JP6366547B2 - Pramipexole formulation package with improved photostability - Google Patents
Pramipexole formulation package with improved photostability Download PDFInfo
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- JP6366547B2 JP6366547B2 JP2015153619A JP2015153619A JP6366547B2 JP 6366547 B2 JP6366547 B2 JP 6366547B2 JP 2015153619 A JP2015153619 A JP 2015153619A JP 2015153619 A JP2015153619 A JP 2015153619A JP 6366547 B2 JP6366547 B2 JP 6366547B2
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- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 title claims description 14
- 229960003089 pramipexole Drugs 0.000 title claims description 13
- 238000009472 formulation Methods 0.000 title description 3
- 239000000203 mixture Substances 0.000 title description 3
- 239000003826 tablet Substances 0.000 claims description 43
- 239000007888 film coating Substances 0.000 claims description 12
- 238000009501 film coating Methods 0.000 claims description 12
- 239000007939 sustained release tablet Substances 0.000 claims description 12
- 239000010410 layer Substances 0.000 claims description 11
- 238000002834 transmittance Methods 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical group O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 6
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 claims description 6
- 239000002981 blocking agent Substances 0.000 claims 1
- 229950010601 pramipexole dihydrochloride monohydrate Drugs 0.000 description 22
- 238000004519 manufacturing process Methods 0.000 description 11
- 229920000915 polyvinyl chloride Polymers 0.000 description 10
- 239000004800 polyvinyl chloride Substances 0.000 description 10
- 239000007941 film coated tablet Substances 0.000 description 8
- 238000004806 packaging method and process Methods 0.000 description 7
- -1 polypropylene Polymers 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 235000012239 silicon dioxide Nutrition 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 4
- 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 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 4
- 229910052782 aluminium Inorganic materials 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 4
- 229950008138 carmellose Drugs 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- 235000012222 talc Nutrition 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229920001342 Bakelite® Polymers 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- 230000006750 UV protection Effects 0.000 description 3
- 239000004637 bakelite Substances 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000007857 degradation product Substances 0.000 description 3
- 239000011888 foil Substances 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 229960003943 hypromellose Drugs 0.000 description 3
- 229920002493 poly(chlorotrifluoroethylene) Polymers 0.000 description 3
- 239000005023 polychlorotrifluoroethylene (PCTFE) polymer Substances 0.000 description 3
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 229920001328 Polyvinylidene chloride Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 239000005033 polyvinylidene chloride Substances 0.000 description 2
- QMNWXHSYPXQFSK-KLXURFKVSA-N pramipexole hydrochloride anhydrous Chemical compound Cl.Cl.C1[C@@H](NCCC)CCC2=C1SC(N)=N2 QMNWXHSYPXQFSK-KLXURFKVSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- UBVSIAHUTXHQTD-UHFFFAOYSA-N 2-n-(4-bromophenyl)-1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(NC=2C=CC(Br)=CC=2)=N1 UBVSIAHUTXHQTD-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- WLDHEUZGFKACJH-ZRUFZDNISA-K Amaranth Chemical compound [Na+].[Na+].[Na+].C12=CC=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(O)=C1\N=N\C1=CC=C(S([O-])(=O)=O)C2=CC=CC=C12 WLDHEUZGFKACJH-ZRUFZDNISA-K 0.000 description 1
- 229940096895 Dopamine D2 receptor agonist Drugs 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229940067573 brown iron oxide Drugs 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000002288 dopamine 2 receptor stimulating agent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000012732 erythrosine Nutrition 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 238000005562 fading Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- LDHBWEYLDHLIBQ-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide;hydrate Chemical compound O.[OH-].[O-2].[Fe+3] LDHBWEYLDHLIBQ-UHFFFAOYSA-M 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明はパーキンソン病の治療に有用なプラミペキソール二塩酸塩一水和物を含む放出が延長された錠剤調合物（徐放錠）に関するものである。 The present invention relates to an extended release tablet formulation (sustained release tablet) comprising pramipexole dihydrochloride monohydrate useful for the treatment of Parkinson's disease.
