JP5551852B2 - Nateglinide-containing preparation with reduced bitterness - Google Patents
Nateglinide-containing preparation with reduced bitterness Download PDFInfo
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- JP5551852B2 JP5551852B2 JP2006531680A JP2006531680A JP5551852B2 JP 5551852 B2 JP5551852 B2 JP 5551852B2 JP 2006531680 A JP2006531680 A JP 2006531680A JP 2006531680 A JP2006531680 A JP 2006531680A JP 5551852 B2 JP5551852 B2 JP 5551852B2
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- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 title claims description 63
- 229960000698 nateglinide Drugs 0.000 title claims description 63
- 238000002360 preparation method Methods 0.000 title claims description 49
- 235000019658 bitter taste Nutrition 0.000 title description 22
- 239000007787 solid Substances 0.000 claims description 44
- 239000000843 powder Substances 0.000 claims description 13
- 229920000609 methyl cellulose Polymers 0.000 claims description 8
- 239000001923 methylcellulose Substances 0.000 claims description 8
- 235000010981 methylcellulose Nutrition 0.000 claims description 8
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 5
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 claims description 5
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 5
- 229950008138 carmellose Drugs 0.000 claims description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 229960000913 crospovidone Drugs 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229940031705 hydroxypropyl methylcellulose 2910 Drugs 0.000 claims description 3
- 238000000034 method Methods 0.000 description 25
- 229920003169 water-soluble polymer Polymers 0.000 description 23
- 238000011156 evaluation Methods 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000003826 tablet Substances 0.000 description 16
- 238000005469 granulation Methods 0.000 description 14
- 230000003179 granulation Effects 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000003960 organic solvent Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 210000000214 mouth Anatomy 0.000 description 10
- 235000019640 taste Nutrition 0.000 description 8
- 238000009472 formulation Methods 0.000 description 7
- 239000008187 granular material Substances 0.000 description 7
- 239000006191 orally-disintegrating tablet Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000005550 wet granulation Methods 0.000 description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- 239000007884 disintegrant Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 229920002785 Croscarmellose sodium Polymers 0.000 description 4
- 206010013911 Dysgeusia Diseases 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 229960001681 croscarmellose sodium Drugs 0.000 description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 230000001953 sensory effect Effects 0.000 description 4
- 238000001694 spray drying Methods 0.000 description 4
- OELFLUMRDSZNSF-OFLPRAFFSA-N (2R)-2-[[oxo-(4-propan-2-ylcyclohexyl)methyl]amino]-3-phenylpropanoic acid Chemical compound C1CC(C(C)C)CCC1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-OFLPRAFFSA-N 0.000 description 3
- 101100120289 Drosophila melanogaster Flo1 gene Proteins 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000007771 core particle Substances 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 229940088679 drug related substance Drugs 0.000 description 3
- -1 hydroxypropoxyl group Chemical group 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000007908 dry granulation Methods 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 238000001125 extrusion Methods 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241000593312 Selfia Species 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 239000007931 coated granule Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229940031702 hydroxypropyl methylcellulose 2208 Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000011236 particulate material Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
-
- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Inorganic Chemistry (AREA)
- Hematology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Zoology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明は、糖尿病薬として有用なナテグリニドの経口固形製剤に関する。 The present invention relates to an oral solid preparation of nateglinide useful as a diabetic drug.
ナテグリニド〔化合物名：Ｎ−（トランス−４−イソプロピルシクロヘキシルカルボニル）−Ｄ−フェニルアラニン〕（特公平４−１５２２１号公報）は食前の経口投与により速やかに血中に吸収され食後の高血糖を改善する（速効短時間型）という優れた作用を示し、糖尿病治療薬として実際に臨床の場で使用されている。
しかし、ナテグリニド原薬そのものは非常に強い苦味を有するため、経口剤として用いる場合、錠剤の表面をコートするなどして苦味を低減させる必要があった。
ところで、医薬品を患者の視点で考えた場合、摂取の容易性が求められている。ナテグリニドは、食後の高血糖を改善するという優れた薬ではあるが、その為に食前の投与が必要であった。しかし、これまでの製剤では投与時、薬剤と同時に水の摂取が必要であり、摂取時に水を必要としないナテグリニド含有製剤が求められていた。
近年経口用の製剤において、服用時に水を必要としない経口用製剤が開発されている。これらの中で、口腔内で薬剤が崩壊しその後消化管において吸収される口腔内（速）崩壊錠と呼ばれる製剤が知られている。
ところが、ナテグリニド原薬は上記の様に非常に強い苦味を有するため、通常の手法で口腔内崩壊錠を製造した場合、服用時に口腔内で苦味を有する為、服用者に不快感を与え実用上問題があった。また、これまでナテグリニドを含有する製剤について幾つか知られているが、上記の課題を解決したものはなかった（特許文献２〜６）。Nateglinide [compound name: N- (trans-4-isopropylcyclohexylcarbonyl) -D-phenylalanine] (Japanese Patent Publication No. 4-15221) is rapidly absorbed into the blood by oral administration before meals to improve postprandial hyperglycemia. It exhibits an excellent action (fast-acting short-time type) and is actually used in clinical settings as a therapeutic agent for diabetes.
