JP2022008041A - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
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- JP2022008041A JP2022008041A JP2021065659A JP2021065659A JP2022008041A JP 2022008041 A JP2022008041 A JP 2022008041A JP 2021065659 A JP2021065659 A JP 2021065659A JP 2021065659 A JP2021065659 A JP 2021065659A JP 2022008041 A JP2022008041 A JP 2022008041A
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 64
- 150000003839 salts Chemical class 0.000 claims abstract description 212
- 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 38
- 229960001508 levocetirizine Drugs 0.000 claims abstract description 38
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims abstract description 32
- 229960001680 ibuprofen Drugs 0.000 claims abstract description 29
- 229960004949 glycyrrhizic acid Drugs 0.000 claims abstract description 28
- 235000019410 glycyrrhizin Nutrition 0.000 claims abstract description 28
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 claims abstract description 28
- 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
- 229960001056 dimemorfan Drugs 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
- 229960001985 dextromethorphan 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 22
- 229960000896 tipepidine Drugs 0.000 claims abstract description 21
- 229960005174 ambroxol Drugs 0.000 claims abstract description 19
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 claims abstract description 19
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 claims abstract description 19
- 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 18
- 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 18
- 229960004399 carbocisteine Drugs 0.000 claims abstract description 18
- 229960002221 methylephedrine Drugs 0.000 claims abstract description 18
- 229960000401 tranexamic acid Drugs 0.000 claims abstract description 18
- 229960003870 bromhexine Drugs 0.000 claims abstract description 14
- OJGDCBLYJGHCIH-UHFFFAOYSA-N bromhexine Chemical compound C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N OJGDCBLYJGHCIH-UHFFFAOYSA-N 0.000 claims abstract description 14
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 claims description 19
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 claims description 19
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 claims description 18
- 239000001685 glycyrrhizic acid Substances 0.000 claims description 18
- BIVBRWYINDPWKA-VLQRKCJKSA-L Glycyrrhizinate dipotassium Chemical compound [K+].[K+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O BIVBRWYINDPWKA-VLQRKCJKSA-L 0.000 claims description 10
- 229940101029 dipotassium glycyrrhizinate Drugs 0.000 claims description 9
- 239000000843 powder Substances 0.000 claims description 9
- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 claims description 8
- 239000008187 granular material Substances 0.000 claims description 8
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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 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
- 229960002335 bromhexine hydrochloride Drugs 0.000 claims description 4
- 229940073563 dl- methylephedrine hydrochloride Drugs 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- YRSGDLIATOURQO-UHFFFAOYSA-N ethyl 4-acetyl-5-oxohexanoate Chemical group CCOC(=O)CCC(C(C)=O)C(C)=O YRSGDLIATOURQO-UHFFFAOYSA-N 0.000 claims description 4
- GVLGAFRNYJVHBC-UHFFFAOYSA-N hydrate;hydrobromide Chemical compound O.Br GVLGAFRNYJVHBC-UHFFFAOYSA-N 0.000 claims description 4
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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
- 239000000203 mixture Substances 0.000 description 46
- 238000000034 method Methods 0.000 description 29
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- 235000001453 Glycyrrhiza echinata Nutrition 0.000 description 7
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 7
- 235000017382 Glycyrrhiza lepidota Nutrition 0.000 description 7
- 229910019142 PO4 Inorganic materials 0.000 description 7
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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 5
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Abstract
Description
本発明は、イブ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 ibuprofen and levocetirizine or a salt thereof.
イブプロフェンは、関節リウマチ、関節痛及び関節炎、神経痛及び神経炎、背腰痛、頸腕症候群、子宮付属器炎、月経困難症、紅斑（結節性紅斑、多形滲出性紅斑、遠心性環状紅斑）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、解熱鎮痛薬に加え、総合感冒薬の解熱鎮痛成分として広く配合されている（非特許文献１）。 Ibuprofen is effective for rheumatoid arthritis, arthralgia and arthritis, nerve pain and neuritis, back and back pain, cervical arm syndrome, uterine adnexitis, menstrual difficulty, erythema (erythema nodosum, polymorphic exudative erythema, efferent annular erythema) In addition, it is also effective in relieving fever and analgesia of acute erythema (including acute erythema with acute bronchitis), and is widely used as an anti-fever analgesic ingredient in general erythema drugs in addition to anti-fever analgesics. (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).
