JP2022008042A - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
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- JP2022008042A JP2022008042A JP2021065660A JP2021065660A JP2022008042A JP 2022008042 A JP2022008042 A JP 2022008042A JP 2021065660 A JP2021065660 A JP 2021065660A JP 2021065660 A JP2021065660 A JP 2021065660A JP 2022008042 A JP2022008042 A JP 2022008042A
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- salt
- pharmaceutical composition
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 53
- 150000003839 salts Chemical class 0.000 claims abstract description 176
- 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 40
- 229960002373 loxoprofen Drugs 0.000 claims abstract description 39
- ZKLPARSLTMPFCP-OAQYLSRUSA-N 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid Chemical compound C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-OAQYLSRUSA-N 0.000 claims abstract description 30
- 229960001508 levocetirizine Drugs 0.000 claims abstract description 30
- JWIXXNLOKOAAQT-UHFFFAOYSA-N tipepidine Chemical compound C1N(C)CCCC1=C(C=1SC=CC=1)C1=CC=CS1 JWIXXNLOKOAAQT-UHFFFAOYSA-N 0.000 claims abstract description 27
- KBEZZLAAKIIPFK-NJAFHUGGSA-N dimemorfan Chemical compound C1C2=CC=C(C)C=C2[C@@]23CCN(C)[C@@H]1[C@H]2CCCC3 KBEZZLAAKIIPFK-NJAFHUGGSA-N 0.000 claims abstract description 24
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 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 23
- 229960001985 dextromethorphan Drugs 0.000 claims abstract description 23
- 229960001056 dimemorfan Drugs 0.000 claims abstract description 23
- 229960000896 tipepidine Drugs 0.000 claims abstract description 23
- 229960004399 carbocisteine Drugs 0.000 claims abstract description 19
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229960003908 pseudoephedrine Drugs 0.000 claims abstract description 14
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 claims abstract description 14
- FMCGSUUBYTWNDP-ONGXEEELSA-N (1R,2S)-2-(dimethylamino)-1-phenyl-1-propanol Chemical compound CN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 FMCGSUUBYTWNDP-ONGXEEELSA-N 0.000 claims abstract description 12
- FMCGSUUBYTWNDP-UHFFFAOYSA-N N-Methylephedrine Natural products CN(C)C(C)C(O)C1=CC=CC=C1 FMCGSUUBYTWNDP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229960002221 methylephedrine Drugs 0.000 claims abstract description 12
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- PUHLHLQBIFRKRD-CSKARUKUSA-N 5-methyl-2-[(E)-2-phenylethenyl]-1,3-benzoxazole Chemical group N=1C2=CC(C)=CC=C2OC=1\C=C\C1=CC=CC=C1 PUHLHLQBIFRKRD-CSKARUKUSA-N 0.000 claims description 5
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 claims description 4
- NTCYWJCEOILKNG-ROLPUNSJSA-N [(1r,2s)-1-hydroxy-1-phenylpropan-2-yl]-dimethylazanium;chloride Chemical group Cl.CN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 NTCYWJCEOILKNG-ROLPUNSJSA-N 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 229940073563 dl- methylephedrine hydrochloride Drugs 0.000 claims description 4
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- 239000006187 pill Substances 0.000 claims description 4
- 229960003447 pseudoephedrine hydrochloride Drugs 0.000 claims description 4
- BALXUFOVQVENIU-KXNXZCPBSA-N pseudoephedrine hydrochloride Chemical group [H+].[Cl-].CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-KXNXZCPBSA-N 0.000 claims description 4
- 239000004503 fine granule Substances 0.000 claims description 3
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- 230000000087 stabilizing effect Effects 0.000 claims description 2
- REJGOFYVRVIODZ-UHFFFAOYSA-N phosphanium;chloride Chemical compound P.Cl REJGOFYVRVIODZ-UHFFFAOYSA-N 0.000 claims 1
- 230000007423 decrease Effects 0.000 abstract description 9
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
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- YGTUPRIZNBMOFV-UHFFFAOYSA-N 2-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(O)C=C1 YGTUPRIZNBMOFV-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 5
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- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 5
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 5
- 150000003891 oxalate salts Chemical class 0.000 description 5
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 5
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 5
- 229940095064 tartrate Drugs 0.000 description 5
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- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
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- 206010049590 Upper respiratory tract inflammation Diseases 0.000 description 4
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- 150000003840 hydrochlorides Chemical class 0.000 description 4
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- 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 3
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Abstract
Description
本発明は、ロキソプロフェンとレボセチリジン又はその塩を含有する医薬組成物に関する。 The present invention relates to a pharmaceutical composition containing loxoprofen and levocetirizine or a salt thereof.
ロキソプロフェンは、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、手術後、外傷後並びに抜歯後の鎮痛・消炎に有効であるほか、急性上気道炎（急性気管支炎を伴う急性上気道炎を含む）の解熱・鎮痛にも有効であり、スイッチＯＴＣ成分として認可された（非特許文献１）。 Loxoprofen is effective for rheumatoid arthritis, osteoarthritis, lumbar pain, shoulder periarthritis, cervicobrachial syndrome, toothache, post-surgery, post-traumatic and post-extraction pain relief and anti-inflammatory, as well as acute upper airway inflammation (acute bronchitis). It is also effective in reducing fever and analgesia (including acute upper airway inflammation with inflammation), and has been approved as a switch OTC component (Non-Patent Document 1).
レボセチリジン及びその塩は、第2世代ヒスタミンＨ１受容体拮抗薬（第２世代抗ヒスタミン薬）として、アレルギー性鼻炎，蕁麻疹，皮膚疾患（湿疹・皮膚炎，皮膚そう痒症）に伴うそう痒に有効である（非特許文献２）。レボセチリジンは、セチリジン塩酸塩の光学異性体のうち、より生理活性の強いＲ－エナンチオマーのみを光学分割したものである。 Levocetilidine and its salts are used as second-generation histamine H1 receptor antagonists (second-generation antihistamines) for allergic rhinitis, urticaria, and pruritus associated with skin diseases (eczema / dermatitis, pruritus dermatitis). It is valid (Non-Patent Document 2). Levocetirizine is an optical resolution of only R-enantiomer, which has stronger bioactivity, among the optical isomers of cetirizine hydrochloride.
カルボシステインは、粘液構成成分調整作用、杯細胞過形成抑制作用、気道炎症抑制作用及び粘膜正常化作用を有し、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、肺結核に対する優れた去痰作用を有する化合物として広く知られており、総合感冒薬や鎮咳去痰薬に広く配合されている（非特許文献３）。 Carbocisteine has mucus component-regulating action, goblet cell hyperplasia inhibitory activity, airway inflammation inhibitory activity, and mucosal normalization activity, and has upper respiratory tract inflammation (pharyngitis, laryngitis), acute bronchitis, bronchial asthma, and chronic bronchitis. It is widely known as a compound having an excellent expectorant action on inflammation, bronchitis, and pulmonary tuberculosis, and is widely used in general anti-inflammatory agents and antitussive expectorants (Non-Patent Document 3).