However, since nateglinide drug substance itself has a very strong bitter taste, when used as an oral preparation, it has been necessary to reduce the bitter taste by coating the surface of the tablet.
By the way, when considering a pharmaceutical from a patient's viewpoint, the ease of ingestion is calculated | required. Nateglinide is an excellent drug that improves postprandial hyperglycemia, but for that purpose it must be administered before meals. However, conventional preparations require intake of water at the same time as the drug at the time of administration, and nateglinide-containing preparations that do not require water at the time of intake have been demanded.
In recent years, oral preparations that do not require water at the time of ingestion have been developed. Among these, a preparation called an intraoral (fast) disintegrating tablet is known in which a drug disintegrates in the oral cavity and is then absorbed in the digestive tract.
However, since nateglinide drug substance has a very strong bitter taste as described above, when an orally disintegrating tablet is produced by a normal method, it has a bitter taste in the oral cavity at the time of taking it, and it is uncomfortable for the user. There was a problem. In addition, some preparations containing nateglinide have been known so far, but none of them solved the above problems (Patent Documents 2 to 6).
本発明は、苦味を感じさせずかつナテグリニドが有する速効短時間型の性質を維持した、ナテグリニド含有経口固形製剤を提供することを目的とする。 An object of the present invention is to provide a nateglinide-containing oral solid preparation that does not give a bitter taste and maintains the fast-acting short-time properties of nateglinide.
上記課題を解決するために鋭意検討した結果、水溶性高分子をナテグリニドに対して特定量使用する事により苦味の低減した経口固形製剤を製造する事ができる事を見出し、本発明を完成させるに到った。
すなわち、本発明は、ナテグリニド及び水溶性高分子を含有する経口固形製剤であって、ナテグリニド１重量部に対して水溶性高分子を固形分換算で０．３〜６重量部含有することを特徴とする前記経口固形製剤を提供する。
本発明はまた、ナテグリニド及び水溶性高分子を含有する苦味の低減した経口固形製剤であって、ナテグリニド１重量部に対して水溶性高分子を固形分換算で０．３〜６重量部含有することを特徴とする前記経口固形製剤を提供する。
本発明はまた、ナテグリニド及び水溶性高分子を有機溶媒に溶解させる工程、及び得られた溶液から粒状物質を形成する工程を含む、ナテグリニド及び水溶性高分子を含有する経口固形製剤ないし苦味の低減した経口固形製剤を製造する方法を提供する。As a result of intensive studies to solve the above problems, it was found that an oral solid preparation with reduced bitterness can be produced by using a specific amount of water-soluble polymer with respect to nateglinide, and the present invention is completed. Arrived.
That is, the present invention is an oral solid preparation containing nateglinide and a water-soluble polymer, characterized by containing 0.3 to 6 parts by weight of the water-soluble polymer in terms of solid content with respect to 1 part by weight of nateglinide. The oral solid preparation is provided.
The present invention also relates to an oral solid preparation with reduced bitterness containing nateglinide and a water-soluble polymer, which contains 0.3 to 6 parts by weight of the water-soluble polymer in terms of solid content with respect to 1 part by weight of nateglinide. The oral solid preparation is provided.
The present invention also reduces oral bitterness or bitterness containing nateglinide and a water-soluble polymer, comprising the steps of dissolving nateglinide and a water-soluble polymer in an organic solvent, and forming a particulate material from the resulting solution. A method for producing an oral solid preparation is provided.
糖尿病薬であるナテグリニドを含有する製剤において、苦味感が低減され、かつナテグリニドが有する速効短時間型の性質を併せ持つ製剤の提供が可能となった。口腔内で崩壊させて使用することができる。 In preparations containing nateglinide, which is a diabetic drug, it has become possible to provide a preparation that has a bitter taste reduction and has the fast-acting short-time properties of nateglinide. It can be used by disintegrating in the oral cavity.