アンブロキソール及びその塩は、肺表面活性物質の分泌促進作用、気道液の分泌促進作用及び線毛運動亢進作用を有し、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、塵肺症、手術後の喀痰喀出困難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、またスイッチＯＴＣ成分として認可され、総合感冒薬や鎮咳去痰薬に配合されている（非特許文献４）。 Ambroxol and its salts have an action to promote the secretion of lung surface active substances, an action to promote the secretion of airway fluid, and an action to enhance the motility of the filiformis, and have acute bronchitis, bronchial asthma, chronic bronchitis, bronchiectasis, pulmonary tuberculosis, It is widely known as a compound having an excellent expectorant action against dust pneumonia and difficulty in sputum production after surgery, and has been approved as a switch OTC component and is incorporated into general sensitizers and antitussive expectorants (Non-Patent Document 4). ..
トラネキサム酸は抗アレルギー・抗炎症作用を有し、扁桃炎、咽喉頭炎における咽頭痛・発赤・充血・腫脹等の症状対する優れた効果を示すことから、総合感冒薬や鎮咳去痰薬、鼻炎薬等に広く配合されている（非特許文献５）。 Tranexamic acid has anti-allergic and anti-inflammatory effects, and has excellent effects on symptoms such as sore throat, redness, congestion, and swelling in tonsillitis and sore throat. Etc. (Non-Patent Document 5).
グリチルリチン酸及びその塩は、カンゾウ（甘草）に含まれる成分として広く知られており、消炎作用、抗アレルギー作用、細胞修復作用等があり、消化性潰瘍や去痰薬としての効果があることが知られている。また、甘味剤や矯味剤としても用いられる（非特許文献６）。 Glycyrrhizic acid and its salts are widely known as components contained in licorice (licorice), have anti-inflammatory, anti-allergic, cell repair, etc., and are known to be effective as digestive ulcers and expectorants. Has been done. It is also used as a sweetening agent and a flavoring agent (Non-Patent Document 6).
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７） 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. Widely used for cough and expectorant difficulty associated with cold, upper respiratory tract inflammation (throat inflammation, nasal catarrh), acute bronchitis, chronic bronchitis, pneumonia, pulmonary tuberculosis, and bronchiectasis (Non-Patent Document 7).
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８）。 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 8).
ブロムヘキシン塩酸塩は、漿液性分泌増加作用、酸性糖蛋白溶解・低分子化作用、肺表面活性物質の分泌促進作用及び線毛運動亢進作用を有することにより、急性気管支炎、慢性気管支炎、肺結核、塵肺症、手術後に対する優れた去痰作用を有する化合物とし広く知られており、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９）。 Bromhexine hydrochloride has acute bronchitis, chronic bronchitis, pulmonary tuberculosis, and has an effect of increasing serous secretion, an effect of dissolving and reducing molecular weight of acidic glycoprotein, an effect of promoting secretion of a lung surface active substance, and an effect of enhancing ciliary motility. It is widely known as a compound having an excellent expectorant action against dust pneumonia and post-surgery, and is widely blended in general cold remedies and antitussive expectorants (Non-Patent Document 9).
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１０）。 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 10).
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１１）。 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 11).
これまで、ＰＯＥソルビタン脂肪酸エステル、グリセリン脂肪酸エステルマクロゴールと、水を含有する基剤に、イブプロフェンと塩酸セチリジンとシクロデキストリンを配合したカプセル剤が知られている（特許文献１）。この文献では、塩酸セチリジンの結晶化による溶解性の低下を、シクロデキストリンの共存により解決する方法が示されている。しかしながら、この技術は、塩酸セチリジンを特殊な溶剤と水を含有する基剤に溶解又は分散させる工程が必要となり、利用できる製剤が軟カプセルに制限され、またその製造工程も限定的であった。 So far, capsules containing POE sorbitan fatty acid ester, glycerin fatty acid ester macrogol, and a water-containing base containing ibprofen, cetilidine hydrochloride, and cyclodextrin have been known (Patent Document 1). This document shows a method for solving the decrease in solubility due to the crystallization of cetirizine hydrochloride by the coexistence of cyclodextrin. However, this technique requires a step of dissolving or dispersing cetirizine hydrochloride in a base containing a special solvent and water, limiting the available formulations to soft capsules and limiting the manufacturing process thereof.