チペピジン及びその塩は延髄の咳中枢を抑制し咳の感受性を低下させることにより鎮咳作用を示すとともに、気管支腺分泌を亢進し気道粘膜線毛上皮運動を亢進することにより去痰作用を示す化合物として、感冒・上気道炎（咽喉頭炎・鼻カタル）・急性気管支炎・慢性気管支炎・肺炎・肺結核・気管支拡張症に伴う咳嗽及び喀痰喀出困難に広く用いられている（非特許文献４） Tipepidin and its salts show antitussive action by suppressing the cough center of the spinal cord and reduce the sensitivity of cough, and as a compound showing expectorant action by enhancing bronchial gland secretion and enhancing airway mucosal hair epithelial motility. It is widely used for cough and expectorant difficulty associated with cold, upper respiratory tract inflammation (pharyngitis, nasal catarrh), acute bronchitis, chronic bronchitis, pneumonia, pulmonary tuberculosis, and bronchiectasis (Non-Patent Document 4).
デキストロメトルファン及びその塩は、延髄にある咳中枢に直接作用し、咳反射を抑制することにより鎮咳作用を示す化合物として、感冒・急性気管支炎・慢性気管支炎・気管支拡張症・肺炎・肺結核・上気道炎（咽喉頭炎，鼻カタル）に伴う咳嗽に広く用いられている（非特許文献５）。 Dextromethorphan and its salts act directly on the cough center in the spinal cord and show antitussive action by suppressing the cough reflex. It is widely used for cough associated with upper respiratory tract inflammation (throat inflammation, nasal catarrh) (Non-Patent Document 5).
プソイドエフェドリン及びその塩は、α受容体を刺激し、鼻粘膜の血管平滑筋を収縮させ、血流を減少させることにより、鼻粘膜の充血や腫脹を軽減し、強い鼻閉改善効果を示すことから、内服用鼻炎薬に広く用いられている（非特許文献６）。 Pseudoephedrine and its salts stimulate α-receptors, constrict the vascular smooth muscles of the nasal mucosa, and reduce blood flow, thereby reducing the congestion and swelling of the nasal mucosa and exhibiting a strong nasal congestion improving effect. , Widely used for oral rhinitis drugs (Non-Patent Document 6).
ジメモルファンリン及びその塩は、延髄の咳中枢に直接作用して鎮咳作用を示す化合物として、上気道炎、肺炎、急性気管支炎、肺結核、珪肺および珪肺結核、肺癌、慢性気管支炎に伴う鎮咳に広く用いられている（非特許文献７）。 Dimemorphanline and its salts are compounds that act directly on the cough center of the spinal cord and exhibit antitussive action, such as upper respiratory tract inflammation, pneumonia, acute bronchitis, pulmonary tuberculosis, silicosis and silicosis, lung cancer, and antitussive associated with chronic bronchitis. Widely used in (Non-Patent Document 7).
メチルエフェドリン及びその塩は、交感神経興奮様薬物であり、β2受容体刺激による気管支拡張作用を有し、総合感冒薬や鎮咳去痰薬に広く配合されている（非特許文献８）。 Methylephedrine and its salts are sympathomimetic-like drugs, have a bronchodilator effect by stimulating β2 receptors, and are widely used in common cold treatments and antitussive expectorants (Non-Patent Document 8).
本発明者らは、ロキソプロフェン又はその塩及びレボセチリジン又はその塩を含有する医薬組成物を製造したところ、レボセチリジン又はその塩の含量が経時的に低下するという驚くべき知見を得た。本発明は、上記事情に鑑みなされたもので、ロキソプロフェン又はその塩とレボセチリジン又はその塩を含有しても、レボセチリジン又はその塩の経時的な含量低下が抑制された医薬組成物を提供することにある。 The present inventors have obtained the surprising finding that when a pharmaceutical composition containing loxoprofen or a salt thereof and levocetirizine or a salt thereof is produced, the content of levocetirizine or a salt thereof decreases with time. The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a pharmaceutical composition in which the decrease in the content of levocetirizine or a salt thereof with time is suppressed even if loxoprofen or a salt thereof and levocetirizine or a salt thereof are contained. be.
そこで、本発明者らが鋭意検討した結果、カルボシステイン、チペピジン及びその塩、デキストロメトルファン及びその塩、プソイドエフェドリン及びその塩、ジメモルファン及びその塩，並びにメチルエフェドリン及びその塩からなる群より選ばれる少なくとも１種を含有させると、意外にもレボセチリジン塩酸塩の経時的な含量低下が抑えられることを見出し、本発明を完成させるに至った。 Therefore, as a result of diligent studies by the present inventors, at least selected from the group consisting of carbocysteine, tipepidine and its salt, dextromethorphan and its salt, pseudoephedrine and its salt, dimemorfan and its salt, and methylephedrine and its salt. It has been found that the inclusion of one of them unexpectedly suppresses the decrease in the content of levocetilysin hydrochloride over time, and has completed the present invention.
すなわち、本発明は
（１）（ａ）ロキソプロフェン又はその塩、（ｂ）レボセチリジン又はその塩、（ｃ）（ｃ１）カルボシステイン、（ｃ２）チペピジン及びその塩、（ｃ３）デキストロメトルファン及びその塩、（ｃ４）プソイドエフェドリン及びその塩、（ｃ５）ジメモルファン及びその塩、並びに（ｃ６）メチルエフェドリン及びその塩からなる群より選ばれる少なくとも１種を含有することを特徴とする医薬組成物、
（２）（ａ）ロキソプロフェン及びその塩がロキソプロフェンナトリウム水和物である（１）に記載の医薬組成物、
（３）（ｂ）レボセチリジンの塩がレボセチリジン塩酸塩である（１）に記載の医薬組成物、
（４）成分（ｃ）が、（ｃ１）カルボシステインである（１）に記載の医薬組成物、
（５）成分（ｃ）が、（ｃ２）チペピジンまたはその塩である（１）に記載の医薬組成物、
（６）チペピジンの塩がチペピジンヒベンズ酸塩である（１）又は（５）に記載の医薬組成物、
（７）成分（ｃ）が、（ｃ３）デキストロメトルファン又はその塩である（１）に記載の医薬組成物、
（８）デキストロメトルファンの塩がデキストロメトルファン臭化水素酸塩水和物である（１）又は（７）に記載の医薬組成物、
（９）成分（ｃ）が、（ｃ４）プソイドエフェドリン又はその塩である（１）に記載の医薬組成物、
（１０）プソイドエフェドリンの塩がプソイドエフェドリン塩酸塩である（１）又は（９）に記載の医薬組成物、
（１１）成分（ｃ）が、（ｃ５）ジメモルファン又はその塩である（１）に記載の医薬組成物、
（１２）ジメモルファンの塩がジメモルファンリン塩酸塩である（１）又は（１１）に記載の医薬組成物、
（１３）成分（ｃ）が、（ｃ６）メチルエフェドリン又はその塩である（１）に記載の医薬組成物、
（１４）メチルエフェドリンの塩がｄｌ－メチルエフェドリン塩酸塩である（１）又は（１３）に記載の医薬組成物、
（１５）剤形が、錠剤、散剤、細粒剤、顆粒剤、丸剤、カプセル剤、経口液剤、又はシロップ剤である（１）～（１４）のいずれかに記載の医薬組成物、
（１６）（ａ）ロキソプロフェン又はその塩及び（ｂ）レボセチリジン又はその塩を含み、（ｂ）レボセチリジン又はその塩が安定化された医薬組成物を製造するための、（ｃ）（ｃ１）カルボシステイン、（ｃ２）チペピジン及びその塩、（ｃ３）デキストロメトルファン及びその塩、（ｃ４）プソイドエフェドリン及びその塩、（ｃ５）ジメモルファン及びその塩、並びに（ｃ６）メチルエフェドリン及びその塩からなる群より選ばれる少なくとも１種の使用、
（１７）（ａ）ロキソプロフェン又はその塩及び（ｂ）レボセチリジン又はその塩を含む医薬組成物中の（ｂ）レボセチリジン又はその塩を安定化するための、（ｃ）（ｃ１）カルボシステイン、（ｃ２）チペピジン及びその塩、（ｃ３）デキストロメトルファン及びその塩、（ｃ４）プソイドエフェドリン及びその塩、（ｃ５）ジメモルファン及びその塩、並びに（ｃ６）メチルエフェドリン及びその塩からなる群より選ばれる少なくとも１種の使用、
である。
That is, the present invention relates to (1) (a) loxoprofen or a salt thereof, (b) levosetilidine or a salt thereof, (c) (c1) carbocysteine, (c2) tipepidin and a salt thereof, (c3) dextromethorphan and a salt thereof. , (C4) Psoid efedrin and a salt thereof, (c5) Dimemorphan and a salt thereof, and (c6) Methyl efedrin and a salt thereof.