本発明の経口固形製剤に含まれるナテグリニドは、特公平４−１５２２１号公報記載の方法等にしたがって合成することができる。その用いる結晶形は特に限定されないが、Ｈ型、もしくはＢ型が好ましく、特にＨ型が安定性の観点で特に好ましい。
本発明の経口固形製剤に含まれる水溶性高分子とは、重量平均分子量が好ましくは約１０００〜約２００万、さらに好ましくは約１万〜約２０万の高分子であって、２５℃における、水、酸性またはアルカリ性を示す水溶液等のいずれかの水系媒体への溶解度が、０．１ｇ／１００ｍＬ以上であることが好ましい。
具体的には、日本薬局方又は米国薬局方に記載のメチルセルロース、ヒドロキシプロピルセルロース（乾燥品を定量するとき、ヒドロキシプロポキシル基を５３．４〜７７．５％含む）、ヒドロキシプロピルメチルセルロース類（例えばヒドロキシプロピルメチルセルロース２２０８、２９０６、２９１０）、ポリビニルピロリドン（例えばポリビニルピロリドンＫ２５、Ｋ３０、Ｋ９０等）、コポリドン、ポリビニルアルコール、アミノアルキルメタアクリレートコポリマーＥ、ポリビニルアセタールジエチルアミノアセテート等があげられ、好ましくは、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２９１０である。
水溶性高分子の添加量は、ナテグリニド１重量部に対して、固形分換算で０．３重量部〜６重量部であり、好ましくは０．５重量部〜３重量部である。Nateglinide contained in the oral solid preparation of the present invention can be synthesized according to the method described in JP-B-4-15221. The crystal form to be used is not particularly limited, but H-type or B-type is preferable, and H-type is particularly preferable from the viewpoint of stability.
The water-soluble polymer contained in the oral solid preparation of the present invention is a polymer having a weight average molecular weight of preferably about 1000 to about 2 million, more preferably about 10,000 to about 200,000 at 25 ° C. The solubility in any aqueous medium such as water, aqueous solution showing acidity or alkalinity is preferably 0.1 g / 100 mL or more.
Specifically, methylcellulose, hydroxypropylcellulose (containing 53.4-77.5% of hydroxypropoxyl group when dry product is quantified), hydroxypropylmethylcelluloses (for example, as described in Japanese Pharmacopoeia or US Pharmacopoeia) Hydroxypropylmethylcellulose 2208, 2906, 2910), polyvinylpyrrolidone (eg, polyvinylpyrrolidone K25, K30, K90, etc.), copolydon, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate and the like, preferably methylcellulose, Hydroxypropylcellulose, hydroxypropylmethylcellulose 2910.
The addition amount of the water-soluble polymer is 0.3 to 6 parts by weight, preferably 0.5 to 3 parts by weight, in terms of solid content, with respect to 1 part by weight of nateglinide.
本発明の経口固形製剤には、ナテグリニドが有する速効短時間型の性質を維持するために崩壊剤をさらに添加することが好ましい。崩壊剤としては、カルボキシメチルスターチナトリウム、カルメロース、カルメロースナトリウム、カルメロースカルシウム、クロスカルメロースナトリウム、クロスポビドン、低置換度ヒドロキシプロピルセルロース（乾燥品を定量するとき、ヒドロキシプロポキシル基を５．０〜１６．０％含む。日本薬局方第１３改正Ｄ−８８５〜Ｄ−８８８参照）、部分アルファー化デンプン等が挙げられ、特にクロスポビドン、カルメロース、クロスカルメロースナトリウムが好ましい。
崩壊剤の添加量は、ナテグリニド１重量部に対して、好ましくは０．０１重量部〜１６重量部であり、好ましくは０．１重量部〜４重量部である。
本発明の経口固形製剤は、口腔内崩壊錠の形態であるのが好ましい。
本発明の経口固形製剤には、その他の配合成分として、通常の経口製剤に用いられる添加剤を使用することができ、特に限定されないが、糖類、澱粉類、結晶セルロース等の賦形剤；結合剤；ステアリン酸マグネシウム、タルク等の滑沢剤；ｐＨ調整剤；着色剤；糖類、メントール等の矯味剤等を配合することができる。
本発明の苦味の低減した経口固形製剤を製造するには、通常の手法を用いる事により製造する事ができるが、例えばナテグリニドと水溶性高分子との混合物または造粒物を錠剤、カプセル剤や顆粒剤、または散剤のような製剤として提供できる。It is preferable to further add a disintegrant to the oral solid preparation of the present invention in order to maintain the fast-acting short-time nature of nateglinide. Disintegrants include sodium carboxymethyl starch, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose (when the dry product is quantified, the hydroxypropoxyl group is 5.0 -16.0% included (see Japanese Pharmacopoeia 13th revision D-885-D-888), partially pregelatinized starch, etc., with crospovidone, carmellose and croscarmellose sodium being particularly preferred.
The amount of the disintegrant added is preferably 0.01 to 16 parts by weight, and preferably 0.1 to 4 parts by weight with respect to 1 part by weight of nateglinide.
The oral solid preparation of the present invention is preferably in the form of an orally disintegrating tablet.
