JP2014058510A - Production method of tablet - Google Patents
Production method of tablet Download PDFInfo
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- JP2014058510A JP2014058510A JP2013170291A JP2013170291A JP2014058510A JP 2014058510 A JP2014058510 A JP 2014058510A JP 2013170291 A JP2013170291 A JP 2013170291A JP 2013170291 A JP2013170291 A JP 2013170291A JP 2014058510 A JP2014058510 A JP 2014058510A
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- salt
- loxoprofen
- tablet
- adhesion
- powder
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 22
- 229960002373 loxoprofen Drugs 0.000 claims abstract description 45
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical compound O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 claims abstract description 38
- 239000000843 powder Substances 0.000 claims abstract description 36
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 32
- 238000005550 wet granulation Methods 0.000 claims abstract description 14
- 229920002472 Starch Polymers 0.000 claims abstract description 13
- 235000019698 starch Nutrition 0.000 claims abstract description 12
- 239000008107 starch Substances 0.000 claims abstract description 12
- 238000009472 formulation Methods 0.000 abstract description 7
- 239000000203 mixture Substances 0.000 abstract description 7
- 239000003826 tablet Substances 0.000 description 32
- 238000001035 drying Methods 0.000 description 10
- 238000011156 evaluation Methods 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 6
- WORCCYVLMMTGFR-UHFFFAOYSA-M loxoprofen sodium Chemical compound [Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 WORCCYVLMMTGFR-UHFFFAOYSA-M 0.000 description 5
- 238000002156 mixing Methods 0.000 description 4
- 239000004570 mortar (masonry) Substances 0.000 description 4
- 239000000654 additive Substances 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000010981 drying operation Methods 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- -1 loxoprofen sodium anhydride Chemical class 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 238000013329 compounding Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 229940116317 potato starch Drugs 0.000 description 2
- 238000005096 rolling process Methods 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000012895 Gastric disease Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940124579 cold medicine Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 238000007909 melt granulation Methods 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229940075430 wheat dextrin Drugs 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は、ロキソプロフェン又はその塩を含有する錠剤の製造方法に関するものである。さらに詳しくは、機器や容器に対する付着性が非常に強いロキソプロフェン又はその塩を含有する錠剤を、これらに付着させることなく製造することができる錠剤の製造方法に関するものである。 The present invention relates to a method for producing a tablet containing loxoprofen or a salt thereof. More specifically, the present invention relates to a method for producing a tablet capable of producing a tablet containing loxoprofen or a salt thereof having very strong adhesion to an apparatus or a container without adhering to the tablet.
ロキソプロフェンはそのナトリウム塩が医療用医薬品として高い実績を誇るフェニルプロピオン酸系消炎鎮痛剤である。本成分は消炎鎮痛剤として医療用での使用実績が高く、またプロドラッグであるため、他のNSAIDsに多く見られる胃障害などの副作用が比較的軽いといった特徴を有している。 Loxoprofen is a phenylpropionic acid anti-inflammatory analgesic whose sodium salt has a proven track record as a pharmaceutical product. This component has been used for medical purposes as an anti-inflammatory analgesic, and is a prodrug, so it has characteristics such as relatively low side effects such as gastric disorders often seen in other NSAIDs.
