JP2015187097A - Solid preparation - Google Patents
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- JP2015187097A JP2015187097A JP2015041972A JP2015041972A JP2015187097A JP 2015187097 A JP2015187097 A JP 2015187097A JP 2015041972 A JP2015041972 A JP 2015041972A JP 2015041972 A JP2015041972 A JP 2015041972A JP 2015187097 A JP2015187097 A JP 2015187097A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 239000007787 solid Substances 0.000 title claims abstract description 24
- 229960002373 loxoprofen Drugs 0.000 claims abstract description 23
- GBFLZEXEOZUWRN-VKHMYHEASA-N S-carboxymethyl-L-cysteine Chemical compound OC(=O)[C@@H](N)CSCC(O)=O GBFLZEXEOZUWRN-VKHMYHEASA-N 0.000 claims abstract description 19
- 229960004399 carbocisteine Drugs 0.000 claims abstract description 18
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 claims abstract description 10
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims abstract description 10
- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 10
- 239000000378 calcium silicate Substances 0.000 claims abstract description 7
- 229910052918 calcium silicate Inorganic materials 0.000 claims abstract description 7
- 239000002775 capsule Substances 0.000 claims abstract description 5
- 239000006187 pill Substances 0.000 claims abstract description 5
- 239000000843 powder Substances 0.000 claims abstract description 5
- 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 description 21
- 239000003826 tablet Substances 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000008187 granular material Substances 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 abstract description 8
- 238000003860 storage Methods 0.000 abstract description 6
- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 abstract 2
- 230000000052 comparative effect Effects 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 238000000034 method Methods 0.000 description 12
- 238000009472 formulation Methods 0.000 description 11
- 238000002845 discoloration Methods 0.000 description 10
- 238000011156 evaluation Methods 0.000 description 7
- 238000005469 granulation Methods 0.000 description 7
- 230000003179 granulation Effects 0.000 description 7
- 230000003993 interaction Effects 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 238000007711 solidification Methods 0.000 description 5
- 230000008023 solidification Effects 0.000 description 5
- 238000007596 consolidation process Methods 0.000 description 4
- 229940079593 drug Drugs 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
- 150000001875 compounds Chemical class 0.000 description 3
- 239000003172 expectorant agent Substances 0.000 description 3
- 230000003419 expectorant effect Effects 0.000 description 3
- -1 loxoprofen sodium anhydride Chemical class 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 229910002012 Aerosil® Inorganic materials 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical compound [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000010436 fluorite Substances 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 2
- 229960000401 tranexamic acid Drugs 0.000 description 2
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 206010009137 Chronic sinusitis Diseases 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
- 201000008197 Laryngitis Diseases 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 206010049590 Upper respiratory tract inflammation Diseases 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 230000000954 anitussive effect Effects 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
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 208000027157 chronic rhinosinusitis Diseases 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
- 239000002537 cosmetic Substances 0.000 description 1
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940066493 expectorants Drugs 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 229960004211 loxoprofen sodium dihydrate Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 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
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- 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、及びカルボシステインを含有した固形製剤に関するものである。 The present invention relates to a solid preparation containing loxoprofen or a salt thereof and carbocysteine.
現在、一般用医薬品においては、複数の薬効成分を配合した製剤が広く使用されている。例えば、総合感冒薬は、解熱鎮痛薬、鎮咳去痰薬、鼻炎薬など多くの成分が配合されている。これらの薬剤は、有効性及び安全性の観点から、製剤としての安定性に優れている必要がある。
ロキソプロフェン又はその塩は、医療用医薬品として高い実績を誇る非ステロイド系解熱鎮痛剤である。本成分は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おり広く用いられている。
Currently, in over-the-counter drugs, preparations containing a plurality of medicinal ingredients are widely used. For example, the common cold medicine contains many components such as antipyretic analgesics, antitussive expectorants and rhinitis drugs. These drugs need to be excellent in stability as a preparation from the viewpoint of effectiveness and safety.
Loxoprofen or a salt thereof is a non-steroidal antipyretic analgesic that has a proven track record as an ethical drug. This component has a feature such that side effects such as gastric disorders are relatively light and is widely used.