In the oral solid preparation of the present invention, additives used in ordinary oral preparations can be used as other ingredients, and although not particularly limited, excipients such as sugars, starches, and crystalline cellulose; Agents; Lubricants such as magnesium stearate and talc; pH adjusters; Colorants; Flavoring agents such as sugars and menthol can be blended.
In order to produce an oral solid preparation with reduced bitterness according to the present invention, it can be produced by using a usual method. For example, a mixture or granulated product of nateglinide and a water-soluble polymer is used as a tablet, It can be provided as a formulation such as granules or powders.
本発明の経口固形製剤を錠剤として提供する場合、ナテグリニドと水溶性高分子との混合物または造粒物に、場合により崩壊剤、またはその他の添加物を添加して打錠することにより錠剤として提供できる。具体的には、組成物を適当な混合機で混合した粉末を、打錠して製造する事もできるし、乾式造粒法（圧扁造粒法等）または湿式造粒法（流動層造粒法、攪拌造粒法、押出造粒法等）またはスプレードライ製法などの通常の造粒方法により造粒物を調製し、場合により崩壊剤、またはその他の添加物を添加して打錠して製造することができる。
湿式造粒法による場合、通常、ナテグリニド及び本発明で用いる水溶性高分子を、適当な有機溶媒に溶解させる。使用できる有機溶媒としては、エタノール、エタノール含量が１０〜９０％のエタノール水、ジクロロメタンとエタノールとの混合溶媒（混合比（体積比）＝例えば、１：９〜９：１）等が挙げられる。
湿式造粒法では、崩壊剤等から構成されるコア粒子を、必要によりその他の成分と共にナテグリニドと水溶性高分子とを有機溶媒に溶解させた溶液で被覆することにより層を形成して、粒状物質を造粒物として得ることができる。
湿式造粒法ではまた、結晶セルロース等の賦形剤等を含有するコア粒子を、ナテグリニドで被覆してナテグリニドの内層を形成し、得られた粒状物質をさらに、必要によりその他の成分と共に本発明で用いることができる水溶性高分子で被覆して外層を形成し、最終的に粒状物質を造粒物として得ることができる。
スプレードライ法による場合もまた、通常、ナテグリニド及び本発明で用いる水溶性高分子を、適当な有機溶媒に溶解させる。有機溶媒としては、湿式造粒法について記載したのと同様のものを使用できる。
打錠に関して、口腔内崩壊錠を製造する場合には、低圧、好ましくは５０Ｎ／ｍ2以下で打錠するのが好ましい。
さらに錠剤は必要に応じてフィルムコーティングを施すことも可能である。フィルムコーティング剤としては、例えば、ヒドロキシプロピルメチルセルロース２９１０を使用することができる。When the oral solid preparation of the present invention is provided as a tablet, it is provided as a tablet by optionally adding a disintegrant or other additives to a mixture or granulated product of nateglinide and a water-soluble polymer and then tableting. it can. Specifically, the powder obtained by mixing the composition with an appropriate mixer can be produced by tableting, and can be produced by dry granulation (such as compaction granulation) or wet granulation (fluidized bed granulation). Granulation method, stirring granulation method, extrusion granulation method, etc.) or granulation product prepared by usual granulation method such as spray-drying method. If necessary, disintegrating agent or other additives may be added and compressed into tablets. Can be manufactured.
In the case of the wet granulation method, nateglinide and the water-soluble polymer used in the present invention are usually dissolved in an appropriate organic solvent. Examples of the organic solvent that can be used include ethanol, ethanol water having an ethanol content of 10 to 90%, a mixed solvent of dichloromethane and ethanol (mixing ratio (volume ratio) = for example, 1: 9 to 9: 1), and the like.
In the wet granulation method, core particles composed of a disintegrant and the like are coated with a solution in which nateglinide and a water-soluble polymer are dissolved in an organic solvent together with other components as necessary to form a layer. The substance can be obtained as a granulated product.
In the wet granulation method, core particles containing excipients such as crystalline cellulose are coated with nateglinide to form an inner layer of nateglinide, and the obtained granular material is further added with other components as necessary. The outer layer is formed by coating with a water-soluble polymer that can be used in the above process, and finally a granular material can be obtained as a granulated product.
In the case of the spray drying method, nateglinide and the water-soluble polymer used in the present invention are usually dissolved in a suitable organic solvent. As the organic solvent, the same solvents as described for the wet granulation method can be used.
Regarding tableting, when producing an orally disintegrating tablet, it is preferable to tablet at a low pressure, preferably 50 N / m 2 or less.
Furthermore, the tablets can be film-coated as necessary. As the film coating agent, for example, hydroxypropylmethylcellulose 2910 can be used.
