JP2013006830A - Method for producing loxoprofen-containing preparation - Google Patents
Method for producing loxoprofen-containing preparation Download PDFInfo
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- JP2013006830A JP2013006830A JP2012114426A JP2012114426A JP2013006830A JP 2013006830 A JP2013006830 A JP 2013006830A JP 2012114426 A JP2012114426 A JP 2012114426A JP 2012114426 A JP2012114426 A JP 2012114426A JP 2013006830 A JP2013006830 A JP 2013006830A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 44
- 229960002373 loxoprofen Drugs 0.000 title claims abstract description 40
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 28
- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 title 1
- 239000007787 solid Substances 0.000 claims abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 41
- 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 35
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 239000000395 magnesium oxide Substances 0.000 claims abstract description 12
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims abstract description 12
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000000843 powder Substances 0.000 claims abstract description 12
- 238000005550 wet granulation Methods 0.000 claims abstract description 7
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 15
- 238000009472 formulation Methods 0.000 claims description 11
- 238000007908 dry granulation Methods 0.000 claims description 7
- 238000007909 melt granulation Methods 0.000 claims description 7
- 239000002552 dosage form Substances 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 5
- JAUGGEIKQIHSMF-UHFFFAOYSA-N dialuminum;dimagnesium;dioxido(oxo)silane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O JAUGGEIKQIHSMF-UHFFFAOYSA-N 0.000 abstract 2
- 239000003826 tablet Substances 0.000 description 37
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 20
- 230000000052 comparative effect Effects 0.000 description 13
- 235000019359 magnesium stearate Nutrition 0.000 description 10
- 238000002156 mixing Methods 0.000 description 9
- 238000000465 moulding Methods 0.000 description 8
- 238000011156 evaluation Methods 0.000 description 7
- 239000008187 granular material Substances 0.000 description 7
- 239000000654 additive Substances 0.000 description 6
- -1 loxoprofen sodium anhydride Chemical class 0.000 description 6
- 239000011812 mixed powder Substances 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 4
- 239000007884 disintegrant Substances 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 230000001953 sensory effect Effects 0.000 description 4
- 230000000996 additive effect Effects 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 238000004040 coloring Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 208000012895 Gastric disease Diseases 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000002845 discoloration Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 238000004898 kneading Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000126 substance Substances 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
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 230000001458 anti-acid effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application 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
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960003630 ketotifen fumarate Drugs 0.000 description 1
- YNQQEYBLVYAWNX-WLHGVMLRSA-N ketotifen fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 YNQQEYBLVYAWNX-WLHGVMLRSA-N 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 201000009240 nasopharyngitis Diseases 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
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 229960003447 pseudoephedrine hydrochloride Drugs 0.000 description 1
- BALXUFOVQVENIU-KXNXZCPBSA-N pseudoephedrine hydrochloride Chemical compound [H+].[Cl-].CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-KXNXZCPBSA-N 0.000 description 1
- 206010041232 sneezing Diseases 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
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Abstract
Description
本発明は、ロキソプロフェン又はその塩とメタケイ酸アルミン酸マグネシウムを含有する固形製剤の製造法に関するものである。さらに詳しくは、ロキソプロフェン又はその塩とメタケイ酸アルミン酸マグネシウム配合時に外観変化を抑制できる固形製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 solid preparation containing loxoprofen or a salt thereof and magnesium aluminate metasilicate. More specifically, the present invention relates to a method for producing a solid preparation capable of suppressing changes in appearance when blending loxoprofen or a salt thereof and magnesium aluminate metasilicate.
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.
