JPWO2014188729A1 - Oral composition - Google Patents
Oral composition Download PDFInfo
- Publication number
- JPWO2014188729A1 JPWO2014188729A1 JP2014540253A JP2014540253A JPWO2014188729A1 JP WO2014188729 A1 JPWO2014188729 A1 JP WO2014188729A1 JP 2014540253 A JP2014540253 A JP 2014540253A JP 2014540253 A JP2014540253 A JP 2014540253A JP WO2014188729 A1 JPWO2014188729 A1 JP WO2014188729A1
- Authority
- JP
- Japan
- Prior art keywords
- composition
- oral composition
- mass
- group
- total amount
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 239000000203 mixture Substances 0.000 title claims abstract description 145
- 150000004671 saturated fatty acids Chemical class 0.000 claims abstract description 22
- 238000002156 mixing Methods 0.000 claims abstract description 16
- 239000004480 active ingredient Substances 0.000 claims abstract description 13
- UQGKUQLKSCSZGY-UHFFFAOYSA-N Olmesartan medoxomil Chemical compound C=1C=C(C=2C(=CC=CC=2)C2=NNN=N2)C=CC=1CN1C(CCC)=NC(C(C)(C)O)=C1C(=O)OCC=1OC(=O)OC=1C UQGKUQLKSCSZGY-UHFFFAOYSA-N 0.000 claims description 44
- 229960001199 olmesartan medoxomil Drugs 0.000 claims description 44
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 42
- 235000021355 Stearic acid Nutrition 0.000 claims description 39
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 39
- 239000008117 stearic acid Substances 0.000 claims description 39
- 239000002051 C09CA08 - Olmesartan medoxomil Substances 0.000 claims description 38
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 33
- 229960004977 anhydrous lactose Drugs 0.000 claims description 31
- 239000000126 substance Substances 0.000 claims description 31
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 30
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 23
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- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 18
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 18
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- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 238000013329 compounding Methods 0.000 claims description 4
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical group CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 abstract description 31
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- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 8
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- 229940045902 sodium stearyl fumarate Drugs 0.000 description 8
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- 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 description 5
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 4
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- -1 (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2- Propyl-1-{[2 ′-(1H-tetrazol-5-yl) -1,1′-biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate Chemical compound 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
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- 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 3
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- FSEKIHNIDBATFG-UHFFFAOYSA-N camostat mesylate Chemical compound CS([O-])(=O)=O.C1=CC(CC(=O)OCC(=O)N(C)C)=CC=C1OC(=O)C1=CC=C([NH+]=C(N)N)C=C1 FSEKIHNIDBATFG-UHFFFAOYSA-N 0.000 description 3
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- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin hydrochloride Natural products CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
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- 238000003860 storage Methods 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
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- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
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- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- 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
- A61P9/12—Antihypertensives
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
特定の医薬品が発するジアセチルに起因する特有な不快臭を改善した経口用組成物を提供する。本発明は、ジアセチルを発生させる有効成分を含む経口用組成物に飽和脂肪酸を配合してなる経口用組成物に関する。本発明の経口用組成物は、不快臭の抑制、良好な製造性、良好な溶出性を有する。Provided is an oral composition having an improved unpleasant odor caused by diacetyl emitted from a specific pharmaceutical product. The present invention relates to an oral composition obtained by blending a saturated fatty acid with an oral composition containing an active ingredient that generates diacetyl. The oral composition of the present invention has an unpleasant odor suppression, good manufacturability, and good dissolution properties.
Description
本発明は、特定の医薬品が発するジアセチルに起因する特有な不快臭を改善した経口用組成物に関する。 The present invention relates to an oral composition having an improved unpleasant odor caused by diacetyl emitted from a specific pharmaceutical product.
現在、医薬品は経口投与製剤の占める割合が高く、その中でも固形製剤が主流であるが、中には特有な不快臭を有する製剤が存在する。これらの不快臭は、服用者の服薬時や医療従事者の調剤時に強い不快感を与えることから、何らかの改善策が求められる。 At present, pharmaceutical preparations have a high proportion of oral preparations. Among them, solid preparations are the mainstream, but some preparations have a specific unpleasant odor. Since these unpleasant odors give a strong unpleasant sensation when the user is taking medicine or when a medical worker is dispensing, some improvement measures are required.
特有な不快臭を有する医薬品成分の例の１つとして、（５−メチル−２−オキソ−１，３−ジオキソレン−４−イル）メチル ４−（１−ヒドロキシ−１−メチルエチル）−２−プロピル−１−{［２’−（１Ｈ−テトラゾール−５−イル）−１，１’−ビフェニル−４−イル］メチル}−１Ｈ−イミダゾール−５−カルボキシレート（以下、「オルメサルタンメドキソミル」という。）が挙げられる。オルメサルタンメドキソミルは、オルメテック（登録商標、以下同）錠として既に製造・販売されている高血圧症治療薬であり、オルメテック錠は有効成分にオルメサルタンメドキソミルを含む素錠の形態の錠剤である。オルメサルタンメドキソミルは、メドキソミルエステルが徐々に切断される過程で臭い原因物質と考えられている低分子の２，３−ブタジオン（以下、「ジアセチル」という。）を放出することが知られている（特許文献１参照）。 One example of a pharmaceutical ingredient having a unique unpleasant odor is (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2- Propyl-1-{[2 ′-(1H-tetrazol-5-yl) -1,1′-biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate (hereinafter referred to as “olmesartan medoxomil”). ). Olmesartan medoxomil is an antihypertensive drug already manufactured and sold as Olmetec (registered trademark, hereinafter the same) tablet. Olmetec tablets are uncoated tablets containing olmesartan medoxomil as an active ingredient. Olmesartan medoxomil is known to release low-molecular 2,3-butadione (hereinafter referred to as “diacetyl”), which is considered to be an odor-causing substance, in the process of gradual cleavage of medoxomil ester (patent). Reference 1).
また、オルメテック錠は有効成分がメトホルミン塩酸塩であるメデット（登録商標、以下同）錠やメトグルコ（登録商標、以下同）錠、有効成分がカモスタットメシル酸塩であるフオイパン（登録商標、以下同）錠と一包化時に、これらの錠剤を着色することも知られており、この原因もオルメテック錠より放出されるジアセチルによるものと考えられている。一包化による錠剤の着色は外観を損なうだけでなく、医薬品そのものの品質にも影響を与える可能性があり、好ましくない。このようなことから、オルメサルタンメドキソミルを含有する医薬品製剤からジアセチルを発生させない、あるいは放出させない工夫が必要とされてきている。 Olmetec tablets are Medet (registered trademark, hereinafter the same) tablets whose active ingredients are metformin hydrochloride and Metogluco (registered trademark, the following) tablets, and Foypan (registered trademarks, the following) whose active ingredients are camostat mesylate. It is also known that these tablets are colored when they are encapsulated with a tablet, and this is considered to be caused by diacetyl released from Olmetec tablets. The coloration of the tablet by encapsulating not only impairs the appearance but also may affect the quality of the drug itself, which is not preferable. For these reasons, there has been a need for a device that does not generate or release diacetyl from a pharmaceutical preparation containing olmesartan medoxomil.
においを発生させない方法として、素錠ににおいの発生を抑制する物質を加える、あるいは発生したジアセチルを吸着する物質を加える方法が考えられる。従来技術としてメドキソミル基を有する化合物を有効成分とする医薬組成物処方中にシクロデキストリンを加える方法が知られている（特許文献１参照）。
しかしながらこの方法で使用されるシクロデキストリンは構造上低分子を包接する機能を有するが、ジアセチルに限らず様々な低分子を包接する恐れがあり、複数の医薬品を併用する場合には他の有効成分と包接して医薬品の効果を低下させる可能性がある。As a method for preventing the generation of odor, a method of adding a substance that suppresses the generation of odor to the uncoated tablet or a substance that adsorbs the generated diacetyl can be considered. As a conventional technique, a method of adding cyclodextrin to a pharmaceutical composition formulation containing a compound having a medoxomil group as an active ingredient is known (see Patent Document 1).
However, cyclodextrin used in this method has a function of inclusion of low molecules in structure, but there is a risk of inclusion of various low molecules, not limited to diacetyl. May reduce the effectiveness of the drug.
一方、オルメサルタンメドキソミルを安定化させる方法として素錠全量当たり０．１〜１質量％、又は有効成分に対して１〜２０質量％のステアリン酸を加えることにより不純物の増加を抑制できる（特許文献２参照）ことが知られている。しかしながら、このようなステアリン酸を含む処方は粉体の流動性が悪く、製造性が悪い（特許文献３参照）点が課題となっている。特許文献３には素錠全量当たり約１質量％のステアリン酸を配合した具体例が記載されており、この量にステアリン酸を配合しただけでも流動性に問題が生じ、工業的な製法には不適切となることが記載されている。また、ステアリン酸をにおいの解決に用いることは記載されていない。 On the other hand, as a method for stabilizing olmesartan medoxomil, an increase in impurities can be suppressed by adding 0.1 to 1% by mass of stearic acid to the whole amount of the uncoated tablet or 1 to 20% by mass based on the active ingredient (Patent Document 2). See). However, such a formulation containing stearic acid has a problem in that the powder has poor fluidity and poor manufacturability (see Patent Document 3). Patent Document 3 describes a specific example in which about 1% by mass of stearic acid is blended with respect to the total amount of uncoated tablets. Even if stearic acid is blended in this amount, a problem arises in fluidity. It is described as inappropriate. In addition, the use of stearic acid to solve odors is not described.
以上のように、ジアセチルを発生し、放出して特有の不快臭を有する錠剤等の製剤において、ジアセチルの発生及び／又はその製剤からの放出を抑制することで、不快臭なく、あるいは不快臭を抑制し、服薬時や医療従事者の調剤時に不快感のない製剤の提供が望まれている。
また、医薬品の一包化時に他剤を着色することのない製剤の提供が望まれている。
さらに、製造性良く、溶出性の良好な組成物を提供することが課題となっている。As described above, in preparations such as tablets that generate and release diacetyl and have a peculiar unpleasant odor, by suppressing the generation of diacetyl and / or release from the preparation, there is no unpleasant odor or unpleasant odor. It is desired to provide a preparation that suppresses and does not cause discomfort when taking medicine or dispensing medical personnel.