本発明の経口固形製剤を顆粒剤又は散剤として提供する場合もまた、乾式造粒法（圧扁造粒法等）または湿式造粒法（流動層造粒法、攪拌造粒法、押出造粒法等）またはスプレードライ製法などの通常の造粒方法により製造することができる。
これらの方法で製造される本発明経口固形製剤は、これまでの製剤と比べ水を必要としないで摂取でき、口腔内で崩壊させた際の苦味が低減されており、かつ現行ナテグリニド錠剤とのｖｉｔｒｏ評価における生物学同等性をも確保されうる製剤である。When the oral solid preparation of the present invention is provided as a granule or powder, the dry granulation method (pressure flat granulation method etc.) or the wet granulation method (fluidized bed granulation method, stirring granulation method, extrusion granulation method) Or the like, or a conventional granulation method such as a spray drying method.
The oral solid preparation of the present invention produced by these methods can be ingested without the need for water compared to conventional preparations, has reduced bitterness when disintegrated in the oral cavity, and is compared with the current nateglinide tablets. It is a preparation that can ensure bioequivalence in vitro evaluation.
本発明の経口固形製剤において、特に、ナテグリニド１重量部に対し固形分換算で１重量部のアミノアルキルメタクリレートコポリマーＥを含有するものであって、粉末状の形態である経口固形製剤は好ましい。
特に、カルメロース及びクロスポビドンを含有するコアと、ナテグリニド１重量部に対し固形分換算で１から２重量部のヒドロキシプロピルメチルセルロース、メチルセルロース、ヒドロキシプロピルセルロース又はポリビニルピロリドンから構成される外層とを含有する粉末状の形態である経口固形製剤もまた好ましい。ここで外層がナテグリニド１重量部に対し、固形分換算で２重量部のヒドロキシプロピルメチルセルロース、メチルセルロース、ヒドロキシプロピルセルロース又はポリビニルピロリドンから構成される経口固形製剤は特に好ましく、また固形分換算で１重量部のヒドロキシプロピルメチルセルロース、メチルセルロース、ヒドロキシプロピルセルロース又はポリビニルピロリドンから構成される経口固形製剤も特に好ましい。
特に、結晶セルロースのコアと、ナテグリニドの内層と、ナテグリニド１重量部に対し固形分換算で０．７重量部のアミノアルキルメタクリレートコポリマーＥの外層とを含有する顆粒形態の経口固形製剤であるのもまた好ましい。
特に、ナテグリニドと、ナテグリニド１重量部に対し固形分換算で１．１重量部のメチルセルロースとクロスカルメロースナトリウムを含有し、硬度が２０〜３０Ｎ／ｍ2である、錠剤の形態である経口固形製剤もまた好ましく、ここで、メチルセルロースが１重量部であり、クロスカルメロースナトリウムが０．１重量部である経口固形製剤がより好ましい。
中でも、ナテグリニドを水溶性高分子に分散させてなる経口固形製剤が好ましい。このような経口固形製剤の製造方法として、例えば、ナテグリニドと水溶性高分子とを有機溶媒に溶解させた後、溶媒を除去する溶媒除去法を用いることが好ましい。
ナテグリニド及び水溶性高分子を有機溶媒に溶解させる工程、及び得られた溶液から粒状物質を形成する工程（例えば噴霧乾燥）を含む、ナテグリニド及び水溶性高分子を含有する苦味の低減した経口固形製剤を製造する方法は好ましい。In the oral solid preparation of the present invention, in particular, an oral solid preparation in a powder form containing 1 part by weight of aminoalkyl methacrylate copolymer E in terms of solid content with respect to 1 part by weight of nateglinide is preferable.
In particular, a powder containing a core containing carmellose and crospovidone and an outer layer composed of 1 to 2 parts by weight of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose or polyvinylpyrrolidone in terms of solid content with respect to 1 part by weight of nateglinide Also preferred are oral solid preparations that are in the form of a tube. Here, an oral solid preparation in which the outer layer is composed of 2 parts by weight of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose or polyvinylpyrrolidone in terms of solid content with respect to 1 part by weight of nateglinide is particularly preferred, and 1 part by weight in terms of solid content Oral solid preparations composed of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose or polyvinylpyrrolidone are also particularly preferred.
In particular, an oral solid preparation in the form of granules containing a core of crystalline cellulose, an inner layer of nateglinide, and an outer layer of 0.7 parts by weight of aminoalkyl methacrylate copolymer E in terms of solid content with respect to 1 part by weight of nateglinide Also preferred.
In particular, nateglinide, an oral solid preparation in the form of a tablet containing 1.1 parts by weight of methylcellulose and croscarmellose sodium in terms of solid content with respect to 1 part by weight of nateglinide and having a hardness of 20-30 N / m 2 Also preferred is an oral solid formulation wherein methylcellulose is 1 part by weight and croscarmellose sodium is 0.1 part by weight.