ロキソプロフェンはその優れた薬理作用から、様々な薬物と配合された検討が既になされている。例えば、ケトチフェンフマル酸塩との配合による解熱作用の増強（特許文献１）や、チキジウム臭化物の配合による胃障害の軽減（特許文献２）、プソイドエフェドリン塩酸塩との配合によるくしゃみ防止（特許文献３）などが挙げられる。
一方、メタケイ酸アルミン酸マグネシウムは制酸剤としての機能に加え、賦形剤として固形製剤の製造において汎用されている成分である。ロキソプロフェン又はその塩及びメタケイ酸アルミン酸マグネシウムを添加した例として、以下の特許文献が確認されている。
１）ロキソプロフェン又はその塩の製剤化において、メタケイ酸アルミン酸マグネシウムをロキソプロフェンナトリウム１００重量部に対して１０〜８０％添加することにより打錠障害を改善（特許文献４）
２）ロキソプロフェン又はその塩、メタケイ酸アルミン酸マグネシウム及び酸化マグネシウムを配合した組成物（特許文献１、２及び５）
しかしながら、ロキソプロフェン又はその塩とメタケイ酸アルミン酸マグネシウム配合時に相互作用を生じることはこれまで知られておらず、示唆もされていない。
Loxoprofen has already been studied in combination with various drugs because of its excellent pharmacological action. For example, enhancement of antipyretic action by blending with ketotifen fumarate (Patent Document 1), reduction of gastric disorder by blending thidium bromide (Patent Document 2), prevention of sneezing by blending with pseudoephedrine hydrochloride (Patent Document 3) Etc.
On the other hand, magnesium aluminate metasilicate is a component widely used in the production of solid preparations as an excipient in addition to the function as an antacid. The following patent documents have been confirmed as an example of adding loxoprofen or a salt thereof and magnesium aluminate metasilicate.
1) In formulation of loxoprofen or a salt thereof, the tableting trouble is improved by adding 10 to 80% of magnesium aluminate metasilicate to 100 parts by weight of loxoprofen sodium (Patent Document 4)
2) A composition containing loxoprofen or a salt thereof, magnesium aluminate metasilicate and magnesium oxide (Patent Documents 1, 2, and 5)
However, it has not been known or suggested to cause an interaction when loxoprofen or a salt thereof and magnesium aluminate metasilicate are mixed.
本発明者らは、ロキソプロフェン又はその塩及びメタケイ酸アルミン酸マグネシウムを含有する医薬用製剤を開発するため、まずはこれら混合品を製剤化させて保存安定性について検討したところ、意外にも、これらの化合物の間に相互作用が生じて褐色状への変色が認められ、商品価値の低下を招くおそれがあった。 In order to develop a pharmaceutical preparation containing loxoprofen or a salt thereof and magnesium aluminate metasilicate, the present inventors first formulated these mixtures and examined their storage stability. There was a possibility that the interaction between the compounds would cause a brown discoloration, leading to a decrease in commercial value.
従って、本発明はロキソプロフェン又はその塩とメタケイ酸アルミン酸マグネシウムを含有しても、外観変化を抑制できる固形製剤を提供することを目的とする。 Therefore, an object of this invention is to provide the solid formulation which can suppress an external appearance change even if it contains loxoprofen or its salt, and magnesium aluminate metasilicate.
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とメタケイ酸アルミン酸マグネシウムを含有する粉体に特定の成分を配合し、かつ湿式造粒法を用いないで製剤化させることにより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固形製剤であって、ロキソプロフェン又はその塩、メタケイ酸アルミン酸マグネシウム及び酸化マグネシウムを含有する粉体を、湿式造粒法を用いないで固形製剤とすることを特徴とする固形製剤の製造方法、
（２）固形製剤の製造方法が直接打錠法であることを特徴とする、（１）に記載の固形製剤の製造方法、
（３）固形製剤の製造方法が乾式造粒法であることを特徴とする、（１）に記載の固形製剤の製造方法、
（４）固形製剤の製造方法が溶融造粒法であることを特徴とする、（１）に記載の固形製剤の製造方法、
（５）固形製剤の剤形が錠剤である（１）〜（４）に記載の固形製剤の製造方法、
（６）固形製剤の剤形が散剤である、（１），（３）又は（４）に記載の固形製剤の製造方法、
である。
As a result of various studies, the present inventors have formulated the above-mentioned problems by formulating a specific component in a powder containing loxoprofen or a salt thereof and magnesium aluminate metasilicate and without using a wet granulation method. The present invention has been completed.
