JP6863401B2 - Solid preparation - Google Patents
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- JP6863401B2 JP6863401B2 JP2019083504A JP2019083504A JP6863401B2 JP 6863401 B2 JP6863401 B2 JP 6863401B2 JP 2019083504 A JP2019083504 A JP 2019083504A JP 2019083504 A JP2019083504 A JP 2019083504A JP 6863401 B2 JP6863401 B2 JP 6863401B2
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- loxoprofen
- tablet
- salt
- silicon dioxide
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- 238000002360 preparation method Methods 0.000 title claims description 39
- 239000007787 solid Substances 0.000 title description 25
- 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 47
- 239000003826 tablet Substances 0.000 claims description 43
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 41
- 229960002373 loxoprofen Drugs 0.000 claims description 39
- 235000012239 silicon dioxide Nutrition 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 24
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 20
- 229930195725 Mannitol Natural products 0.000 claims description 20
- 239000000594 mannitol Substances 0.000 claims description 20
- 235000010355 mannitol Nutrition 0.000 claims description 20
- 239000000377 silicon dioxide Substances 0.000 claims description 20
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims description 18
- 239000008187 granular material Substances 0.000 claims description 10
- 210000000214 mouth Anatomy 0.000 claims description 8
- 239000006191 orally-disintegrating tablet Substances 0.000 claims description 8
- 150000005846 sugar alcohols Chemical class 0.000 claims description 5
- 229930006000 Sucrose Natural products 0.000 claims description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims 2
- 229960000913 crospovidone Drugs 0.000 claims 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims 2
- 238000000748 compression moulding Methods 0.000 claims 1
- 239000006185 dispersion Substances 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
- 230000000052 comparative effect Effects 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 108010011485 Aspartame Proteins 0.000 description 8
- 229920002261 Corn starch Polymers 0.000 description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 8
- 239000000605 aspartame Substances 0.000 description 8
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 8
- 235000010357 aspartame Nutrition 0.000 description 8
- 229960003438 aspartame Drugs 0.000 description 8
- 239000008120 corn starch Substances 0.000 description 8
- 238000011156 evaluation Methods 0.000 description 8
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 8
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 8
- 229960004211 loxoprofen sodium dihydrate Drugs 0.000 description 8
- 235000019359 magnesium stearate Nutrition 0.000 description 8
- 239000007910 chewable tablet Substances 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 229940068682 chewable tablet Drugs 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 235000013365 dairy product Nutrition 0.000 description 4
- -1 loxoprofen sodium anhydride Chemical class 0.000 description 4
- 239000000654 additive Substances 0.000 description 3
- 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 description 3
- 238000002845 discoloration Methods 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000000954 anitussive effect Effects 0.000 description 2
- 229940124584 antitussives Drugs 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000001055 chewing effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 206010008334 Cervicobrachial syndrome Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010034464 Periarthritis Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 208000037883 airway inflammation Diseases 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940124575 antispasmodic agent Drugs 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000011161 development Methods 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
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000004083 gastrointestinal agent Substances 0.000 description 1
- 229940127227 gastrointestinal drug Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229920003112 high viscosity grade hydroxypropyl cellulose Polymers 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明は、ロキソプロフェン又はその塩を含有する固形製剤に関し、適度な硬度を有し、外観安定性にも優れた、水なしで服用可能な固形製剤に関する。 The present invention relates to a solid preparation containing loxoprofen or a salt thereof, and relates to a solid preparation having an appropriate hardness and excellent appearance stability, which can be taken without water.
ロキソプロフェンは、非ステロイド性消炎鎮痛剤（ＮＳＡＩＤ）の一種であり、関節リウマチ、変形性関節症、腰痛症、肩関節周囲炎、頸肩腕症候群、歯痛、急性上気道炎や、手術後・外傷後・抜歯後等の消炎・鎮痛・解熱に有効なものとして知られている（非特許文献１）。
ロキソプロフェンナトリウムは薬物同士または機器、容器に対する付着性が強いため、特別に配慮した処方でなければ製剤化が困難である。これらの問題を解消する例として、添加物の総吸水能が１．７以上、好ましくは２．０以上とするロキソプロフェンナトリウム製剤（特許文献１）及び高粘度ヒドロキシプロピルセルロース、軟質無水ケイ酸及びステアリン酸マグネシウムを含み、その総吸水能が１．４以上１．７未満である製剤基剤とよりなるロキソプロフェンナトリウム製剤（特許文献２）がある。
Loxoprofen is a type of non-steroidal anti-inflammatory drug (NSAID), and is used for rheumatoid arthritis, osteoarthritis, low back pain, periarthritis shoulder, cervicobrachial syndrome, toothache, acute upper airway inflammation, and after surgery and trauma. -It is known to be effective for anti-inflammatory, analgesic, and fever-relieving after tooth extraction (Non-Patent Document 1).