ロキソプロフェン又はその塩は機器、容器に対する付着性が非常に強い薬物であり、その製剤化にあたっては付着性を留意した製剤設計を選択する必要があった。ロキソプロフェン又はその塩の付着性を改善するための検討は既に数多くなされており、例えば製剤中の「総吸水能」を１．７以上にする方法（特許文献１）や、メタケイ酸アルミン酸マグネシウム又は微粉性ポリエチレングリコールを配合する方法（特許文献２又は３）、またはロキソプロフェンナトリウムと糖類を含む粒状物にセルロース系製剤原料を含有する溶液を噴霧し、乾燥する方法（特許文献４）等が知られている。しかしながら、これらの技術は全て湿式造粒法により製した顆粒を使用した技術であり、一般的に付着性の高い薬物に対して選択される手法である。
一方、湿式造粒法を用いないでロキソプロフェン又はその塩の付着性を改善した技術として、例えば吸水性添加剤と部分アルファー化デンプン及び結晶セルロースを含む粉体を直接打錠法によって製する方法がある（特許文献５）。しかしながら、当該技術においては、直接打錠法での製造を実現するためにロキソプロフェン又はその塩以外にも特定の添加剤を複数必要とし、またその配合量も限定して製剤化する必要があった。
Loxoprofen or a salt thereof is a drug having a very strong adhesion to equipment and containers, and it was necessary to select a formulation design with attention to the adhesion when formulating the drug. Many studies have already been made to improve the adhesion of loxoprofen or a salt thereof. For example, a method of increasing the “total water absorption capacity” in the preparation to 1.7 or more (Patent Document 1), magnesium aluminate metasilicate, Known is a method of blending finely divided polyethylene glycol (Patent Document 2 or 3), or a method of spraying a solution containing a cellulosic preparation material onto a granular material containing sodium loxoprofen and a saccharide and drying (Patent Document 4) ing. However, these techniques are all techniques using granules produced by wet granulation, and are generally selected for drugs with high adhesion.
On the other hand, as a technique for improving the adhesion of loxoprofen or a salt thereof without using a wet granulation method, for example, there is a method of producing a powder containing a water-absorbing additive, partially pregelatinized starch and crystalline cellulose by a direct tableting method. Yes (Patent Document 5). However, in this technology, in order to realize the production by the direct tableting method, a plurality of specific additives other than loxoprofen or a salt thereof are required, and the formulation amount must be limited. .
本発明は、ロキソプロフェン又はその塩を含有する医薬用製剤を開発するため、湿式造粒法を用いなくてもロキソプロフェン又はその塩の付着を起こすことがなく、しかも簡便な方法で製剤化する錠剤の製造方法を提供することを目的とする。 In order to develop a pharmaceutical preparation containing loxoprofen or a salt thereof, the present invention does not cause adhesion of loxoprofen or a salt thereof without using a wet granulation method, and is a tablet that is formulated by a simple method. An object is to provide a manufacturing method.
本発明者らは種々検討した結果、ロキソプロフェン又はその塩を含有する粉体を打錠操作前に乾燥させることにより、湿式造粒法を用いなくても上記課題が解決できることを見出し、本発明を完成させた。
すなわち、本発明は、
（１）ロキソプロフェン又はその塩を含有する錠剤の製造方法であって、ロキソプロフェン又はその塩を含有する粉体を乾燥した後、湿式造粒法を使用せずに製造することを特徴とする、前記製造方法。
（２）ロキソプロフェン又はその塩、及びデンプンを含有する粉体を乾燥した後、湿式造粒法を使用せずに製造することを特徴とする、（１）に記載の製造方法、
（３）デンプンの含有量が、ロキソプロフェン又はその塩１質量部に対して０．３〜５．０質量部である、（２）に記載の製造方法、
である。
As a result of various studies, the present inventors have found that the above problems can be solved without using a wet granulation method by drying a powder containing loxoprofen or a salt thereof before a tableting operation. Completed.
That is, the present invention
(1) A method for producing a tablet containing loxoprofen or a salt thereof, wherein the powder containing loxoprofen or a salt thereof is dried and then produced without using a wet granulation method, Production method.
(2) The production method according to (1), wherein the powder containing loxoprofen or a salt thereof and starch is dried and then produced without using a wet granulation method,
(3) The production method according to (2), wherein the starch content is 0.3 to 5.0 parts by mass with respect to 1 part by mass of loxoprofen or a salt thereof.
It is.
本発明では、湿式造粒法を用いなくてもロキソプロフェン又はその塩の付着を抑制することができ、高い付着性に由来する打錠障害を起こすことがない錠剤の製造方法を提供することが可能となった。 In the present invention, it is possible to provide a method for producing a tablet that can suppress adhesion of loxoprofen or a salt thereof without using a wet granulation method and does not cause a tableting failure due to high adhesion. It became.
