JP6051761B2 - Solid preparation - Google Patents
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- JP6051761B2 JP6051761B2 JP2012231302A JP2012231302A JP6051761B2 JP 6051761 B2 JP6051761 B2 JP 6051761B2 JP 2012231302 A JP2012231302 A JP 2012231302A JP 2012231302 A JP2012231302 A JP 2012231302A JP 6051761 B2 JP6051761 B2 JP 6051761B2
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- loxoprofen
- salt
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- magnesium aluminate
- solid preparation
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- 238000002360 preparation method Methods 0.000 title claims description 30
- 239000007787 solid Substances 0.000 title claims description 25
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical class O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 claims description 37
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 16
- GDVKFRBCXAPAQJ-UHFFFAOYSA-A dialuminum;hexamagnesium;carbonate;hexadecahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-]C([O-])=O GDVKFRBCXAPAQJ-UHFFFAOYSA-A 0.000 claims description 13
- 229960001545 hydrotalcite Drugs 0.000 claims description 13
- 229910001701 hydrotalcite Inorganic materials 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 238000005550 wet granulation Methods 0.000 claims description 6
- 238000009472 formulation Methods 0.000 claims description 5
- 229960002373 loxoprofen Drugs 0.000 description 36
- 150000003839 salts Chemical class 0.000 description 28
- 239000003826 tablet Substances 0.000 description 27
- 230000000052 comparative effect Effects 0.000 description 11
- 238000011156 evaluation Methods 0.000 description 9
- 238000002156 mixing Methods 0.000 description 8
- 239000000843 powder Substances 0.000 description 7
- 239000008187 granular material Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 230000003993 interaction Effects 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 230000001953 sensory effect Effects 0.000 description 5
- 238000002845 discoloration Methods 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 208000012895 Gastric disease Diseases 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 229940069428 antacid Drugs 0.000 description 2
- 239000003159 antacid agent Substances 0.000 description 2
- 230000001458 anti-acid effect Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000004040 coloring Methods 0.000 description 2
- 238000013329 compounding Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- -1 loxoprofen sodium anhydride Chemical class 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229940024546 aluminum hydroxide gel Drugs 0.000 description 1
- SMYKVLBUSSNXMV-UHFFFAOYSA-K aluminum;trihydroxide;hydrate Chemical compound O.[OH-].[OH-].[OH-].[Al+3] SMYKVLBUSSNXMV-UHFFFAOYSA-K 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- 239000011230 binding agent 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
- 238000007796 conventional method Methods 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
- 238000007907 direct compression Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 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
- 229960002449 glycine Drugs 0.000 description 1
- 235000013905 glycine and its sodium salt Nutrition 0.000 description 1
- 238000002955 isolation Methods 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
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 238000007909 melt granulation Methods 0.000 description 1
- 239000004570 mortar (masonry) Substances 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
- 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
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 206010041232 sneezing Diseases 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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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ことを特徴とする固形製剤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に関するものである。 The present invention relates to a solid preparation comprising loxoprofen or a salt thereof and magnesium aluminate metasilicate. More specifically, the present invention relates to a solid preparation capable of suppressing a change 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、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 a high track record in medical use as an anti-inflammatory analgesic and has features such as relatively light side effects such as gastric disorders.
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１質量部に対して０．１−０．８質量部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, tableting troubles are improved by adding 0.1-0.8 parts by mass of magnesium aluminate metasilicate to 1 part by mass of loxoprofen sodium (Patent Document 4)
2) A composition containing loxoprofen or a salt thereof, magnesium aluminate metasilicate and magnesium oxide (
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、メタケイ酸アルミン酸マグネシウム及び合成ヒドロタルサイトを含有することを特徴とする固形製剤、
（２）ロキソプロフェン又はその塩１質量部に対して０．０５〜８．４質量部のメタケイ酸アルミン酸マグネシウム及び１．０〜２２．３質量部の合成ヒドロタルサイトを含有する（１）に記載の固形製剤、
（３）固形製剤の製造方法が湿式造粒法又は直接打錠法である、（１）または（２）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 found that the above-mentioned problems can be solved by blending a specific component into a powder containing loxoprofen or a salt thereof and magnesium aluminate metasilicate, and completed the present invention.
That is, the present invention
(1) A solid preparation characterized by containing loxoprofen or a salt thereof, magnesium aluminate metasilicate and synthetic hydrotalcite,
(2) (1) containing 0.05 to 8.4 parts by mass of magnesium aluminate metasilicate and 1.0 to 22.3 parts by mass of synthetic hydrotalcite with respect to 1 part by mass of loxoprofen or a salt thereof. The described solid preparation,
(3) The method for producing a solid preparation according to (1) or (2), wherein the method for producing the solid preparation is a wet granulation method or a direct tableting method,
It is.
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 pharmaceutical preparation of 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.