今までに、イブプロフェンとレボセチリジン又はその塩との間に、レボセチリジン又はその塩の含量低下に直接影響を与えるような相互作用が生じるか否かについては、知られていない。 To date, it is not known whether there is an interaction between ibuprofen and levocetirizine or a salt thereof that directly affects the reduction in the content of levocetirizine or a salt thereof.
本発明者らは、イブプロフェン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、イブプロフェン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 a surprising finding that when a pharmaceutical composition containing ibuprofen 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 ibuprofen and levocetirizine or a salt thereof are contained, but the decrease in the content of levocetirizine or a salt thereof with time is suppressed.
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、アンブロキソール及びその塩、トラネキサム酸、グリチルリチン酸及びその塩、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、ブロムヘキシン及びその塩、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, carbocisteine, ambroxol and its salt, tranexamic acid, glycyrrhizinic acid and its salt, tipepidine and its salt, dextromethorphan and its salt, bromhexine and its salt, dimemorfan and It has been found that the inclusion of the salt and at least one selected from the group consisting of methylefedrin and the salt thereof unexpectedly suppresses a 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）イブプロフェン、（ｂ）レボセチリジン又はその塩、（ｃ）（ｃ１）カルボシステイン、（ｃ２）アンブロキソール及びその塩、（ｃ３）トラネキサム酸、（ｃ４）グリチルリチン酸及びその塩、（ｃ５）チペピジン及びその塩、（ｃ６）デキストロメトルファン及びその塩、（ｃ７）ブロムヘキシン及びその塩、（ｃ８）ジメモルファン及びその塩、並びに（ｃ９）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）（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、
（３）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、
（４）成分（ｃ）が、（ｃ２）アンブロキソール又はその塩である（１）に記載の医薬組成物、
（５）アンブロキソールの塩がアンブロキソール塩酸塩である（１）又は（４）に記載の医薬組成物、
（６）成分（ｃ）が、（ｃ３）トラネキサム酸である（１）に記載の医薬組成物、
（７）成分（ｃ）が、（ｃ４）グリチルリチン酸又はその塩である（１）に記載の医薬組成物、
（８）グリチルリチン酸の塩がグリチルリチン酸二カリウムである（１）又は（７）に記載の医薬組成物、
（９）成分（ｃ）が、（ｃ５）チペピジン又はその塩である（１）に記載の医薬組成物、
（１０）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（９）に記載の医薬組成物、
（１１）成分（ｃ）が、（ｃ６）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、
（１２）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（１１）に記載の医薬組成物、
（１３）成分（ｃ）が、（ｃ７）ブロムヘキシン又はその塩である（１）に記載の医薬組成物、
（１４）ブロムヘキシンの塩がブロムヘキシン塩酸塩である（１）又は（１３）に記載の医薬品組成物、
（１５）成分（ｃ）が、（ｃ８）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、
（１６）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（１５）に記載の医薬組成物、
（１７）成分（ｃ）が、（ｃ９）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、
（１８）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（１７）に記載の医薬組成物、
（１９）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）～（１８）のいずれかに記載の医薬組成物、
（２０）（ａ）イブプロフェン及び（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）アンブロキソール及びその塩、（ｃ３）トラネキサム酸、（ｃ４）グリチルリチン酸及びその塩、（ｃ５）チペピジン及びその塩、（ｃ６）デキストロメトルファン及びその塩、（ｃ７）ブロムヘキシン及びその塩、（ｃ８）ジメモルファン及びその塩、並びに（ｃ９）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、
（２１）（ａ）イブプロフェン及び（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）アンブロキソール及びその塩、（ｃ３）トラネキサム酸、（ｃ４）グリチルリチン酸及びその塩、（ｃ５）チペピジン及びその塩、（ｃ６）デキストロメトルファン及びその塩、（ｃ７）ブロムヘキシン及びその塩、（ｃ８）ジメモルファン及びその塩、並びに（ｃ９）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) ibprofen, (b) levosetilidine or a salt thereof, (c) (c1) carbocysteine, (c2) ambroxol and a salt thereof, (c3) tranexamic acid, (c4) glycyrrhizin. It consists of an acid and its salt, (c5) tipepidin and its salt, (c6) dextromethorphan and its salt, (c7) bromhexine and its salt, (c8) dimemorphan and its salt, and (c9) methylephedrine and its salt. A pharmaceutical composition comprising at least one selected from the group,
(2) The pharmaceutical composition according to (1), wherein the salt of levocetirizine is levocetirizine hydrochloride.