本発明の錠剤に用いられるロキソプロフェン又はその塩には、ロキソプロフェンのみならず、ロキソプロフェンの薬学上許容される塩、さらには水やアルコール等との溶媒和物が含まれる。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。本発明において、ロキソプロフェン又はその塩としては、ロキソプロフェンナトリウム水和物が好ましい。 The loxoprofen or a salt thereof used in the tablet of the present invention includes not only loxoprofen but also a pharmaceutically acceptable salt of loxoprofen, and further a solvate with water, alcohol and the like. These are known compounds, and can be produced by known methods, or commercially available products can be used. In the present invention, loxoprofen or a salt thereof is preferably loxoprofen sodium hydrate.
本発明の錠剤中におけるロキソプロフェン又はその塩の含有量は、その薬効を示す量であれば特に限定されるものではないが、錠剤全質量に対して、ロキソプロフェンナトリウム無水物換算で好ましくは１０．０〜５０．０質量％、最も好ましいのは１５．０〜３５．０質量％である。 The content of loxoprofen or a salt thereof in the tablet of the present invention is not particularly limited as long as it shows the medicinal effect, but is preferably 10.0 in terms of loxoprofen sodium anhydride relative to the total mass of the tablet. -50.0% by mass, most preferably 15.0-35.0% by mass.
また、本発明では、ロキソプロフェンまたはその塩を含有する粉体にさらにデンプンを含有したものが付着抑制の面で好ましい。本発明のデンプンとしては、部分α化デンプン、トウモロコシデンプン、バレイショデンプン、コメデンプン、コムギデンプン、デキストリンなどを挙げることができ、特にバレイショデンプンが好ましい。デンプンの含有量は、錠剤全質量に対して２．０〜５０．０質量％、好ましくは５．０〜５０．０質量％、特に好ましくは１０．０〜５０．０質量％、最も好ましくは１５．０〜４０．０質量％が付着抑制の面で好ましい。 In the present invention, a powder containing loxoprofen or a salt thereof and further containing starch is preferred in terms of adhesion suppression. Examples of the starch of the present invention include partially pregelatinized starch, corn starch, potato starch, rice starch, wheat starch, and dextrin, and potato starch is particularly preferred. The starch content is 2.0 to 50.0% by mass, preferably 5.0 to 50.0% by mass, particularly preferably 10.0 to 50.0% by mass, most preferably the total mass of the tablet. 15.0-40.0 mass% is preferable in terms of adhesion suppression.
また、本発明の乾燥前の粉体中に含まれるロキソプロフェン又はその塩とデンプンの含有比は、ロキソプロフェンナトリウム無水物換算１質量部に対し、デンプンが０．３〜５．０質量部、好ましくは１．０〜５．０質量部であるものが付着抑制の面で好ましい。本発明のロキソプロフェン又はその塩を含有する粉体には、さらに必要に応じて他の有効成分、例えば総合感冒薬、解熱鎮痛剤等や、他の公知の添加剤、例えば、賦形剤、崩壊剤、結合剤、滑沢剤、抗酸化剤、コーティング剤、着色剤、矯味矯臭剤、界面活性剤、可塑剤等を混合することができる。 Moreover, the content ratio of loxoprofen or a salt thereof and starch contained in the powder before drying of the present invention is 0.3 to 5.0 parts by mass, preferably 1 to 3 parts by mass, preferably 1 part by mass in terms of loxoprofen sodium anhydride. What is 1.0-5.0 mass parts is preferable at the surface of adhesion suppression. The powder containing loxoprofen or a salt thereof of the present invention may further contain other active ingredients as necessary, for example, general cold medicine, antipyretic analgesics, and other known additives such as excipients, disintegration. Agents, binders, lubricants, antioxidants, coating agents, colorants, flavoring agents, surfactants, plasticizers, and the like can be mixed.