(2) The pharmaceutical composition according to (1), wherein (a) loxoprofen and a salt thereof are loxoprofen sodium hydrate.
(3) The pharmaceutical composition according to (1), wherein the salt of levocetirizine is levocetirizine hydrochloride.
(4) The pharmaceutical composition according to (1), wherein the component (c) is (c1) carbocisteine.
(5) The pharmaceutical composition according to (1), wherein the component (c) is (c2) tipepidine or a salt thereof.
(6) The pharmaceutical composition according to (1) or (5), wherein the salt of tipepidine is tipepidine hibenzate.
(7) The pharmaceutical composition according to (1), wherein the component (c) is (c3) dextromethorphan or a salt thereof.
(8) The pharmaceutical composition according to (1) or (7), wherein the salt of dextromethorphan is dextromethorphan hydrobromic acid hydrate.
(9) The pharmaceutical composition according to (1), wherein the component (c) is (c4) pseudoephedrine or a salt thereof.
(10) The pharmaceutical composition according to (1) or (9), wherein the salt of pseudoephedrine is pseudoephedrine hydrochloride.
(11) The pharmaceutical composition according to (1), wherein the component (c) is (c5) dimemorfan or a salt thereof.
(12) The pharmaceutical composition according to (1) or (11), wherein the salt of dimemorfan is dimemorfan phosphate hydrochloride.
(13) The pharmaceutical composition according to (1), wherein the component (c) is (c6) methylephedrine or a salt thereof.
(14) The pharmaceutical composition according to (1) or (13), wherein the salt of methylephedrine is dl-methylephedrine hydrochloride.
(15) The pharmaceutical composition according to any one of (1) to (14), wherein the dosage form is a tablet, a powder, a fine granule, a granule, a pill, a capsule, an oral solution, or a syrup.
(C) (c1) Carbocysteine for producing a pharmaceutical composition comprising (16) (a) loxoprofen or a salt thereof and (b) levosetilidine or a salt thereof, and (b) levosetilidine or a salt thereof stabilized. , (C2) Tipepidin and its salt, (c3) Dextromethorphan and its salt, (c4) Psoid efedrin and its salt, (c5) Dimemorphan and its salt, and (c6) Methylefedrin and its salt. Use of at least one type,
(C) (c1) Carbocysteine, (c2) for stabilizing (b) levosetilidine or a salt thereof in a pharmaceutical composition comprising (17) (a) loxoprofen or a salt thereof and (b) levosetilidine or a salt thereof. ) Chipepidin and its salt, (c3) dextromethorphan and its salt, (c4) pseudoephedrine and its salt, (c5) dimemorphan and its salt, and (c6) methylefedrin and its salt at least one selected from the group. Use of,
Is.
本発明により、ロキソプロフェン又はその塩及びレボセチリジン又はその塩を含有し、レボセチリジン又はその塩の安定性に優れた医薬組成物の提供が可能となった。 INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to provide a pharmaceutical composition containing loxoprofen or a salt thereof and levocetirizine or a salt thereof and having excellent stability of levocetirizine or a salt thereof.
本発明に用いられるロキソプロフェンは、化学式Ｃ１５Ｈ１８Ｏ３で示される化合物であり、医薬的に許容されるものであれば特に限定はしない。ロキソプロフェンは、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。また、ロキソプロフェンの塩は医薬的に許容されるものであれば特に限定されないが、例えば、ナトリウム塩、カリウム塩、カルシウム塩等が挙げられ、特に好ましくはナトリウム二水和物である。ロキソプロフェン又はその塩は、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。本発明の医薬組成物中におけるロキソプロフェンの含有量は、その薬効を示す量であれば特に限定されないが、通常５～９５質量％、好ましくは５～９０質量％、５～８５質量％、５～８０質量％、５～７０質量％、５～６０質量％である。 The loxoprofen used in the present invention is a compound represented by the chemical formula C15 H 18 O 3 , and is not particularly limited as long as it is pharmaceutically acceptable. Loxoprofen can be produced by a known method, or a commercially available product can be used. The salt of loxoprofen is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include sodium salt, potassium salt, calcium salt and the like, and sodium dihydrate is particularly preferable. Loxoprofen or a salt thereof can be produced by a known method, or a commercially available product can be used. The content of loxoprofen in the pharmaceutical composition of the present invention is not particularly limited as long as it exhibits its medicinal effect, but is usually 5 to 95% by mass, preferably 5 to 90% by mass, 5 to 85% by mass, 5 to It is 80% by mass, 5 to 70% by mass, and 5 to 60% by mass.
本発明に用いられるレボセチリジンは、化学式Ｃ２１Ｈ２５ＣｌＮ２Ｏ３示される化合物であり、医薬的に許容されるものであれば特に限定はしない。また、レボセチリジンの塩は医薬的に許容されるものであれば特に限定されないが、例えば、塩酸塩、臭化水素酸塩、リン酸塩等の無機酸の塩、及び酢酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、フマル酸塩、マレイン酸塩、乳酸塩、リンゴ酸塩、クエン酸塩、酒石酸塩、ヒベンズ酸塩、炭酸塩等の有機酸塩等が挙げられ、特に好ましくは塩酸塩である。レボセチリジン又はその塩は、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。本発明の医薬組成物中におけるレボセチリジン又はその塩の含有量（レボセチリジン又はその塩のうちの２種以上が含有される場合にはそれらの合計含有量、以下同じ）は、その薬効を示す量であれば特に限定されないが、通常０．００１～５０質量％、０．０１～５０質量％、好ましくは０．０１～１０質量％、０．１～１０質量％である。 The levocetirizine used in the present invention is a compound represented by the chemical formula C 21 H 25 ClN 2 O 3 , and is not particularly limited as long as it is pharmaceutically acceptable. The salt of levosetilidine is not particularly limited as long as it is pharmaceutically acceptable, and for example, salts of inorganic acids such as hydrochlorides, hydrobromates, and phosphates, and acetates and oxalates. Examples thereof include organic acid salts such as malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, hibenzate, carbonate and the like, and hydrochloric acid is particularly preferable. It's salt. Levocetirizine or a salt thereof can be produced by a known method, or a commercially available product can be used. The content of levosetilidine or a salt thereof in the pharmaceutical composition of the present invention (when two or more of levosetilidine or a salt thereof are contained, the total content thereof, the same shall apply hereinafter) is an amount indicating the medicinal effect. If there is, it is not particularly limited, but is usually 0.001 to 50% by mass, 0.01 to 50% by mass, preferably 0.01 to 10% by mass, and 0.1 to 10% by mass.