プラミペキソールは選択的ドパミンＤ２受容体作動薬であり、化学的には（Ｓ）−２−アミノ−４，５，６，７−テトラヒドロ−６−プロピルアミノベンゾチアゾールとして表される。プラミペキソール二塩酸塩一水和物はパーキンソン病の治療薬として用いられる。 Pramipexole is a selective dopamine D2 receptor agonist and is chemically represented as (S) -2-amino-4,5,6,7-tetrahydro-6-propylaminobenzothiazole. Pramipexole dihydrochloride monohydrate is used as a treatment for Parkinson's disease.
プラミペキソール二塩酸塩一水和物は錠剤に含有された形態で医療現場に上記の治療薬として提供されている。プラミペキソール二塩酸塩一水和物を含有する素錠は両面アルミや、赤色の包装用シートで覆われた製品が既に販売されている。特許文献１及び２では、特定波長の光を遮ることによって製剤の退色や安定性を改善する方法が知られている。
しかし、フィルムコーティングを施したプラミペキソール二塩酸塩一水和物を含有する徐放錠についての光安定性の評価やその改善方法を示す先行文献は乏しいのが現状である。
Pramipexole dihydrochloride monohydrate is provided as a therapeutic agent in the medical field in the form of a tablet. As for the uncoated tablets containing pramipexole dihydrochloride monohydrate, products covered with double-sided aluminum and a red packaging sheet are already on the market. In Patent Documents 1 and 2, a method for improving fading and stability of a preparation by blocking light of a specific wavelength is known.
However, at present, there are few prior literatures showing the evaluation of photostability and how to improve the sustained release tablets containing pramipexole dihydrochloride monohydrate subjected to film coating.
本発明の課題は、プラミペキソール二塩酸塩一水和物を含有するフィルムコーティング徐放錠について、プラミペキソール二塩酸塩一水和物の光に対する化学的な安定性を向上させ、原薬由来の分解産物（類縁体）の発生量を抑制することである。 An object of the present invention is to improve the chemical stability of pramipexole dihydrochloride monohydrate with respect to light for a film-coated sustained-release tablet containing pramipexole dihydrochloride monohydrate, and to provide a degradation product derived from the drug substance It is to suppress the generation amount of (analog).
本発明者は、プラミペキソール二塩酸塩一水和物を含有する徐放錠の安定性を改善するため、その処方や形態、製造方法に関して鋭意検討を重ねた。まず、遮光剤を含むフィルムコーティング層で錠剤を覆ったが、プラミペキソール二塩酸塩一水和物の光安定性を十分に改善することはできなかった。そこで、プラミペキソール二塩酸塩一水和物を含有するフィルムコーティング徐放錠を特定波長を遮るシートで覆うことで、内容物の錠剤が外部から視認可能である上で、光に対する安定性を十分に改善することが可能になった。その知見に基づき、本発明者はさらに鋭意検討を重ねて下記の発明を完成させた。 In order to improve the stability of sustained-release tablets containing pramipexole dihydrochloride monohydrate, the present inventor has intensively studied the formulation, form, and production method. First, the tablets were covered with a film coating layer containing a light-shielding agent, but the light stability of pramipexole dihydrochloride monohydrate could not be sufficiently improved. Therefore, by covering the film-coated sustained-release tablets containing pramipexole dihydrochloride monohydrate with a sheet that blocks specific wavelengths, the tablets of the contents are visible from the outside, and the stability to light is sufficient. It became possible to improve. Based on this knowledge, the present inventor made further studies and completed the following invention.