(3) The pharmaceutical composition according to (1), wherein the component (c) is (c1) carbocisteine.
(4) The pharmaceutical composition according to (1), wherein the component (c) is (c2) ambroxol or a salt thereof.
(5) The pharmaceutical composition according to (1) or (4), wherein the salt of ambroxol is ambroxol hydrochloride.
(6) The pharmaceutical composition according to (1), wherein the component (c) is (c3) tranexamic acid.
(7) The pharmaceutical composition according to (1), wherein the component (c) is (c4) glycyrrhizic acid or a salt thereof.
(8) The pharmaceutical composition according to (1) or (7), wherein the salt of glycyrrhizic acid is dipotassium glycyrrhizinate.
(9) The pharmaceutical composition according to (1), wherein the component (c) is (c5) tipepidine or a salt thereof.
(10) The pharmaceutical composition according to (1) or (9), wherein the salt of tipepidine is tipepidine hibenzate.
(11) The pharmaceutical composition according to (1), wherein the component (c) is (c6) dextromethorphan or a salt thereof.
(12) The pharmaceutical composition according to (1) or (11), wherein the salt of dextromethorphan is dextromethorphan hydrobromic acid hydrate.
(13) The pharmaceutical composition according to (1), wherein the component (c) is (c7) bromhexine or a salt thereof.
(14) The pharmaceutical composition according to (1) or (13), wherein the salt of bromhexine is bromhexine hydrochloride.
(15) The pharmaceutical composition according to (1), wherein the component (c) is (c8) dimemorfan or a salt thereof.
(16) The pharmaceutical composition according to (1) or (15), wherein the salt of dimemorfan is dimemorfan phosphate hydrochloride.
(17) The pharmaceutical composition according to (1), wherein the component (c) is (c9) methylephedrine or a salt thereof.
(18) The pharmaceutical composition according to (1) or (17), wherein the salt of methylephedrine is dl-methylephedrine hydrochloride.
(19) The pharmaceutical composition according to any one of (1) to (18), 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, (c2) for producing a pharmaceutical composition comprising (20) (a) ibprofen and (b) levosetilidine or a salt thereof and (b) levosetilidine or a salt thereof stabilized. ) Ambroxol and its salt, (c3) tranexamic acid, (c4) glycyrrhizinic acid and its salt, (c5) tipepidin and its salt, (c6) dextromethorphan and its salt, (c7) bromhexin and its salt, (c7) Use of at least one selected from the group consisting of c8) dimemorphan and its salt, and (c9) methylephedrine and its salt.
(C) (c1) Carbocysteine, (c2) Ambroki for stabilizing (b) levosetilidine or a salt thereof in a pharmaceutical composition comprising (21) (a) ibprofen and (b) levosetilidine or a salt thereof. Sole and its salt, (c3) tranexamic acid, (c4) glycyrrhizinic acid and its salt, (c5) tipepidin and its salt, (c6) dextromethorphan and its salt, (c7) bromhexin and its salt, (c8) dimemorphan And its salt, and the use of at least one selected from the group consisting of (c9) methylephedrine and its salts,
Is.