Loxoprofen sodium has strong adhesion to drugs, devices, and containers, so it is difficult to formulate it unless it is formulated with special consideration. As an example of solving these problems, a loxoprofen sodium preparation (Patent Document 1) in which the total water absorption capacity of the additive is 1.7 or more, preferably 2.0 or more, high-viscosity hydroxypropyl cellulose, soft silicic anhydride and stearate. There is a loxoprofen sodium preparation (Patent Document 2) containing magnesium acid and comprising a preparation base having a total water absorption capacity of 1.4 or more and less than 1.7.
一方、水なしで服用可能な製剤は、特に小児や高齢者など嚥下能力の低い人達にも服用しやすい優れた製剤である（非特許文献２）。また、水なしで服用可能なため、服用シーンを選ばず、水がない状況下でも服用できるというメリットがある。そのため、利便性を考え、ロキソプロフェン又はその塩を含有する口腔内崩壊錠の研究がなされている。
しかし、ロキソプロフェンを配合した製剤は崩壊性が極めて悪いため、特に水なしで服用する製剤の開発にあたっては、その改善が要求される。
On the other hand, a preparation that can be taken without water is an excellent preparation that is easy to take even for people with low swallowing ability such as children and the elderly (Non-Patent Document 2). In addition, since it can be taken without water, it has the advantage that it can be taken in any situation and even in the absence of water. Therefore, for convenience, studies on orally disintegrating tablets containing loxoprofen or a salt thereof have been conducted.
However, since the preparation containing loxoprofen has extremely poor disintegration property, improvement is required especially in the development of a preparation to be taken without water.
今までに、ロキソプロフェン又はその塩を含有する口腔内崩壊錠又はチュアブル錠の例として、ロキソプロフェン、シクロデキストリン誘導体及び結合剤からなる口腔内速溶性製剤（特許文献３）がある。しかしながら、特許文献３の製剤は、凍結乾燥法により製造するものであり、特殊な設備が必要である。また、ロキソプロフェンによる口腔・咽喉頭部への不快感を改善したチュアブル錠が報告されている（特許文献４）。しかしながら、特許文献４では崩壊性などの錠剤物性については言及されていない。
これまで錠剤の硬度と崩壊性、及び外観安定性に着目した、水なしで服用可能なロキソプロフェン含有製剤の例は、報告されていない。
So far, as an example of an orally disintegrating tablet or a chewable tablet containing loxoprofen or a salt thereof, there is an orally fast-soluble preparation composed of loxoprofen, a cyclodextrin derivative and a binder (Patent Document 3). However, the preparation of Patent Document 3 is produced by a freeze-drying method, and requires special equipment. In addition, a chewable tablet that improves the discomfort of the oral cavity and throat due to loxoprofen has been reported (Patent Document 4). However, Patent Document 4 does not mention the physical characteristics of tablets such as disintegration.
So far, no example of a loxoprofen-containing preparation that can be taken without water has been reported, focusing on the hardness and disintegration property of tablets and the appearance stability.
本発明者らは、ロキソプロフェン又はその塩を含有する水なし服用固形製剤を製造するにあたって、その崩壊性を改善するため、一般的な崩壊剤の配合を試みた。しかしながら、崩壊剤の配合量を増やしても、崩壊性の改善には至らなかった。
したがって、本発明の目的は、ロキソプロフェン又はその塩を含有する製剤に関し、適度な硬度を有し、口腔内で速やかに崩壊でき、かつ、外観安定性にも優れた水なしで服用可能な固形製剤を提供することである。
In producing a waterless solid preparation containing loxoprofen or a salt thereof, the present inventors have attempted to formulate a general disintegrant in order to improve the disintegration property. However, even if the amount of the disintegrant was increased, the disintegration property was not improved.
Therefore, an object of the present invention is a solid preparation containing loxoprofen or a salt thereof, which has an appropriate hardness, can be rapidly disintegrated in the oral cavity, and has excellent appearance stability and can be taken without water. Is to provide.
本発明者らは、上記目的を達成するために種々の検討を行ったところ、二酸化ケイ素をロキソプロフェン又はその塩１質量部に対し０．１〜０．４５質量部含有せしめると、口腔内において速やかな崩壊性を示しながら、外観安定性に優れた水なしで服用可能な固形製剤が得られることを見出し、本発明を完成した。 The present inventors conducted various studies to achieve the above object, and found that when silicon dioxide was contained in an amount of 0.1 to 0.45 parts by mass with respect to 1 part by mass of loxoprofen or a salt thereof, it was rapidly in the oral cavity. The present invention has been completed by finding that a solid preparation that can be taken without water and has excellent appearance stability while exhibiting excellent disintegration property can be obtained.