That is, the present invention
(1) A solid preparation containing loxoprofen or a salt thereof, wherein the powder containing loxoprofen or a salt thereof, magnesium aluminate metasilicate and magnesium oxide is made into a solid preparation without using a wet granulation method. A method for producing a solid preparation,
(2) The method for producing a solid preparation according to (1), wherein the method for producing the solid preparation is a direct tableting method,
(3) The method for producing a solid preparation according to (1), wherein the method for producing the solid preparation is a dry granulation method,
(4) The method for producing a solid preparation according to (1), wherein the method for producing the solid preparation is a melt granulation method,
(5) The method for producing a solid preparation according to (1) to (4), wherein the dosage form of the solid preparation is a tablet,
(6) The method for producing a solid preparation according to (1), (3) or (4), wherein the dosage form of the solid preparation is a powder;
It is.
本発明で製造された固形製剤は、ロキソプロフェン又はその塩とメタケイ酸アルミン酸マグネシウムの相互作用を抑制できる。従って、長期にわたって製剤の着色が防止されたロキソプロフェン又はその塩とメタケイ酸アルミン酸マグネシウムを含有する固形製剤を提供することができる。 The solid preparation produced in the present invention can suppress the interaction between loxoprofen or a salt thereof and magnesium aluminate metasilicate. Therefore, it is possible to provide a solid preparation containing loxoprofen or a salt thereof and magnesium aluminate metasilicate in which coloring of the preparation is prevented over a long period of time.
本発明の固形製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。
Loxoprofen or a salt thereof used in the solid preparation 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, as loxoprofen or a salt thereof,
Loxoprofen sodium hydrate is preferred.
本発明の固形製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、固形製剤全質量に対して、ロキソプロフェンナトリウム無水物換算で１．７〜６０．０質量％、好ましくは３．０〜５０．０質量％、特に好ましくは４．０〜４０．０質量％、最も好ましいのは５．０〜３５．０質量％である。 The content of loxoprofen or a salt thereof in the solid preparation of the present invention is not particularly limited as long as it is an amount showing its medicinal effect, but is 1.7 in terms of loxoprofen sodium anhydride relative to the total mass of the solid preparation. -60.0% by mass, preferably 3.0-50.0% by mass, particularly preferably 4.0-40.0% by mass, and most preferably 5.0-35.0% by mass.
本発明の固形製剤中におけるメタケイ酸アルミン酸マグネシウムの含有量は、固形製剤全質量に対して１．０〜５５．０質量％、好ましくは２．０〜３５．０質量％である。 Content of magnesium metasilicate aluminate in the solid formulation of this invention is 1.0-55.0 mass% with respect to solid formulation total mass, Preferably it is 2.0-35.0 mass%.
また、本発明の固形製剤中における酸化マグネシウムの含有量は、３．０〜５５．０質量％、好ましくは５．０〜３５．０質量％含有するものが着色抑制の面で好ましい。
また、本発明の固形製剤中に含まれるロキソプロフェン又はその塩に対するメタケイ酸アルミン酸マグネシウムと酸化マグネシウムの含有比は、ロキソプロフェンナトリウム無水物換算で１質量部に対し、メタケイ酸アルミン酸マグネシウムは０．０５〜８．３質量部、好ましくは０．１０〜１．７質量部、酸化マグネシウムは０．２７〜２．８質量部、好ましくは０．６９〜１．４質量部含有するものが、着色抑制の面で好ましい。
Further, the content of magnesium oxide in the solid preparation of the present invention is preferably 3.0 to 55.0% by mass, and more preferably 5.0 to 35.0% by mass in terms of suppression of coloring.
In addition, the content ratio of magnesium aluminate metasilicate and magnesium oxide to loxoprofen or a salt thereof contained in the solid preparation of the present invention is 0.05 parts by mass with respect to 1 part by mass in terms of anhydrous loxoprofen sodium. ~ 8.3 parts by mass, preferably 0.10 to 1.7 parts by mass, magnesium oxide containing 0.27 to 2.8 parts by mass, preferably 0.69 to 1.4 parts by mass suppresses coloring It is preferable in terms of
本発明の湿式造粒法を用いない固形製剤の製造方法としては、直接打錠法、乾式造粒法及び溶融造粒法という方法が挙げられる。 Examples of the method for producing a solid preparation that does not use the wet granulation method of the present invention include a direct tableting method, a dry granulation method, and a melt granulation method.