本発明に用いられるカルボシステインは、化学式Ｃ５Ｈ９ＮＯ４Ｓで示される化合物であり、医薬的に許容されるものであれば特に限定はしないが、通常、Ｌ－カルボシステインが使用される。カルボシステインは、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。本発明の医薬組成物中におけるカルボシステインの含有量は、特に限定されないが、通常１～９５質量％、５～８５質量％、好ましくは１０～７０質量％である。 The carbocisteine used in the present invention is a compound represented by the chemical formula C 5 H 9 NO 4 S, and is not particularly limited as long as it is pharmaceutically acceptable, but L-carbocisteine is usually used. .. Carbocisteine can be produced by a known method, or a commercially available product can be used. The content of carbocisteine in the pharmaceutical composition of the present invention is not particularly limited, but is usually 1 to 95% by mass, 5 to 85% by mass, preferably 10 to 70% by mass.
本発明に用いられるチペピジンは、化学式Ｃ１５Ｈ１７ＮＳ２で示される化合物又はその塩であり、これらのうちの一種を単独で用いても二種以上を組み合わせて用いてもよい。このようなチペピジン又はその塩としては、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。また、チペピジン又はその塩は医薬的に許容されるものであれば特に限定されないが、前記塩とは、例えば、塩酸塩、臭化水素酸塩、リン酸塩等の無機酸の塩、及び酢酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、フマル酸塩、マレイン酸塩、乳酸塩、リンゴ酸塩、クエン酸塩、酒石酸塩、ヒベンズ酸塩、炭酸塩等の有機酸塩等が挙げられ、特に好ましくはヒベンズ酸塩である。本発明の医薬組成物中におけるチペピジン又はその塩の含有量（チペピジン又はその塩のうちの２種以上が含有される場合にはそれらの合計含有量、以下同じ）は、その薬効を示す量であれば特に限定されないが、通常０．１～５０質量％、０．１～３０質量％、好ましくは１～３０質量％である。 The tipepidine used in the present invention is a compound represented by the chemical formula C15 H 17 NS 2 or a salt thereof, and one of these may be used alone or in combination of two or more. As such tipepidine or a salt thereof, it can be produced by a known method or a commercially available product can be used. The tipepidin or a salt thereof is not particularly limited as long as it is pharmaceutically acceptable, but the salt is, for example, a salt of an inorganic acid such as a hydrochloride, a hydrobromide, a phosphate, and an acetic acid. Examples include salts, oxalates, malonates, succinates, fumarates, maleates, lactates, malates, citrates, tartrates, hibenzates, organic acid salts such as carbonates, etc. It is particularly preferable to use hibenzate. The content of tipepidine or a salt thereof in the pharmaceutical composition of the present invention (when two or more of tipepidine or a salt thereof are contained, the total content thereof, the same shall apply hereinafter) is an amount indicating the medicinal effect. If there is, it is not particularly limited, but it is usually 0.1 to 50% by mass, 0.1 to 30% by mass, and preferably 1 to 30% by mass.
本発明に用いられるデキストロメトルファンは、化学式Ｃ１８Ｈ２５ＮＯで示される化合物又はその塩であり、これらのうちの一種を単独で用いても二種以上を組み合わせて用いてもよい。このようなデキストロメトルファン又はその塩としては、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。また、デキストロメトルファン又はその塩は医薬的に許容されるものであれば特に限定されないが、前記塩とは、例えば、塩酸塩、臭化水素酸塩、リン酸塩等の無機酸の塩、及び酢酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、フマル酸塩、マレイン酸塩、乳酸塩、リンゴ酸塩、クエン酸塩、酒石酸塩、臭化水素酸塩、フェノールフタリン塩、炭酸塩等の有機酸塩等が挙げられ、特に好ましくは臭化水素酸塩である。本発明の医薬組成物中におけるデキストロメトルファン又はその塩の含有量（デキストロメトルファン又はその塩のうちの２種以上が含有される場合にはそれらの合計含有量、以下同じ）は、その薬効を示す量であれば特に限定されないが、通常０．１～９０質量％、０．１～５０質量％、好ましくは０．５～３０質量％である。 The dextromethorphan used in the present invention is a compound represented by the chemical formula C 18 H 25 NO or a salt thereof, and one of these may be used alone or in combination of two or more. As such dextromethorphan or a salt thereof, it can be produced by a known method, or a commercially available product can be used. The dextrometholphan or a salt thereof is not particularly limited as long as it is pharmaceutically acceptable, but the salt is, for example, a salt of an inorganic acid such as a hydrochloride salt, a hydrobromide salt, or a phosphate salt. And acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, hydrobromide, phenolphthaline salt, carbonic acid Examples thereof include organic acid salts such as salts, and particularly preferably hydrobromide. The content of dextromethorphan or a salt thereof in the pharmaceutical composition of the present invention (if two or more of dextromethorphan or a salt thereof are contained, the total content thereof, the same shall apply hereinafter) is the medicinal effect thereof. The amount is not particularly limited as long as it indicates the above, but is usually 0.1 to 90% by mass, 0.1 to 50% by mass, and preferably 0.5 to 30% by mass.
本発明に用いられるプソイドエフェドリンは、化学式Ｃ１０Ｈ１５ＮＯ示される化合物であり、医薬的に許容されるものであれば特に限定はしない。また、プソイドエフェドリンの塩は医薬的に許容されるものであれば特に限定されないが、例えば、塩酸塩、臭化水素酸塩、リン酸塩等の無機酸の塩、及び酢酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、フマル酸塩、マレイン酸塩、乳酸塩、リンゴ酸塩、クエン酸塩、酒石酸塩、ヒベンズ酸塩、炭酸塩等の有機酸塩等が挙げられ、特に好ましくは塩酸塩である。プソイドエフェドリン又はその塩は、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。本発明の医薬組成物中におけるプソイドエフェドリン又はその塩の含有量（プソイドエフェドリン又はその塩のうちの２種以上が含有される場合にはそれらの合計含有量、以下同じ）は、その薬効を示す量であれば特に限定されないが、通常１～９５質量％、好ましくは１．５～９０質量％、１．５～８５質量％、１．５～８０質量％、１．５～７０質量％、１．５～２０質量％である。 The pseudoephedrine used in the present invention is a compound represented by the chemical formula C 10 H 15 NO, and is not particularly limited as long as it is pharmaceutically acceptable. The salt of pseudoefedrin is not particularly limited as long as it is pharmaceutically acceptable, and for example, salts of inorganic acids such as hydrochlorides, hydrobromates, and phosphates, and acetates and oxalates. Examples thereof include organic acid salts such as malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, hibenzate, carbonate and the like, and hydrochloric acid is particularly preferable. It's salt. Pseudoephedrine or a salt thereof can be produced by a known method, or a commercially available product can be used. The content of pseudoephedrine or a salt thereof in the pharmaceutical composition of the present invention (when two or more of pseudoephedrine or a salt thereof are contained, the total content thereof, the same shall apply hereinafter) is an amount indicating the medicinal effect. If there is no particular limitation, it is usually 1 to 95% by mass, preferably 1.5 to 90% by mass, 1.5 to 85% by mass, 1.5 to 80% by mass, 1.5 to 70% by mass, 1. It is 5 to 20% by mass.