すなわち、本発明は
（１）ロキソプロフェン又はその塩、及び二酸化ケイ素を含有し、二酸化ケイ素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０．１〜０．４５質量部であることを特徴とする、水なしで服用可能な固形製剤、
（２）口腔内崩壊錠又はチュアブル錠である（１）に記載の固形製剤、
（３）ロキソプロフェン又はその塩がロキソプロフェンナトリウムである、（１）に記載の固形製剤、
（４）二酸化ケイ素が、軽質無水ケイ酸である、（１）に記載の固形製剤、
（５）ロキソプロフェン又はその塩の含有量が、製剤全質量に対し５．０〜４０．０質量％である（１）に記載の固形製剤、
（６）さらに、糖又は糖アルコールを含有する、（１）〜（５）のいずれかに記載の固形製剤、
（７）糖又は糖アルコールが、マンニトール、ショ糖及び粉糖からなる群から選ばれる少なくとも１種である、（６）に記載の固形製剤、
である。
That is, the present invention is characterized by (1) containing loxoprofen or a salt thereof and silicon dioxide, and the content of silicon dioxide is 0.1 to 0.45 parts by mass with respect to 1 part by mass of loxoprofen or a salt thereof. Solid preparations that can be taken without water,
(2) The solid preparation according to (1), which is an orally disintegrating tablet or a chewable tablet.
(3) The solid preparation according to (1), wherein loxoprofen or a salt thereof is loxoprofen sodium.
(4) The solid preparation according to (1), wherein the silicon dioxide is light anhydrous silicic acid.
(5) The solid preparation according to (1), wherein the content of loxoprofen or a salt thereof is 5.0 to 40.0% by mass with respect to the total mass of the preparation.
(6) The solid preparation according to any one of (1) to (5), which further contains sugar or sugar alcohol.
(7) The solid preparation according to (6), wherein the sugar or sugar alcohol is at least one selected from the group consisting of mannitol, sucrose and powdered sugar.
Is.
本発明により、口腔内で速やかに崩壊し且つ、所望の適度な硬度を有し、外観安定性に優れたロキソプロフェン又はその塩を含有する水なしで服用可能な固形製剤の製造が可能となった。 INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to produce a solid preparation that rapidly disintegrates in the oral cavity, has a desired appropriate hardness, and has excellent appearance stability and can be taken without water containing loxoprofen or a salt thereof. ..
以下、本発明のロキソプロフェン又はその塩を含有する水なしで服用可能な固形製剤について詳述し説明する。 Hereinafter, the solid preparation that can be taken without water containing loxoprofen or a salt thereof of the present invention will be described in detail.
本発明の製剤中におけ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二水和物（化学名：Monosodium 2-[4-[(2-oxocyclopentyl)methyl]phenyl]propanoate dihydrate）が好ましい。
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０．５〜５０．０質量％、好ましくは１．０〜５０．０質量％、特に好ましくは１．０〜４０．０質量％、最も好ましいのは５．０〜４０．０質量％である。
The loxoprofen or a salt thereof in the preparation of the present invention includes not only loxoprofen but also a pharmaceutically acceptable salt of loxoprofen and a solvate with water, alcohol or the like. These are known compounds and can be produced by known methods, or commercially available compounds can be used. In the present invention, as loxoprofen or a salt thereof, loxoprofen sodium dihydrate (chemical name: Monosodium 2- [4-[(2-oxocyclopentyl) methyl] phenyl] propanoate dihydrate) is preferable.
The content of loxoprofen or a salt thereof in the solid preparation of the present invention is not particularly limited as long as it exhibits its medicinal effect, but is 0.5 in terms of loxoprofen sodium anhydride with respect to the total mass of the solid preparation. It is ~ 50.0% by mass, preferably 1.0 to 50.0% by mass, particularly preferably 1.0 to 40.0% by mass, and most preferably 5.0 to 40.0% by mass.