本発明の医薬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 pharmaceutical preparation of the present invention includes not only loxoprofen but also a pharmaceutically acceptable salt of loxoprofen, and further a solvate with water, alcohol or 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１．７〜８０．０質量％、好ましくは３．０〜７２．０質量％、特に好ましくは４．０〜６２．０質量％、最も好ましいのは４．０〜５２．０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. -80.0% by mass, preferably 3.0-72.0% by mass, particularly preferably 4.0-62.0% by mass, most preferably 4.0-52.0% 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１．０〜７０．０質量％、好ましくは３．５〜６２．０質量％、特に好ましくは４．０〜５０．０質量％である。 The content of magnesium aluminate metasilicate in the solid preparation of the present invention is 1.0 to 70.0 mass%, preferably 3.5 to 62.0 mass%, particularly preferably 4 based on the total mass of the solid preparation. 0.0 to 50.0% by mass.
また、本発明の固形製剤中における合成ヒドロタルサイトの含有量は、２５．０〜９０．０質量％、好ましくは２５．０〜６５．０質量％，特に好ましくは３５．０〜６３．０質量％含有するものが着色抑制の面で好ましい。 The content of the synthetic hydrotalcite in the solid preparation of the present invention is 25.0 to 90.0% by mass, preferably 25.0 to 65.0% by mass, particularly preferably 35.0 to 63.0. What is contained by mass% is preferable in terms of suppression of coloring.
本発明の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配合比は、ロキソプロフェン又はその塩１質量部に対してメタケイ酸アルミン酸マグネシウムは０．０５〜８．４質量部、好ましくは０．０５〜２．５質量部、特に好ましくは０．１０〜２．５質量部、最も好ましくは０．１０〜２．０質量部である。また、本発明のロキソプロフェン又はその塩と合成ヒドロタルサイトとの配合比は、ロキソプロフェン又はその塩１質量部に対して合成ヒドロタルサイトは１．０〜２２．３質量部、好ましくは１．０〜１２．０質量部、最も好ましくは１．０〜４．５質量部である。本発明の固形製剤の剤形としては散剤、細粒剤、顆粒剤、丸剤、錠剤（フィルムコーティング錠、糖衣錠、積層錠を含む）、カプセル剤、ドライシロップ剤、トローチ剤等の経口製剤や外用剤などの非経口製剤が挙げられるが、特にカプセル剤、錠剤又は散剤が好ましい。
本発明の固形製剤は、常法により製造することができ、その方法は特に限定されるものではないが、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合成ヒドロタルサイトを隔離せずに接触するように配合してもその相互作用が抑制されることから、これら３種の成分を共存するように配合することが、本発明を実施する上で意義が大きい。
上記固形製剤の具体的形態として、例えば以下の形態が挙げられる。
１．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合成ヒドロタルサイトを混合して得た散剤、顆粒剤等及びこれを被覆した製剤。
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合成ヒドロタルサイトを混合し、造粒して得た散剤、顆粒剤等及びこれを被覆した製剤。
３．１または２の製剤を含む錠剤、及びこれを被覆した製剤。
本発明の固形製剤の製造方法としては、直接打錠法、湿式造粒法、乾式造粒法及び溶融造粒法という方法が挙げられ、この中でも直接打錠法および湿式造粒法が好ましい。
The compounding ratio of loxoprofen or a salt thereof and magnesium aluminate metasilicate of the present invention is 0.05 to 8.4 parts by mass, preferably 0.05 parts by mass of magnesium aluminate metasilicate per 1 part by mass of loxoprofen or a salt thereof. To 2.5 parts by mass, particularly preferably 0.10 to 2.5 parts by mass, and most preferably 0.10 to 2.0 parts by mass. The compounding ratio of loxoprofen or a salt thereof and synthetic hydrotalcite of the present invention is 1.0 to 22.3 parts by mass, preferably 1.0 to 1 part by mass of loxoprofen or a salt thereof. ˜12.0 parts by mass, most preferably 1.0 to 4.5 parts by mass. The dosage form of the solid preparation of the present invention includes powders, fine granules, granules, pills, tablets (including film-coated tablets, sugar-coated tablets, laminated tablets), capsules, dry syrups, lozenges, etc. Examples include parenteral preparations such as drugs, but capsules, tablets or powders are particularly preferable.
The solid preparation of the present invention can be produced by a conventional method, and the method is not particularly limited. However, loxoprofen or a salt thereof, magnesium aluminate metasilicate and synthetic hydrotalcite are contacted without isolation. Even if it mix | blends so that the interaction is suppressed, it is significant in implementing this invention to mix | blend so that these 3 types of components may coexist.
Specific examples of the solid preparation include the following forms.
1. Powders, granules, etc. obtained by mixing loxoprofen or a salt thereof, magnesium aluminate metasilicate and synthetic hydrotalcite, and preparations coated therewith.
2. Powders, granules, etc. obtained by mixing and granulating loxoprofen or a salt thereof, magnesium aluminate metasilicate and synthetic hydrotalcite, and a preparation coated therewith.