本発明に用いられるジメモルファンは、化学式１８Ｈ２５ＮＣ示される化合物であり、医薬的に許容されるものであれば特に限定はしない。また、ジメモルファンの塩は医薬的に許容されるものであれば特に限定されないが、例えば、塩酸塩、臭化水素酸塩、リン酸塩等の無機酸の塩、及び酢酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、フマル酸塩、マレイン酸塩、乳酸塩、リンゴ酸塩、クエン酸塩、酒石酸塩、ヒベンズ酸塩、炭酸塩等の有機酸塩等が挙げられ、特に好ましくはリン酸塩である。ジメモルファン又はその塩は、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。本発明の医薬組成物中におけるジメモルファン又はその塩の含有量（ジメモルファン又はその塩のうちの２種以上が含有される場合にはそれらの合計含有量、以下同じ）は、その薬効を示す量であれば特に限定されないが、通常０．０１～５０質量％、好ましくは０．１～３０質量％である。 The dimemorfan used in the present invention is a compound represented by the chemical formula 18 H25 NC, and is not particularly limited as long as it is pharmaceutically acceptable. The salt of dimemorphan is not particularly limited as long as it is pharmaceutically acceptable, and for example, salts of inorganic acids such as hydrochlorides, hydrobromates, and phosphates, and acetates and oxalates. Examples thereof include organic acid salts such as malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, hibenzate, carbonate and the like, and phosphorus is particularly preferable. It is a salt salt. Dimemorfan or a salt thereof can be produced by a known method, or a commercially available product can be used. The content of dimemorfan or a salt thereof in the pharmaceutical composition of the present invention (when two or more of dimemorfan or a salt thereof are contained, the total content thereof, the same shall apply hereinafter) is an amount indicating the medicinal effect. If there is, it is not particularly limited, but it is usually 0.01 to 50% by mass, preferably 0.1 to 30% by mass.
本発明に用いられるメチルエフェドリンは、化学式Ｃ１１Ｈ１７ＮＯ示される化合物であり、医薬的に許容されるものであれば特に限定はしない。また、メチルエフェドリンの塩は医薬的に許容されるものであれば特に限定されないが、例えば、塩酸塩、臭化水素酸塩、リン酸塩等の無機酸の塩、及び酢酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、フマル酸塩、マレイン酸塩、乳酸塩、リンゴ酸塩、クエン酸塩、酒石酸塩、ヒベンズ酸塩、炭酸塩等の有機酸塩等が挙げられ、特に好ましくは塩酸塩である。メチルエフェドリン又はその塩は、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。本発明の医薬組成物中におけるメチルエフェドリン又はその塩の含有量（メチルエフェドリン又はその塩のうちの２種以上が含有される場合にはそれらの合計含有量、以下同じ）は、その薬効を示す量であれば特に限定されないが、通常０．０１～５０質量％、好ましくは０．０５～１０質量％である。 The methylephedrine used in the present invention is a compound represented by the chemical formula C 11 H 17 NO, and is not particularly limited as long as it is pharmaceutically acceptable. The salt of methylephedrine is not particularly limited as long as it is pharmaceutically acceptable, and for example, salts of inorganic acids such as hydrochlorides, hydrobromates, and phosphates, and acetates and oxalates. , Malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, hibenzate, organic acid salts such as carbonate, etc. are particularly preferable. It is a hydrochloride. Methylephedrine or a salt thereof can be produced by a known method, or a commercially available product can be used. The content of methylephedrine or a salt thereof in the pharmaceutical composition of the present invention (when two or more of methylephedrine or a salt thereof are contained, the total content thereof, the same shall apply hereinafter) indicates the medicinal effect. The amount is not particularly limited, but is usually 0.01 to 50% by mass, preferably 0.05 to 10% by mass.
また、（ａ）ロキソプロフェン又はその塩と（ｂ）レボセチリジン又はその塩の配合比は、特に限定されないが、レボセチリジン及びその塩１質量部に対し、ロキソプロフェン６質量部以上、１２質量部以上が好ましい。レボセチリジン及びその塩の経時的な含量低下が顕著になるからである。上限は特に限定されないが、３６質量部、１８質量部としてもよい。 The blending ratio of (a) loxoprofen or a salt thereof and (b) levosetilidine or a salt thereof is not particularly limited, but is preferably 6 parts by mass or more and 12 parts by mass or more of loxoprofen with respect to 1 part by mass of levosetilidine and its salt. This is because the content of levocetirizine and its salt decreases significantly with time. The upper limit is not particularly limited, but may be 36 parts by mass or 18 parts by mass.
また、（ａ）レボセチリジン及びその塩と、（ｃ）カルボシステインの配合比は、発明の効果の点からレボセチリジン及びその塩１質量部に対し、カルボシステインを４質量部以上が好ましく、２５質量部以上、５０質量部以上でもよい。また、上限は特に限定されず、１５０質量部、７５質量部としてもよい。 Further, the compounding ratio of (a) levosetilidine and its salt to (c) carbocisteine is preferably 4 parts by mass or more, preferably 25 parts by mass, based on 1 part by mass of levosetilidine and its salt, from the viewpoint of the effect of the invention. As mentioned above, it may be 50 parts by mass or more. The upper limit is not particularly limited, and may be 150 parts by mass or 75 parts by mass.
（ａ）レボセチリジン及びその塩と、（ｃ）チペピジン及びその塩の配合比は、レボセチリジン及びその塩１質量部に対し、発明の効果の点からチペピジン及びその塩を１質量部、２質量部以上が好ましく、２．５質量部以上、５質量部以上がより好ましく、４質量部以上としてもよい。また、上限は特に限定されず、１５質量部、７．５質量部、３．７５質量部としてもよい。 The compounding ratio of (a) levosetilidine and its salt and (c) tipepidin and its salt is 1 part by mass or more of tipepidine and its salt with respect to 1 part by mass of levosetilidine and its salt from the viewpoint of the effect of the invention. It is preferably 2.5 parts by mass or more, more preferably 5 parts by mass or more, and may be 4 parts by mass or more. The upper limit is not particularly limited, and may be 15 parts by mass, 7.5 parts by mass, or 3.75 parts by mass.