一方、カルボシステインは上気道炎（咽頭炎、喉頭炎）、急性気管支炎、気管支喘息、慢性気管支炎、気管支拡張症、肺結核等の疾患における去痰作用、慢性副鼻腔炎等の疾患における排膿作用を有しており、安全性の高い去痰剤として医療用での使用実績が高い。 On the other hand, carbocysteine is an expectorant action in diseases such as upper respiratory tract inflammation (pharyngitis, laryngitis), acute bronchitis, bronchial asthma, chronic bronchitis, bronchiectasis, pulmonary tuberculosis, and drainage action in diseases such as chronic sinusitis It has a high track record in medical use as a highly safe expectorant.
ロキソプロフェンとカルボシステインが配合した固形製剤は知られており、これらを配合した際に相互作用を生じるため、相互作用を抑制する方法として、今までにトラネキサム酸を加えて混合することによって防止する方法が報告されている（特許文献１、２）。 Solid formulations containing loxoprofen and carbocysteine are known, and interaction occurs when these are added, so as a method to suppress the interaction by adding tranexamic acid so far and mixing Have been reported (Patent Documents 1 and 2).
しかし、この方法によると、ロキソプロフェンとカルボシステインの相互作用を抑制するためには、医薬有効成分のトラネキサム酸を配合しなければならなかった。また、ロキソプロフェンとカルボシステイン含有製剤にあっては、打錠して錠剤とした場合は、特に相互作用が顕著に生じることを本発明者らは発見した。 However, according to this method, in order to suppress the interaction between loxoprofen and carbocysteine, it was necessary to add tranexamic acid, which is a pharmaceutical active ingredient. Further, the present inventors have found that in the case of a preparation containing loxoprofen and carbocysteine, the interaction is particularly prominent when tableted into tablets.
本発明者らは、このような事情に鑑み、ロキソプロフェンとカルボシステインを含有する医薬用製剤の安定化について種々検討した結果、意外にも、特定の流動化剤を配合すると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）（ａ）ロキソプロフェン又はその塩、（ｂ）カルボシステイン、及び（ｃ）軽質無水ケイ酸及び／又はケイ酸カルシウムを含有することを特徴とする固形製剤、
（２）固形製剤が、錠剤、顆粒剤、散剤、カプセル剤又は丸剤である（１）に記載の固形製剤、
である。
In view of such circumstances, the present inventors have conducted various studies on the stabilization of pharmaceutical preparations containing loxoprofen and carbocysteine. The headline and the present invention were completed.
That is, the present invention
(1) (a) loxoprofen or a salt thereof, (b) carbocysteine, and (c) a light anhydrous silicic acid and / or calcium silicate,
(2) The solid preparation according to (1), wherein the solid preparation is a tablet, granule, powder, capsule or pill,
It is.
本発明の医薬製剤は、ロキソプロフェンとカルボシステイン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及び固結が防止されたロキソプロフェンとカルボシステイン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 and carbocysteine. Therefore, it is possible to provide a solid preparation containing loxoprofen and carbocysteine in which the preparation is prevented from being colored and consolidated for a long 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２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, loxoprofen or a salt thereof is preferably loxoprofen sodium dihydrate.
また、本発明の固形製剤に用いられるカルボシステインは、第１６改正日本薬局方に記載されているＬ−カルボシステインであり、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。 The carbocysteine used in the solid preparation of the present invention is L-carbocysteine described in the 16th revised Japanese pharmacopoeia and can be produced by a known method or commercially available.
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５〜３０質量％が好ましい。 The content of loxoprofen or a salt thereof in the solid preparation of the present invention is not particularly limited as long as it shows the medicinal effect, but is 5 to 30 in terms of loxoprofen sodium anhydride relative to the total mass of the solid preparation. Mass% is preferred.
本発明の固形製剤中におけるカルボシステインの含有量は、固形製剤全質量に対して２０〜５０質量％が好ましい。 The carbocysteine content in the solid preparation of the present invention is preferably 20 to 50% by mass relative to the total mass of the solid preparation.
本発明の特定の流動化剤とは、（ｃ）成分として示す軽質無水ケイ酸及び／又はケイ酸カルシウムを意味する。 The specific fluidizing agent of the present invention means light anhydrous silicic acid and / or calcium silicate shown as component (c).
軽質無水ケイ酸とは、第１６改正日本薬局方（ＪＰ１６）に記載された公知の化合物であり、日本アエロジル社製のアエロジル、フロイント産業社製のアドソリダー１０１及び
富士シリシア化学社製のサイリシアなどがある。
Light anhydrous silicic acid is a known compound described in the 16th revised Japanese Pharmacopoeia (JP16), such as Aerosil manufactured by Nippon Aerosil Co., Ltd., AdSolider 101 manufactured by Freund Sangyo Co., Ltd., and Silicia manufactured by Fuji Silysia Chemical Co., Ltd. is there.