In addition, it is desired to provide a preparation that does not color other agents when the medicine is packaged.
Furthermore, providing a composition with good manufacturability and good elution is an issue.
本発明者らは、上記課題に鑑み、経口用製剤からのジアセチルの発生及び／又はその放出抑制を目的に鋭意検討した結果、素錠に対し、先行技術よりも更に多い５〜１５質量％ステアリン酸を加えることによりにおいを抑制できることを見出した。
また、素錠に対して高含量のステアリン酸を加えると前述の通り流動性が低下する問題が生じるが、無水乳糖、乳糖水和物、白糖、などの流動性の高い特定の添加剤を多量に用いることで製造性良く錠剤を製造することができることを見出した。
そして、ステアリン酸を含む本願の素錠では、主薬の溶出性が低下するという新たな問題が生じたが、特定の崩壊剤（例えば、クロスポビドン、アルファー化デンプン又はこれらの混合物）を用いることにより溶出遅延を防止し、溶出性も改善できることを見出し、本発明を完成させた。In view of the above-mentioned problems, the present inventors have intensively studied for the purpose of generating diacetyl from oral preparations and / or suppressing the release thereof, and as a result, 5-15% by mass stearin is more than the prior art. It was found that the odor can be suppressed by adding an acid.
In addition, when high content of stearic acid is added to the uncoated tablet, there is a problem that the fluidity is lowered as described above, but a large amount of specific additives with high fluidity such as anhydrous lactose, lactose hydrate, sucrose, etc. It was found that tablets can be produced with good manufacturability when used in the above.
And in the uncoated tablet of the present application containing stearic acid, there was a new problem that the dissolution of the active ingredient was lowered, but by using a specific disintegrant (for example, crospovidone, pregelatinized starch or a mixture thereof) The inventors have found that elution delay can be prevented and elution can be improved, and the present invention has been completed.
すなわち、本発明の第１の態様は以下の経口用組成物である。
（１−１）ａ) 有効成分としてメドキソミル基を持つ薬剤、及び、
ｂ) 組成物全量に対して５〜１５質量％の炭素数が１２〜２２の飽和脂肪酸、
を含有してなる経口用組成物。
（１−２）メドキソミル基を持つ薬剤がオルメサルタンメドキソミルである（１−１）に記載の経口用組成物。
（１−３）炭素数が１２〜２２の飽和脂肪酸がステアリン酸及び／又はパルミチン酸である（１−１）又は（１−２）に記載の経口用組成物。
（１−４）経口用組成物が、さらにｃ) 崩壊剤としてクロスポビドン、若しくはアルファー化デンプン、又はこれらの混合物を含む（１−１）〜（１−３）のいずれか１項に記載の経口用組成物。
（１−５）崩壊剤としてクロスポビドン、若しくはアルファー化デンプン、又はこれらの混合物が、組成物全量に対して２〜２０質量％である（１−４）に記載の経口用組成物。
（１−６）経口用組成物が、さらにｄ) 賦形剤として無水乳糖、乳糖水和物、白糖、トレハロース、及びマンニトールからなる群から選ばれる少なくとも１つを含む（１−１）〜（１−５）のいずれか１項に記載の経口用組成物。
（１−７）経口用組成物が、さらにｄ) 賦形剤として無水乳糖、乳糖水和物、及び白糖からなる群から選ばれる少なくとも１つを含む（１−１）〜（１−６）に記載の経口用組成物。
（１−８）経口用組成物が、さらにｄ) 賦形剤として無水乳糖及び／又は白糖を含む（１−１）〜（１−７）のいずれか１項に記載の経口用組成物。
（１−９）賦形剤の配合量が、組成物全量に対して６５〜９０質量％、好ましくは７０〜９０質量％である（１−６）〜（１−８）のいずれか１項に記載の経口用組成物。
（１−１０）経口用組成物が、錠剤である（１−１）〜（１−９）のいずれか１項に記載の経口用組成物。
（１−１１）ａ) 有効成分としてメドキソミル基を持つ薬剤、
ｂ) 組成物全量に対して５〜１５質量％のステアリン酸又はパルミチン酸から選ばれる飽和脂肪酸、
ｃ) 組成物全量に対して２〜２０質量％の、クロスポビドン、若しくはアルファー化デンプン、又はこれらの混合物、からなる群より選ばれる少なくとも１つの崩壊剤、
ｄ) 組成物全量に対して６５〜９０質量％の、無水乳糖、乳糖水和物、白糖、トレハロース、及びマンニトールからなる群から選ばれる少なくとも１つの賦形剤、
を含有してなる経口用組成物。
（１−１２）賦形剤が、無水乳糖及び／又は白糖である（１−１１）に記載の経口用組成物。
（１−１３）賦形剤が、無水乳糖である（１−１１）又は（１−１２）に記載の経口用組成物。
（１−１４）メドキソミル基を持つ薬剤の配合量が、組成物全量に対して２〜２５質量％である、（１−１１）〜（１−１３）のいずれか１項に記載の経口用組成物。
（１−１５）メドキソミル基を持つ薬剤が、オルメサルタンメドキソミルである（１−１１）〜（１−１４）のいずれか１項に記載の経口用組成物。
（１−１６）経口用組成物が、錠剤である（１−１１）〜（１−１５）のいずれか１項に記載の経口用組成物。
（１−１７）経口用組成物が、コーティング製剤の素錠である（１−１）〜（１−１６）のいずれか１項に記載の経口用組成物。
（１−１８）素錠が、さらにコーティング用組成物でコーティングされたコーティング層を有している（１−１７）に記載の経口用組成物。
（１−１９）ａ) オルメサルタンメドキソミル、
ｂ) 組成物全量に対して５〜１５質量％のステアリン酸又はパルミチン酸から選ばれる飽和脂肪酸、
ｃ) クロスポビドン、アルファー化デンプン、及びこれらの混合物、からなる群より選ばれる少なくとも１つの崩壊剤、
ｄ) 無水乳糖、乳糖水和物、及び白糖からなる群から選ばれる少なくとも１つの賦形剤、
を含有してなる、錠剤の形態である経口用組成物。
（１−２０）ａ) 組成物全体に対して１〜２５質量％のオルメサルタンメドキソミル、
ｂ) 組成物全量に対して５〜１５質量％のステアリン酸、
ｃ) 組成物全量に対して２〜２０質量％の、クロスポビドン、アルファー化デンプン、及びこれらの混合物、からなる群より選ばれる少なくとも１つの崩壊剤、
ｄ) 組成物全量に対して６５〜９０質量％の、無水乳糖及び／又は乳糖水和物である賦形剤、
を含有してなる、錠剤の形態である経口用組成物。
（１−２１）経口用組成物を２０ｍＬ容積のガラスバイアルに入れて密封し、２５℃４週間保存した時のジアセチルの放出量をガスクロマトグラフィーで測定した場合に、メドキソミル基を持つ薬剤１ｍｇあたり２００ｎｇ／ｍｇ以下であることを特徴とする（１−１）〜（１−２０）のいずれか１項に記載の経口用組成物。
（１−２２）経口用組成物を２０ｍＬ容積のガラスバイアルに入れて密封し、４０℃５日間保存した時のジアセチルの放出量をガスクロマトグラフィーで測定した場合に、メドキソミル基を持つ薬剤１ｍｇあたり２００ｎｇ／ｍｇ以下であることを特徴とする（１−１）〜（１−２１）のいずれか１項に記載の経口用組成物。
（１−２３）経口用組成物につき、日本薬局方溶出試験パドル法にて試験を行い（試験液：日本薬局方溶出試験液２液、回転数：５０回転）試験開始後１５分における溶出率が５０％以上であることを特徴とする（１−１）〜（１−２２）のいずれか１項に記載の経口用組成物。
（１−２４）メドキソミル基を持つ薬剤１０ｍｇに相当する経口用組成物を２０ｍＬ容積のガラスバイアルに入れて密封し、４０℃５日間保存した時の類縁物質の合計値が１％以下であることを特徴とする（１−１）〜（１−２３）のいずれか１項に記載の経口用組成物。That is, the first aspect of the present invention is the following oral composition.
(1-1) a) a drug having a medoxomil group as an active ingredient, and
b) Saturated fatty acid having 12 to 22 carbon atoms of 5 to 15% by mass relative to the total amount of the composition,
An oral composition comprising
(1-2) The oral composition according to (1-1), wherein the drug having a medoxomil group is olmesartan medoxomil.
(1-3) The oral composition according to (1-1) or (1-2), wherein the saturated fatty acid having 12 to 22 carbon atoms is stearic acid and / or palmitic acid.
(1-4) The oral composition further comprises c) crospovidone, pregelatinized starch, or a mixture thereof as a disintegrant, according to any one of (1-1) to (1-3). Oral composition.
(1-5) The oral composition according to (1-4), wherein crospovidone, pregelatinized starch, or a mixture thereof as a disintegrant is 2 to 20% by mass relative to the total amount of the composition.
(1-6) The oral composition further comprises d) at least one selected from the group consisting of anhydrous lactose, lactose hydrate, sucrose, trehalose, and mannitol as an excipient (1-1) to (1-1) The composition for oral administration according to any one of 1-5).
(1-7) The oral composition further includes at least one selected from the group consisting of d) anhydrous lactose, lactose hydrate, and sucrose as an excipient (1-1) to (1-6) Orally.
(1-8) The oral composition according to any one of (1-1) to (1-7), wherein the oral composition further comprises d) anhydrous lactose and / or sucrose as an excipient.
(1-9) Any one of (1-6) to (1-8), wherein the compounding amount of the excipient is 65 to 90% by mass, preferably 70 to 90% by mass, based on the total amount of the composition Orally.
(1-10) The oral composition according to any one of (1-1) to (1-9), wherein the oral composition is a tablet.