Among these, an oral solid preparation in which nateglinide is dispersed in a water-soluble polymer is preferable. As a method for producing such an oral solid preparation, for example, it is preferable to use a solvent removal method in which nateglinide and a water-soluble polymer are dissolved in an organic solvent and then the solvent is removed.
An oral solid preparation with reduced bitterness containing nateglinide and a water-soluble polymer, comprising a step of dissolving nateglinide and a water-soluble polymer in an organic solvent, and a step of forming a granular substance from the resulting solution (for example, spray drying) The method of producing is preferred.
本発明の経口固形製剤が顆粒形態であるとき、粒子の平均粒径は０．０５〜０．８５ｍｍであるのが好ましい。
本発明の経口固形製剤が口腔内崩壊錠の形態であるとき、その硬度は５０Ｎ／ｍ2以下であるのが好ましく、さらに２０〜３０Ｎ／ｍ2であるのが好ましい。
本発明の経口固形製剤は、好ましくは、口腔内で、唾液により速やかに崩壊し、そのまま唾液とともに嚥下可能な製剤である。しかし、もちろん水と共に服用することも可能である。本発明の製剤は、口腔内に入れたとき、６０秒以内に崩壊するのが望ましい。When the oral solid preparation of the present invention is in the form of granules, the average particle size of the particles is preferably 0.05 to 0.85 mm.
When oral solid preparation of the present invention is in the form of orally-disintegrating tablets, hardness is preferably at most 50 N / m 2, still more preferably from 20-30 N / m 2.
The oral solid preparation of the present invention is preferably a preparation that is rapidly disintegrated by saliva in the oral cavity and can be swallowed as it is. However, of course, it can be taken with water. Desirably, the formulation of the present invention disintegrates within 60 seconds when placed in the oral cavity.
実施例１〜６
ナテグリニドと表１に示す水溶性高分子を１：１で十分に混合し、圧扁造粒機（ローラーコンパクター、ターボ工業）により圧扁化することによりナテグリニド含有粉末製剤を得た。後述の味評価と同じようにしてこの粉末製剤の味評価を実施したところ、苦味が軽減していた。
実施例７〜１２
ナテグリニドと表２に示す水溶性高分子を有機溶媒（エタノール、または５０％エタノール水、またはジクロロメタン／エタノール＝６：４）に固形分の重量％が１０％となるように溶解させて、スプレードライヤー（ＧＳ３１０、ヤマト科学）にて噴霧し、噴霧乾燥されたナテグリニド含有粉末製剤を得た。
実施例１３〜１６
ナテグリニドと表３に示す水溶性高分子を有機溶媒（ジクロロメタン／エタノール＝６：４）に溶解させた溶液を、流動層造粒機（ＦＬＯ−１型、フロイント産業）を用いて、表３中の造粒時添加部記載の粉体に流動層内で噴き付け、造粒物を得た。得られた造粒物に、後添加部記載の添加物を添加し、ナテグリニド含有粉末製剤を得た。
実施例１７
ナテグリニドのエタノール水溶液を結晶セルロースの球形核粒子（セルフィアＣＰ５０７、旭化成（株））に噴霧することによりレイアリングした核粒子に表４記載の水溶性高分子を流動層造粒機（ＦＬＯ−１型、フロイント産業）を用いてコーティングし、ナテグリニド含有フィルムコート顆粒を得た。
味評価
上記実施例１から１７で得た粉末製剤について官能評価による味評価を実施した。評価はナテグリニドとして１０ｍｇに相当する製剤を口腔内で溶解させて味評価を実施した。また、評価は５段階で行った。表５に評価基準を、表２〜４に味評価結果を示す。Examples 1-6
Nateglinide and the water-soluble polymer shown in Table 1 were mixed thoroughly at 1: 1, and nateglinide-containing powder formulation was obtained by pressing with a pressing granulator (Roller Compactor, Turbo Industries). When the taste evaluation of this powder preparation was carried out in the same manner as the taste evaluation described later, the bitterness was reduced.
Examples 7-12
Nateglinide and the water-soluble polymer shown in Table 2 are dissolved in an organic solvent (ethanol, 50% ethanol water, or dichloromethane / ethanol = 6: 4) so that the solid content is 10% by weight, and a spray dryer Sprayed with (GS310, Yamato Kagaku) to obtain a spray-dried nateglinide-containing powder formulation.