本発明の具体的な構成は、下記（１）〜（６）によって記述されているものである。
（１）２００〜５００ｎｍの範囲の波長の光透過率が３０％以下である透明性を有したシートで包装され、フィルムコーティング層で覆われた、プラミペキソール含有徐放錠。
（２）２００〜５５０ｎｍの範囲の波長の光透過率が３０％以下である透明性を有したシートで包装された、前記（１）に記載の錠剤。
（３）ポリ塩化ビニル、ポリプロピレン、ポリ塩化ビニリデン、ポリクロロトリフルオロエチレンより選ばれるシートで包装された、前記（１）又は（２）に記載の錠剤。
（４）フィルムコーティング層に遮光剤が含有され、遮光剤が酸化チタン、タルク、黄酸化鉄、黄色三二酸化鉄、褐色酸化鉄、三二酸化鉄、食用黄色４号、食用黄色５号、食用黄色４号アルミニウムレーキ、食用赤色２号、食用赤色３号、食用赤色１０２号より選ばれる、前記（１）〜（３）のいずれかに記載の錠剤。
（５）遮光剤が酸化チタンである、前記（４）に記載の錠剤。
（６）プラミペキソールの含有量が錠剤全重量に対して、０．５〜１．０重量％である、前記（１）〜（５）のいずれかに記載の錠剤。
The specific configuration of the present invention is described by the following (1) to (6).
(1) A pramipexole-containing sustained-release tablet packaged with a transparent sheet having a light transmittance of 30% or less in a wavelength range of 200 to 500 nm and covered with a film coating layer.
(2) The tablet according to (1), packaged with a transparent sheet having a light transmittance of a wavelength in the range of 200 to 550 nm of 30% or less.
(3) The tablet according to (1) or (2), which is packaged with a sheet selected from polyvinyl chloride, polypropylene, polyvinylidene chloride, and polychlorotrifluoroethylene.
(4) The film coating layer contains a light-shielding agent, and the light-shielding agent is titanium oxide, talc, yellow iron oxide, yellow ferric oxide, brown iron oxide, ferric oxide, edible yellow No. 4, edible yellow No. 5, edible yellow The tablet in any one of said (1)-(3) chosen from No. 4 aluminum lake, edible red No. 2, edible red No. 3, and edible red No. 102.
(5) The tablet according to (4), wherein the light-shielding agent is titanium oxide.
(6) The tablet according to any one of (1) to (5), wherein the content of pramipexole is 0.5 to 1.0% by weight based on the total weight of the tablet.
本発明によれば、プラミペキソール二塩酸塩一水和物を含有するフィルムコーティング徐放錠について、プラミペキソール二塩酸塩一水和物の光に対する化学的な安定性を向上させ、原薬由来の分解産物（類縁体）の発生量を抑制する効果が期待される。 According to the present invention, for film-coated sustained-release tablets containing pramipexole dihydrochloride monohydrate, the chemical stability of pramipexole dihydrochloride monohydrate to light is improved, and the degradation product derived from the drug substance The effect of suppressing the amount of (analog) generated is expected.
以下で本発明に係るプラミペキソール二塩酸塩一水和物を含有する錠剤の処方及び製造方法、錠剤包装用シートを詳細に説明する。但し、以下の記載は本発明を説明するための例示であり、本発明をこの記載範囲にのみ限定する趣旨ではない。 Hereinafter, the formulation and production method of a tablet containing pramipexole dihydrochloride monohydrate according to the present invention, and a tablet packaging sheet will be described in detail. However, the following description is an example for explaining the present invention, and is not intended to limit the present invention to this description range.
本発明に係るプラミペキソール二塩酸塩一水和物を含有する錠剤は、プラミペキソール二塩酸塩一水和物を含有する素錠の周囲がフィルムコーティング層によって覆われた、フィルムコーティング錠である。また、本発明の錠剤は徐放錠である。 The tablet containing pramipexole dihydrochloride monohydrate according to the present invention is a film-coated tablet in which the periphery of the uncoated tablet containing pramipexole dihydrochloride monohydrate is covered with a film coating layer. The tablet of the present invention is a sustained release tablet.