（ａ）レボセチリジン及びその塩と、（ｃ）デキストロメトルファン及びその塩の配合比は、レボセチリジン及びその塩１質量部に対し、発明の効果の点からデキストロメトルファン及びその塩を０．５質量部以上、０．８質量部以上、１質量部以上が好ましく、１．６質量部以上、２．４質量部以上、３．２質量部以上がより好ましい。また、上限は特に限定されず、１０質量部としてもよく、９．６質量部、４質量部としてもよい。 The compounding ratio of (a) levosetilidine and its salt and (c) dextrometholphan and its salt is 0.5% by mass of dextromethruphan and its salt from the viewpoint of the effect of the invention with respect to 1 part by mass of levosetilidine and its salt. More than parts, 0.8 parts by mass or more, 1 part by mass or more is preferable, and 1.6 parts by mass or more, 2.4 parts by mass or more, and 3.2 parts by mass or more are more preferable. The upper limit is not particularly limited, and may be 10 parts by mass, 9.6 parts by mass, or 4 parts by mass.
（ａ）レボセチリジン及びその塩と、（ｃ）プソイドエフェドリン及びその塩の配合比は、レボセチリジン及びその塩１質量部に対し、発明の効果の点からプソイドエフェドリン及びその塩を２質量部以上、４質量部以上、４．５質量部以上、９質量部以上が好ましく、また、上限は特に限定されず、２７質量部、１３．５質量部、１２質量部としてもよい。 The compounding ratio of (a) levosetilidine and its salt and (c) pseudoephedrine and its salt is 2 parts by mass or more and 4 parts by mass of psoid efedrin and its salt with respect to 1 part by mass of levosetilidine and its salt from the viewpoint of the effect of the invention. As described above, 4.5 parts by mass or more and 9 parts by mass or more are preferable, and the upper limit is not particularly limited, and may be 27 parts by mass, 13.5 parts by mass, or 12 parts by mass.
（ａ）レボセチリジン及びその塩と、（ｃ）ジメモルファン及びその塩の配合比は、レボセチリジン及びその塩１質量部に対し、発明の効果の点からジメモルファン及びその塩を０．５質量部以上、１質量部以上、２質量部以上、４質量部以上が好ましく、また、上限は特に限定されず、１０質量部としてもよく、９．６質量部、４質量部としてもよい。 The mixing ratio of (a) levosetilidine and its salt and (c) dimemorphan and its salt is 0.5 parts by mass or more of dimemorphan and its salt with respect to 1 part by mass of levosetilidine and its salt from the viewpoint of the effect of the invention. It is preferably 2 parts by mass or more and 4 parts by mass or more, and the upper limit is not particularly limited, and may be 10 parts by mass or 9.6 parts by mass or 4 parts by mass.
（ａ）レボセチリジン及びその塩と、（ｃ）メチルエフェドリン及びその塩の配合比は、レボセチリジン及びその塩１質量部に対し、発明の効果の点からメチルエフェドリン及びその塩を０．５質量部以上、１質量部以上、２質量部以上、４質量部以上が好ましく、また、上限は特に限定されず、１５質量部、７．５質量部、３．７５質量部としてもよい。 The compounding ratio of (a) levosetilidine and its salt and (c) methylefedrin and its salt is 0.5 parts by mass or more of methylefedrin and its salt with respect to 1 part by mass of levosetilidine and its salt from the viewpoint of the effect of the invention. It is preferably 1 part by mass or more, 2 parts by mass or more and 4 parts by mass or more, and the upper limit is not particularly limited and may be 15 parts by mass, 7.5 parts by mass or 3.75 parts by mass.
本発明の医薬組成物中には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、賦形剤、崩壊剤、結合剤、流動化剤、滑沢剤、清涼化剤、着色剤、甘味剤、吸着剤、懸濁剤、抗酸化剤、安定化剤、界面活性剤、可塑剤、可溶化剤、乳化剤、ｐH調節剤、緩衝剤、矯味矯臭剤、清涼化剤、香料、コーティング剤などを配合することができる。 In the pharmaceutical composition of the present invention, other active ingredients, excipients, disintegrants, binders, fluidizers, lubricants, which are usually used, within a qualitative and quantitative range that does not impair the effects of the present invention. Cooling agents, colorants, sweeteners, adsorbents, suspending agents, antioxidants, stabilizers, surfactants, plasticizers, solubilizers, emulsifiers, pH adjusters, buffers, flavoring agents, cooling agents Agents, fragrances, coating agents and the like can be blended.
本発明の医薬組成物に配合できる他の有効成分としては、例えば、解熱鎮痛剤、抗ヒスタミン剤、鎮咳剤、ノスカピン類、気管支拡張剤、去痰剤、催眠鎮静剤、ビタミン類、抗炎症剤、胃粘膜保護剤、生薬類、漢方処方、カフェイン類等があげられ、これらからなる群より選ばれる１種又は２種以上を含有しても良い。 Other active ingredients that can be incorporated into the pharmaceutical composition of the present invention include, for example, antipyretic analgesics, antihistamines, antitussives, noscapines, bronchodilators, sputum sedatives, hypnotic sedatives, vitamins, anti-inflammatory agents, gastric mucosa protection. Examples thereof include agents, crude drugs, Chinese herbal formulas, caffeines and the like, and one or more selected from the group consisting of these may be contained.
本発明の医薬組成物に配合できる賦形剤としては、例えば、乳糖、デンプン類、結晶セルロース、ショ糖、糖アルコール等が挙げられ、崩壊剤としては、低置換度ヒドロキシプロピルセルロース、デンプングリコール酸ナトリウム、クロスポビドン、カルメロース、カルメロースナトリウム、カルメロースカルシウム、アルファー化デンプン等が挙げられ、結合剤としては、ヒドロキシプロピルセルロース、ヒプロメロース、ゼラチン、アルファー化デンプン、ポリビニルピロリドン、プルラン等が挙げられ、流動化剤としては、軽質無水ケイ酸、含水二酸化ケイ素等が挙げられ、滑沢剤としては、ショ糖脂肪酸エステル、硬化油、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム等が挙げられ、清涼化剤としては、メントール、ハッカ油、ユーカリ油等が挙げられる。 Examples of excipients that can be blended in the pharmaceutical composition of the present invention include lactose, starches, crystalline cellulose, sucrose, sugar alcohol and the like, and examples of disintegrants include low-substituted hydroxypropyl cellulose and starch glycolic acid. Examples thereof include sodium, crospovidone, carmellose, carmellose sodium, carmellose calcium, pregelatinized starch and the like, and examples of the binder include hydroxypropyl cellulose, hypromellose, gelatin, pregelatinized starch, polyvinylpyrrolidone, purulan and the like. Examples of the agent include light anhydrous silicic acid, hydrous silicon dioxide and the like, and examples of the lubricant include sucrose fatty acid ester, hardened oil, stearic acid, magnesium stearate, calcium stearate and the like, and examples of the refreshing agent include sucrose fatty acid ester. Examples include menthol, starch oil, eucalyptus oil and the like.