直接打錠法とは、主薬単独あるいはそれに賦形剤、崩壊剤、粉末状の結合剤など適当な添加剤を加えた混合粉末に滑沢剤を加えたものを打錠機で強圧成形して圧縮体を製する方法である。上記固形製剤の直接打錠法による場合の具体的方法としては、例えば、ロキソプロフェンナトリウム無水物換算で１質量部に対して０．１０〜１．７質量部のメタケイ酸アルミン酸マグネシウム、０．６９〜１．４質量部の酸化マグネシウムを混合し、これに適宜ステアリン酸マグネシウム等の添加剤を加え、これら混合粉末を打錠機で強圧成形する方法が挙げられる。 The direct tableting method is a method in which the active ingredient alone or a mixed powder obtained by adding appropriate additives such as excipients, disintegrants, and powdered binders to which a lubricant is added is pressed with a tableting machine. This is a method for producing a compressed body. As a specific method in the case of the direct tableting method of the above solid preparation, for example, 0.10 to 1.7 parts by mass of magnesium aluminate metasilicate with respect to 1 part by mass in terms of loxoprofen sodium anhydride, 0.69 There is a method in which ~ 1.4 parts by mass of magnesium oxide is mixed, an additive such as magnesium stearate is appropriately added thereto, and the mixed powder is subjected to high pressure molding with a tableting machine.
乾式造粒法とは、主薬単独あるいはそれに賦形剤、崩壊剤、粉末状の結合剤など適当な添加剤を加えた混合粉末に滑沢剤を加え、これを打錠機で強圧成形して圧縮体を製し、ついでこれを粉砕、整粒する方法である。上記固形製剤の乾式造粒法による場合の具体的方法としては、例えば、ロキソプロフェンナトリウム無水物換算で１質量部に対して０．１０〜１．７質量部のメタケイ酸アルミン酸マグネシウム、０．６９〜１．４質量部の酸化マグネシウムを混合し、これに適宜ステアリン酸マグネシウム等の添加剤を加え、これらを含む混合粉末を打錠機で強圧成形し、製した錠剤を粉砕する方法が挙げられる。 The dry granulation method is a method in which a lubricant is added to an active ingredient alone or a mixed powder to which an appropriate additive such as an excipient, a disintegrant, and a powdered binder is added, and this is subjected to high pressure molding with a tableting machine. This is a method in which a compact is produced, and then pulverized and sized. As a specific method in the case of the dry granulation method of the solid preparation, for example, 0.10 to 1.7 parts by mass of magnesium aluminate metasilicate with respect to 1 part by mass in terms of loxoprofen sodium anhydride, 0.69 A method of mixing ~ 1.4 parts by mass of magnesium oxide, adding an additive such as magnesium stearate to the mixture, forming a mixed powder containing these with high pressure using a tableting machine, and crushing the tablets produced is included. .
溶融造粒法とは、主薬単独あるいはそれに賦形剤、崩壊剤など適宜添加剤を加えた混合粉末に低融点物質を加えて加熱処理を加えることにより、低融点物質を溶融させて造粒する方法である。上記固形製剤の溶融造粒法による場合の具体的方法としては、例えば、ロキソプロフェンナトリウム無水物換算で１質量部に対して０．１０〜１．７質量部のメタケイ酸アルミン酸マグネシウム、０．６９〜１．４質量部の酸化マグネシウムを加えた混合粉末に、０．１〜１．０質量部のマクロゴール６０００もしくはショ糖脂肪酸エステルとタルク等を含む混合粉末を流動層造粒機にて流動させながら加熱して造粒する方法が挙げられる。 The melt granulation method is to granulate by melting the low melting point substance by adding the low melting point substance to the active ingredient alone or a mixed powder to which additives such as excipients and disintegrants are added as appropriate, followed by heat treatment. Is the method. As a specific method in the case of the melt granulation method of the above solid preparation, for example, 0.10 to 1.7 parts by mass of magnesium aluminate metasilicate with respect to 1 part by mass in terms of loxoprofen sodium anhydride, 0.69 Flowing a mixed powder containing 0.1 to 1.0 parts by weight of macrogol 6000 or sucrose fatty acid ester and talc, etc. in a fluidized bed granulator with ~ 1.4 parts by weight of magnesium oxide added And granulating the mixture while heating.