本発明に係る素錠に含まれるプラミペキソール二塩酸塩一水和物は錠剤の全重量に対して０．０５〜１．０重量％であり、カルメロースカルシウムは錠剤の全重量に対して３０．０〜４４．０重量％で、ヒドロキシプロピルセルロースは錠剤の全重量に対して５５．０〜６９．０重量％で、滑沢剤は錠剤の全重量に対して０．１〜２．０重量％で含まれることが好ましい。 The pramipexole dihydrochloride monohydrate contained in the uncoated tablet according to the present invention is 0.05 to 1.0% by weight based on the total weight of the tablet, and carmellose calcium is 30% based on the total weight of the tablet. 0 to 44.0% by weight, hydroxypropylcellulose is 55.0 to 69.0% by weight based on the total weight of the tablet, and lubricant is 0.1 to 2.0% by weight based on the total weight of the tablet. % Is preferably included.
本発明に係る滑沢剤は、例えばステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、フマル酸ステアリルナトリウム、ショ糖脂肪酸エステル、ステアリルアルコール、ステアリン酸から選ばれる１又は２種以上の化合物であり、好ましくはステアリン酸マグネシウムである。
本発明に係る素錠には流動化剤を含有することができる。本発明に係る流動化剤は、例えば軽質無水ケイ酸、タルク、含水二酸化ケイ素等が挙げられ、好ましくは軽質無水ケイ酸である。軽質無水ケイ酸の好ましい含有量は錠剤重量の０．１〜１．０重量％である。
本発明に係る素錠には必要に応じて、医薬品添加物として許容される着色剤等を含むことができる。
The lubricant according to the present invention is, for example, one or more compounds selected from magnesium stearate, calcium stearate, talc, sodium stearyl fumarate, sucrose fatty acid ester, stearyl alcohol and stearic acid, preferably stearin Magnesium acid.
The uncoated tablet according to the present invention may contain a fluidizing agent. Examples of the fluidizing agent according to the present invention include light anhydrous silicic acid, talc, hydrous silicon dioxide and the like, preferably light anhydrous silicic acid. The preferred content of light silicic acid is 0.1 to 1.0% by weight of the tablet weight.
The uncoated tablet according to the present invention can contain a coloring agent acceptable as a pharmaceutical additive, if necessary.
本発明に係る素錠は、全ての錠剤成分を混合して打錠する直接打錠法で製造されるか、あるいは湿式造粒法を介した製法、即ちプラミペキソール二塩酸塩一水和物を錠剤成分中に均一に混合するために、流動層造粒機を用いてカルメロースカルシウムに水に溶解したプラミペキソール二塩酸塩一水和物をスプレーして乾燥し、得られた造粒粉末に残りの成分を混合し、これを打錠することによって製造可能である。スプレーする液には結合剤としてヒドロキシプロピルセルロースの一部を溶解せしめることができるし、他の結合剤、例えばヒプロメロース等を溶解することも可能である。結合剤の添加量は好ましくは錠剤重量の０．５〜２．０重量％である。 The uncoated tablet according to the present invention is produced by a direct tableting method in which all tablet components are mixed and tableted, or a production method through a wet granulation method, that is, pramipexole dihydrochloride monohydrate is tableted. In order to mix uniformly into the ingredients, sprayed pramipexole dihydrochloride monohydrate dissolved in water into carmellose calcium using a fluid bed granulator and dried, and the remaining granulated powder was obtained. It can be produced by mixing the ingredients and compressing them. In the liquid to be sprayed, a part of hydroxypropylcellulose can be dissolved as a binder, and other binders such as hypromellose can also be dissolved. The amount of binder added is preferably 0.5 to 2.0% by weight of the tablet weight.
本発明に係るフィルムコーティング錠剤の製造方法については、特に限定されないが、商業的に製造する場合はフィルムコーティング機を用いたコーティング法が用いられる。得られた素錠をフィルムコーティング機に仕込み、フィルム成分を水に懸濁してこれをスプレー・乾燥すれば、本発明のフィルムコーティング錠が得られる。フィルムコーティング層は２．０〜１８．０ｍｇ、好ましくは６．０〜１４．０ｍｇであり、２層からなることが好ましい。酸化チタンはフィルムコーティング層全重量に対して０．１〜１０．０重量％含まれることが好ましい。 Although it does not specifically limit about the manufacturing method of the film coating tablet which concerns on this invention, The coating method using a film coating machine is used when manufacturing commercially. The obtained uncoated tablet is charged into a film coating machine, the film components are suspended in water, and sprayed and dried to obtain the film-coated tablet of the present invention. The film coating layer is 2.0 to 18.0 mg, preferably 6.0 to 14.0 mg, and preferably consists of two layers. The titanium oxide is preferably contained in an amount of 0.1 to 10.0% by weight with respect to the total weight of the film coating layer.