ケイ酸カルシウムとは吸油量の高い賦形剤として知られ医薬品や化粧品に広く使用される公知の化合物であり、富田製薬社製のフローライトＲやエーザイフード・ケミカル社製のフローライトＲＥなどがある。 Calcium silicate is a known compound that is known as an excipient with a high oil absorption and is widely used in pharmaceuticals and cosmetics. Examples include Fluorite R manufactured by Tomita Pharmaceutical and Fluorite RE manufactured by Eisai Food Chemical. is there.
また、本発明の固形製剤中における（ｃ）成分の含有量は固形製剤全質量に対して０．５質量％〜３０質量％が好ましく、さらに好ましくは１〜２５質量％である。 Moreover, 0.5 mass%-30 mass% are preferable with respect to the solid formulation total mass, and, as for content of (c) component in the solid formulation of this invention, More preferably, it is 1-25 mass%.
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、特に顆粒剤、散剤、カプセル剤、丸剤又は錠剤が好ましい。その剤型に応じて、任意の慣用の方法で製造すればよい。また、造粒法としては、流動層造粒法、押し出し造粒法、転動造粒法、噴霧造粒法が挙げられるが、好ましくは攪拌造粒法である
製造法としては、例えば、（ａ）成分、（ｂ）成分、及び（ｃ）成分を混合し、製造する。また、（ａ）成分、（ｂ）成分、及び（ｃ）成分を混合後、造粒して製造する。また、（ａ）成分を含む造粒物と（ｂ）成分を含む造粒物を別々に製造し、これらを混合後、（ｃ）成分を添加して製造する。その際、（ａ）成分を含む造粒物又は（ｂ）成分を含む造粒物中に（ｃ）成分を含んでもよく、その場合は、造粒物を混合した後、（ｃ）成分の添加は必須ではない。
このように製造した後、これらを被覆しても良い。また、適宜有効成分や慣用の添加剤を配合し、打錠すれば錠剤を得ることができる。
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 granules, powders, capsules, pills or tablets are particularly preferable. What is necessary is just to manufacture by arbitrary usual methods according to the dosage form. Examples of the granulation method include a fluidized bed granulation method, an extrusion granulation method, a rolling granulation method, and a spray granulation method, and preferably a stirring granulation method. A) component, (b) component, and (c) component are mixed and manufactured. Moreover, after mixing (a) component, (b) component, and (c) component, it granulates and manufactures. Moreover, the granulated material containing (a) component and the granulated material containing (b) component are manufactured separately, and after mixing these, (c) component is added and manufactured. In that case, the granulated product containing the component (a) or the granulated product containing the component (b) may contain the component (c). In that case, after mixing the granulated product, Addition is not essential.
After manufacturing in this way, these may be coated. Moreover, if an active ingredient and a conventional additive are mix | blended suitably and it compresses, a tablet can be obtained.
本発明の医薬製剤には、ロキソプロフェン又はその塩及びカルボシステインと、軽質無水ケイ酸又はケイ酸カルシウム以外にも、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、可塑剤等を配合することができる。 In addition to loxoprofen or a salt thereof and carbocysteine and light anhydrous silicic acid or calcium silicate, other known additives such as excipients, disintegrants, binding agents are included in the pharmaceutical preparation of the present invention. Agents, lubricants, antioxidants, coating agents, colorants, flavoring agents, surfactants, plasticizers and the like can be blended.
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。 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.
（実施例１〜２及び比較例１〜３）
製剤の製造方法
表１に示す各成分及び分量を秤量、混合し得られた医薬組成物４００ｍｇずつを秤量し、卓上簡易錠剤成型機（商品名：ＨＡＮＤＴＡＢ；市橋精機社製）を用いて１２ｋＮで打錠し、錠剤径１１ｍｍの錠剤を得た。
(Examples 1-2 and Comparative Examples 1-3)
Manufacturing method of formulation Each component and the amount shown in Table 1 are weighed and weighed and mixed, and 400 mg of the obtained pharmaceutical composition is weighed, and 12 kN using a tabletop simple tablet molding machine (trade name: HANDTAB; manufactured by Ichibashi Seiki Co., Ltd.). Tableting was performed to obtain a tablet having a tablet diameter of 11 mm.