本発明の医薬組成物は、日本薬局方の製剤通則に規定されている剤形であれば特に限定
されず、通常使用され得る任意の剤形をとることができる。例えば、錠剤、散剤、細粒剤
、顆粒剤、丸剤、カプセル剤などの固形製剤、又は経口液剤、シロップ剤などの液剤が挙
げられる。好ましくは錠剤、散剤、細粒剤、顆粒剤、丸剤、カプセル剤（好ましくは硬カプセル剤）である。日本薬局方の製剤通則に規定されている錠剤には、口腔内崩壊錠、チュアブル錠、発泡錠、分散錠及び溶解錠、フィルムコーティング錠、糖衣錠、有核錠、積層錠などが含まれる。また、錠剤に割線や識別性向上のためのマーク、刻印を設けることができる。さらに、本製剤の錠剤は、丸錠であってもよいし、異型錠であってもよい。
The pharmaceutical composition of the present invention is not particularly limited as long as it is in the dosage form specified in the general formulation rules of the Japanese Pharmacopoeia, and can be in any dosage form that can be normally used. Examples thereof include solid preparations such as tablets, powders, fine granules, granules, pills and capsules, and liquid preparations such as oral liquids and syrups. It is preferably a tablet, a powder, a fine granule, a granule, a pill, or a capsule (preferably a hard capsule). The tablets specified in the general formulation rules of the Japanese Pharmacopoeia include orally disintegrating tablets, chewable tablets, effervescent tablets, dispersion tablets and dissolving tablets, film-coated tablets, sugar-coated tablets, nucleated tablets, laminated tablets and the like. In addition, a score line, a mark for improving distinctiveness, and an engraving can be provided on the tablet. Further, the tablet of this preparation may be a round tablet or a variant tablet.
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。
例えば、（ａ）ロキソプロフェン又はその塩（以下、（ａ）成分ともいう）、（ｂ）レボセチリジン又はその塩（以下、（ｂ）成分ともいう）、（ｃ）カルボシステイン、チペピジン及びその塩、デキストロメトルファン及びその塩、プソイドエフェドリン及びその塩、ジメモルファン及びその塩，並びにメチルエフェドリン及びその塩からなる群より選ばれる少なくとも１種（以下、（ｃ）成分ともいう）を単に混合するだけでも良く、混合後に造粒しても良く、得られた造粒物を被覆してもよい。また、（ａ）成分、（ｂ）成分又は（ｃ）成分は必ずしも同一の造粒物に含まれている必要はない。 例えば、（ａ）成分と（ｃ）成分を含有する造粒物を製造後に、（ｂ）成分を混合する、あるいは、（ａ）成分と（ｂ）成分を含有する造粒物を製造後に、（ｃ）成分を混合する、あるいは、（ａ）成分と（ｃ）成分を含有する造粒物と、（ｂ）成分と（ｃ）成分を含有する造粒物を製造後、２つの造粒物を混合する、等である。
The solid preparation of the present invention can be produced by a conventional method, and the method is not particularly limited.
For example, (a) loxoprofen or a salt thereof (hereinafter, also referred to as a component (a)), (b) levosetilidine or a salt thereof (hereinafter, also referred to as a component (b)), (c) carbocysteine, tipepidin and a salt thereof, dexto. At least one selected from the group consisting of rometorphan and its salt, pseudoefedrin and its salt, dimemorfane and its salt, and methylefedrin and its salt (hereinafter, also referred to as component (c)) may be simply mixed or mixed. It may be granulated later, or the obtained granulated product may be coated. Further, the component (a), the component (b) or the component (c) do not necessarily have to be contained in the same granulated product. For example, after producing the granulated product containing the component (a) and the component (c), the component (b) is mixed, or after the granulated product containing the component (a) and the component (b) is produced. After producing (c) a mixture of components, or a granulated product containing (a) and (c) components, and a granulated product containing (b) and (c) components, two granulations are performed. Mix things, etc.
造粒方法も特に限定されず、湿式造粒法、乾式造粒法又は溶融造粒法などにより製造できるが、好ましくは湿式造粒法である。湿式造粒法には、例えば撹拌造粒法、流動層造粒法、練合造粒法、押し出し造粒法、転動流動造粒法が挙げられる。また得られた造粒物に適宜上記有効成分や賦形剤などの慣用の製剤添加剤を配合してもよい。また、このようにして得た混合物を打錠して錠剤とすることもできる。錠剤を製造する場合は、直接打錠法により製造してもよい。 The granulation method is not particularly limited, and the product can be produced by a wet granulation method, a dry granulation method, a melt granulation method, or the like, but a wet granulation method is preferable. Examples of the wet granulation method include a stirring granulation method, a fluidized bed granulation method, a kneading granulation method, an extrusion granulation method, and a rolling flow granulation method. Further, a conventional pharmaceutical additive such as the above active ingredient or an excipient may be appropriately added to the obtained granulated product. Further, the mixture thus obtained can be tableted into tablets. When the tablet is produced, it may be produced by the direct tableting method.
以下に実施例、対照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。
（対照例１）
レボセチリジン塩酸塩に適量の水／アルコール混液を加え混合した後乾燥し組成物を得た。
（比較例１）
レボセチリジン塩酸塩１質量部に対し、ロキソプロフェンナトリウム水和物１０質量部を量り取り混合し、これに適量の水／アルコール混液を加え混合した後乾燥し組成物を得た。
（比較例２）
レボセチリジン塩酸塩１質量部に対し、ロキソプロフェンナトリウム水和物１０質量部及び結晶セルロース４質量部を量り取り混合し、これに適量の水／アルコール混液を加え混合した後乾燥し組成物を得た。
（実施例１）
レボセチリジン塩酸塩１質量部に対し、ロキソプロフェンナトリウム水和物１０質量部及びＬ－カルボシステイン４質量部を量り取り混合し、これに適量の水／アルコール混液を加え混合した後乾燥し組成物を得た。
（実施例２）
レボセチリジン塩酸塩１質量部に対し、ロキソプロフェンナトリウム水和物１０質量部及びチペピジンヒベンズ酸塩４質量部を量り取り混合し、これに適量の水／アルコール混液を加え混合した後乾燥し組成物を得た。
（実施例３）
レボセチリジン塩酸塩１質量部に対し、ロキソプロフェンナトリウム水和物１０質量部及びデキストロメトルファン臭化水素酸塩水和物４質量部を量り取り混合し、これに適量の水／アルコール混液を加え混合した後乾燥し組成物を得た。
（実施例４）
レボセチリジン塩酸塩１質量部に対し、ロキソプロフェンナトリウム水和物１０質量部、プソイドエフェドリン塩酸塩２質量部及び乳糖７質量部を量り取り混合し、これに適量の水／アルコール混液を加え混合した後乾燥し組成物を得た。
Hereinafter, the present invention will be described in more detail with reference to Examples, Control Examples and Comparative Examples, but the present invention is not limited to these Examples and the like.
(Control Example 1)
An appropriate amount of water / alcohol mixture was added to levocetirizine hydrochloride, mixed, and then dried to obtain a composition.
(Comparative Example 1)
10 parts by mass of loxoprofen sodium hydrate was weighed and mixed with 1 part by mass of levocetirizine hydrochloride, an appropriate amount of water / alcohol mixed solution was added thereto, and the mixture was mixed and dried to obtain a composition.
(Comparative Example 2)
10 parts by mass of loxoprofen sodium hydrate and 4 parts by mass of crystalline cellulose were weighed and mixed with 1 part by mass of levocetirizine hydrochloride, an appropriate amount of water / alcohol mixed solution was added thereto, and the mixture was mixed and dried to obtain a composition.