本発明に係るフィルムコーティング錠剤は、遮光機能及び透明性を有したシートで包装される。本発明に係る遮光機能及び透明性を有したシートは、５００ｎｍ以下（又は２００〜５００ｎｍの範囲としても良く、特に３７０〜５００ｎｍの範囲が遮光機能に重要である。）の波長の光透過率が３０％以下（さらに好ましくは１０％以下）であり、さらに５５０ｎｍ以下（又は２００〜５５０ｎｍの範囲としても良く、特に３７０〜５５０ｎｍの範囲が遮光機能に重要である。）の波長の光透過率が３０％以下（さらに好ましくは１０％以下で、最も好ましくは２％以下）であることが好ましい。遮光機能及び透明性を有したシートの使用可能な素材は、ポリ塩化ビニル、ポリプロピレン、ポリ塩化ビニリデン、ポリクロロトリフルオロエチレン等が挙げられるが、最も好ましくはポリ塩化ビニルである。
また、遮光機能及び透明性を有したシートとアルミ箔で本発明に係るフィルムコーティング錠剤を挟んで覆い、加熱シールすることで、本発明の遮光機能及び透明性を有したシートで包装されたプラミペキソール錠剤を得ることが可能である。
The film-coated tablet according to the present invention is packaged with a sheet having a light shielding function and transparency. The sheet having a light shielding function and transparency according to the present invention has a light transmittance of a wavelength of 500 nm or less (or a range of 200 to 500 nm, and particularly a range of 370 to 500 nm is important for the light shielding function). The light transmittance of a wavelength of 30% or less (more preferably 10% or less), and further 550 nm or less (or 200 to 550 nm, particularly important is a range of 370 to 550 nm). It is preferably 30% or less (more preferably 10% or less, most preferably 2% or less). Examples of materials that can be used for the sheet having a light shielding function and transparency include polyvinyl chloride, polypropylene, polyvinylidene chloride, and polychlorotrifluoroethylene. Most preferred is polyvinyl chloride.
Further, the film coated tablet according to the present invention is sandwiched and covered with an aluminum foil and a sheet having a light shielding function and transparency, and heat sealed, so that pramipexole packaged with the sheet having the light shielding function and transparency of the present invention It is possible to obtain tablets.
（１）プラミペキソール二塩酸塩一水和物０．７５ｇとカルメロースカルシウム１４．２５ｇを均一に混合して２０倍散を作成し、これにカルメロースカルシウム１６０．７５ｇ、ヒドロキシプロピルセルロース２７９．７５ｇ、軽質無水ケイ酸２．０ｇを加えて均一に混合し、更にステアリン酸マグネシウム２．５ｇを加えて混合して打錠用末を得た。得られた打錠用末をロータリー打錠機（ＶＥＬＡ５、菊水製作所社製）で打錠して１錠重量２３０ｍｇの素錠を得た。
（２）次いで素錠をコーティング機（ＤＲＣ−２００、パウレック社製）に投入し、これに、予めヒプロメロース２３．１ｇ、酸化チタン１４．４ｇ、タルク２．５ｇを精製水３６０ｇに加え、均一分散させた液を噴霧し、１錠重量２３８．０ｍｇになるまでコーティング・乾燥し、次いで予めヒプロメロース９．４ｇ、酸化チタン０．６ｇを精製水９０ｇに加え、均一分散した駅を噴霧し、1錠２４０．０ｍｇになるまでコーティング・乾燥して２層フィルムコーティング徐放錠を得た。
（３）次いでＰＴＰ包装機を用いて、ポリ塩化ビニル（＊１）及びポリクロロトリフルオロエチレンで構成された多層フィルムを加熱成形後、２層フィルムコーティング錠を充てんし、アルミ箔をセットして加熱シールした。ＰＴＰシートの中身の錠剤が外部から視認できるように、包装体とアルミ箔で挟んで加熱シールした。其のシール品を裁断して錠剤含有ＰＴＰシート製品を製造した。
＊１：厚さ２５０μｍの、紫外線防止機能を付与し、赤色に着色したポリ塩化ビニルの包装用シート（住友ベークライトＵＶ３赤１−３９１）であり、波長５９０ｎｍ以下の光を遮断（少なくとも２００〜５９０ｎｍの範囲内の波長の光透過率が２％以下）するものに限って使用した。