本発明では、ロキソプロフェン又はその塩を含有する粉体を得た後、打錠する前に乾燥を行う必要がある。本発明の粉体の乾燥条件は特に限定されないが、ロキソプロフェン又はその塩の付着抑制の効果の面から、粉体の水分含有量は０〜２．４％、好ましくは０％〜２．０％、より好ましくは０％〜１．２％となるよう乾燥するとよい。使用できる乾燥機としては、例えば流動層乾燥機や真空乾燥機等が挙げられるが、特に流動層乾燥機が好ましい。流動層乾燥機とは、缶体に温めた流動化空気を供給し、内部に投入した粉体を流動循環させながら乾燥することを目的とする装置である。なお、流動層乾燥機には、上記機能を有する流動層造粒機、流動層造粒乾燥機、転動機能を併せ持つ転動流動層造粒乾燥機等が含まれる。流動条件として、給気温度は６０℃以上とし、給気風量はロキソプロフェン又はその塩を含有する粉体が均一に流動循環するために必要な流動化空気を供給できる風量とし、流動時間は乾燥が進行するのに充分な時間とする。本願では、流動層乾燥機（FL-MINI；フロイント産業社製）を使用した。 In the present invention, after obtaining a powder containing loxoprofen or a salt thereof, it is necessary to dry before tableting. Although the drying conditions of the powder of the present invention are not particularly limited, the moisture content of the powder is 0 to 2.4%, preferably 0% to 2.0% from the viewpoint of the effect of suppressing adhesion of loxoprofen or a salt thereof. More preferably, it is good to dry so that it may become 0%-1.2%. Examples of the dryer that can be used include a fluidized bed dryer and a vacuum dryer. A fluidized bed dryer is particularly preferable. A fluidized bed dryer is an apparatus for supplying warmed fluidized air to a can body and drying while flowing and circulating the powder charged therein. The fluidized bed dryer includes a fluidized bed granulator having the above function, a fluidized bed granulator, a rolling fluidized bed granulator having a rolling function, and the like. As the flow conditions, the supply air temperature is set to 60 ° C. or more, the supply air volume is set to an air volume capable of supplying fluidized air necessary for the powder containing loxoprofen or a salt thereof to uniformly flow and circulate, and the flow time is set to be dry. Allow enough time to proceed. In the present application, a fluidized bed dryer (FL-MINI; manufactured by Freund Corporation) was used.
また、ロキソプロフェン又はその塩を含有する粉体の水分含有量の測定は、本願では加熱乾燥式水分計（型式：MX-50；エー・アンド・デイ）を使用した。測定条件は、仕込み量を５ｇ、加熱温度を７０℃、加熱時間を３０分として粉体水分の測定を実施した。
このようにして得られた水分含有量の低いロキソプロフェン又はその塩を含有する粉体は、湿式造粒法を使用せずに錠剤に製造される。湿式造粒法を使用しない錠剤の製造方法としては、乾式造粒法や溶融造粒法等の造粒法を使用し常法により錠剤を製造する方法も含むが、最も好ましいのはいかなる造粒法も使用することなく打錠する方法である。
In the present application, the moisture content of the powder containing loxoprofen or a salt thereof was measured using a heat drying moisture meter (model: MX-50; A & D). The measurement conditions were such that the amount of powder was measured with a charging amount of 5 g, a heating temperature of 70 ° C. and a heating time of 30 minutes.
The powder containing loxoprofen having a low water content or a salt thereof thus obtained is produced into a tablet without using a wet granulation method. The method for producing tablets without using the wet granulation method includes a method for producing tablets by a conventional method using a granulation method such as a dry granulation method or a melt granulation method, but most preferred is any granulation method. It is also a method of tableting without using a method.
本発明の錠剤には、チュアブル錠も含まれる。本発明により製造された錠剤は、そのまま使用しても良いし、これにフィルムコートや糖衣などの被覆を施してもよい。また、積層錠としてもよい。 The tablets of the present invention include chewable tablets. The tablet produced according to the present invention may be used as it is, or may be coated with a film coat or sugar coating. Moreover, it is good also as a laminated tablet.