本発明により、イブプロフェン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 ibuprofen 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イブプロフェンは、化学式Ｃ１３Ｈ１８Ｏ２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。イブプロフェンは、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。本発明の医薬組成物中におけるイブ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１０～９０質量％、１５～８５質量％、１５～８０質量％、２０～７０質量％、２０～６０質量％である。 The ibuprofen used in the present invention is a compound represented by the chemical formula C 13 H 18 O 2 , and is not particularly limited as long as it is pharmaceutically acceptable. Ibuprofen can be produced by a known method, or a commercially available product can be used. The content of ibuprofen 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 10 to 90% by mass, 15 to 85% by mass, 15 to It is 80% by mass, 20 to 70% by mass, and 20 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、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％、０．０１～３０質量％、好ましくは０．１～１０質量％、０．２～７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, and carbonate, and the hydrochloride is particularly preferable. 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 30% by mass, preferably 0.1 to 10% by mass, and 0.2 to 7% 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アンブロキソールは、化学式Ｃ１３Ｈ１８Ｂｒ２Ｎ２Ｏ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。このようなアンブロキソール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、アンブロキソール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、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。本発明の医薬組成物中におけるアンブロキソール又はその塩の含有量（アンブロキソール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 ambroxol used in the present invention is a compound represented by the chemical formula C 13 H 18 Br 2 N 2 O or a salt thereof, and one of these may be used alone or in combination of two or more. good. As such ambroxol or a salt thereof, it can be produced by a known method, or a commercially available product can be used. The ambroxol 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 organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, etc. Particularly preferred is hydrochloride. The content of ambroxol or a salt thereof in the pharmaceutical composition of the present invention (if two or more of ambroxol 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 0.01 to 50% by mass, preferably 0.1 to 30% by mass.
本発明に用いられるトラネキサム酸は、化学式Ｃ８Ｈ１５ＮＯ２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。トラネキサム酸は、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イトラネキサム酸の含有量は、その薬効を示す量であれば特に限定されないが、通常１～９５質量％、３～９５質量％、好ましくは５～７０質量％、８～８５質量％、１０～６５質量％である。 The tranexamic acid used in the present invention is a compound represented by the chemical formula C 8 H 15 NO 2 , and is not particularly limited as long as it is pharmaceutically acceptable. Tranexamic acid can be produced by a known method, or a commercially available product can be used. The content of tranexamic acid in the pharmaceutical composition of the present invention is not particularly limited as long as it exhibits its medicinal effect, but is usually 1 to 95% by mass, 3 to 95% by mass, preferably 5 to 70% by mass. It is 8 to 85% by mass and 10 to 65% by mass.
本発明におけるグリチルリチン酸又はその塩は、カンゾウ（甘草）に含まれる成分として広く知られており、市販品にて入手するか、公知の製造方法によって製造することができ、生薬由来であっても良い。 グリチルリチン酸又はその塩は、成分そのものであってもよいし、生薬又は漢方薬に含有されていてもよい。特に、グリチルリチン酸類を含む生薬として、カンゾウ（カンゾウエキスやカンゾウ末）を用いることができ、カンゾウ中には、グリチルリチン酸は遊離酸及び塩の両方の形態で存在する。 グリチルリチン酸の塩としては、薬学上許容される塩であれば特に限定されないが、例えばグリチルリチン酸三ナトリウム、グリチルリチン酸二ナトリウム、グリチルリチン酸二アンモニウム、グリチルリチン酸モノアンモニウム、グリチルリチン酸二カリウム、グリチルリチン酸モノカリウムが挙げられる。グリチルリチン酸及びその塩として、好ましくはグリチルリチン酸、グリチルリチン酸二カリウムであり、特に好ましくはグリチルリチン酸二カリウムである。本発明の医薬組成物中におけるグリチルリチン酸及びその塩の含有量（グリチルリチン酸及びその塩を２種以上含む場合はそれらの総量、以下同じ）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、通常グリチルリチン酸として０．０１～５０質量％、好ましくは０．１～３０質量％である。 Glycyrrhizic acid or a salt thereof in the present invention is widely known as a component contained in licorice (licorice), and can be obtained as a commercially available product or can be produced by a known production method, even if it is derived from a crude drug. good. Glycyrrhizic acid or a salt thereof may be an ingredient itself, or may be contained in a crude drug or a Chinese herbal medicine. In particular, licorice (licorice extract or licorice powder) can be used as a crude drug containing glycyrrhizic acid, and glycyrrhizic acid is present in both free acid and salt forms in licorice. The salt of glycyrrhizic acid is not particularly limited as long as it is a pharmaceutically acceptable salt, and for example, trisodium glycyrrhizinate, disodium glycyrrhizinate, diammonium glycyrrhizinate, monoammonium glycyrrhizinate, dipotassium glycyrrhizinate, monoglycyrrhizinate Includes potassium. The glycyrrhizic acid and its salt are preferably glycyrrhizic acid and dipotassium glycyrrhizinate, and particularly preferably dipotassium glycyrrhizinate. The content of glycyrrhizic acid and its salt in the pharmaceutical composition of the present invention (the total amount thereof when two or more kinds of glycyrrhizic acid and its salt are contained, the same shall apply hereinafter) is particularly limited as long as it exhibits its medicinal effect. Although it is not a substance, it is usually 0.01 to 50% by mass, preferably 0.1 to 30% by mass as glycyrrhizic acid.