(1-11) a) a drug having a medoxomil group as an active ingredient,
b) a saturated fatty acid selected from 5 to 15% by weight of stearic acid or palmitic acid based on the total amount of the composition,
c) at least one disintegrant selected from the group consisting of crospovidone, or pregelatinized starch, or a mixture thereof in an amount of 2 to 20% by weight based on the total amount of the composition;
d) at least one excipient selected from the group consisting of anhydrous lactose, lactose hydrate, sucrose, trehalose, and mannitol, in an amount of 65 to 90% by mass based on the total amount of the composition;
An oral composition comprising
(1-12) The oral composition according to (1-11), wherein the excipient is anhydrous lactose and / or sucrose.
(1-13) The oral composition according to (1-11) or (1-12), wherein the excipient is anhydrous lactose.
(1-14) Oral use according to any one of (1-11) to (1-13), wherein the amount of the drug having a medoxomil group is 2 to 25% by mass relative to the total amount of the composition Composition.
(1-15) The oral composition according to any one of (1-11) to (1-14), wherein the drug having a medoxomil group is olmesartan medoxomil.
(1-16) The oral composition according to any one of (1-11) to (1-15), wherein the oral composition is a tablet.
(1-17) The oral composition according to any one of (1-1) to (1-16), wherein the oral composition is an uncoated tablet of the coating preparation.
(1-18) The oral composition according to (1-17), wherein the uncoated tablet further has a coating layer coated with the coating composition.
(1-19) a) Olmesartan medoxomil,
b) a saturated fatty acid selected from 5 to 15% by weight of stearic acid or palmitic acid based on the total amount of the composition;
c) at least one disintegrant selected from the group consisting of crospovidone, pregelatinized starch, and mixtures thereof;
d) at least one excipient selected from the group consisting of anhydrous lactose, lactose hydrate, and sucrose;
An oral composition in the form of a tablet, comprising
(1-20) a) 1 to 25% by mass of olmesartan medoxomil with respect to the whole composition,
b) 5 to 15% by weight of stearic acid, based on the total amount of the composition,
c) at least one disintegrant selected from the group consisting of crospovidone, pregelatinized starch, and mixtures thereof in an amount of 2 to 20% by weight based on the total amount of the composition;
d) 65-90% by weight of excipients that are anhydrous lactose and / or lactose hydrate, based on the total amount of the composition;
An oral composition in the form of a tablet, comprising
(1-21) When the amount of diacetyl released when the oral composition is sealed in a 20 mL glass vial and stored at 25 ° C. for 4 weeks is measured by gas chromatography, The oral composition according to any one of (1-1) to (1-20), which is 200 ng / mg or less.
(1-22) When the amount of diacetyl released when the oral composition is sealed in a 20 mL glass vial and stored at 40 ° C. for 5 days is measured by gas chromatography, per 1 mg of drug having a medoxomil group The oral composition according to any one of (1-1) to (1-21), which is 200 ng / mg or less.
(1-23) Oral composition was tested by the Japanese Pharmacopoeia dissolution test paddle method (test solution: Japanese Pharmacopoeia dissolution test solution, 2 rotations: 50 rotations) dissolution rate 15 minutes after the start of the test The composition for oral administration according to any one of (1-1) to (1-22), characterized in that is 50% or more.
(1-24) An oral composition corresponding to 10 mg of a drug having a medoxomil group is sealed in a 20 mL glass vial and stored at 40 ° C. for 5 days, and the total value of related substances is 1% or less. The oral composition according to any one of (1-1) to (1-23), wherein
本発明の第２の態様は以下の経口用組成物の製造方法である。
（２−１）ａ) 有効成分としてメドキソミル基を持つ薬剤、
ｂ) 組成物全量に対して５〜１５質量％の炭素数が１２〜２２の飽和脂肪酸、
ｃ) 組成物全量に対して２〜２０質量％の、クロスポビドン、アルファー化デンプン、及びこれらの混合物、からなる群より選ばれる少なくとも１つの崩壊剤、
ｄ) 組成物全量に対して６５〜９０質量％の、無水乳糖、乳糖水和物、白糖、トレハロース、及びマンニトールからなる群から選ばれる少なくとも１つの賦形剤、を含有する錠剤の形態の経口用組成物の製造方法であって、
前記ａ）ないしｄ）を混合する工程を含むことを特徴とする製造方法。
（２−２）メドキソミル基を持つ薬剤がオルメサルタンメドキソミルである（２−１）に記載の製造方法。
（２−３）炭素数が１２〜２２の飽和脂肪酸がステアリン酸及び／又はパルミチン酸である（２−１）又は（２−２）に記載の製造方法。
（２−４）ａ) 有効成分としてメドキソミル基を持つ薬剤、
ｂ) 組成物全量に対して５〜１５質量％のステアリン酸又はパルミチン酸から選ばれる飽和脂肪酸、
ｃ) 組成物全量に対して２〜２０質量％の、クロスポビドン、アルファー化デンプン、及びこれらの混合物、からなる群より選ばれる少なくとも１つの崩壊剤、
ｄ) 組成物全量に対して６５〜９０質量％の、無水乳糖、乳糖水和物、及び白糖からなる群から選ばれる少なくとも１つの賦形剤、を含有する錠剤の形態の経口用組成物の製造方法であって、
前記ａ）ないしｄ）を混合する工程を含むことを特徴とする製造方法。
（２−５）前記ａ）ないしｄ）の混合し、かかる混合物を乾式造粒する工程を含むことを特徴とする（２−４）に記載の製造方法。
（２−６）前記ａ）ないしｄ）の混合工程の後に打錠する工程を含むことを特徴とする（２−４）又は（２−５）に記載の製造方法。
（２−７）前記ａ）ないしｄ）を混合し、かかる混合物を打錠してスラッグ錠とし、かかる錠を整粒し、整粒後の粉末を打錠する、工程を含む（２−１）〜（２−６）に記載の製造方法。
（２−８）ａ) オルメサルタンメドキソミル、
ｂ) 組成物全量に対して５〜１５質量％のステアリン酸、
ｃ) 組成物全量に対して２〜２０質量％の、クロスポビドン、アルファー化デンプン、及びこれらの混合物、からなる群より選ばれる少なくとも１つの崩壊剤、
ｄ) 組成物全量に対して６５〜９０質量％の、無水乳糖、乳糖水和物、及び白糖からなる群から選ばれる少なくとも１つの賦形剤、を含有する錠剤の形態の経口用組成物の製造方法であって、
前記ａ）ないしｄ）を混合する工程、かかる混合物を打錠してスラッグ錠とする工程、かかる錠を整粒する工程、整粒後の粉末を打錠する工程を含む（２−１）〜（２−７）に記載の製造方法。
なお、上記製造方法において、前記ａ）ないしｄ）を混合する際、またはその後の工程において、更なる成分を含むことは妨げない。The second aspect of the present invention is the following method for producing an oral composition.
(2-1) a) a drug having a medoxomil group as an active ingredient,
b) Saturated fatty acid having 12 to 22 carbon atoms of 5 to 15% by mass relative to the total amount of the composition,
c) at least one disintegrant selected from the group consisting of crospovidone, pregelatinized starch, and mixtures thereof in an amount of 2 to 20% by weight based on the total amount of the composition;
d) Oral in the form of a tablet containing 65 to 90% by mass based on the total amount of the composition, at least one excipient selected from the group consisting of anhydrous lactose, lactose hydrate, sucrose, trehalose, and mannitol. A method for producing a composition for use, comprising:
The manufacturing method characterized by including the process of mixing said a) thru | or d).
(2-2) The production method according to (2-1), wherein the drug having a medoxomil group is olmesartan medoxomil.
(2-3) The production method according to (2-1) or (2-2), wherein the saturated fatty acid having 12 to 22 carbon atoms is stearic acid and / or palmitic acid.
(2-4) a) a drug having a medoxomil group as an active ingredient,
b) a saturated fatty acid selected from 5 to 15% by weight of stearic acid or palmitic acid based on the total amount of the composition;
c) at least one disintegrant selected from the group consisting of crospovidone, pregelatinized starch, and mixtures thereof in an amount of 2 to 20% by weight based on the total amount of the composition;
d) An oral composition in the form of a tablet containing 65 to 90% by mass of at least one excipient selected from the group consisting of anhydrous lactose, lactose hydrate, and sucrose, based on the total amount of the composition A manufacturing method comprising:
The manufacturing method characterized by including the process of mixing said a) thru | or d).
(2-5) The production method according to (2-4), comprising the steps of mixing a) to d) and dry granulating the mixture.
(2-6) The production method according to (2-4) or (2-5), comprising a step of tableting after the mixing step a) to d).
(2-7) including the steps of mixing a) to d), compressing the mixture to form a slug tablet, sizing the tablet, and tableting the sized powder (2-1) ) To (2-6).
(2-8) a) Olmesartan medoxomil,
b) 5 to 15% by weight of stearic acid, based on the total amount of the composition,
c) at least one disintegrant selected from the group consisting of crospovidone, pregelatinized starch, and mixtures thereof in an amount of 2 to 20% by weight based on the total amount of the composition;
d) An oral composition in the form of a tablet containing 65 to 90% by mass of at least one excipient selected from the group consisting of anhydrous lactose, lactose hydrate, and sucrose, based on the total amount of the composition A manufacturing method comprising:
Including the steps of mixing a) to d), tableting the mixture to form a slag tablet, sizing the tablet, and tableting the powder after sizing (2-1) to The production method according to (2-7).
In addition, in the said manufacturing method, when mixing said a) thru | or d) or in a subsequent process, it does not prevent containing a further component.
本発明の経口用組成物は、ジアセチルの発生及び又はその放出が飽和脂肪酸を含まない場合と比較して顕著に抑制されており、においがしない、又はにおいが顕著に抑制されている。したがって、本発明の経口用組成物は、臭いの放出を抑制するためのコーティングをしなくても服用性が良好な錠剤や顆粒剤とできる。
また、本発明の経口用組成物は、流動性の高い特定の添加剤を多量に配合することにより流動性にも優れており、多量のステアリン酸などの飽和脂肪酸を含有しているにもかかわらず製造性に優れており、工業的な製造も可能である。さらに、本発明の経口用組成物は、薬剤の溶出性が良好である。本発明の経口用組成物は、好ましくはいずれか２つの効果を兼ね備える。更に好ましくは全ての効果を兼ね備える。In the oral composition of the present invention, the generation and / or release of diacetyl is significantly suppressed as compared with the case where no saturated fatty acid is contained, and no odor or odor is significantly suppressed. Therefore, the oral composition of the present invention can be made into tablets and granules having good dosing properties without coating for suppressing odor release.