本発明の二酸化ケイ素においては、例えば軽質無水ケイ酸、重質無水ケイ酸、含水二酸化ケイ素などが挙げられるが、好ましくは軽質無水ケイ酸である。また、本発明の固形製剤中に含まれる二酸化ケイ素の含有量は、ロキソプロフェンまたはその塩１質量部に対して、好ましくは０．１〜０．４５質量部、特に好ましくは０．２〜０．３質量部である。さらに二酸化ケイ素の含有量は流動性、錠剤物性及び圧縮成形性という観点から固形製剤全質量に対して上限値は６．５質量％となる。 Examples of the silicon dioxide of the present invention include light anhydrous silicic acid, heavy anhydrous silicic acid, and hydrous silicon dioxide, and light anhydrous silicic acid is preferable. The content of silicon dioxide contained in the solid preparation of the present invention is preferably 0.1 to 0.45 parts by mass, particularly preferably 0.2 to 0, based on 1 part by mass of loxoprofen or a salt thereof. 3 parts by mass. Further, the upper limit of the silicon dioxide content is 6.5% by mass with respect to the total mass of the solid preparation from the viewpoint of fluidity, tablet physical properties and compression moldability.
本発明の糖又は糖アルコールとしては、例えばマンニトール、エリスリトール、キシリトール、ソルビトール、マルチトール、ショ糖、粉糖、ブドウ糖、乳糖等が挙げられるがより好ましいのは、マンニトール、ショ糖又は粉糖である。 Examples of the sugar or sugar alcohol of the present invention include mannitol, erythritol, xylitol, sorbitol, maltitol, sucrose, powdered sugar, glucose, lactose and the like, but more preferable are mannitol, sucrose or powdered sugar. ..
本発明の二酸化ケイ素の添加方法は、特に限定されるものではない。例えばロキソプロフェンと同時に配合し造粒する内部添加、造粒溶媒中に二酸化ケイ素を分散させて造粒する液添加、ロキソプロフェンを含有する顆粒に二酸化ケイ素を混合する後末添加による方法等が挙げられる。 The method for adding silicon dioxide of the present invention is not particularly limited. Examples thereof include an internal addition in which loxoprofen is blended and granulated at the same time, a liquid addition in which silicon dioxide is dispersed in a granulating solvent to granulate, and a post-addition method in which silicon dioxide is mixed with loxoprofen-containing granules.
本発明の水なしで服用な可能な固形製剤としては、例えば口腔内崩壊錠やチュアブル錠、顆粒剤が挙げられる。口腔内崩壊錠とは、通常の咀嚼条件での口腔内における崩壊時間が極めて速い錠剤を意味する。また、チュアブル錠とは、噛み砕いて服用する錠剤を意味する。口腔内崩壊錠またはチュアブル錠は服用しやすく、例えば、通常の錠剤を服用しにくい、小児や老人への投与にも、好適な剤型である。 Examples of the solid preparation that can be taken without water of the present invention include orally disintegrating tablets, chewable tablets, and granules. The orally disintegrating tablet means a tablet having an extremely fast disintegrating time in the oral cavity under normal chewing conditions. The chewable tablet means a tablet to be taken by chewing. Orally disintegrating tablets or chewable tablets are easy to take, for example, a dosage form suitable for administration to children and the elderly who are difficult to take ordinary tablets.
また、本発明の固形製剤中にはロキソプロフェン又はその塩の他に、本発明の効果を損なわない質的、量的範囲で、通常用いられる他の有効成分（例えば鎮咳去痰剤、気管支拡張剤、中枢興奮剤、抗ヒスタミン薬、催眠鎮静薬、鎮痙薬、胃腸薬、制酸剤、解熱鎮痛消炎薬、ビタミン剤、制吐剤、生薬など）を配合しうる。 In addition to loxoprofen or a salt thereof, other active ingredients usually used in the solid preparation of the present invention (for example, antitussive expectorant, bronchodilator, etc.) within a qualitative and quantitative range that does not impair the effect of the present invention. Central stimulants, antihistamines, hypnotic sedatives, antispasmodics, gastrointestinal drugs, antacids, antitussives, analgesics and anti-inflammatory drugs, vitamins, antiemetics, crude drugs, etc.) can be combined.
本発明の固形製剤には、本発明の効果に支障のない限り、水なしで服用可能な固形製剤の製造に一般に用いられる種々の添加剤を含んでいてもよい。このような添加剤として、例えば、賦形剤、崩壊剤、結合剤、酸味剤、発泡剤、甘味剤、嬌味剤、香料、滑沢剤、着色剤等が挙げられる。本発明の口腔内崩壊錠またはチュアブル錠の大きさ、形状は、特に限定されず、また、割線を有する分割錠としてもよい。 The solid preparation of the present invention may contain various additives generally used for producing a solid preparation that can be taken without water, as long as the effects of the present invention are not impaired. Examples of such additives include excipients, disintegrants, binders, acidulants, foaming agents, sweeteners, flavoring agents, flavors, lubricants, colorants and the like. The size and shape of the orally disintegrating tablet or chewable tablet of the present invention are not particularly limited, and may be a split tablet having a score line.