以下に、本発明を実施例及び比較例に基づきさらに詳細に説明する。尚、本発明の錠剤の製造方法は実施例に記載された製造方法に限定されるものではない。
（実施例１〜１０及び比較例１〜２）
（１）製剤（錠剤）の製造方法
下記表１、２の配合比に従い、各種原料を実施例１〜６及び比較例１は６０００錠分、実施例７〜１０及び比較例２は３０００錠分ビニールで混合した後、篩を通した。実施例１、４〜６の場合、篩通過後の粉体を流動層乾燥機（商品名：FL-MINI；フロイント産業）に充てんし、給気温度８０℃、給気風量０．３〜０．５ｍ３／分の条件にて流動させながら１時間乾燥を行った。また実施例２〜３の場合、篩通過後の粉体を流動層乾燥機に充てんし、給気温度８０℃、給気風量０．３〜０．５ｍ３／分の条件にて流動させながら、実施例２については３０分、実施例３については１４分乾燥操作を行った。また実施例７〜１０の場合、篩通過後の粉体を流動層乾燥機に充てんし、給気温度８０℃、給気風量０．２５〜０．５ｍ３／分の条件にて流動させながら、実施例７については５５分、実施例８については１８分、実施例９〜１０については２０分乾燥操作を行った。また、比較例１、２については、乾燥操作を実施しなかった。各種粉体は加熱乾燥式水分計（型式：MX-50；エー・アンド・デイ）に５ｇ仕込み、加熱温度７０℃、加熱時間３０分の条件で粉体水分の測定を実施した。
上記操作により得た粉体を実施例１〜６及び比較例１は高速ロータリー式打錠機（商品名：バーゴ１９；菊水製作所）によって、回転数３０ｒｐｍ、圧縮圧８００ｋｇｆ、錠剤径７ｍｍφ、普通面の杵を４本用いて５分間打錠し、１錠あたり１８１ｍｇの錠剤を得た。また、実施例７〜１０及び比較例２は高速ロータリー式打錠機（商品名：コレクト１２HU；菊水製作所）によって、回転数３０ｒｐｍ、圧縮圧１８００ｋｇｆ、錠剤径７ｍｍφ、普通面の杵を１本用いて５分間打錠し、１錠あたり１８１ｍｇの錠剤を得た。
Below, this invention is demonstrated further in detail based on an Example and a comparative example. In addition, the manufacturing method of the tablet of this invention is not limited to the manufacturing method described in the Example.
(Examples 1-10 and Comparative Examples 1-2)
(1) Preparation Method of Formulation (Tablet) According to the blending ratios in Tables 1 and 2 below, Examples 1 to 6 and Comparative Example 1 are 6000 tablets, and Examples 7 to 10 and Comparative Example 2 are 3000 tablets. After mixing with vinyl, it was passed through a sieve. In Examples 1 and 4 to 6, the powder after passing through the sieve is packed in a fluidized bed dryer (trade name: FL-MINI; Freund Sangyo), the supply air temperature is 80 ° C., and the supply air flow is 0.3 to 0. Drying was performed for 1 hour while flowing under conditions of 0.5 m 3 / min. In the case of Examples 2 to 3, the powder after passing through the sieve is packed in a fluidized bed dryer and fluidized under conditions of a supply air temperature of 80 ° C. and a supply air volume of 0.3 to 0.5 m 3 / min. The drying operation was performed for Example 2 for 30 minutes and for Example 3 for 14 minutes. In the case of Examples 7 to 10, the powder after passing through the sieve is packed in a fluidized bed dryer, and is allowed to flow under conditions of a supply air temperature of 80 ° C. and a supply air volume of 0.25 to 0.5 m 3 / min. The drying operation was performed for 55 minutes for Example 7, 18 minutes for Example 8, and 20 minutes for Examples 9-10. Moreover, about Comparative Examples 1 and 2, drying operation was not implemented. Various powders were placed in a heat-drying moisture meter (model: MX-50; A & D), and the moisture content of the powder was measured under the conditions of a heating temperature of 70 ° C. and a heating time of 30 minutes.