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０．１～５０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 50% by mass, preferably 0.5 to 30% by mass.
本発明に用いられるブロムヘキシンは、化学式Ｃ１４Ｈ２０Ｂｒ２Ｎ２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良い。このようなブロムヘキシ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、ブロムヘキシ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、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。本発明の固形組成物中におけるブロムヘキシン又はその塩の含有量（ブロムヘキシ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０．０１～３０質量％、好ましくは０．１～３０質量％、０．２～３０質量％である。 The bromhexine used in the present invention is a compound represented by the chemical formula C 14 H 20 Br 2 N 2 or a salt thereof, and one of these may be used alone or in combination of two or more. As such bromhexine or a salt thereof, it can be produced by a known method or a commercially available product can be used. The bromhexine 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 thereof include organic acid salts such as salts, oxalates, malonates, succinates, fumarates, maleates, lactates, malates, citrates, tartrates and carbonates, which are particularly preferable. Is a hydrochloride. The content of bromhexine or a salt thereof in the solid composition of the present invention (if two or more of bromhexine 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 30% by mass, preferably 0.1 to 30% by mass, and 0.2 to 30% 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）イブプロフェンと（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、イブプロフェン１０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、１２０質量部、６０質量部としてもよく２０質量部、４０質量部としてもよい。 The compounding ratio of (a) ibuprofen and (b) levocetirizine or a salt thereof is not particularly limited, but is preferably 10 parts by mass or more of ibuprofen with respect to 1 part by mass of levocetirizine 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 120 parts by mass or 60 parts by mass, or 20 parts by mass or 40 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、７５質量部、１５０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 75 parts by mass or 150 parts by mass.
（ａ）レボセチリジン及びその塩と、（ｃ）アンブロキソール及びその塩の配合比は、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、アンブロキソール及びその塩を１．５質量部以上、３質量部以上が好ましく、４質量部以上でもよい。また、上限は特に限定されず、９質量部としてもよく、４．５質量部としてもよい。 The compounding ratio of (a) levosetilidine and its salt and (c) ambroxol and its salt is 1.5 mass by mass of ambroxol and its salt with respect to 1 part by mass of levosetilidine and its salt from the viewpoint of the effect of the invention. 3 parts or more is preferable, and 4 parts by mass or more may be used. Further, the upper limit is not particularly limited, and may be 9 parts by mass or 4.5 parts by mass.
（ａ）レボセチリジン及びその塩と、（ｃ）トラネキサム酸の配合比は、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トラネキサム酸を４質量部以上が好ましく、９．３質量部以上、１８．６質量部以上としてもよい。上限は特に限定されず、１５０質量部としてもよく、１００質量部、７５質量部、５６質量部としてもよい。 The blending ratio of (a) levosetilidine and its salt to (c) tranexamic acid is preferably 4 parts by mass or more, preferably 9.3 parts by mass, based on 1 part by mass of levosetilidine and its salt, from the viewpoint of the effect of the present invention. As mentioned above, it may be 18.6 parts by mass or more. The upper limit is not particularly limited, and may be 150 parts by mass, 100 parts by mass, 75 parts by mass, or 56 parts by mass.