本発明の固形製剤の製造に当たっては、特に制約なく従来から行われている製造方法を使用することができる。本発明のロキソプロフェン又はその塩を含有する水なしで服用可能な固形製剤は、口腔内で優れた崩壊性を示すものであり、好ましくは日本薬局方による崩壊試験において、崩壊時間が６０秒以内、さらに好ましくは３０秒以内である。また製剤工程、さらには流通過程において損傷することのない適度な強度を有し、錠剤硬度は引張強度に換算して０．５ＭＰａ以上の外観安定性が良好な製剤である。 In the production of the solid preparation of the present invention, a conventional production method can be used without particular limitation. The solid preparation of the present invention containing loxoprofen or a salt thereof, which can be taken without water, exhibits excellent disintegration property in the oral cavity, and preferably has a disintegration time of 60 seconds or less in a disintegration test by the Japanese Pharmacopoeia. More preferably, it is within 30 seconds. Further, the tablet has an appropriate strength that is not damaged in the formulation process and the distribution process, and the tablet hardness is 0.5 MPa or more in terms of tensile strength, and the appearance stability is good.
以下に実施例及び比較例を挙げ、本発明をより詳しく説明するが、本発明はこれら実施例等に限定されるものではない。なお、錠剤の引張強度が０．５ＭＰａ以上となるよう、以下の機器及び条件で錠剤径９．５ｍｍの錠剤を製造した。 Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples and the like. A tablet having a tablet diameter of 9.5 mm was produced under the following equipment and conditions so that the tensile strength of the tablet was 0.5 MPa or more.
実施例１〜２、比較例１〜３
機器 ：卓上簡易錠剤成型機（商品名：ＨＡＮＤＴＡＢ；市橋精機）
打錠圧：３〜１０ｋＮ
実施例３〜５
機器 ：小型回転式錠剤機（商品名：ＶＥＬＡ５；菊水製作所）
打錠圧：５〜７ｋＮ
Examples 1-2, Comparative Examples 1-3
Equipment: Desktop simple tablet molding machine (trade name: HANDTAB; Ichihashi Seiki)
Locking pressure: 3 to 10 kN
Examples 3-5
Equipment: Small rotary tablet machine (trade name: VELA5; Kikusui Seisakusho)
Locking pressure: 5-7 kN
（実施例１）
ロキソプロフェンナトリウム二水和物２０４．３ｍｇ、軽質無水ケイ酸２７ｍｇ、マンニトール６１４．４ｍｇ、トウモロコシデンプン２６０ｍｇ、ヒドロキシプロピルセルロース６３ｍｇを混合した粉体に、マンニトール１５４ｍｇ、軽質無水ケイ酸６ｍｇを溶解・分散させた水溶液を添加した後、乳鉢で練合し、十分乾燥させた。その後２２メッシュの篩に通し、造粒物を製造した。得られた造粒物にステアリン酸マグネシウム１０ｍｇ、アスパルテーム３６ｍｇ、クロスポピドン１２３．６ｍｇを混合した後、打錠し、錠剤を得た。
(Example 1)
154 mg of mannitol and 6 mg of light anhydrous silicic acid were dissolved and dispersed in a powder obtained by mixing 204.3 mg of loxoprofen sodium dihydrate, 27 mg of light anhydrous silicic acid, 614.4 mg of mannitol, 260 mg of corn starch, and 63 mg of hydroxypropyl cellulose. After adding the aqueous solution, the mixture was kneaded in a dairy pot and sufficiently dried. Then, it was passed through a 22-mesh sieve to produce a granulated product. The obtained granulated product was mixed with 10 mg of magnesium stearate, 36 mg of aspartame, and 123.6 mg of crospopidone, and then tableted to obtain tablets.
（実施例２）
ロキソプロフェンナトリウム二水和物２０４．３ｍｇ、軽質無水ケイ酸５４ｍｇ、マンニトール１２２８．８ｍｇ、トウモロコシデンプン５２０ｍｇ、ヒドロキシプロピルセルロース１２６ｍｇを混合した粉体に、マンニトール３０８ｍｇ、軽質無水ケイ酸１２ｍｇを溶解・分散させた水溶液を添加した後、乳鉢で練合し、十分乾燥させた。その後、実施例１と同様に造粒物を製造し、得られた造粒物にステアリン酸マグネシウム、アスパルテーム、クロスポピドンを表１に示すように秤量し混合した後、打錠し、錠剤を得た。
(Example 2)
Mannitol 308 mg and light silicon dioxide 12 mg were dissolved and dispersed in a powder containing 204.3 mg of loxoprofen sodium dihydrate, 54 mg of light silicon dioxide, mannitol 1228.8 mg, corn starch 520 mg, and hydroxypropyl cellulose 126 mg. After adding the aqueous solution, the mixture was kneaded in a dairy pot and sufficiently dried. Then, a granulated product was produced in the same manner as in Example 1, and magnesium stearate, aspartame, and crospopidone were weighed and mixed with the obtained granulated product as shown in Table 1, and then tableted to obtain a tablet. It was.