本発明の医薬製剤には、ロキソプロフェン又はその塩とメタケイ酸アルミン酸マグネシウム以外にも、必要に応じて他の有効成分、例えば総合感冒薬や、解熱鎮痛剤等の配合が可能である。 In addition to loxoprofen or a salt thereof and magnesium aluminate metasilicate, the pharmaceutical preparation of the present invention can contain other active ingredients, for example, a common cold medicine, an antipyretic analgesic, and the like as necessary.
本発明の固形製剤の剤形は、特に限定されるべきものでないが、散剤、細粒剤、顆粒剤、丸剤、錠剤（フィルムコーティング錠、積層錠を含む）、カプセル剤、ドライシロップ剤等が挙げられる。 The dosage form of the solid preparation of the present invention is not particularly limited, but powders, fine granules, granules, pills, tablets (including film-coated tablets and laminated tablets), capsules, dry syrups, etc. Can be mentioned.
本発明の医薬製剤は、ロキソプロフェン又はその塩と、メタケイ酸アルミン酸マグネシウム及び酸化マグネシウムを配合し、必要に応じて他の公知の添加剤、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、可塑剤等を混合して湿式造粒法を用いない方法、好ましくは直接打錠法、乾式造粒法もしくは溶融造粒法により製造することができる。 The pharmaceutical preparation of the present invention comprises loxoprofen or a salt thereof, magnesium aluminate metasilicate and magnesium oxide, and other known additives such as excipients, disintegrants, binders, lubricants as necessary. A method in which a wet granulation method is not used by mixing an agent, an antioxidant, a coating agent, a colorant, a flavoring agent, a surfactant, a plasticizer, etc., preferably a direct tableting method, a dry granulation method or a melt granulation method. It can be produced by a grain method.
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、本発明の固形製剤の製造方法は実施例に記載された処方例に限定されるものではない。
（実施例１〜３及び比較例１〜５）
（１）製剤（錠剤）の製造方法
下記表１の配合比に従い、各種原料（ステアリン酸マグネシウムを除く）をビニールで混合した後、篩を通した。実施例１及び比較例１〜２の直接打錠法の場合、篩通過後の粉体１００錠分に対してステアリン酸マグネシウムを添加・混合し、卓上簡易錠剤成型機（商品名：ＨＡＮＤＴＡＢ；市橋精機）を用いて錠剤径１０ｍｍの錠剤を得た。比較例３の湿式造粒法の場合、篩通過後の粉体１００錠分に対して精製水を加えて乳鉢で練合させ、５０℃条件下に２時間整置して十分乾燥させた後に、錠剤製造用の顆粒を得た。乾燥後、得た顆粒にステアリン酸マグネシウムを添加・混合し、卓上簡易錠剤成型機を用いて錠剤径１０ｍｍの錠剤を得た。実施例２及び比較例４の乾式造粒法の場合、篩通過後の粉体１００錠分に対してステアリン酸マグネシウム（表１に示す配合量の半量）を添加・混合し、卓上簡易錠剤成型機を用いて、錠剤径が１２ｍｍ径の錠剤を得た。得た錠剤を粗砕機（型式：KC-HUK；小西医療器）で粗砕し、これにステアリン酸マグネシウム（表１に示す配合量の半量）を添加・混合し、卓上簡易錠剤成型機を用いて錠剤径が１０ｍｍの錠剤を得た。実施例３及び比較例５の溶融造粒法の場合、篩通過後の粉体１５００錠分を流動層乾燥機（商品名：FL-MINI；フロイント産業）に充てんし、給気温度９０℃、給気風量０．３〜０．５ｍ3／分の条件にて流動させながら２時間加熱して造粒を行った。造粒後、得た顆粒にステアリン酸マグネシウムを添加・混合し，卓上簡易錠剤成型機を用いて、錠剤径が１０ｍｍの錠剤を得た。得た錠剤は、２５℃６０％ＲＨ条件下に１日整置させた後にガラス瓶に入れて密閉し、６５℃条件下に２週間保存させた後に製剤の外観評価を行った。
Below, this invention is demonstrated further in detail based on an Example and a comparative example. In addition, the manufacturing method of the solid formulation of this invention is not limited to the formulation example described in the Example.