Examples 13-16
In Table 3, a solution obtained by dissolving nateglinide and the water-soluble polymer shown in Table 3 in an organic solvent (dichloromethane / ethanol = 6: 4) was used in a fluidized bed granulator (FLO-1 type, Freund Sangyo). Were sprayed in the fluidized bed to the powder described in the addition part during granulation to obtain a granulated product. Additives described in the post-addition part were added to the obtained granulated product to obtain a nateglinide-containing powder formulation.
Example 17
Fluidized bed granulator (FLO-1 type) is prepared by spraying an aqueous solution of nateglinide with ethanol onto spherical core particles of crystalline cellulose (Selfia CP507, Asahi Kasei Co., Ltd.). , Freund Sangyo Co., Ltd.) to obtain nateglinide-containing film-coated granules.
Taste evaluation The taste evaluation by sensory evaluation was implemented about the powder formulation obtained in the said Examples 1-17. Evaluation was performed by dissolving a preparation corresponding to 10 mg as nateglinide in the oral cavity. Moreover, evaluation was performed in five steps. Table 5 shows the evaluation criteria, and Tables 2 to 4 show the taste evaluation results.
上記官能評価結果から分かるように、本発明製剤は、苦味の低いナテグリニド含有経口固形製剤を提供するものである。
官能評価結果から分かるように、ナテグリニドを水溶性高分子中に分散することにより、ナテグリニド特有の強い苦味を低減することが出来た。
実施例１８
ナテグリニドと表６に示す高分子を有機溶媒（ジクロロメタン／エタノール＝６：４）に溶解させた溶液を、流動層造粒機（ＦＬＯ−１型、フロイント産業）を用いて、表６中の造粒時添加部記載の粉体に流動層内で噴き付け、造粒物を得た。得られた造粒物に、後添加部記載の添加物を添加し、低圧打錠によりナテグリニド含有口腔内崩壊錠製剤を得た。
上記実施例で得た口腔内崩壊錠について、官能評価による味評価（１錠を口腔内で溶解させた）及びｖｉｔｒｏ評価による生物学的同等性評価（溶出試験、対「ファスティック」９０ｍｇ錠）を実施した。表６に評価結果を示す。As can be seen from the sensory evaluation results, the preparation of the present invention provides a nateglinide-containing oral solid preparation with low bitterness.
As can be seen from the sensory evaluation results, the strong bitterness peculiar to nateglinide could be reduced by dispersing nateglinide in the water-soluble polymer.
Example 18
Using a fluidized bed granulator (FLO-1 type, Freund Industries), a solution prepared by dissolving nateglinide and the polymer shown in Table 6 in an organic solvent (dichloromethane / ethanol = 6: 4) was used. It sprayed in the fluidized bed to the powder described in the addition part at the time of granulation, and the granulated material was obtained. Additives described in the post-addition part were added to the resulting granulated product, and a nateglinide-containing orally disintegrating tablet preparation was obtained by low-pressure tableting.
For the orally disintegrating tablets obtained in the above examples, taste evaluation by sensory evaluation (one tablet was dissolved in the oral cavity) and bioequivalence evaluation by vitro evaluation (dissolution test, vs. “Fastic” 90 mg tablet) Carried out. Table 6 shows the evaluation results.
表６から分かるように、ナテグリニド特有の強い苦味が低減されており、かつＶｉｔｒｏ評価において、溶出性が同等であることが確認された。このことから、ナテグリニドの苦味が低減され、かつ現行ナテグリニド錠剤との生物学的同等性を確保できた口腔内崩壊錠を開発することが出来たことが理解される。 As can be seen from Table 6, it was confirmed that the strong bitterness peculiar to nateglinide was reduced and the dissolution was equivalent in the Vitro evaluation. From this, it is understood that an orally disintegrating tablet in which the bitter taste of nateglinide was reduced and bioequivalence with the current nateglinide tablet was secured could be developed.
比較例１
現在市販されているナテグリニド製剤（「ファスティック」９０ｍｇ錠）１錠を口腔内で溶解させて、味評価を実施した。評価の結果、苦味が非常に強かったため、途中で錠剤を吐き出した。後味も数時間残る結果となった。Comparative Example 1
One tablet of nateglinide currently marketed (“Fastic” 90 mg tablet) was dissolved in the oral cavity to evaluate the taste. As a result of the evaluation, since the bitterness was very strong, the tablet was spit out on the way. The aftertaste also remained for several hours.
ナテグリニド原薬のトウモロコシデンプンによる１０倍散品１０ｍｇ（ナテグリニド１ｍｇ含有）を口腔内で溶解させて、前述の味評価に従い評価した。
結果、苦味：１、後味の有無：３、後味：１、合計：５、であった。
苦味が強く後味も数時間残る結果となった。
10 mg of nateglinide drug substance corn starch 10 mg (containing 1 mg of nateglinide) was dissolved in the oral cavity and evaluated according to the aforementioned taste evaluation.