（実施例３）
ロキソプロフェンナトリウム二水和物２０４．３ｍｇ、軽質無水ケイ酸１５．７ｍｇ、マンニトール３５７．２ｍｇ、トウモロコシデンプン１５１．２ｍｇを混合した粉体に、マンニトール１５４ｍｇ、軽質無水ケイ酸６ｍｇ、ヒドロキシプロピルセルロース６３ｍｇを溶解・分散させた水溶液を加えて、流動層造粒機にて造粒物を製造した。得られた造粒物にステアリン酸マグネシウム１０．８ｍｇ、アスパルテーム３２．４ｍｇ、クロスポピドン１０８ｍｇ、香料２２．７ｍｇを混合した後、打錠し、錠剤を得た。
(Example 3)
Loxoprofen sodium dihydrate 204.3 mg, light anhydrous silicic acid 15.7 mg, mannitol 357.2 mg, and corn starch 151.2 mg are mixed, and 154 mg of mannitol, 6 mg of light anhydrous silicic acid, and 63 mg of hydroxypropyl cellulose are dissolved in the powder. -A dispersed aqueous solution was added to produce a granulated product with a fluidized layer granulator. The obtained granulated product was mixed with 10.8 mg of magnesium stearate, 32.4 mg of aspartame, 108 mg of crospopidone, and 22.7 mg of fragrance, and then tableted to obtain tablets.
（実施例４）
ロキソプロフェンナトリウム二水和物２０４．３ｍｇ、軽質無水ケイ酸２４ｍｇを混合した粉体に、軽質無水ケイ酸１８ｍｇを溶解・分散させた水溶液を加えて、流動層造粒機にて造粒物ａを製造した。また、軽質無水ケイ酸７ｍｇ、マンニトール６３７．３ｍｇ、トウモロコシデンプン２５６ｍｇ、ヒドロキシプロピルセルロース３７ｍｇ、粉糖７４ｍｇを混合した粉体に、マンニトール１２６．７ｍｇを溶解・分散させた水溶液を加えて、流動層造粒機にて造粒物ｂを製造した。得られた造粒物ａ、造粒物ｂにステアリン酸マグネシウム１０ｍｇ、アスパルテーム３６ｍｇ、クロスポピドン１２３ｍｇを混合した後、打錠し、錠剤を得た。
(Example 4)
An aqueous solution prepared by dissolving and dispersing 18 mg of light anhydrous silicic acid was added to a powder obtained by mixing 204.3 mg of loxoprofen sodium dihydrate and 24 mg of light anhydrous silicic acid, and the granulated product a was prepared by a fluidized bed granulator. Manufactured. Further, a fluid layer structure is formed by adding an aqueous solution in which 126.7 mg of mannitol is dissolved and dispersed in a powder obtained by mixing 7 mg of light anhydrous silicic acid, 637.3 mg of mannitol, 256 mg of corn starch, 37 mg of hydroxypropyl cellulose and 74 mg of powdered sugar. Granulated material b was produced by a granulator. The obtained granulated product a and granulated product b were mixed with 10 mg of magnesium stearate, 36 mg of aspartame, and 123 mg of crospopidone, and then tableted to obtain tablets.
（実施例５）
ロキソプロフェンナトリウム二水和物２０４．３ｍｇ、軽質無水ケイ酸２４ｍｇを混合した粉体に、軽質無水ケイ酸１８ｍｇを溶解・分散させた水溶液を加えて、流動層造粒機にて造粒物ａを製造した。また、軽質無水ケイ酸２．５ｍｇ、マンニトール２２３ｍｇ、トウモロコシデンプン８９．６ｍｇ、ヒドロキシプロピルセルロース１３ｍｇ、粉糖２５．９ｍｇを混合した粉体に、マンニトール４４．３ｍｇを溶解・分散させた水溶液を加えて、流動層造粒機にて造粒物ｂを製造した。得られた造粒物ａ、造粒物ｂと、ステアリン酸マグネシウム４．６ｍｇ、アスパルテーム３６ｍｇ、クロスポピドン５５．３ｍｇを混合した後、打錠し、錠剤を得た。
(Example 5)
An aqueous solution prepared by dissolving and dispersing 18 mg of light anhydrous silicic acid was added to a powder obtained by mixing 204.3 mg of loxoprofen sodium dihydrate and 24 mg of light anhydrous silicic acid, and the granulated product a was prepared by a fluidized bed granulator. Manufactured. Further, an aqueous solution prepared by dissolving and dispersing 44.3 mg of mannitol was added to a powder obtained by mixing 2.5 mg of light anhydrous silicic acid, 223 mg of mannitol, 89.6 mg of corn starch, 13 mg of hydroxypropyl cellulose and 25.9 mg of powdered sugar. , Granulated material b was produced by a fluidized layer granulator. The obtained granulated product a and granulated product b were mixed with 4.6 mg of magnesium stearate, 36 mg of aspartame, and 55.3 mg of crospopidone, and then tableted to obtain tablets.