(Examples 1-3 and Comparative Examples 1-5)
(1) Manufacturing method of formulation (tablet) According to the mixing ratio shown in Table 1 below, various raw materials (excluding magnesium stearate) were mixed with vinyl, and then passed through a sieve. In the case of the direct compression method of Example 1 and Comparative Examples 1 and 2, magnesium stearate is added to and mixed with 100 powders after passing through a sieve, and a tabletop simple tablet molding machine (trade name: HANDTAB; Ichibashi) A tablet with a tablet diameter of 10 mm was obtained using a precision machine. In the case of the wet granulation method of Comparative Example 3, after adding purified water to 100 tablets after passing through a sieve and kneading them in a mortar, placing them at 50 ° C. for 2 hours and sufficiently drying them Granules for tablet production were obtained. After drying, magnesium stearate was added to and mixed with the obtained granules, and tablets with a tablet diameter of 10 mm were obtained using a tabletop simple tablet molding machine. In the case of the dry granulation method of Example 2 and Comparative Example 4, magnesium stearate (half amount of the blending amount shown in Table 1) is added to and mixed with 100 powders after passing through the sieve, and simple tabletop tablet molding Using a machine, tablets with a tablet diameter of 12 mm were obtained. The obtained tablets are crushed with a crusher (model: KC-HUK; Konishi Medical Device), and magnesium stearate (half the amount shown in Table 1) is added to and mixed with this, using a tabletop simple tablet molding machine. Thus, a tablet with a tablet diameter of 10 mm was obtained. In the case of the melt granulation method of Example 3 and Comparative Example 5, 1500 powders after passing through the sieve are packed into a fluidized bed dryer (trade name: FL-MINI; Freund Sangyo), and the supply temperature is 90 ° C. Granulation was carried out by heating for 2 hours while flowing under the condition of an air supply rate of 0.3 to 0.5 m 3 / min. After granulation, magnesium stearate was added to and mixed with the obtained granules, and tablets with a tablet diameter of 10 mm were obtained using a tabletop simple tablet molding machine. The obtained tablets were placed for 1 day under conditions of 25 ° C. and 60% RH, then sealed in a glass bottle, and stored for 2 weeks under conditions of 65 ° C., and then the appearance of the preparation was evaluated.
（２）色差測定
実施例及び比較例で得られた錠剤について、直後品をコントロールとして６５℃条件下に２週間保存させたサンプルの色差測定を実施した。色差の測定には分光測色計（商品名：SE6000；日本電色工業）を用い、以下の［数１］により算出した。各ポイントにつき５錠のサンプルについて色差を測定し、ΔＥ*(ab)が低いほど色調が変化していないことを示す。
(2) Color difference measurement About the tablet obtained by the Example and the comparative example, the color difference measurement of the sample preserve | saved for two weeks on 65 degreeC conditions was implemented for the tablet immediately after that as a control. For the measurement of the color difference, a spectrocolorimeter (trade name: SE6000; Nippon Denshoku Industries Co., Ltd.) was used, and the color difference was calculated by the following [Equation 1]. The color difference is measured for 5 samples for each point, and the lower ΔE * (ab) indicates that the color tone does not change.
ΔＬ*=６５℃２週間保存品のＬ*値−直後品のＬ*値（Ｌ*：明度 ＋は白方向，−は黒方向）
Δａ*=６５℃２週間保存品のａ*値−直後品のａ*値（ａ*：色度 ＋は赤方向，−は緑方向）
Δｂ*=６５℃２週間保存品のｂ*値−直後品のｂ*値（ｂ*：色度 ＋は黄方向，−は青方向）
ΔL * = 65 ℃ 2 week storage product L * value - immediately after product L * value (L *: lightness + white direction, - the black direction)
Δa * = 65 ℃ 2 week storage product of a * value - immediately after the goods of a * value (a *: chromaticity + red direction, - green direction)
Δb * = 65 ℃ 2 week storage product of b * value - immediately after article b * value (b *: Chromaticity + Huang direction, - the blue direction)
（３）官能評価
実施例及び比較例で得られた錠剤について、専門パネラー３名による外観評価を実施した。製剤の外観の評価は、６５℃環境下に２週間保存したサンプルと直後品との相対比較により行い、以下に記す５段階評価することによって行った。外観変化の許容の判定基準を平均値「２．０」以下とし、さらに好ましくは「１．０」以下と設定した。
色差測定結果及び官能評価結果を表１に示す。
《判定基準》
0：変化なし
1：わずかに変化を認める
2：変化を認めるが許容できる
3：明らかな変化を認める（許容できない）
4：著しい変化を認める
(3) Sensory evaluation About the tablet obtained by the Example and the comparative example, the external appearance evaluation by 3 expert panelists was implemented. The evaluation of the appearance of the preparation was performed by a relative comparison between a sample stored for 2 weeks in a 65 ° C. environment and the immediately following product, and evaluated by the following five-step evaluation. The criterion for accepting the appearance change was set to an average value of “2.0” or less, more preferably “1.0” or less.