In Examples 1 to 6 and Comparative Example 1, the powder obtained by the above operation was rotated by a high-speed rotary type tableting machine (trade name: Burgo 19; Kikusui Seisakusho), rotation speed 30 rpm, compression pressure 800 kgf, tablet diameter 7 mmφ, normal surface Tableting was carried out for 5 minutes using 4 cocoons of No. 1 to obtain 181 mg tablets per tablet. In Examples 7 to 10 and Comparative Example 2, a high-speed rotary type tableting machine (trade name: Collect 12HU; Kikusui Seisakusho) was used with a rotation speed of 30 rpm, a compression pressure of 1800 kgf, a tablet diameter of 7 mmφ, and a single regular punch. For 5 minutes to obtain 181 mg tablets per tablet.
（２）付着性の評価１
下記２項目にて付着性の評価を行った。
押し上げ圧
表１、２に示す処方で５分間打錠操作を行った際の押し上げ圧の上限値と下限値を測定した。押し上げ圧は値が高いほど付着性が高いことを示しており、許容範囲は、押し上げ圧の上限値が「４０ｋｇｆ」以下であり、さらに好ましくは「３０ｋｇｆ」以下である。
外観評価
表１に示す処方で打錠操作を行った後の回転盤及び臼・杵への粉付着の状況を確認し、以下に記す４段階評価を行った。外観評価の許容の判定基準を「１」以下とし、さらに好ましくは「０」と設定した。
《判定基準》
０：付着なし
１：回転盤及び杵・臼にわずかに付着が認められる
２：回転盤及び杵・臼に付着が認められる（許容できない）
３：回転盤及び杵・臼に明らかな付着が認められる
押し上げ圧の測定結果及び外観評価結果を表１、２に示す。
(2) Adhesion evaluation 1
Adhesion was evaluated by the following two items.
The upper and lower limits of the push-up pressure when the formulation shown in the push-up pressure Tables 1 and 2 was subjected to 5 minutes tableting operation were measured. The higher the push-up pressure value, the higher the adhesion, and the allowable range is that the upper limit value of the push-up pressure is “40 kgf” or less, more preferably “30 kgf” or less.
Appearance evaluation After tableting operation according to the formulation shown in Table 1, the state of powder adhesion to the rotary disc and the mortar and pestle was confirmed, and the following four-level evaluation was performed. The acceptance criterion for appearance evaluation was set to “1” or less, more preferably “0”.
<Criteria>
0: No adhesion 1: Slight adhesion is observed on the rotating disc and pestle / mortar 2: Adhesion is observed on the rotating disc, mortar / mortar (unacceptable)
3: Obvious adhesion is observed on the rotating disk and the pestle and die.
表１、２から明らかなように、ロキソプロフェンナトリウムを含む粉体を乾燥させない場合（比較例１、２）では、押し上げ圧及び外観評価結果ともに高い値を示し、機器本体へ著しい粉付着が認められた。これに対し、ロキソプロフェンナトリウムを含む粉体を乾燥させた場合（実施例１〜１０）では、押し上げ圧及び外観評価結果ともに低い値を示し、粉体水分を下げるほど付着性を改善できることが分かった。また、デンプンの配合量の影響を確認したところ（実施例１、４〜１０）、デンプンの配合量を増やすと押し上げ圧及び外観評価結果はともに低い値を示し、デンプンが付着性の改善に寄与することが判明した。以上の結果より、ロキソプロフェンナトリウムを含む粉体を打錠前に乾燥させることによって、造粒工程を経なくても付着性を改善でき、簡便な手法での製剤化が可能となった。 As is clear from Tables 1 and 2, when the powder containing loxoprofen sodium was not dried (Comparative Examples 1 and 2), both the pushing pressure and the appearance evaluation result showed high values, and remarkable powder adhesion was observed on the device body. It was. On the other hand, in the case where the powder containing loxoprofen sodium was dried (Examples 1 to 10), both the pushing pressure and the appearance evaluation result showed low values, and it was found that the adhesion can be improved as the powder moisture is lowered. . Moreover, when the influence of the compounding amount of starch was confirmed (Examples 1, 4 to 10), when the compounding amount of starch was increased, both the pushing pressure and the appearance evaluation result showed low values, and starch contributed to the improvement of adhesion. Turned out to be. From the above results, by drying the powder containing loxoprofen sodium before tableting, the adhesiveness could be improved without going through the granulation step, and the formulation by a simple technique became possible.