（比較例１）
ロキソプロフェンナトリウム二水和物２０４．３ｍｇ、マンニトール６４７．４ｍｇ、トウモロコシデンプン２６０ｍｇ、ヒドロキシプロピルセルロース６３ｍｇを混合した粉体に、マンニトール１５４ｍｇを溶解・分散させた水溶液を添加した後、乳鉢で練合し、十分乾燥させた。その後、実施例１と同様に造粒物を製造し、得られた造粒物にステアリン酸マグネシウム、アスパルテーム、クロスポピドンを表１に示すように秤量し混合した後、打錠し、錠剤を得た。
。
(Comparative Example 1)
To a powder obtained by mixing 204.3 mg of loxoprofen sodium dihydrate, 647.4 mg of mannitol, 260 mg of corn starch, and 63 mg of hydroxypropyl cellulose, an aqueous solution in which 154 mg of mannitol was dissolved and dispersed was added, and then kneaded in a mortar. It was sufficiently dried. Then, a granulated product was produced in the same manner as in Example 1, and magnesium stearate, aspartame, and crospopidone were weighed and mixed with the obtained granulated product as shown in Table 1, and then tableted to obtain a tablet. It was.
..
（比較例２）
ロキソプロフェンナトリウム二水和物２０４．３ｍｇ、軽質無水ケイ酸９０ｍｇ、マンニトール５５２ｍｇ、トウモロコシデンプン２６０ｍｇ、ヒドロキシプロピルセルロース６３ｍｇを混合した粉体に、マンニトール１５４ｍｇ、軽質無水ケイ酸６ｍｇを溶解・分散させた水溶液を添加した後、乳鉢で練合し、十分乾燥させた。その後、実施例１と同様に、造粒物を製造し、得られた造粒物にステアリン酸マグネシウム、アスパルテーム、クロスポピドンを表１に示す通りに秤量し混合した後、打錠し、錠剤を得た。
(Comparative Example 2)
An aqueous solution prepared by dissolving and dispersing 154 mg of mannitol and 6 mg of light anhydrous silicic acid in a powder obtained by mixing 204.3 mg of loxoprofen sodium dihydrate, 90 mg of light anhydrous silicic acid, 552 mg of mannitol, 260 mg of corn starch and 63 mg of hydroxypropyl cellulose. After the addition, it was kneaded in a dairy pot and sufficiently dried. Then, in the same manner as in Example 1, a granulated product was produced, and magnesium stearate, aspartame, and crospopidone were weighed and mixed with the obtained granulated product as shown in Table 1, then tableted and tablets were obtained. Obtained.
（比較例３）
ロキソプロフェンナトリウム二水和物２０４．３ｍｇ、メタケイ酸アルミン酸マグネシウム２７ｍｇ、マンニトール６１４．４ｍｇ、トウモロコシデンプン２６０ｍｇ、ヒドロキシプロピルセルロース６３ｍｇを混合した粉体に、マンニトール１５４ｍｇ、メタケイ酸アルミン酸マグネシウム６ｍｇを溶解・分散させた水溶液を添加した後、乳鉢で練合し、十分乾燥させた。その後、実施例１と同様に、造粒物を製造し、得られた造粒物にステアリン酸マグネシウム、アスパルテーム、クロスポピドンを表１に示すように秤量し混合した後、打錠し、錠剤を得た。
実施例１〜５及び比較例１〜３の処方を表１に示す。
(Comparative Example 3)
Dissolve and disperse 154 mg of mannitol and 6 mg of magnesium aluminometasilicate in a powder containing 204.3 mg of sodium loxoprofen dihydrate, 27 mg of magnesium aluminometasilicate, 614.4 mg of mannitol, 260 mg of corn starch, and 63 mg of hydroxypropyl cellulose. After adding the aqueous solution, the mixture was kneaded in a dairy pot and sufficiently dried. Then, in the same manner as in Example 1, a granulated product was produced, and magnesium stearate, aspartame, and crospopidone were weighed and mixed with the obtained granulated product as shown in Table 1, and then tableted to obtain a tablet. Obtained.