In addition, the oral composition of the present invention is excellent in fluidity by blending a large amount of a specific additive having high fluidity, even though it contains a large amount of saturated fatty acid such as stearic acid. It is excellent in manufacturability and can be manufactured industrially. Furthermore, the oral composition of the present invention has good drug elution. The oral composition of the present invention preferably has any two effects. More preferably, it has all the effects.
以下に本発明を詳しく説明する。
本発明ではジアセチルの発生及び／又はその放出の抑制のために、飽和脂肪酸を配合することを必須とするものである。本発明における飽和脂肪酸としては、総炭素数が１２〜２２、好ましくは１５〜２０、より好ましくは１６〜１８の直鎖の飽和脂肪酸が挙げられる。具体的にはステアリン酸、パルミチン酸、ミリスチン酸、アラキジン酸、ベヘン酸、ラウリン酸などが挙げられ、特にステアリン酸又はパルミチン酸が好ましく、より好ましくはステアリン酸が挙げられる。これらの飽和脂肪酸は、２種以上を混合して使用することもできる。飽和脂肪酸は、本発明の経口用組成物の総質量に対して、５〜１５質量％含むことが好ましく、５〜１０質量％含むことがより好ましく、さらに好ましくは７〜９質量％である。
ステアリン酸としては、市販のものを使用することができ、例えば、ステアリン酸（新日本理化、日本精化）、精製ステアリン酸（花王）、ステアリン酸シリーズ（ライオン）、日局ステアリン酸（日油、油化産業）等が挙げられる。The present invention is described in detail below.
In the present invention, it is essential to add a saturated fatty acid in order to suppress the generation and / or release of diacetyl. Examples of the saturated fatty acid in the present invention include linear saturated fatty acids having a total carbon number of 12 to 22, preferably 15 to 20, and more preferably 16 to 18. Specific examples include stearic acid, palmitic acid, myristic acid, arachidic acid, behenic acid, lauric acid, stearic acid or palmitic acid is particularly preferable, and stearic acid is more preferable. These saturated fatty acids can be used in combination of two or more. The saturated fatty acid is preferably contained in an amount of 5 to 15% by mass, more preferably 5 to 10% by mass, and further preferably 7 to 9% by mass, based on the total mass of the oral composition of the present invention.
As the stearic acid, commercially available ones can be used. For example, stearic acid (Shin Nippon Rika, Nippon Seika), purified stearic acid (Kao), stearic acid series (lion), JP stearic acid (NOF) , Oil industry).
本発明の経口用組成物は、さらに崩壊剤を含有していてもよい。崩壊剤としては、オルメサルタンメドキソミルの分解への影響が小さいものであれば特に限定されない。使用する崩壊剤が薬剤の分解などに影響を与えるか否かは、後述する試験例（例えば、試験例５参照）を参照して検査することができる。本発明の経口用組成物における、好ましい崩壊剤としては、例えば、ポリビニルピロリドン、クロスポビドン、アルファー化デンプン、カルメロースおよびその塩、クロスカルメロースナトリウム、トウモロコシデンプン、バレイショデンプン、ヒドロキシプロピルスターチなどが挙げられる。カルメロースの塩としてはカルメロースカルシウム、カルメロースナトリウムなどが挙げられる。ポリビニルピロリドンとしては、例えば、アイフタクトＫ−３０（第一工業製薬）、コリドン（ＢＡＳＦジャパン）、プラスドン（アイエスピー・ジャパン、五協産業）などが挙げられる。クロスポビドンとしては、例えば、クロスポビドン（ＤＳＰ五協フード＆ケミカル）、コリドン（ＢＡＳＦジャパン）、ポリプラスドン（アイエスピー・ジャパン）等が挙げられる。アルファー化デンプンとしては、例えば、ＳＷＥＬＳＴＡＲ（旭化成ケミカルズ）、ＬＹＣＡＴＡＢ ＰＧＳ（ロケットジャパン）、アミコール（日澱化学）等が挙げられる。アルファー化デンプンには部分アルファー化デンプンも含まれる。部分アルファー化デンプンとしては、例えば、ＬＹＣＡＴＡＢ Ｃ（ロケットジャパン）、ＰＣＳ（旭化成ケミカルズ）、スターチ１５００（日本カラコン）、フアイボーズ（日澱化学）等が挙げられる。
本発明の経口用組成物に、さらに崩壊剤を配合することにより、経口用組成物の溶出性を顕著に改善することができる。
ここで、本発明の経口用組成物で用いる崩壊剤は飽和脂肪酸を含んでいても製造性が良好であれば特に限定されないが、崩壊剤として好ましい範囲は経口用組成物全体に対して２質量％以上であり、より好ましくは３質量％以上、さらに好ましくは４質量％以上である。また、好ましくは２〜２０質量％、さらに好ましくは２〜１５質量％、とりわけ好ましくは３〜１０質量％が良い。
また、飽和脂肪酸と崩壊剤の質量比は１：０．２〜１：４が好ましく、１：０．５〜１：１．５がより好ましい。The oral composition of the present invention may further contain a disintegrant. The disintegrant is not particularly limited as long as it has a small effect on the degradation of olmesartan medoxomil. Whether or not the disintegrant to be used affects the decomposition of the drug can be examined with reference to a test example (for example, see Test Example 5) described later. Preferred disintegrants in the oral composition of the present invention include, for example, polyvinylpyrrolidone, crospovidone, pregelatinized starch, carmellose and salts thereof, croscarmellose sodium, corn starch, potato starch, hydroxypropyl starch and the like. . Examples of the salt of carmellose include carmellose calcium and carmellose sodium. Examples of polyvinyl pyrrolidone include Aifact K-30 (Daiichi Kogyo Seiyaku), Kollidon (BASF Japan), Plusdon (IS Japan, Gokyo Sangyo), and the like. Examples of crospovidone include crospovidone (DSP Gokyo Food & Chemical), Kollidon (BASF Japan), and polyplastidone (ISP Japan). Examples of the alpha starch include SWELSTAR (Asahi Kasei Chemicals), LYCATAB PGS (Rocket Japan), Amicol (Nissho Chemical), and the like. Alphalated starch also includes partially pregelatinized starch. Examples of partially pregelatinized starch include LYCATAB C (Rocket Japan), PCS (Asahi Kasei Chemicals), Starch 1500 (Nippon Colorcon), and Fiboze (Nissho Chemical).
By further adding a disintegrant to the oral composition of the present invention, the dissolution property of the oral composition can be remarkably improved.
Here, the disintegrant used in the oral composition of the present invention is not particularly limited as long as the disintegrant contains a saturated fatty acid as long as the productivity is good, but the preferred range as the disintegrant is 2 mass with respect to the whole oral composition. % Or more, more preferably 3% by mass or more, and further preferably 4% by mass or more. Moreover, 2-20 mass% is preferable, More preferably, it is 2-15 mass%, Most preferably, 3-10 mass% is good.
The mass ratio of saturated fatty acid to disintegrant is preferably 1: 0.2 to 1: 4, more preferably 1: 0.5 to 1: 1.5.
飽和脂肪酸と共に素錠に含む賦形剤としては、オルメサルタンメドキソミルの分解への影響が小さいものであれば特に限定されないが、例えば、無水乳糖、乳糖水和物、白糖、トレハロース、マンニトール、ソルビトール、マルチトール、キシリトールなどが挙げられ、無水乳糖、白糖が好ましい。無水乳糖がより好ましい。無水乳糖しては、例えば、ＳｕｐｅｒＴａｂ（ＤＦＥ Ｐｈａｒｍａ）、Ｌａｃｔｏｐｒｅｓｓ Ａｎｈｙｄｒｏｕｓ（ＤＦＥ Ｐｈａｒｍａ）が挙げられる。白糖としては、例えば、白糖（三井製糖、台糖、日新製糖）等が挙げられる。ここで、本発明の経口用組成物で用いられる賦形剤はステアリン酸などの飽和脂肪酸を含んでいても流動性が改善され、製造性が良好となるものであれば特に限定されないが、賦形剤として好ましい範囲は経口用組成物全体の６５質量％以上であり、より好ましくは７０質量％以上、さらに好ましくは７５質量％以上である。また、好ましくは６５〜９０質量％、より好ましくは７０〜９０質量％、さらに好ましくは７０〜８５質量％、とりわけ好ましくは７５〜８５質量％である。
また、ステアリン酸と賦形剤の質量比は１：３〜１：２０が好ましく、１：５〜１：１５がより好ましい。The excipient contained in the uncoated tablet together with the saturated fatty acid is not particularly limited as long as it has a small effect on the degradation of olmesartan medoxomil. For example, anhydrous lactose, lactose hydrate, sucrose, trehalose, mannitol, sorbitol, Examples include tall and xylitol, and anhydrous lactose and sucrose are preferred. Anhydrous lactose is more preferred. Examples of anhydrous lactose include SuperTab (DFE Pharma) and Lactopress Anhydrous (DFE Pharma). Examples of sucrose include sucrose (Mitsui Sugar, Taikaku, Nissin Sugar). Here, the excipient used in the oral composition of the present invention is not particularly limited as long as it has improved fluidity and good manufacturability even if it contains a saturated fatty acid such as stearic acid. A preferred range for the dosage form is 65% by mass or more of the whole oral composition, more preferably 70% by mass or more, and further preferably 75% by mass or more. Moreover, Preferably it is 65-90 mass%, More preferably, it is 70-90 mass%, More preferably, it is 70-85 mass%, Most preferably, it is 75-85 mass%.
The mass ratio of stearic acid and excipient is preferably 1: 3 to 1:20, more preferably 1: 5 to 1:15.