(Example 1)
Weigh 10 parts by mass of loxoprofen sodium hydrate and 4 parts by mass of L-carbocisteine with respect to 1 part by mass of levocetirizine hydrochloride, add an appropriate amount of water / alcohol mixture, mix, and then dry to obtain a composition. rice field.
(Example 2)
10 parts by mass of loxoprofen sodium hydrate and 4 parts by mass of tipepidine hibenzate were weighed and mixed with 1 part by mass of levosetilidine hydrochloride, and an appropriate amount of water / alcohol mixture was added and mixed, and then dried to obtain a composition. rice field.
(Example 3)
Weigh 10 parts by mass of loxoprofen sodium hydrate and 4 parts by mass of dextromethorphan hydrobromide hydrate with respect to 1 part by mass of levosetilidine hydrochloride, add an appropriate amount of water / alcohol mixture to the mixture, and then mix. It was dried to obtain a composition.
(Example 4)
10 parts by mass of loxoprofen sodium hydrate, 2 parts by mass of pseudoephedrine hydrochloride and 7 parts by mass of lactose were weighed and mixed with 1 part by mass of levosetilidine hydrochloride, and an appropriate amount of water / alcohol mixture was added and mixed, and then dried. The composition was obtained.
（試験方法）
対照例、比較例及び実施例の組成物を６５℃にて１４日間保存し、１４日後における組成物中のレボセチリジン塩酸塩の残存率をＨＰＬＣ法により評価した。
表１に、６５℃１４日保存後のレボセチリジン塩酸塩残存率（％）を示した。
(Test method)
The compositions of Control Examples, Comparative Examples and Examples were stored at 65 ° C. for 14 days, and the residual ratio of levocetirizine hydrochloride in the composition after 14 days was evaluated by the HPLC method.
Table 1 shows the residual rate (%) of levocetirizine hydrochloride after storage at 65 ° C. for 14 days.
表１に示すように、ロキソプロフェンナトリウム水和物とレボセチリジン塩酸塩を配合した比較例１～２ではレボセチリジン塩酸塩の含量に低下が確認された。一方、Ｌ－カルボシステイン、チペピジンヒベンズ酸塩、デキストロメトルファン臭化水素酸塩水和物、及びプソイドエフェドリン塩酸塩を配合した実施例１～４では、レボセチリジン塩酸塩の含量の低下を抑制することができた。 As shown in Table 1, in Comparative Examples 1 and 2 in which loxoprofen sodium hydrate and levocetirizine hydrochloride were blended, a decrease in the content of levocetirizine hydrochloride was confirmed. On the other hand, in Examples 1 to 4 in which L-carbocisteine, tipepidine hibenzate, dextromethorphan hydrobromide hydrate, and pseudoephedrine hydrochloride were blended, the decrease in the content of levosetilidine hydrochloride could be suppressed. rice field.
（実施例５）
レボセチリジン塩酸塩１質量部に対し、ロキソプロフェンナトリウム水和物１０質量部、チペピジンヒベンズ酸塩１質量部を量り取り混合し、これに適量の水／アルコール混液を加え混合した後乾燥し組成物を得た。
（実施例６）
レボセチリジン塩酸塩１質量部に対し、ロキソプロフェンナトリウム水和物１０質量部、デキストロメトルファン臭化水素酸塩水和物１．６質量部を量り取り混合し、これに適量の水／アルコール混液を加え混合した後乾燥し組成物を得た。
（実施例７）
レボセチリジン塩酸塩１質量部に対し、ロキソプロフェンナトリウム水和物１０質量部、ジメモルファンリン酸塩１質量部を量り取り混合し、これに適量の水／アルコール混液を加え混合した後乾燥し組成物を得た。
（実施例８）
レボセチリジン塩酸塩１質量部に対し、ロキソプロフェンナトリウム水和物１０質量部、ｄｌ－メチルエフェドリン塩酸塩１質量部を量り取り混合し、これに適量の水／アルコール混液を加え混合した後乾燥し組成物を得た。
(Example 5)
10 parts by mass of loxoprofen sodium hydrate and 1 part by mass of tipepidine hibenzate were weighed and mixed with 1 part by mass of levosetilidine hydrochloride, and an appropriate amount of water / alcohol mixture was added and mixed, and then dried to obtain a composition. rice field.
(Example 6)
Weigh 10 parts by mass of loxoprofen sodium hydrate and 1.6 parts by mass of dextromethorphan hydrobromide hydrate with 1 part by mass of levosetilidine hydrochloride, and add an appropriate amount of water / alcohol mixture to mix. Then, it was dried to obtain a composition.
(Example 7)
Weigh 10 parts by mass of loxoprofen sodium hydrate and 1 part by mass of dimemorphan phosphate with 1 part by mass of levosetilidine hydrochloride, add an appropriate amount of water / alcohol mixture, mix, and then dry the composition. Got
(Example 8)
10 parts by mass of loxoprofen sodium hydrate and 1 part by mass of dl-methylephedrine hydrochloride were weighed and mixed with 1 part by mass of levosetilidine hydrochloride, an appropriate amount of water / alcohol mixed solution was added thereto, and the mixture was dried and dried. Got
（試験方法）
実施例の組成物を６５℃にて１４日間保存し、１４日後における組成物中のレボセチリジン塩酸塩の残存率をＨＰＬＣ法により評価した。
表２に、６５℃１４日保存後のレボセチリジン塩酸塩残存率（％）を示した。
(Test method)
The composition of the example was stored at 65 ° C. for 14 days, and the residual ratio of levocetirizine hydrochloride in the composition after 14 days was evaluated by the HPLC method.
Table 2 shows the residual rate (%) of levocetirizine hydrochloride after storage at 65 ° C. for 14 days.
表１の比較例１～２で確認されたレボセチリジン塩酸塩の含量の低下が、チペピジンヒベンズ酸塩、デキストロメトルファン臭化水素酸塩水和物、ジメモルファンリン酸塩及びｄｌ－メチルエフェドリン塩酸塩を配合した実施例５～８では抑制されていることが明らかとなった。 The decrease in the content of levosetilidine hydrochloride confirmed in Comparative Examples 1 and 2 in Table 1 was due to the decrease in the content of tipepidin hibenzate, dextromethorphan hydrobromide hydrate, dimemorphan phosphate and dl-methylephedrine hydrochloride. It was clarified that it was suppressed in Examples 5 to 8 in which the above was blended.
以下に製剤調製例を挙げる。
製剤例１～１２
表３及び表４記載の処方例について、公知の技術を用いて錠剤、散剤又は顆粒剤を製造する。得られる散剤又は顆粒剤を、公知の技術を用いて、硬カプセルに充填し、硬カプセル剤を製造する。
Examples of pharmaceutical product preparation are given below.
Formulation Examples 1 to 12
For the formulation examples shown in Tables 3 and 4, tablets, powders or granules are produced using known techniques. The obtained powder or granule is filled into a hard capsule using a known technique to produce a hard capsule.
本発明により、ロキソプロフェン又はその塩及びレボセチリジン又はその塩を含有し、レボセチリジン及びその塩の安定性に優れた医薬組成物の提供が可能となった。 INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to provide a pharmaceutical composition containing loxoprofen or a salt thereof and levocetirizine or a salt thereof and having excellent stability of levocetirizine and the salt thereof.
Claims (17)
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