(1) 0.75 g of pramipexole dihydrochloride monohydrate and 14.25 g of carmellose calcium were uniformly mixed to prepare a 20-fold powder. To this, 160.75 g of carmellose calcium, 279.75 g of hydroxypropylcellulose, 2.0 g of light anhydrous silicic acid was added and mixed uniformly, and 2.5 g of magnesium stearate was further added and mixed to obtain a tableting powder. The obtained tableting powder was tableted with a rotary tableting machine (VELA5, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain an uncoated tablet having a tablet weight of 230 mg.
(2) Next, the uncoated tablet is put into a coating machine (DRC-200, manufactured by Paulek), and 23.1 g of hypromellose, 14.4 g of titanium oxide, and 2.5 g of talc are added to 360 g of purified water in advance and uniformly dispersed. Spray the solution, coat and dry until one tablet weight is 238.0 mg, then add 9.4 g of hypromellose and 0.6 g of titanium oxide to 90 g of purified water in advance, spray the uniformly dispersed station, 1 tablet It was coated and dried to 240.0 mg to obtain a two-layer film-coated sustained release tablet.
(3) Next, using a PTP packaging machine, heat-mold a multilayer film composed of polyvinyl chloride (* 1) and polychlorotrifluoroethylene, fill it with a two-layer film-coated tablet, and set an aluminum foil. Heat sealed. The PTP sheet was heat-sealed by sandwiching it between the package and aluminum foil so that the tablets inside the PTP sheet could be seen from the outside. The sealed product was cut to produce a tablet-containing PTP sheet product.
* 1: Polyvinyl chloride packaging sheet (Sumitomo Bakelite UV3 Red 1-391) with a thickness of 250 μm that has an ultraviolet protection function and is colored red, and blocks light with a wavelength of 590 nm or less (at least 200 to 590 nm). The light transmittance of wavelengths within the range of 2% or less) was used.
実施例１（１）、（２）に従って、プラミペキソール二塩酸塩一水和物を含有するフィルムコーティング徐放錠を製造し、実施例１（３）の製造方法に従って、錠剤含有ＰＴＰシート製品を製造した。但し、実施例１（３）の製造方法に従った際に使用したポリ塩化ビニルは、厚さ２５０μｍの、紫外線防止機能を付与し、赤色に着色したポリ塩化ビニルの包装用シート（住友ベークライトＵＶ３赤２−４８１）であり、波長５５０ｎｍ以下の光を遮断（少なくとも２００〜５５０ｎｍの範囲内の波長の光透過率が２％以下）するものに限って使用した。 A film-coated sustained release tablet containing pramipexole dihydrochloride monohydrate is produced according to Example 1 (1), (2), and a tablet-containing PTP sheet product is produced according to the production method of Example 1 (3). did. However, the polyvinyl chloride used when the manufacturing method of Example 1 (3) was followed had a thickness of 250 μm, provided with a UV protection function, and was colored in a red colored polyvinyl chloride packaging sheet (Sumitomo Bakelite UV3). It was used only for red 2-481) and blocking light having a wavelength of 550 nm or less (light transmittance of a wavelength in the range of at least 200 to 550 nm was 2% or less).