（３）付着性の評価２
実施例１の配合比に従い、各種原料を６０００錠分ビニールで混合した後、篩を通した。篩通過後の粉体を流動層乾燥機に充てんし、給気温度８０℃、給気風量０．３〜０．５ｍ３／分の条件にて流動させながら１時間乾燥を行った。各種粉体は加熱乾燥式水分計に５ｇ仕込み、加熱温度７０℃、加熱時間３０分の条件で粉体水分の測定を実施した。
上記操作により得た粉体を高速ロータリー式打錠機（商品名：バーゴ１９；菊水製作所）によって、回転数３０ｒｐｍ、圧縮圧８００ｋｇｆ、１錠重量１８１ｍｇ、錠剤径７ｍｍφ、普通面の杵を１本用いて２時間連続打錠し、付着性の評価を行った。
粉体水分、押し上げ圧及び上記判定基準に従って評価した外観評価結果を表３に示す。
(3) Adhesion evaluation 2
According to the mixing ratio of Example 1, various raw materials were mixed with 6000 tablets of vinyl and then passed through a sieve. The powder after passing through the sieve was packed in a fluidized bed dryer, and dried for 1 hour while flowing under conditions of an air supply temperature of 80 ° C. and an air supply air volume of 0.3 to 0.5 m 3 / min. Various powders were placed in a heat-drying moisture meter in an amount of 5 g, and the moisture content of the powder was measured under conditions of a heating temperature of 70 ° C. and a heating time of 30 minutes.
Using a high-speed rotary tableting machine (trade name: Burgo 19; Kikusui Seisakusho), the powder obtained by the above operation is rotated at 30 rpm, compression pressure 800 kgf, tablet weight 181 mg, tablet diameter 7 mmφ, and one normal surface wrinkle Using this, tableting was continued for 2 hours, and adhesion was evaluated.
Table 3 shows the appearance evaluation results evaluated in accordance with the powder moisture, the pushing-up pressure, and the above criteria.
表３から明らかなとおり、２時間の連続打錠を行っても押し上げ圧及び外観評価結果の増加傾向は認められず、安定して錠剤を製造できることが分かった。 As is apparent from Table 3, even when continuous tableting for 2 hours was performed, the increase in the pushing pressure and the appearance evaluation results were not observed, and it was found that tablets could be produced stably.
本発明により、湿式造粒法を用いなくてもロキソプロフェン又はその塩の付着性を抑制でき、安定して錠剤を製造することが可能となった。 According to the present invention, adhesion of loxoprofen or a salt thereof can be suppressed without using a wet granulation method, and a tablet can be stably produced.
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| JP2000016936A (en) * | 1998-06-30 | 2000-01-18 | Ryukakusan Co Ltd | Solid preparation containing loxoprofen sodium |
| JP2006143650A (en) * | 2004-11-19 | 2006-06-08 | Asahi Kasei Chemicals Corp | Method for producing tablet containing medicine having high adhesiveness |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2000016936A (en) * | 1998-06-30 | 2000-01-18 | Ryukakusan Co Ltd | Solid preparation containing loxoprofen sodium |
| JP2006143650A (en) * | 2004-11-19 | 2006-06-08 | Asahi Kasei Chemicals Corp | Method for producing tablet containing medicine having high adhesiveness |
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