本発明における経口用組成物の形態は特に限定されないが、例えば錠剤、カプセル剤、散剤、細粒剤、顆粒剤、トローチ剤などを挙げることができ、特に錠剤の形態が好ましい。 Although the form of the oral composition in this invention is not specifically limited, For example, a tablet, a capsule, a powder, a fine granule, a granule, a troche etc. can be mentioned, Especially the form of a tablet is preferable.
本発明の経口用組成物は、このまま医薬製剤とすることもできるが、さらにコーティング層を形成させることもできる。本発明の経口用組成物は、それ自体で薬剤に起因する不快臭を抑制することができるので、不快臭を抑制するためのコーティング層は特に必要ではないが、製剤として必要に応じてコーティング層を設けることもできる。その場合、コーティング層の成分や膜厚には特に制限はないが、薬剤の不快臭をさらに効果的に抑制できる程度の膜厚であることが好ましく、例えば、１μｍ〜３００μｍ、好ましくは１μｍ〜２００μｍ、特に好ましくは１〜５０μｍである。 The oral composition of the present invention can be used as a pharmaceutical preparation as it is, but a coating layer can be further formed. Since the oral composition of the present invention can suppress unpleasant odor caused by the drug itself, a coating layer for suppressing the unpleasant odor is not particularly necessary, but a coating layer as necessary as a preparation. Can also be provided. In that case, although there is no restriction | limiting in particular in the component and film thickness of a coating layer, It is preferable that it is a film thickness which can suppress the unpleasant odor of a chemical | medical agent more effectively, for example, 1 micrometer-300 micrometers, Preferably it is 1 micrometer-200 micrometers. Especially preferably, it is 1-50 micrometers.
本発明の経口用組成物は、前記してきた成分に加えて、さらに必要に応じて、製剤技術分野で公知の各種の製剤担体を広く使用できる。例えば、上述のもの以外の乳糖、白糖、マンニトール、塩化ナトリウム、ブドウ糖、デンプン、炭酸カルシウム、カオリン、結晶セルロース、ケイ酸塩等の賦形剤、水、エタノール、単シロップ、ブドウ糖液、デンプン液、ゼラチン液、カルボキシメチルセルロース、カルボキシメチルセルロースＮａ、セラック、メチルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ポリビニルアルコール、ゼラチン、デキストリン、プルラン等の結合剤；クエン酸、無水クエン酸、クエン酸ナトリウム、クエン酸ナトリウム二水和物、無水リン酸一水素ナトリウム、無水リン酸二水素ナトリウム、リン酸水素ナトリウム、無水リン酸水素二ナトリウム等のｐＨ調整剤；カルメロースカルシウム、低置換度ヒドロキシプロピセルロース、カルメロース、クロスカルメロースナトリウム、部分アルファー化デンプン、乾燥デンプン、カルボキシメチルスターチナトリウム、クロスポビドン、ポリソルベート８０等の崩壊剤；ラウリル硫酸ナトリウム等の吸収促進剤；精製タルク、ステアリン酸塩、フマル酸ステアリルナトリウム、ショ糖脂肪酸エステル、ポリエチレングリコール、コロイド状ケイ酸等の滑沢剤等が例示できる。
滑沢剤は０．５〜５質量％加えることが好ましい。In addition to the above-described components, the oral composition of the present invention can use a wide variety of known pharmaceutical carriers in the pharmaceutical technology field as necessary. For example, lactose other than those mentioned above, sucrose, mannitol, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, silicate and other excipients, water, ethanol, simple syrup, glucose solution, starch solution, Binders such as gelatin solution, carboxymethylcellulose, carboxymethylcellulose Na, shellac, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, gelatin, dextrin, pullulan; citric acid, anhydrous citric acid, sodium citrate, sodium citrate PH adjusters such as hydrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, sodium hydrogen phosphate, anhydrous disodium hydrogen phosphate; carmellose calcium, low substituted hydroxy Disintegrating agents such as lopicellulose, carmellose, croscarmellose sodium, partially pregelatinized starch, dried starch, sodium carboxymethyl starch, crospovidone, polysorbate 80; absorption promoters such as sodium lauryl sulfate; purified talc, stearate, fumarate Examples thereof include lubricants such as sodium stearyl acid, sucrose fatty acid ester, polyethylene glycol and colloidal silicic acid.
It is preferable to add 0.5 to 5% by mass of the lubricant.
本発明の経口用組成物は、クロスポビドン、若しくはアルファー化デンプン、又はこれらの混合物、からなる群より選ばれる少なくとも１つの崩壊剤と、無水乳糖、乳糖水和物、及び白糖からなる群から選ばれる少なくとも１つの賦形剤を含むことが出来、崩壊剤と賦形剤の組合せは特に限定されないが、クロスポビドンと無水乳糖、クロスポビドンと乳糖水和物、クロスポビドンと白糖、アルファー化デンプンと無水乳糖、アルファー化デンプンと乳糖水和物、アルファー化デンプンと白糖、クロスポビドンとアルファー化デンプンの混合物と無水乳糖、クロスポビドンとアルファー化デンプンの混合物と乳糖水和物、クロスポビドンとアルファー化デンプンの混合物と白糖、の組合せが好ましい。特に好ましくは、クロスポビドンと無水乳糖、クロスポビドンと乳糖水和物、クロスポビドンと白糖、の組合せであり、最も好ましい組み合わせは、クロスポビドンと無水乳糖、である。 The oral composition of the present invention is selected from the group consisting of at least one disintegrant selected from the group consisting of crospovidone, pregelatinized starch, or a mixture thereof, and anhydrous lactose, lactose hydrate, and sucrose. The combination of disintegrant and excipient is not particularly limited, but crospovidone and anhydrous lactose, crospovidone and lactose hydrate, crospovidone and sucrose, pregelatinized starch and Anhydrous lactose, pregelatinized starch and lactose hydrate, pregelatinized starch and white sugar, mixture of crospovidone and pregelatinized starch and anhydrous lactose, mixture of crospovidone and pregelatinized starch and lactose hydrate, crospovidone and pregelatinized starch And a combination of sucrose. Particularly preferred is a combination of crospovidone and anhydrous lactose, crospovidone and lactose hydrate, crospovidone and sucrose, and the most preferred combination is crospovidone and anhydrous lactose.
本発明における経口用組成物に用いられる薬剤は、不快なにおいを発するものであれば特に限定されないが、本発明の目的からするとメドキソミル基（（５−メチル−２−オキソ−１，３−ジオキソール−４−イル）メチル）を有するものが適しており、ジアセチルを発生させるものが特に好適である。不快なにおいを発するものとは、実際においを発生させているだけでなく、発生させるおそれがある場合も含まれる。
例えば、高血圧薬であるオルメサルタンメドキソミル、抗菌薬であるプルリフロキサシン、塩酸レナンピシリンなどが挙げられる。
本発明の経口用組成物における前記薬剤の配合量には特に制限はないが、組成物全量に対して１質量％以上であり、より好ましくは２質量％以上、さらに好ましくは３質量％以上である。また、好ましくは１〜２５質量％、さらに好ましくは２〜２０質量％、特に好ましくは３〜１５質量％、とりわけ好ましくは７〜１２質量％が良い。
また、必要に応じて他の薬剤を併用することもできる。オルメサルタンメドキソミル等の薬剤を含む配合剤でもよい。The drug used in the oral composition in the present invention is not particularly limited as long as it produces an unpleasant odor, but for the purpose of the present invention, a medoxomil group ((5-methyl-2-oxo-1,3-dioxole) is used. Those having -4-yl) methyl) are suitable, and those that generate diacetyl are particularly preferred. What emits an unpleasant odor includes not only the fact that an odor is actually generated, but also a case where there is a possibility of generating the odor.
Examples thereof include olmesartan medoxomil, which is a hypertensive drug, purifloxacin, which is an antibacterial drug, and lenampicillin hydrochloride.
Although there is no restriction | limiting in particular in the compounding quantity of the said medicine in the composition for oral use of this invention, It is 1 mass% or more with respect to the composition whole quantity, More preferably, it is 2 mass% or more, More preferably, it is 3 mass% or more. is there. Further, it is preferably 1 to 25% by mass, more preferably 2 to 20% by mass, particularly preferably 3 to 15% by mass, and particularly preferably 7 to 12% by mass.
In addition, other drugs can be used in combination as necessary. A compounding agent containing a drug such as olmesartan medoxomil may be used.
本発明の経口用組成物は一包化しても他薬剤と配合変化を起こしにくく、着色等の品質低下を抑制することを特徴とする。このような他薬剤としてはジアセチルが原因で配合変化を起こす薬剤であれば特に限定されないが、例えば、グアニジノ基を有する薬剤などが挙げられる。グアニジノ基を有する薬剤としては、メトホルミン、メシル酸カモスタット、ザナミビル水和物、酢酸セトロレリクス、マレイン酸テガセロド、酢酸デスモプレシン、エプティフィバチド、ビバリルジン、酢酸ガニレリクス、酢酸ブセレリン、ファモチジン、パモ酸トリプトレリン、ピナシジル、ヒストレリン、チモぺンタチン、メシル酸アドレノクロムグアニルヒドラゾン、シメチジン、塩酸ベネキサートベータデクス、塩酸グスペリムス、メシル酸ナファモスタット、酢酸グアナベンズ、アルガトロバン、これらの製薬学上許容しうる塩などが挙げられる。メトホルミン塩酸塩は糖尿病治療薬であり、カモスタットメシル酸塩は逆流性食道炎治療薬である。 The oral composition of the present invention is characterized in that even if it is encapsulated, it hardly changes in composition with other drugs and suppresses quality deterioration such as coloring. Such other drug is not particularly limited as long as it causes a change in formulation due to diacetyl, and examples thereof include a drug having a guanidino group. Examples of drugs having a guanidino group include metformin, camostat mesylate, zanamivir hydrate, cetrorelix acetate, tegaserod maleate, desmopressin acetate, eptifibatide, bivalirudine, ganirelix acetate, buserelin acetate, famotidine, triptorelin pamoate, pinacidil, Histrelin, thymopentatin, adrenochrome guanylhydrazone mesylate, cimetidine, benexate hydrochloride betadex, gusperimus hydrochloride, nafamostat mesylate, guanabenz acetate, argatroban, and pharmaceutically acceptable salts thereof. Metformin hydrochloride is a therapeutic agent for diabetes, and camostat mesilate is a therapeutic agent for reflux esophagitis.