［比較例１]
実施例１（１）、（２）に従って、プラミペキソール二塩酸塩一水和物を含有するフィルムコーティング徐放錠を製造し、実施例１（３）の製造方法に従って、錠剤含有ＰＴＰシート製品を製造した。但し、実施例１（３）の製造方法に従った際に使用したポリ塩化ビニルは、厚さ２５０μｍの、透明の紫外線防止機能を付与したポリ塩化ビニルの包装用シート（住友ベークライトＵＶ３透明０１１）であり、波長３７０ｎｍ以下の光を遮断（少なくとも２００〜３７０ｎｍの範囲内の波長の光透過率が２％以下）するものに限って使用した。
[Comparative Example 1]
A film-coated sustained release tablet containing pramipexole dihydrochloride monohydrate is produced according to Example 1 (1), (2), and a tablet-containing PTP sheet product is produced according to the production method of Example 1 (3). did. However, the polyvinyl chloride used when the production method of Example 1 (3) was followed was a 250 μm thick polyvinyl chloride packaging sheet provided with a transparent ultraviolet protection function (Sumitomo Bakelite UV3 Transparent 011). And used only for light that blocks light having a wavelength of 370 nm or less (light transmittance of a wavelength in the range of at least 200 to 370 nm is 2% or less).
［比較例２]
実施例１（１）、（２）に従って、プラミペキソール二塩酸塩一水和物を含有するフィルムコーティング錠剤を製造し、実施例１（３）の製造方法にほぼ従って、錠剤含有ＰＴＰシート製品を製造した。但し、実施例１（３）の製造方法に従った際にポリ塩化ビニルは用いなかった。
[Comparative Example 2]
A film-coated tablet containing pramipexole dihydrochloride monohydrate is produced according to Example 1 (1), (2), and a tablet-containing PTP sheet product is produced substantially in accordance with the production method of Example 1 (3). did. However, polyvinyl chloride was not used when the production method of Example 1 (3) was followed.
［試験例１］
実施例１、２及び比較例１、２で製造した製剤を、光照射（積算１２０万Ｌｕｘ・ｈｒ／２５℃６０％ＲＨ）した後、プラミペキソールの総類縁物質量をＨＰＬＣ法（定量方法は面積百分率法を使用した）で測定した。測定した結果を表１に示した。
After the preparations produced in Examples 1 and 2 and Comparative Examples 1 and 2 were irradiated with light (total of 1,200,000 Lux · hr / 25 ° C. 60% RH), the total amount of pramipexole related substances was determined by HPLC (quantitative method is area The percentage method was used). The measurement results are shown in Table 1.
表１において、本発明に係る実施例１、２の錠剤は光照射前後のプラミペキソール由来の総類縁体の増加量が顕著に低いことが観察されたが、比較例１、２の錠剤では光照射前後のプラミペキソールの総類縁体の増加量が高いことが観察された。そのため本発明によって、特定波長を遮光する半透明な包装用シートで覆うことでプラミペキソール含有フィルムコーティング錠剤は十分な光安定性を確保することが可能であることが示された。 In Table 1, it was observed that the increase in the total analogs derived from pramipexole before and after light irradiation of the tablets of Examples 1 and 2 according to the present invention was remarkably low, but the tablets of Comparative Examples 1 and 2 were irradiated with light. A high increase in the total analog of pramipexole before and after was observed. Therefore, according to the present invention, it was shown that pramipexole-containing film-coated tablets can ensure sufficient light stability by covering with a translucent packaging sheet that shields a specific wavelength.
本発明によれば、保存条件下でのプラミペキソールの光に対する化学的な安定性が向上し、分解産物（類縁体）の発生量が抑制された、プラミペキソールを含有するフィルムコーティング錠剤製品を医療現場に提供することが可能となる。
According to the present invention, a film coated tablet product containing pramipexole containing pramipexole, which has improved chemical stability to light of pramipexole under storage conditions and reduced the generation amount of degradation products (analogues), has been introduced to the medical field. It becomes possible to provide.
Claims (2)
It said sheet is a sheet having a transparency light transmittance at a wavelength in the range of 200~550nm is 2% or less, the tablet of claim 1.
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