（実施例３）
製剤の製造方法
表２に示す各成分（Ａ）、（Ｂ）の各成分及び分量を秤量し均一に混合した後、得られた各々の混合粉末を湿式攪拌造粒法により造粒し、造粒物Ａおよび造粒物Ｂを得た。得られた２種の造粒物と軽質無水ケイ酸１３．５ｇ及び低置換度ヒドロキシプロピルセルロース８１ｇ、ステアリン酸マグネシウム１３．５ｇを混合した後、ロータリー打錠機（商品名：ＶＩＲＧＯ５１９ＳＳ１ＡＺ；菊水製作所社製）を用いて１５００ｋｇｆで打錠し、錠剤径９ｍｍの錠剤を得た。
(Example 3)
Preparation Method of Formulation Each component and the amount of each component (A) and (B) shown in Table 2 are weighed and mixed uniformly, and then each obtained mixed powder is granulated by wet stirring granulation method, Granule A and granulated product B were obtained. After mixing the obtained two types of granules, 13.5 g of light anhydrous silicic acid, 81 g of low substituted hydroxypropylcellulose, and 13.5 g of magnesium stearate, a rotary tableting machine (trade name: VIRGO519SS1AZ; Kikusui Seisakusho Co., Ltd.) And tableting with a tablet diameter of 9 mm was obtained.
（実施例４）
製剤の製造方法
表３に示すＣ成分及び分量を秤量し、実施例３と同様に造粒し造粒物を得た。得られた造粒物と軽質無水ケイ酸５４ｇ、低置換度ヒドロキシプロピルセルロース９０ｇ及びステアリン酸マグネシウム９ｇを混合した後、実施例３と同様に打錠し、錠剤径９ｍｍの錠剤を得た。
Example 4
Preparation Method of Formulation The C component and the amount shown in Table 3 were weighed and granulated in the same manner as in Example 3 to obtain a granulated product. The obtained granulated product was mixed with 54 g of light anhydrous silicic acid, 90 g of low-substituted hydroxypropylcellulose and 9 g of magnesium stearate, and then tableted in the same manner as in Example 3 to obtain tablets with a tablet diameter of 9 mm.
（１）外観評価
実施例１〜３及び比較例１〜３により得られた錠剤について、固結状態を専門パネラー２名により目視にて観察した。評価は、実施例１〜３及び比較例１〜３は６５℃条件下に３日間保存したサンプル、実施例４は４０℃７５％RH条件下に６箇月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４段階で評価した。評価結果を表４に示す。
＜評価基準＞
− ：固結なし
＋ ：わずかに凝集を認める
＋＋ ：固結を認める
＋＋＋：明らかな固結を認める
(1) Appearance evaluation About the tablet obtained by Examples 1-3 and Comparative Examples 1-3, the solidification state was observed visually by two special panelists. Evaluations were as follows: Examples 1 to 3 and Comparative Examples 1 to 3 were samples stored for 3 days under the condition of 65 ° C. The evaluation was performed by comparison and evaluated in the following four stages. The evaluation results are shown in Table 4.
<Evaluation criteria>
-: No consolidation +: Slight aggregation is observed ++: Consolidation is recognized +++: Clear consolidation is recognized
（２）色差測定
実施例１〜３及び比較例１〜３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３日間保存したサンプルの色差測定を実施した。測定には分光色差計（商品名：ＳＥ６０００；日本電色工業）を用い、以下の［数１］を用い算出した。各サンプルについて色差を測定し、ΔE*(ab)が小さ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 in Examples 1-3 and Comparative Examples 1-3, the color difference measurement of the sample preserve | saved for three days on 65 degreeC conditions was implemented for the tablet immediately after that as a control. For the measurement, a spectral color difference meter (trade name: SE6000; Nippon Denshoku Industries Co., Ltd.) was used, and the following [Equation 1] was used for calculation. The color difference is measured for each sample, and the smaller ΔE * (ab), the less the color tone changes.