Table 1 shows the color difference measurement results and sensory evaluation results.
<Criteria>
0: No change
1: Slight change
2: Acceptable change but acceptable
3: Acknowledging obvious changes (unacceptable)
4: Recognize significant changes
試験結果から明らかなように、ロキソプロフェンとメタケイ酸アルミン酸マグネシウムを含有する錠剤は色差結果及び官能評価結果ともに高い値を示し、褐色状への著しい変色が認められた（比較例１，比較例４及び比較例５）。これに対し、実施例１，実施例２及び実施例３で示した錠剤は色差結果及び官能評価結果ともに低い値を示し、外観変化が抑制された錠剤であった。また、ロキソプロフェン、メタケイ酸アルミン酸マグネシウム及び酸化マグネシウムを含有する粉体に精製水を添加し、練合させた顆粒を用いて製した錠剤は著しく変色し（比較例３）、練合操作を加えると色調変化を抑制できないことが判明した。 As is clear from the test results, the tablets containing loxoprofen and magnesium aluminate metasilicate showed high values for both the color difference results and the sensory evaluation results, and significant discoloration to brown was observed (Comparative Examples 1 and 4). And Comparative Example 5). In contrast, the tablets shown in Example 1, Example 2 and Example 3 showed low values for both the color difference result and the sensory evaluation result, and were tablets whose appearance change was suppressed. In addition, a tablet made using granules kneaded with purified water added to powder containing loxoprofen, magnesium aluminate metasilicate and magnesium oxide is remarkably discolored (Comparative Example 3) and subjected to kneading operation. It was found that color change could not be suppressed.
（４）下記表２の配合比に従い、各種原料（ステアリン酸マグネシウムを除く）を８０錠分ビニールで混合した後、篩を通した。篩通過後の粉体に対してステアリン酸マグネシウムを添加・混合し、卓上簡易錠剤成型機（商品名：ＨＡＮＤＴＡＢ；市橋精機）を用いて直接打錠法により径１０ｍｍの錠剤を得た。 (4) According to the mixing ratio shown in Table 2 below, various raw materials (excluding magnesium stearate) were mixed with 80 tablets of vinyl and then passed through a sieve. Magnesium stearate was added to and mixed with the powder after passing through a sieve, and tablets with a diameter of 10 mm were obtained by a direct tableting method using a tabletop simple tablet molding machine (trade name: HANDTAB; Ichihashi Seiki).
本発明により、ロキソプロフェン又はその塩とメタケイ酸アルミン酸マグネシウムとの相互作用の抑制が可能となった。従って、保存安定性が優れた、ロキソプロフェン又はその塩及びメタケイ酸アルミン酸マグネシウムを含む固形製剤を提供することが可能となった。 According to the present invention, the interaction between loxoprofen or a salt thereof and magnesium aluminate metasilicate can be suppressed. Therefore, it has become possible to provide a solid preparation containing loxoprofen or a salt thereof and magnesium aluminate metasilicate having excellent storage stability.
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| JP2014240370A (en) * | 2013-06-12 | 2014-12-25 | 興和株式会社 | Pharmaceutical composition comprising loxoprofen |
| JP2016020330A (en) * | 2014-06-18 | 2016-02-04 | 大正製薬株式会社 | Solid preparations |
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