3. A tablet containing the preparation of 1 or 2, and a preparation coated therewith.
Examples of the method for producing the solid preparation of the present invention include a direct tableting method, a wet granulation method, a dry granulation method and a melt granulation method, and among these, the direct tableting method and the wet granulation method are preferable.
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及び合成ヒドロタルサイト以外にも、総合感冒薬及び解熱鎮痛剤との配合が考えられる成分との配合が可能である。 In addition to loxoprofen or a salt thereof, magnesium metasilicate aluminate, and synthetic hydrotalcite, the pharmaceutical preparation of the present invention can be combined with a component that can be combined with a general cold medicine and an antipyretic analgesic.
本発明の固形製剤は、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及び合成ヒドロタルサイトを配合し、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もよい。 The solid preparation of the present invention comprises loxoprofen or a salt thereof, magnesium aluminate metasilicate and synthetic hydrotalcite, and other known additives such as an excipient, a disintegrant, a binder, Lubricants, antioxidants, coating agents, coloring agents, flavoring agents, surfactants, plasticizers and the like may be mixed.
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、本発明はこれらの実施例等に何ら限定されるものではない。
（実施例１〜４、比較例１〜１０及び参考例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（ステアリン酸マグネシウムを除く）を１００錠分ビニールで混合した後、篩を通した。実施例１〜４、比較例１、３〜１０、参考例１の直接打錠法の場合、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）を用いて錠剤径１０ｍｍの錠剤を得た。比較例２及び参考例２の湿式造粒法の場合、篩通過後の粉体に対して精製水を加えて乳鉢で練合させ、５０℃条件下に２時間静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。得た錠剤は、２５℃６０％ＲＨ条件下に１日静置させた後にガラス瓶に入れて密閉し、６５℃条件下に３日間保存させた後に製剤の外観評価を行った。
（２）官能評価
実施例、比較例及び参考例で得られた錠剤について、官能評価によって専門パネラー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３日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」以下と設定した。
官能評価結果を表１〜２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
Below, this invention is demonstrated further in detail based on an Example and a comparative example. The present invention is not limited to these examples.
(Examples 1-4, Comparative Examples 1-10 and Reference Examples 1-2)
(1) Manufacturing method of formulation (tablet) According to the blending ratios of Tables 1 and 2 below, various raw materials (excluding magnesium stearate) were mixed with 100 tablets of vinyl and then passed through a sieve. In the case of the direct compression method of Examples 1 to 4, Comparative Examples 1, 3 to 10 and Reference Example 1, magnesium stearate is added to and mixed with the powder after passing through the sieve, and a simple tabletop tablet molding machine (product) Name: HANDTAB; Ichibashi Seiki) was used to obtain tablets with a tablet diameter of 10 mm. In the case of the wet granulation method of Comparative Example 2 and Reference Example 2, purified water was added to the powder after passing through the sieve, kneaded in a mortar, and allowed to stand at 50 ° C. for 2 hours and sufficiently dried. Later, 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. The obtained tablets were allowed to stand for 1 day at 25 ° C. and 60% RH, sealed in a glass bottle, and stored for 3 days under 65 ° C., and then the appearance of the preparation was evaluated.
(2) Sensory evaluation About the tablet obtained by the Example, the comparative example, and the reference example, the external appearance evaluation by 3 expert panelists was implemented by sensory evaluation. Evaluation of the appearance of the preparation was carried out by a relative comparison between a sample stored for 3 days 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.
The sensory evaluation results are shown in Tables 1-2.
<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、ロキソプロフェンナトリウムのみを含有する粉体を直接打錠法、又は湿式造粒法を用いて製した錠剤は変色しないが（参考例１、参考例２）、ロキソプロフェンナトリウム１質量部に対してメタケイ酸アルミン酸マグネシウムを０．０５質量部以上配合すると変色が認められ（比較例１〜２、４〜８）、特に、比較例１〜２及び比較例４の錠剤の官能評価結果は、高い値を示し、錠剤表面に斑点状の、著しい変色が認められた。これに対し、実施例１〜４に示した合成ヒドロタルサイトを含有する錠剤の官能評価結果は低い値を示し、外観変化が抑制された錠剤であった。一方、合成ヒドロタルサイトと同じ制酸剤として知られる乾燥水酸化アルミニウムゲル、アミノ酢酸又は炭酸水素ナトリウムを含有する錠剤の官能評価結果は高い値を示し、錠剤表面に斑点状の、著しい変色が認められた（比較例３、９、１０）。
As is clear from the test results, although tablets containing only loxoprofen sodium using a direct tableting method or a wet granulation method do not change color (Reference Example 1, Reference Example 2),
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.
Claims (3)
製剤の製造方法。 The manufacturing method of the solid formulation of Claim 1 or 2 whose manufacturing method of a solid formulation is a wet granulation method or a direct tableting method.
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