（ａ）レボセチリジン及びその塩と、（ｃ）グリチルリチン酸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グリチルリチン酸として０．１２質量部以上、０．２質量部以上が好ましく、１.２質量部以上がより好ましく、２．４質量部以上としてもよい。上限は特に限定されず、１２質量部としてもよく、１０質量部、８質量部としてもよい。 The compounding ratio of (a) levosetilidine and its salt and (c) glycyrrhizinic acid and its salt was 0.12 parts by mass or more as glycyrrhizinic acid with respect to 1 part by mass of levosetilidine and its salt, 0. 2 parts by mass or more is preferable, 1.2 parts by mass or more is more preferable, and 2.4 parts by mass or more may be used. The upper limit is not particularly limited, and may be 12 parts by mass, 10 parts by mass, or 8 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質量部以上、２質量部以上が好ましく、２．５質量部以上、４質量部以上、５質量部以上がより好ましい。また、上限は特に限定されず、１５質量部としてもよく、１０質量部、７．５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 and 2 parts by mass 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. The above is preferable, and 2.5 parts by mass or more, 4 parts by mass or more, and 5 parts by mass or more are more preferable. The upper limit is not particularly limited, and may be 15 parts by mass, 10 parts by mass, or 7.5 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、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、５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 mass by mass of dextromethruphan and its salt with respect to 1 part by mass of levosetilidine and its salt from the viewpoint of the effect of the invention. More than parts, 0.8 parts by mass or more, preferably 1 part by mass or more, and more preferably 1.6 parts by mass or more and 3.2 parts by mass or more. Further, the upper limit is not particularly limited, and may be 10 parts by mass or 5 parts by mass.
（ａ）レボセチリジン及びその塩と、（ｃ）ブロムヘキシ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ブロムヘキシン及びその塩を０．１質量部以上、０．２質量部以上、０．８質量部以上が好ましく、１.２質量部以上がより好ましく、２．４質量部以上としてもよい。上限は特に限定されず、１２質量部としてもよく、１０質量部、８質量部としてもよい。 The compounding ratio of (a) levosetilidine and its salt and (c) bromhexine and its salt is 0.1 part by mass or more and 0 by mass of bromhexine 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, preferably 0.8 parts by mass or more, more preferably 1.2 parts by mass or more, and may be 2.4 parts by mass or more. The upper limit is not particularly limited, and may be 12 parts by mass, 10 parts by mass, or 8 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）イブプロフェン（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、アンブロキソール及びその塩、トラネキサム酸、グリチルリチン酸及びその塩、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、ブロムヘキシン及びその塩、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) ibprofen (hereinafter, also referred to as (a) component), (b) levosetilidine or a salt thereof (hereinafter, also referred to as (b) component), (c) carbocysteine, ambroxol and a salt thereof, tranexamic acid. , Glycyrrhizic acid and its salt, tipepidin and its salt, dextromethorphan and its salt, bromuhexin and its salt, dimemorphan and its salt, and methylephedrine and its salt at least one selected from the group (hereinafter, (c)). It may be simply mixed (also referred to as a component), granulated after mixing, or coated with the obtained granulated product. 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、イブプロフェン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、イブプロフェン１０質量部及びプランルカスト水和物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１）
レボセチリジン塩酸塩１質量部に対し、イブプロフェン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、イブプロフェン１０質量部及びアンブロキソール塩酸塩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、イブプロフェン１０質量部及びトラネキサム酸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、イブプロフェン１０質量部及びグリチルリチン酸二カリウム４質量部（グリチルリチン酸として２．４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５）
レボセチリジン塩酸塩１質量部に対し、イブプロフェン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６）
レボセチリジン塩酸塩１質量部に対し、イブプロフェン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。
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 ibuprofen 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 ibuprofen and 4 parts by mass of pranlukast hydrate were weighed and mixed with respect to 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)
10 parts by mass of ibuprofen and 4 parts by mass of L-carbocisteine were weighed and mixed with respect to 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 2)
10 parts by mass of ibuprofen and 4 parts by mass of ambroxol hydrochloride were weighed and mixed with respect to 1 part by mass of levosetilidine hydrochloride, an appropriate amount of water / alcohol mixed solution was added thereto, and the mixture was mixed and dried to obtain a composition.
(Example 3)
10 parts by mass of ibuprofen and 4 parts by mass of tranexamic acid were weighed and mixed with respect to 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 4)
10 parts by mass of ibuprofen and 4 parts by mass of dipotassium glycyrrhizinate (2.4 parts by mass as glycyrrhizic acid) were weighed and mixed with 1 part by mass of levosetilidine hydrochloride, and an appropriate amount of water / alcohol mixed solution was added and mixed. It was dried to obtain a composition.
(Example 5)
10 parts by mass of ibuprofen and 4 parts by mass of tipepidine hibenzate were weighed and mixed with respect to 1 part by mass of levocetirizine hydrochloride, an appropriate amount of water / alcohol mixed solution was added thereto, and the mixture was dried to obtain a composition.