The formulations of Examples 1 to 5 and Comparative Examples 1 to 3 are shown in Table 1.
（試験例）
＜評価方法＞
実施例１〜５及び比較例１〜３の錠剤について、以下の各試験方法により硬度試験、崩壊時間の測定及び外観評価を行った。
（１）硬度試験
シュロイニゲル錠剤硬度計（シュロイニゲル社製）を用いて測定した。実施例１〜５の錠剤の硬度を３回ずつ測定した。また得られた結果を下記の［数１］を用い計算し、引張強度を算出し、その平均値を求めた。
(Test example)
<Evaluation method>
The tablets of Examples 1 to 5 and Comparative Examples 1 to 3 were subjected to a hardness test, measurement of disintegration time and appearance evaluation by each of the following test methods.
(1) Hardness test Measured using a Schleunigel tablet hardness tester (manufactured by Schroinigel). The hardness of the tablets of Examples 1 to 5 was measured three times each. Further, the obtained result was calculated using the following [Equation 1], the tensile strength was calculated, and the average value was calculated.
F：錠剤硬度（Ｎ）
D：錠剤直径（mm）
ｔ：錠剤厚さ（mm）
F: Tablet hardness (N)
D: Tablet diameter (mm)
t: Tablet thickness (mm)
表２に示すように、実施例１〜５及び比較例１〜３の錠剤は、引張強度がすべて０．５ＭＰａ以上であり、適度な強度を有する錠剤であることが分かった。 As shown in Table 2, it was found that the tablets of Examples 1 to 5 and Comparative Examples 1 to 3 were all tablets having a tensile strength of 0.5 MPa or more and an appropriate strength.
（２）崩壊試験
日本薬局方第十六改正に記載されている崩壊試験法に従い測定した。それぞれの錠剤の崩壊時間を３回ずつ測定し、その平均値を求めた。
(2) Disintegration test Measured according to the disintegration test method described in the 16th revision of the Japanese Pharmacopoeia. The disintegration time of each tablet was measured three times, and the average value was calculated.
（３）外観評価
得られた錠剤を、密栓した状態で保存し、６５℃条件下に２週間保存した後の外観を専門パネラー２名で観察し、製造直後品との相対比較で下記の評価基準に従い行った。
(3) Appearance evaluation The obtained tablets were stored in a sealed state, and the appearance after storage under 65 ° C. conditions for 2 weeks was observed by two specialized panelists, and the following evaluation was made by relative comparison with the product immediately after production. It went according to the standard.
＜評価基準＞
著しい変色：＋＋
やや変色：＋
変色なし：−
（結果）
それぞれの錠剤の崩壊時間、外観評価結果を表３に示す。
<Evaluation criteria>
Significant discoloration: ++
Slight discoloration: +
No discoloration:-
(result)
Table 3 shows the disintegration time and appearance evaluation results of each tablet.
表３に示すように、実施例１〜５の錠剤は、崩壊時間が６０秒以内であり、かつ、外観評価においても良好な結果を示した。特に、実施例４及び実施例５の錠剤は、崩壊時間が３０秒以内の優れた崩壊性を示した。一方、処方中に二酸化ケイ素を含有していない比較例１や、二酸化ケイ素の含有量がロキソプロフェンナトリウム１質量部に対して０．４５質量部を超える量を配合した比較例２、二酸化ケイ素の代わりにメタケイ酸アルミン酸マグネシウムを含有した比較例３は崩壊時間、外観評価のいずれかについて満足できなかった。 As shown in Table 3, the tablets of Examples 1 to 5 had a disintegration time of 60 seconds or less and showed good results in the appearance evaluation. In particular, the tablets of Example 4 and Example 5 showed excellent disintegration property with a disintegration time of 30 seconds or less. On the other hand, in Comparative Example 1 in which silicon dioxide is not contained in the formulation, in Comparative Example 2 in which the content of silicon dioxide exceeds 0.45 parts by mass with respect to 1 part by mass of sodium loxoprofene, instead of silicon dioxide. Comparative Example 3 containing magnesium aluminometasilicate was not satisfactory in either the disintegration time or the appearance evaluation.
本発明によれば、口腔内で水がなくても速やかに崩壊あるいは溶解し、かつ所望の適度な硬度を有し、外観安定性に優れたロキソプロフェンまたはその塩を含有した製剤の提供が可能となる。 According to the present invention, it is possible to provide a preparation containing loxoprofen or a salt thereof, which rapidly disintegrates or dissolves in the oral cavity without water, has a desired appropriate hardness, and has excellent appearance stability. Become.
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