The results were bitterness: 1, presence / absence of aftertaste: 3, aftertaste: 1, total: 5.
The bitterness was strong and the aftertaste remained for several hours.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| JP2006531680A JP5551852B2 (en) | 2004-08-10 | 2005-08-10 | Nateglinide-containing preparation with reduced bitterness |
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| JP2004233797 | 2004-08-10 | ||
| JP2004233797 | 2004-08-10 | ||
| JP2006531680A JP5551852B2 (en) | 2004-08-10 | 2005-08-10 | Nateglinide-containing preparation with reduced bitterness |
| PCT/JP2005/014647 WO2006016602A1 (en) | 2004-08-10 | 2005-08-10 | Nateglinide-containing preparation reduced in bitterness |
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| JP2012048419A Division JP5578492B2 (en) | 2004-08-10 | 2012-03-05 | Nateglinide-containing preparation with reduced bitterness |
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| JP2006531680A Expired - Fee Related JP5551852B2 (en) | 2004-08-10 | 2005-08-10 | Nateglinide-containing preparation with reduced bitterness |
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| EP2050448A4 (en) * | 2006-08-08 | 2012-01-04 | Kissei Pharmaceutical | Oral disintegrating tablet having masked bitter taste and method for production thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS519712A (en) * | 1974-07-15 | 1976-01-26 | Meiji Seika Co | KEIKOYOIYAKUHINSOSEIBUTSUNO SEIHO |
| JP2001019639A (en) * | 1999-07-07 | 2001-01-23 | Nitto Yakuhin Kogyo Kk | Solid cold preparation |
| JP2001518490A (en) * | 1997-10-03 | 2001-10-16 | エラン コーポレーシヨン ピーエルシー | Taste-masked preparation |
| JP2002179558A (en) * | 2000-10-06 | 2002-06-26 | Takeda Chem Ind Ltd | Solid preparation |
| JP2004010611A (en) * | 2002-06-06 | 2004-01-15 | Nisshin Yakuhin Kogyo Kk | Masking composition |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS519712B2 (en) * | 1972-12-29 | 1976-03-29 | ||
| JPH0717866A (en) * | 1993-06-16 | 1995-01-20 | Meiji Seika Kaisha Ltd | Medicinal composition |
| AR028299A1 (en) * | 1999-09-17 | 2003-05-07 | Novartis Ag | A PHARMACEUTICAL COMPOSITION THAT INCLUDES NATEGLINIDA, A PROCESS FOR ITS PREPARATION AND THE USE OF SUCH COMPOSITION FOR THE PREPARATION OF A MEDICINAL PRODUCT FOR THE TREATMENT OF METABOLIC DISORDERS, ESPECIALLY DIABETES, OR A DISEASE OR CONDITION ASSOCIATED WITH DIABETY. |
| ATE399000T1 (en) * | 1999-12-28 | 2008-07-15 | Ajinomoto Kk | ANTIDIABETES PREPARATION FOR ORAL ADMINISTRATION |
| ATE406885T1 (en) * | 2000-10-24 | 2008-09-15 | Ajinomoto Kk | PREPARATIONS CONTAINING NATEGLINIDE |
| GEP20063856B (en) * | 2001-09-26 | 2006-06-26 | Pharmacia Corp | Organoleptically acceptable intraorally disintegrating compositions |
-
2005
- 2005-08-10 WO PCT/JP2005/014647 patent/WO2006016602A1/en active Application Filing
- 2005-08-10 JP JP2006531680A patent/JP5551852B2/en not_active Expired - Fee Related
- 2005-08-10 KR KR1020077003164A patent/KR20070040389A/en active IP Right Grant
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS519712A (en) * | 1974-07-15 | 1976-01-26 | Meiji Seika Co | KEIKOYOIYAKUHINSOSEIBUTSUNO SEIHO |
| JP2001518490A (en) * | 1997-10-03 | 2001-10-16 | エラン コーポレーシヨン ピーエルシー | Taste-masked preparation |
| JP2001019639A (en) * | 1999-07-07 | 2001-01-23 | Nitto Yakuhin Kogyo Kk | Solid cold preparation |
| JP2002179558A (en) * | 2000-10-06 | 2002-06-26 | Takeda Chem Ind Ltd | Solid preparation |
| JP2004010611A (en) * | 2002-06-06 | 2004-01-15 | Nisshin Yakuhin Kogyo Kk | Masking composition |
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| KR20130018956A (en) | 2013-02-25 |
| WO2006016602A1 (en) | 2006-02-16 |
| JP2012121911A (en) | 2012-06-28 |
| JPWO2006016602A1 (en) | 2008-05-01 |
| KR20070040389A (en) | 2007-04-16 |
| JP5578492B2 (en) | 2014-08-27 |
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