エフ・エフ・アイ製)、アセスルファムカリウム(キリン協和フーズ製)、タウマチン(三栄源エフ・エフ・アイ製)、軽質無水ケイ酸(CABOT製)、シュガーフレーバー(小川香料製)およびステアリン酸マグネシウム(太平化学産業製)を用いた。
製造方法としては、ロスバスタチンカルシウム、黄色三二酸化鉄、酸化マグネシウム、結晶セルロース、無水リン酸水素カルシウム、カルメロース、スクラロース、アセスルファムカリウム、タウマチン、軽質無水ケイ酸およびシュガーフレーバーを混合して有効成分層用の混合末を製造した。黄色三二酸化鉄、結晶セルロース、無水リン酸水素カルシウム、カルメロース、スクラロース、アセスルファムカリウム、タウマチン、軽質無水ケイ酸およびシュガーフレーバーを混合して外層用の混合末を製造した。外層用混合末、有効成分層用混合末、外層用混合末の順に、ステアリン酸マグネシウムを塗布した杵及び臼に充填し、製剤実験用圧縮試験機ABM100S型静的圧縮機(JTトーシ製)によって打錠し、錠剤とした。このときの杵の形状は丸型、実施例7~9及び比較例3の杵の直径は6.5mmであった。
実施例1~6と同様である。
光照射後の類縁体量の合計を表14に示す。その結果、黄色三二酸化鉄を含まない比較例3に対し、黄色三二酸化鉄を0.08w/w%以上含む実施例7~9の類縁体量は著しく低減することができた。黄色三二酸化鉄の配合量が多いほど、類縁体の生成量が減ることもわかった。
Claims (18)
- 有効成分としての(E)-7-[4-(4-フルオロフェニル)-6-イソプロピル-2-[メチル(メチルスルホニル)アミノ]ピリミジン-5-イル]-(3R,5S)-3,5-ジヒドロキシヘプト-6-エン酸または薬学的に認容できるその塩、光安定化剤、および無機塩または塩基性酸化物を含有する多層錠剤。
- 有効成分を含有する有効成分層、および有効成分層と隣接する外層からなる二層構造である請求項1記載の多層錠剤。
- 有効成分を含有する有効成分層、および有効成分層を挟む外層を含む請求項1記載の多層錠剤。
- 三層構造である請求項3記載の多層錠剤。
- 有効成分層に光安定化剤を含有する請求項2~4のいずれかに記載の多層錠剤。
- 有効成分層に無機塩または塩基性酸化物を含有する請求項2~4のいずれかに記載の多層錠剤。
- 有効成分層に光安定化剤、および無機塩または塩基性酸化物を含有する請求項2~4のいずれかに記載の多層錠剤。
- 少なくとも1つの外層に光安定化剤を含有する請求項2~4のいずれかに記載の多層錠剤。
- 有効成分層に光安定化剤、および無機塩または塩基性酸化物を含有し、少なくとも1つの外層に光安定化剤を含有する請求項2~4のいずれかに記載の多層錠剤。
- 光安定化剤が食用タール色素、食用レーキ化したタール色素、食用天然色素、酸化鉄および酸化チタンからなる群から選択される1以上である請求項1~9のいずれかに記載の多層錠剤。
- 光安定化剤が食用赤色2号、食用赤色3号、食用赤色102号、食用赤色104号、食用赤色105号、食用赤色106号、食用黄色4号、食用黄色5号、食用緑色3号、食用青色1号、食用青色2号、食用赤色3号アルミニウムレーキ、食用黄色4号アルミニウムレーキ、食用黄色5号アルミニウムレーキ、食用青色1号アルミニウムレーキ、食用青色2号アルミニウムレーキ、カルミン、銅クロロフィリンナトリウム、銅クロロフィル、ベンガラ、三二酸化鉄、黄色三二酸化鉄、黒酸化鉄、黄酸化鉄および酸化チタンからなる群から選択される1以上である請求項10記載の多層錠剤。
- 光安定化剤が三二酸化鉄、黄色三二酸化鉄、黒酸化鉄、黄酸化鉄および酸化チタンからなる群から選択される1以上である請求項10記載の多層錠剤。
- 光安定化剤が黄色三二酸化鉄である請求項10記載の多層錠剤。
- 無機塩または塩基性酸化物が酸化マグネシウム、水酸化マグネシウム、炭酸マグネシウム、水酸化アルミナマグネシウム、水酸化アルミニウム、水酸化アルミニウムゲル、水酸化アルミニウム・炭酸水素ナトリウム共沈物、水酸化ナトリウム、ケイ酸カルシウム、第三リン酸カルシウム、酢酸カルシウム、グルコン酸カルシウム、グリセロリン酸カルシウム、炭酸カルシウム、無水炭酸ナトリウム、炭酸ナトリウム水和物およびクエン酸ナトリウム水和物からなる群から選択される1以上である請求項1~10のいずれかに記載の多層錠剤。
- 無機塩または塩基性酸化物が酸化マグネシウムである請求項14記載の多層錠剤。
- 光安定化剤が黄色三二酸化鉄であり、無機塩または塩基性酸化物が酸化マグネシウムである請求項1~15のいずれかに記載の多層錠剤。
- 有効成分が(E)-7-[4-(4-フルオロフェニル)-6-イソプロピル-2-[メチル(メチルスルホニル)アミノ]ピリミジン-5-イル]-(3R,5S)-3,5-ジヒドロキシヘプト-6-エン酸のカルシウム塩である請求項1~16のいずれかに記載の多層錠剤。
- 口腔内崩壊錠剤である請求項1~17のいずれかに記載の多層錠剤。
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- 2015-11-10 WO PCT/JP2015/081526 patent/WO2016076280A1/ja active Application Filing
- 2015-11-10 EP EP15858595.0A patent/EP3219318A4/en not_active Withdrawn
- 2015-11-10 CN CN201580060779.9A patent/CN107072997A/zh active Pending
- 2015-11-10 BR BR112017009521A patent/BR112017009521A2/pt not_active Application Discontinuation
- 2015-11-10 JP JP2016550875A patent/JP6075818B2/ja active Active
- 2015-11-10 KR KR1020177015106A patent/KR20170083071A/ko unknown
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2017
- 2017-05-03 US US15/585,903 patent/US10398694B2/en not_active Expired - Fee Related
- 2017-05-10 CL CL2017001186A patent/CL2017001186A1/es unknown
- 2017-06-02 CO CONC2017/0005544A patent/CO2017005544A2/es unknown
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WO2017204215A1 (ja) * | 2016-05-27 | 2017-11-30 | 日本化薬株式会社 | ラパマイシン又はその誘導体を含有する医薬組成物 |
JPWO2017204215A1 (ja) * | 2016-05-27 | 2019-04-04 | 日本化薬株式会社 | ラパマイシン又はその誘導体を含有する医薬組成物 |
Also Published As
Publication number | Publication date |
---|---|
JPWO2016076280A1 (ja) | 2017-04-27 |
BR112017009521A2 (pt) | 2017-12-19 |
CL2017001186A1 (es) | 2018-01-05 |
EP3219318A1 (en) | 2017-09-20 |
CO2017005544A2 (es) | 2017-08-10 |
EP3219318A4 (en) | 2018-07-11 |
US20170231989A1 (en) | 2017-08-17 |
US10398694B2 (en) | 2019-09-03 |
CN107072997A (zh) | 2017-08-18 |
KR20170083071A (ko) | 2017-07-17 |
JP6075818B2 (ja) | 2017-02-08 |
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