ΔL*＝６５℃３日間保存品のL*値−直後品のL*値（L*：明度 ＋は白方向、−は黒方向）
Δa*＝６５℃３日間保存品のa*値−直後品のa*値（a*：色度 ＋は赤方向、−は緑方向）
Δb*＝６５℃３日間保存品のb*値−直後品のb*値（b*：色度 ＋は黄方向、−は青方向）
ΔL * = 65 ℃ 3 days storage goods L * value - immediately after product L * value (L *: lightness + white direction, - the black direction)
Δa * = 65 ℃ 3 days storage goods of a * value - immediately after the goods of a * value (a *: chromaticity + red direction, - green direction)
Δb * = 65 ℃ 3 days storage goods a b * value - immediately after article b * value (b *: Chromaticity + Huang direction, - the blue direction)
試験結果から明らかなように、ロキソプロフェン及びカルボシステインを含有する製剤（比較例１）は固結し、かつΔE*(ab)は高い値を示し、著しく変色することが認められた。これに対し、ケイ酸カルシウム（実施例１）、軽質無水ケイ酸（実施例２〜４）を含有した製剤は固結は認められず、ΔE*(ab)は比較例１よりも低い値を示し、変色が抑制できた。一方、他の流動化剤であるメタケイ酸アルミン酸マグネシウム（比較例２）を添加した製剤は、ΔE*(ab)は低い値を示したが斑点が確認され、またタルク（比較例３）を添加した製剤では、固結、変色ともに抑制されないことが明らかとなった。 As is apparent from the test results, the preparation containing loxoprofen and carbocysteine (Comparative Example 1) solidified, and ΔE * (ab) showed a high value, and it was observed that the color changed significantly. On the other hand, no solidification was observed in the preparation containing calcium silicate (Example 1) and light anhydrous silicic acid (Examples 2 to 4), and ΔE * (ab) was lower than that of Comparative Example 1. The discoloration could be suppressed. On the other hand, the formulation to which magnesium metasilicate aluminate (Comparative Example 2) as another fluidizing agent was added showed a low value of ΔE * (ab), but spots were confirmed and talc (Comparative Example 3) was added. It was revealed that neither the caking nor the discoloration was suppressed by the added preparation.
(実施例５及び比較例４〜５)
（１）製剤の製造方法
表５に示す各成分及び分量を秤量、混合し製剤を得た。得た製剤は、ガラス瓶に入れて密閉し、６５℃条件下に１週間保存させた後に製剤の外観評価を行った。
（２）外観評価
実施例５及び比較例４〜５で得られた製剤について、専門パネラー２名による外観評価を実施した。６５℃条件下に１週間保存したサンプルの固結状態と変色を比較例４との相対比較により、以下に記す４段階で評価した。結果を表６に示す。
＜固結状態判定基準＞
− ：変化なし
＋ ：わずかに凝集を認める
＋＋ ：固結を認める
＋＋＋：明らかな固結を認める
＜変色判定基準＞
− ：変化なし
＋ ：わずかに変色を認める
＋＋ ：変色を認める
＋＋＋：明らかな変色を認める
(Example 5 and Comparative Examples 4 to 5)
(1) Manufacturing method of formulation Each component and quantity shown in Table 5 were weighed and mixed to obtain a formulation. The obtained preparation was sealed in a glass bottle and stored for 1 week at 65 ° C., and then the appearance of the preparation was evaluated.
(2) Appearance evaluation About the preparation obtained in Example 5 and Comparative Examples 4-5, the appearance evaluation by 2 expert panelists was implemented. The solidification state and discoloration of the sample stored at 65 ° C. for 1 week were evaluated by the relative comparison with Comparative Example 4 in the following four stages. The results are shown in Table 6.
<Consolidation state criteria>
-: No change +: Slight aggregation is observed ++: Solidification is recognized +++: Clear solidification is recognized <Discoloration criteria>
-: No change +: Slight discoloration is recognized ++: Discoloration is recognized +++: Obvious discoloration is recognized
表６から明らかなように、ロキソプロフェンとカルボシステインのみを混合したものは変色及び著しい固結が見られた（比較例４）。これに対し、軽質無水ケイ酸を添加した固形製剤は変色及び固結が抑制された（実施例５）。一方、他の流動化剤であるメタケイ酸アルミン酸マグネシウムを添加した製剤は、固結の抑制はできたが、変色を抑制することはできず、全体が褐色へと変色した。 As is clear from Table 6, discoloration and significant caking were observed in the mixture of loxoprofen and carbocysteine alone (Comparative Example 4). In contrast, discoloration and caking were suppressed in the solid preparation to which light silicic acid was added (Example 5). On the other hand, the preparation to which magnesium metasilicate aluminate, which is another fluidizing agent, was able to suppress caking, but could not suppress discoloration, and the whole color changed to brown.
本発明により、ロキソプロフェン又はその塩及びカルボシステイン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カルボシステインを含有する固形製剤を提供することが可能となる。 According to the present invention, the interaction with loxoprofen or a salt thereof and carbocysteine can be suppressed. Therefore, it is possible to provide a solid preparation containing loxoprofen or a salt thereof and carbocysteine having excellent storage stability.
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