本発明の経口用組成物を錠剤として製造する方法としては、特に限定されないが、直打法や乾式造粒後の打錠が好ましい。 The method for producing the oral composition of the present invention as a tablet is not particularly limited, but direct compression or tableting after dry granulation is preferred.
本発明において、不快臭の有無は後述する試験例１の「性状：においの確認」により行うことが出来る。具体的には、メドキソミル基を有する薬剤１０ｍｇにつき、製造直後、あるいは２０ｍＬの容積のガラスバイアルに入れ密封し、所定の温度・期間保存した後の錠剤のにおいを後述する評価基準で０．５単位で評価する。
においは評点で表すが、１．５以下が好ましく、１．０以下がより好ましく、０．５以下がさらに好ましい。評点の具体的な定義は後述する。In the present invention, the presence or absence of an unpleasant odor can be determined by “property: confirmation of odor” in Test Example 1 described later. Specifically, for 10 mg of a drug having a medoxomil group, the odor of a tablet immediately after production or sealed in a glass vial with a volume of 20 mL and stored for a predetermined temperature and period is 0.5 units according to the evaluation criteria described later. Evaluate with.
The odor is expressed by a score, but is preferably 1.5 or less, more preferably 1.0 or less, and further preferably 0.5 or less. The specific definition of the score will be described later.
ジアセチルの定量は、後述する試験例２のガスクロマトグラフィーにより行うことが出来る。この方法ではにおいの原因であるジアセチルの量を定量的に評価できる。
メドキソミル基を有する薬剤１０ｍｇにつき、２０ｍＬの容積のガラスバイアルに密封して保管した場合のジアセチルの値は、メドキソミル基を持つ薬剤の量に対する値で表し、メドキソミル基を持つ薬剤１ｍｇ当たり４０℃５日間では２００ｎｇ／ｍｇ以下が好ましく、１００ｎｇ／ｍｇ以下がより好ましく、７０ｎｇ／ｍｇ以下がさらに好ましい。また２５℃４週間では２００ｎｇ／ｍｇ以下が好ましく、１００ｎｇ／ｍｇ以下がより好ましく、７０ｎｇ／ｍｇ以下がさらに好ましい。The quantification of diacetyl can be performed by gas chromatography of Test Example 2 described later. This method can quantitatively evaluate the amount of diacetyl that causes odor.
When 10 mg of drug having a medoxomil group is stored in a 20 mL glass vial in a sealed state, the value of diacetyl is expressed as a value relative to the amount of the drug having a medoxomil group, and 40 days at 40 ° C. per 1 mg of the drug having a medoxomil group. Is preferably 200 ng / mg or less, more preferably 100 ng / mg or less, and even more preferably 70 ng / mg or less. Further, at 25 ° C. for 4 weeks, it is preferably 200 ng / mg or less, more preferably 100 ng / mg or less, and even more preferably 70 ng / mg or less.
オルメサルタンメドキソミルなどのメドキソミル基を持つ薬剤の特有な不快臭はジアセチルが原因である。そのため、においの評点をヒトによる評価で行った場合でも、においの評点とジアセチルの値には一定の相関がみられた。
においの評点が１．５以下であれば、ジアセチルは約２００ｎｇ／ｍｇ以下であり、１．０であれば約１００ｎｇ／ｍｇ以下であり、０．５であれば約７０ｎｇ／ｍｇ以下であると考えられる。The unique unpleasant odor of drugs having a medoxomil group such as olmesartan medoxomil is due to diacetyl. Therefore, even when the odor score was evaluated by a human, a certain correlation was observed between the odor score and the diacetyl value.
If the odor rating is 1.5 or less, diacetyl is about 200 ng / mg or less, 1.0 is about 100 ng / mg or less, and 0.5 is about 70 ng / mg or less. Conceivable.
本発明における経口用組成物は良好な溶出性を有していることが好ましい。本発明の経口用組成物１錠につき、日本薬局方溶出試験パドル法にて試験を行った場合（試験液：日本薬局方溶出試験液２液、回転数：５０回転）、試験開始後１５分における溶出率が５０％以上、好ましくは６０％以上、より好ましくは８０％以上であるとよい。 The oral composition in the present invention preferably has good dissolution properties. When one tablet for oral composition of the present invention was tested by the Japanese Pharmacopoeia dissolution test paddle method (test solution: Japanese Pharmacopoeia dissolution test solution, 2 rotations: 50 rotations), 15 minutes after the start of the test The elution rate is 50% or more, preferably 60% or more, more preferably 80% or more.
次に、実施例及び比較例を示し、本発明をさらに具体的に説明するが、本発明はこれらに限定されるものではない。
＜素錠の製法＞Next, although an example and a comparative example are shown and the present invention is explained still more concretely, the present invention is not limited to these.
<Production method of uncoated tablets>
実施例１
オルメサルタンメドキソミル２０．０ｇ、無水乳糖１６７．０ｇ、ステアリン酸１７．０ｇ、クロスポビドン１０．０ｇ、フマル酸ステアリルナトリウム２．０ｇを混合後、直径７．０ｍｍ、１錠あたりの質量１０８ｍｇとなるように打錠して素錠を得た。Example 1
After mixing olmesartan medoxomil 20.0 g, anhydrous lactose 167.0 g, stearic acid 17.0 g, crospovidone 10.0 g, and sodium stearyl fumarate 2.0 g, the diameter is 7.0 mm and the mass per tablet is 108 mg. Tableting was performed to obtain an uncoated tablet.
実施例２
オルメサルタンメドキソミル２０．０ｇ、無水乳糖１６７．０ｇ、ステアリン酸１７．０ｇ、アルファー化デンプン１０．０ｇ、フマル酸ステアリルナトリウム２．０ｇを混合後、直径７．０ｍｍ、１錠あたりの質量１０８ｍｇとなるように打錠して素錠を得た。Example 2
After mixing olmesartan medoxomil 20.0 g, anhydrous lactose 167.0 g, stearic acid 17.0 g, pregelatinized starch 10.0 g, and sodium stearyl fumarate 2.0 g, the diameter is 7.0 mm and the mass per tablet is 108 mg. To obtain a plain tablet.
実施例３
オルメサルタンメドキソミル２０．０ｇ、無水乳糖１６２．０ｇ、ステアリン酸１７．０ｇ、アルファー化デンプン１５．０ｇ、フマル酸ステアリルナトリウム２．０ｇを混合後、直径７．０ｍｍ、１錠あたりの質量１０８ｍｇとなるように打錠して素錠を得た。Example 3
After mixing olmesartan medoxomil 20.0 g, anhydrous lactose 162.0 g, stearic acid 17.0 g, pregelatinized starch 15.0 g, and sodium stearyl fumarate 2.0 g so that the diameter becomes 7.0 mm and the mass per tablet 108 mg To obtain a plain tablet.
実施例４
オルメサルタンメドキソミル２０．０ｇ、無水乳糖１７７．０ｇ、ステアリン酸１７．０ｇ、フマル酸ステアリルナトリウム２．０ｇを混合後、直径７．０ｍｍ、１錠あたりの質量１０８ｍｇとなるように打錠して素錠を得た。Example 4
After mixing olmesartan medoxomil 20.0g, anhydrous lactose 177.0g, stearic acid 17.0g, and sodium stearyl fumarate 2.0g, it was compressed to 7.0mm in diameter and 108mg in weight per tablet. Got.
実施例５
オルメサルタンメドキソミル２０．０ｇ、白糖１７７．０ｇ、ステアリン酸１７．０ｇ、フマル酸ステアリルナトリウム２．０ｇを混合後、直径７．０ｍｍ、１錠あたりの質量１０８ｍｇとなるように打錠して素錠を得た。Example 5
After mixing 20.0 g of olmesartan medoxomil, 177.0 g of sucrose, 17.0 g of stearic acid, and 2.0 g of sodium stearyl fumarate, the tablet was compressed to a diameter of 7.0 mm and a mass of 108 mg per tablet. Obtained.
比較例１
オルメサルタンメドキソミル２０．０ｇ、無水乳糖１９４．０ｇ、フマル酸ステアリルナトリウム２．０ｇを混合後、直径７．０ｍｍ、１錠あたりの質量１０８ｍｇとなるように打錠して素錠を得た。Comparative Example 1
Olmesartan medoxomil 20.0 g, anhydrous lactose 194.0 g, and sodium stearyl fumarate 2.0 g were mixed, and then tableted to a diameter of 7.0 mm and a mass of 108 mg per tablet to obtain an uncoated tablet.
表１に実施例１〜５、及び比較例１の処方（有効成分含量を１０ｍｇとした時の各成分含量）を示す。 Table 1 shows the formulations of Examples 1 to 5 and Comparative Example 1 (contents of each component when the active ingredient content is 10 mg).
実施例６
実施例３と同様の組成につき、乾式造粒を使用して錠剤を製造した。
オルメサルタンメドキソミル２０．０ｇ、無水乳糖８１．０ｇ、ステアリン酸１７．０ｇ、アルファー化デンプン１５．０ｇ、フマル酸ステアリルナトリウム１．０ｇを混合後、直径１２．０ｍｍ、１錠あたりの質量約０．３ｇとなるように打錠してスラッグ錠を得た。スラッグ錠を整粒機にて整粒し、整粒後の粉末１１５．０ｇに無水乳糖６９．５２ｇ、フマル酸ステアリルナトリウム０．８６ｇを加えて混合後、直径７．０ｍｍ、１錠あたりの質量１０８ｍｇとなるように打錠して素錠を得た。Example 6
For the same composition as in Example 3, tablets were produced using dry granulation.