(Example 6)
Weigh 10 parts by mass of ibprofene 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, mix, and then dry the composition. Got
（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、イブプロフェン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、アンブロキソール塩酸塩、トラネキサム酸、グリチルリチン酸二カリウム、チペピジンヒベンズ酸塩及びデキストロメトルファン臭化水素酸塩水和物を配合した実施例１～６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 ibuprofen and levocetirizine hydrochloride were blended, a decrease in the content of levocetirizine hydrochloride was confirmed. On the other hand, in Examples 1 to 6 in which L-carbocisteine, ambroxol hydrochloride, tranexamic acid, dipotassium glycyrrhizinate, tippidin hibenzate and dextromethorphan hydrobromic acid hydrate were blended, the levosetilidine hydrochloride was used. The decrease in content could be suppressed.
（実施例７）
レボセチリジン塩酸塩１質量部に対し、イブプロフェン１０質量部及びブロムヘキシン塩酸塩０．２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、イブプロフェン１０質量部及びアンブロキソール塩酸塩１．５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９）
レボセチリジン塩酸塩１質量部に対し、イブプロフェン１０質量部及びグリチルリチン酸二カリウム０．２質量部（グリチルリチン酸として０．１２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１０）
レボセチリジン塩酸塩１質量部に対し、イブプロフェン１０質量部及び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１１）
レボセチリジン塩酸塩１質量部に対し、イブプロフェン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０．８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１２）
レボセチリジン塩酸塩１質量部に対し、イブプロフェン１０質量部及び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１３）
レボセチリジン塩酸塩１質量部に対し、イブプロフェン１０質量部及び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 7)
10 parts by mass of ibuprofen and 0.2 parts by mass of bromhexine hydrochloride were weighed and mixed with respect to 1 part by mass of levosetilidine hydrochloride, an appropriate amount of water / alcohol mixed solution was added thereto, and the mixture was mixed and dried to obtain a composition.
(Example 8)
10 parts by mass of ibuprofen and 1.5 parts by mass of ambroxol hydrochloride were weighed and mixed with 1 part by mass of levosetilidine hydrochloride, an appropriate amount of water / alcohol mixture was added thereto, and the mixture was mixed and dried to obtain a composition. ..
(Example 9)
Weigh 10 parts by mass of ibuprofen and 0.2 parts by mass of dipotassium glycyrrhizinate (0.12 parts by mass as glycyrrhizic acid) 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 10)
10 parts by mass of ibuprofen and 1 part by mass of tipepidine hibenzate were weighed and mixed with respect to 1 part by mass of levocetirizine hydrochloride, an appropriate amount of water / alcohol mixed solution was added thereto, and the mixture was dried to obtain a composition.
(Example 11)
Weigh 10 parts by mass of ibprofene and 0.8 parts by mass of dextromethorphan hydrobromide hydrate to 1 part by mass of levosetilidine hydrochloride, add an appropriate amount of water / alcohol mixture to this, mix, and then dry. The composition was obtained.
(Example 12)
10 parts by mass of ibuprofen and 1 part by mass of dimemorphan phosphate were weighed and mixed with respect to 1 part by mass of levosetilidine hydrochloride, an appropriate amount of water / alcohol mixed solution was added thereto, and the mixture was mixed and dried to obtain a composition.
(Example 13)
10 parts by mass of ibuprofen and 1 part by mass of dl-methylephedrine hydrochloride were weighed and mixed with respect to 1 part by mass of levocetirizine hydrochloride, an appropriate amount of water / alcohol mixed solution was added thereto, and the mixture was dried to obtain a composition.
（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、ブロムヘキシン塩酸塩、アンブロキソール塩酸塩、グリチルリチン酸二カリウム、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７～１３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 hydration of bromhexin hydrochloride, ambroxol hydrochloride, dipotassium glycyrrhizinate, tipepidin hibenzate, and dextrometholphan hydrochloride hydrate. It was clarified that it was suppressed in Examples 7 to 13 in which the substance, dimemorphan phosphate and dl-methylephedrine hydrochloride were 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、イブプロフェン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 ibuprofen and levocetirizine or a salt thereof and having excellent stability of levocetirizine and a salt thereof.
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