After mixing olmesartan medoxomil 20.0g, anhydrous lactose 81.0g, stearic acid 17.0g, pregelatinized starch 15.0g, sodium stearyl fumarate 1.0g, diameter 12.0mm, mass per tablet about 0.3g Tableting was performed to obtain a slug tablet. Slug tablets were sized using a sizing machine, 69.52 g of anhydrous lactose and 0.86 g of sodium stearyl fumarate were added to and mixed with 115.0 g of the sized powder, and the mass per tablet was 7.0 mm in diameter. Tableting was performed to obtain 108 mg to obtain an uncoated tablet.
錠剤の特性を以下の方法で評価した。
試験例１＜性状：においの確認＞
製造直後のにおい、あるいは錠剤１錠を２０ｍＬ容量のガラスバイアルに入れ、密栓し、所定の条件に保存後のにおいを評価した。
ここでにおいの評点は下記の通りとし、０．５刻みで評点を付けた。
０．０ におわない
１．０ ごく僅かににおう
２．０ 僅かににおう
３．０ におう
４．０ 強くにおう
５．０ 非常に強くにおう
表２に試験結果を示す。実施例１〜６、比較例１の製剤を製造直後、又は２５℃４週間保管した場合の比較例１の結果をまとめて表２に示す。なお、製剤は２０ｍＬ容量のガラスバイアルで密封して保管しており、かかる場合には外気の湿度の影響は無い。以下において同じである。The characteristics of the tablets were evaluated by the following methods.
Test Example 1 <Properties: Confirmation of Odor>
The odor immediately after production or one tablet in a 20 mL glass vial was sealed and sealed, and the odor after storage under predetermined conditions was evaluated.
Here, the odor scores are as follows, and the scores are given in 0.5 increments.
0.0 Slightly 1.0 Slightly smell 2.0 Slightly smell 3.0 Smell 4.0 Smell strongly 5.0 Smell very strongly
Table 2 shows the test results. Table 2 summarizes the results of Comparative Example 1 when the preparations of Examples 1 to 6 and Comparative Example 1 were stored immediately after production or stored at 25 ° C. for 4 weeks. The preparation is sealed and stored in a 20 mL capacity glass vial. In such a case, there is no influence of the humidity of the outside air. The same applies to the following.
試験例２＜ガスクロマトグラフィーによるジアセチルの定量＞
オルメサルタンメドキソミル１０ｍｇを含有する錠剤１錠を、２０ｍＬ容量のガスクロマトグラフィー用のバイアルに入れ、密栓した。このバイアルを所定の条件に保存後、ヘッドスペースガスをガスクロマトグラフィーにインジェクションし、ジアセチルの濃度を測定した。
実施例１、３、４、比較例１の製剤を２５℃４週間、４０℃５日それぞれ保管した場合の試験例２の結果をまとめて表３に示す。なお、試験結果にはオルメサルタンメドキソミル１ｍｇあたりより発生したジアセチル量（ｎｇ/ｍｇ）を示した。ガスクロマトグラフィーの測定条件を下に示す。
［ガスクロマトグラフィーの測定条件］
装置：ガスクロマトグラフ 品番（アジレントテクノロジー（株））
検出器：水素炎イオン化検出器
分析カラム：ＤＢ−ＷＡＸ （アジレントテクノロジー（株）、０．５３ｍｍｉ．ｄ．×３０ｍ、膜厚：１．００μｍ）
カラム温度：５０℃
キャリヤーガス ：ヘリウム
流量：５．０ｍＬ／ｍｉｎ
注入口温度：２００℃
検出器温度：２５０℃
注入量：１．０ｍＬTest Example 2 <Quantitative determination of diacetyl by gas chromatography>
One tablet containing 10 mg of olmesartan medoxomil was placed in a 20 mL capacity gas chromatography vial and sealed. After storing this vial under predetermined conditions, headspace gas was injected into gas chromatography, and the concentration of diacetyl was measured.
Table 3 summarizes the results of Test Example 2 when the preparations of Examples 1, 3, 4 and Comparative Example 1 were stored at 25 ° C. for 4 weeks and at 40 ° C. for 5 days, respectively. The test results show the amount of diacetyl (ng / mg) generated from 1 mg of olmesartan medoxomil. The measurement conditions for gas chromatography are shown below.
[Measurement conditions for gas chromatography]
Equipment: Gas chromatograph part number (Agilent Technology Co., Ltd.)
Detector: Hydrogen flame ionization detector Analytical column: DB-WAX (Agilent Technology Co., Ltd., 0.53 mmid × 30 m, film thickness: 1.00 μm)
Column temperature: 50 ° C
Carrier gas: Helium flow rate: 5.0 mL / min
Inlet temperature: 200 ° C
Detector temperature: 250 ° C
Injection volume: 1.0 mL
表２より、ステアリン酸を含有する実施例１〜５は製造直後のにおいの評定が０．５〜１．５であるのに対し、比較例１の処方では２．５となっており、飽和脂肪酸を含有している本発明の経口用組成物は、明らかににおいが抑制できていることが確認できた。
表３には、においの原因物質のジアセチルの評価結果を示す。２５℃で４週間保存した場合、比較例１に対し、ステアリン酸を含有する実施例１、３はジアセチルの量が充分抑制されており、においが少ないことが確認できる。また、４０℃５日の加速試験においてもステアリン酸を含有する実施例４と含まない比較例１の差は明らかである。From Table 2, Examples 1 to 5 containing stearic acid have an odor rating of 0.5 to 1.5 immediately after production, whereas the prescription of Comparative Example 1 is 2.5 and is saturated. It was confirmed that the oral composition of the present invention containing a fatty acid clearly suppressed odor.
Table 3 shows the evaluation result of diacetyl as a causative substance of odor. When stored at 25 ° C. for 4 weeks, it can be confirmed that in Examples 1 and 3 containing stearic acid, the amount of diacetyl is sufficiently suppressed as compared with Comparative Example 1, and the smell is small. Further, even in an accelerated test at 40 ° C. for 5 days, the difference between Example 4 containing stearic acid and Comparative Example 1 not containing it is clear.
実施例３は直打法で、実施例６は実施例３と同様の処方であるが、乾式造粒をした後に打錠し、製造している。表２は製造直後及び２５℃４週間のにおいの評点を表しているが、ほぼ同じ結果であり、いずれの方法でも製造できることが確認できる。 Example 3 is a direct compression method, and Example 6 has the same formulation as Example 3. However, after dry granulation, the tablet is compressed and manufactured. Table 2 shows the odor scores immediately after production and at 25 ° C. for 4 weeks. The results are almost the same, and it can be confirmed that any method can be used.
試験例３＜類縁物質の評価＞
高速液体クロマトグラフィーにて試料溶液と標準溶液を分析し、錠剤中の類縁物質量（％）を測定した。ここで、類縁物質とはオルメサルタンメドキソミル原薬等に含まれる不純物や、オルメサルタンメドキソミルの分解物のことを指す。類縁物質量は標準溶液に含まれるオルメサルタンメドキソミルより算出し、試料溶液に含まれる類縁物質の量を％で表したものをいう。また、最大値、とは高速液体クロマトグラフィーで評価した時の一番大きいピークの類縁物質量を表し、合計値とは類縁物質のピークを合計した場合の類縁物質量を表す。
＜試料溶液＞
錠剤１錠の質量を精密に量った後、この錠剤を乳鉢にて磨り潰し、メスフラスコに精密に量り取った。これにアセトニトリルを加えて超音波照射を行った後、アセトニトリルを加えて正確に２０ｍＬとした。この液４ｍＬを正確に取り、アセトニトリル１ｍＬを加えた後、移動相Ａを加えて正確に１０ｍＬとし、試料溶液とした。
＜標準溶液＞
別に、オルメサルタンメドキソミル２０．０ｍｇを精密に量りとり、アセトニトリルを加えて正確に５０ｍＬとした。この液１ｍＬを正確に量りとり、アセトニトリルを加えて正確に１００ｍＬとし、さらにこの液１ｍＬを正確に量りとり、アセトニトリルを４ｍＬ加えた後、移動相Ａを加えて正確に１０ｍＬとした液を標準溶液とした。
＜分析条件＞
検出器：紫外吸光光度計（測定波長：２２５ｎｍ）
カラム温度：３０℃付近の一定温度
移動相Ａ：リン酸水素二カリウム３．４ｇを水に溶かし１０００ｍＬとした溶液
移動相Ｂ：アセトニトリルTest Example 3 <Evaluation of Related Substances>
The sample solution and the standard solution were analyzed by high performance liquid chromatography, and the amount of related substances (%) in the tablets was measured. Here, the related substances refer to impurities contained in olmesartan medoxomil drug substance and the like, and degradation products of olmesartan medoxomil. The amount of the related substance is calculated from olmesartan medoxomil contained in the standard solution and represents the amount of the related substance contained in the sample solution expressed in%. The maximum value represents the amount of the related substance of the largest peak when evaluated by high performance liquid chromatography, and the total value represents the amount of the related substance when the peaks of the related substances are totaled.
<Sample solution>
After precisely weighing the weight of one tablet, this tablet was ground in a mortar and accurately weighed into a volumetric flask. Acetonitrile was added to this and irradiated with ultrasonic waves, and then acetonitrile was added to make exactly 20 mL. 4 mL of this solution was accurately taken, 1 mL of acetonitrile was added, and then mobile phase A was added to make exactly 10 mL to obtain a sample solution.
<Standard solution>
Separately, 20.0 mg of olmesartan medoxomil was accurately weighed and acetonitrile was added to make exactly 50 mL. Accurately measure 1 mL of this solution, add acetonitrile to make exactly 100 mL, further measure exactly 1 mL of this solution, add 4 mL of acetonitrile, and then add mobile phase A to make exactly 10 mL. It was.
<Analysis conditions>
Detector: UV absorptiometer (measurement wavelength: 225 nm)
Column temperature: Constant temperature mobile phase around 30 ° C. A: Solution mobile phase B: acetonitrile in which 3.4 g of dipotassium hydrogen phosphate was dissolved in water to make 1000 mL
実施例１〜５、比較例１の製剤を製造直後、４０℃５日間それぞれ保管した場合の試験例３の結果をまとめて表５に示す。 Table 5 summarizes the results of Test Example 3 when the preparations of Examples 1 to 5 and Comparative Example 1 were stored immediately after production and at 40 ° C. for 5 days, respectively.
表５は、製造直後及び４０℃５日間保存後に錠剤中に生じた類縁物質量（％）を表している。
４０℃５日間保存後の類縁物質量（％）は、実施例４と比較して比較例１では増加しており、ステアリン酸を配合することにより、類縁物質の増加が抑制されていることが確認できる。
一方製造直後の評価では、実施例１〜５、比較例１は最大値と合計値共にほぼ同様な類縁物質の結果となっている。表２で比較例１は実施例１〜５と比較してにおいの評定が高かったのに対し、類縁物質には差が無い。においの原因のジアセチルはオルメサルタンメドキソミルの分解によって生じると考えられるが、類縁物質に差が無い程度であっても、においの評点の差が顕著に出たことから、においは必ずしも類縁物質の値と相関しないことが分かる。Table 5 shows the amount (%) of related substances generated in the tablets immediately after production and after storage at 40 ° C. for 5 days.
The amount of related substance (%) after storage at 40 ° C. for 5 days is increased in Comparative Example 1 as compared with Example 4, and the addition of stearic acid suppresses the increase in related substances. I can confirm.
On the other hand, in the evaluation immediately after the production, Examples 1 to 5 and Comparative Example 1 are substantially the same as the result of the related substances in both the maximum value and the total value. In Table 2, Comparative Example 1 had a higher odor rating than Examples 1-5, while there was no difference in related substances. Diacetyl, the cause of odor, is thought to be generated by the degradation of olmesartan medoxomil, but even if there is no difference in the related substances, the difference in odor rating is significant, so the odor is not necessarily the value of the related substances. It can be seen that there is no correlation.
試験例４＜溶出試験＞
実施例１、４、比較例１、市販のオルメテック錠１０ｍｇの錠剤１錠について、日本薬局方溶出試験のパドル法により下記条件により溶出試験を実施した。表６には各錠剤からのオルメサルタンメドキソミルの溶出率（％）を示す。
＜試験条件＞
試験液：日本薬局方溶出試験２液
回転数：５０ｒｐｍ
試験液温度：３７℃
試験液量：９００ｍＬTest Example 4 <Elution test>
Examples 1 and 4, Comparative Example 1 and one commercially available Olmetec tablet 10 mg tablet were subjected to a dissolution test under the following conditions by the paddle method of the Japanese Pharmacopoeia dissolution test. Table 6 shows the dissolution rate (%) of olmesartan medoxomil from each tablet.
<Test conditions>
Test solution: Japanese Pharmacopoeia dissolution test 2 solution Rotation speed: 50rpm
Test solution temperature: 37 ° C
Test solution volume: 900 mL
なお、表６中のオルメテック錠は、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルセルロース、結晶セルロース、乳糖水和物、及びステアリン酸マグネシウムを添加物として含有する錠剤である。 The Olmetec tablets in Table 6 are tablets containing low-substituted hydroxypropylcellulose, hydroxypropylcellulose, crystalline cellulose, lactose hydrate, and magnesium stearate as additives.
表６は製造した錠剤の溶出性を表している。実施例４はステアリン酸を含む処方であるが、ステアリン酸を含有していない比較例１と比べ、溶出性が大幅に低下していることが確認できる。一方、崩壊剤を使用した実施例１では、崩壊剤を含有していない実施例４の処方に比べて、溶出性が顕著に改善されており、崩壊剤を含有させることにより、においの抑制に加えて溶出性にも優れる錠剤となっていることが確認できた。 Table 6 shows the dissolution properties of the tablets produced. Although Example 4 is a formulation containing stearic acid, it can be confirmed that the dissolution properties are significantly reduced as compared with Comparative Example 1 which does not contain stearic acid. On the other hand, in Example 1 using a disintegrating agent, the dissolution property was remarkably improved as compared with the formulation of Example 4 not containing a disintegrating agent. In addition, it was confirmed that the tablets had excellent dissolution properties.
試験例５＜配合変化試験＞
オルメサルタンメドキソミルと下記表７（性状：においの確認（６０℃１週間 密封環境））及び表８（類縁物質（６０℃１週間 密封環境））に記載の各崩壊剤を１：１の比率で混合し、６０℃１週間密封環境下で保存した場合のにおい（表７）および類縁物質の評価（表８）を行った。方法は前述の方法に準ずる。Test Example 5 <Combination change test>
Olmesartan medoxomil and each disintegrant listed in Table 7 below (Property: Confirmation of odor (60 ° C, 1 week sealed environment)) and Table 8 (Related substances (60 ° C, 1 week sealed environment)) were mixed at a ratio of 1: 1. Then, the odor (Table 7) and the evaluation of related substances (Table 8) when stored in a sealed environment at 60 ° C. for 1 week were performed. The method follows the method described above.
オルメサルタンメドキソミル及びステアリン酸を含む処方では溶出性が低下するため、崩壊剤をさらに添加することが好ましいが、ヒプロメロースやヒドロキシプロピルセルロース、結晶セルロースでは、オルメサルタンメドキソミルの類縁物質を増大させるため、これらを含有させることは好ましくない。
一方、クロスポビドンやアルファー化デンプンは類縁物質の増大は小さく、においの発生も他の崩壊剤と比較して少ないため、本発明の経口用組成物における崩壊剤として適していると考えられる。In formulations containing olmesartan medoxomil and stearic acid, it is preferable to add a disintegrating agent because the dissolution is reduced, but hypromellose, hydroxypropylcellulose, and crystalline cellulose contain these in order to increase the related substances of olmesartan medoxomil. It is not preferable to make it.
On the other hand, crospovidone and pregelatinized starch are considered to be suitable as disintegrants in the oral composition of the present invention because the increase in related substances is small and the generation of odor is small compared to other disintegrants.
Claims (10)
ｂ）組成物全量に対して５〜１５質量％の炭素数が１２〜２２の飽和脂肪酸；
を含有してなる経口用組成物。a) a drug having a medoxomil group as an active ingredient; and
b) 5 to 15% by mass of saturated fatty acid having 12 to 22 carbon atoms based on the total amount of the composition;
An oral composition comprising
ｂ) 組成物全量に対して５〜１５質量％のステアリン酸又はパルミチン酸から選ばれる飽和脂肪酸；及び、
ｃ) 組成物全量に対して２〜２０質量％の、クロスポビドン、アルファー化デンプン、及びこれらの混合物、からなる群より選ばれる少なくとも１つの崩壊剤；
を含有してなる経口用組成物。a) Olmesartan medoxomil;
b) a saturated fatty acid selected from 5 to 15% by weight of stearic acid or palmitic acid based on the total amount of the composition; and
c) at least one disintegrant selected from the group consisting of crospovidone, pregelatinized starch, and mixtures thereof in an amount of 2 to 20% by weight based on the total amount of the composition;
An oral composition comprising
ｂ) 組成物全量に対して５〜１５質量％のステアリン酸；
ｃ) 組成物全量に対して２〜２０質量％の、クロスポビドン、アルファー化デンプン、及びこれらの混合物、からなる群より選ばれる少なくとも１つの崩壊剤；並びに、
ｄ) 組成物全量に対して６５〜９０質量％の、無水乳糖、乳糖水和物、白糖、トレハロース、及びマンニトールからなる群から選ばれる少なくとも１つの賦形剤、
を含有してなる経口用組成物。a) 1 to 25% by weight of olmesartan medoxomil based on the total amount of the composition;
b) 5 to 15% by weight of stearic acid relative to the total amount of the composition;
c) at least one disintegrant selected from the group consisting of crospovidone, pregelatinized starch, and mixtures thereof, based on 2-20% by weight of the total composition; and
d) at least one excipient selected from the group consisting of anhydrous lactose, lactose hydrate, sucrose, trehalose, and mannitol, in an amount of 65 to 90% by mass based on the total amount of the composition;
An oral composition comprising
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| WO2007128478A2 (en) * | 2006-05-04 | 2007-11-15 | Lek Pharmaceuticals D.D. | Pharmaceutical composition |
| JP2008543728A (en) * | 2005-06-27 | 2008-12-04 | 第一三共株式会社 | Angiotensin II receptor antagonist and pharmaceutical composition containing calcium antagonist |
| JP2011500505A (en) * | 2006-09-15 | 2011-01-06 | 第一三共株式会社 | Solid formulation of olmesartan medoxomil and amlodipine |
| JP2012513978A (en) * | 2008-12-30 | 2012-06-21 | アブディ イブラヒム イラク サナイ ベ ティカレット アノニム シルケティ | Olmesartan formulation |
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| KR100888131B1 (en) * | 2006-10-10 | 2009-03-11 | 한올제약주식회사 | Combination preparation for Cardiovascular disease therapy by Chronotherapy theory. |
| JP5554699B2 (en) * | 2008-03-13 | 2014-07-23 | 第一三共株式会社 | Improving dissolution properties of formulations containing olmesartan medoxomil |
| TR201005867A1 (en) * | 2010-07-16 | 2012-02-21 | Sanovel İlaç Sanayi̇ Ve Ti̇caret Anoni̇m Şi̇rketi̇ | Olmesartan pharmaceutical compositions. |
| JP5680898B2 (en) * | 2010-08-10 | 2015-03-04 | 京都薬品工業株式会社 | Fast disintegrating tablets with reduced bitterness |
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| JP2008543728A (en) * | 2005-06-27 | 2008-12-04 | 第一三共株式会社 | Angiotensin II receptor antagonist and pharmaceutical composition containing calcium antagonist |
| WO2007128478A2 (en) * | 2006-05-04 | 2007-11-15 | Lek Pharmaceuticals D.D. | Pharmaceutical composition |
| JP2011500505A (en) * | 2006-09-15 | 2011-01-06 | 第一三共株式会社 | Solid formulation of olmesartan medoxomil and amlodipine |
| JP2012513978A (en) * | 2008-12-30 | 2012-06-21 | アブディ イブラヒム イラク サナイ ベ ティカレット アノニム シルケティ | Olmesartan formulation |
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