JP5238779B2 - Nasal drops - Google Patents
Nasal drops Download PDFInfo
- Publication number
- JP5238779B2 JP5238779B2 JP2010208416A JP2010208416A JP5238779B2 JP 5238779 B2 JP5238779 B2 JP 5238779B2 JP 2010208416 A JP2010208416 A JP 2010208416A JP 2010208416 A JP2010208416 A JP 2010208416A JP 5238779 B2 JP5238779 B2 JP 5238779B2
- Authority
- JP
- Japan
- Prior art keywords
- nasal drop
- nasal
- acid
- component
- salts
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000007923 nasal drop Substances 0.000 title claims description 58
- 229940100662 nasal drops Drugs 0.000 title description 16
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 36
- -1 polyoxyethylene Polymers 0.000 claims description 28
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 24
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical class C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 claims description 23
- 229940092705 beclomethasone Drugs 0.000 claims description 22
- 235000002639 sodium chloride Nutrition 0.000 claims description 20
- 229940041616 menthol Drugs 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 claims description 18
- 229960004926 chlorobutanol Drugs 0.000 claims description 18
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 16
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 16
- 241000723346 Cinnamomum camphora Species 0.000 claims description 13
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- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims description 12
- HDSBZMRLPLPFLQ-UHFFFAOYSA-N Propylene glycol alginate Chemical compound OC1C(O)C(OC)OC(C(O)=O)C1OC1C(O)C(O)C(C)C(C(=O)OCC(C)O)O1 HDSBZMRLPLPFLQ-UHFFFAOYSA-N 0.000 claims description 12
- 229960004194 lidocaine Drugs 0.000 claims description 12
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- 239000002562 thickening agent Substances 0.000 claims description 11
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 claims description 9
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 claims description 8
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- 239000002202 Polyethylene glycol Substances 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 8
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- PUFQVTATUTYEAL-UHFFFAOYSA-N cinchocaine Chemical compound C1=CC=CC2=NC(OCCCC)=CC(C(=O)NCCN(CC)CC)=C21 PUFQVTATUTYEAL-UHFFFAOYSA-N 0.000 claims description 8
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- 235000011187 glycerol Nutrition 0.000 claims description 8
- 229920001223 polyethylene glycol Polymers 0.000 claims description 8
- BBEJNBLSSWFDSN-UHFFFAOYSA-N methylamino benzoate Chemical compound CNOC(=O)C1=CC=CC=C1 BBEJNBLSSWFDSN-UHFFFAOYSA-N 0.000 claims description 7
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- 229960000244 procainamide Drugs 0.000 claims description 7
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 claims description 7
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- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 3
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- 229920002125 Sokalan® Polymers 0.000 claims description 2
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- 235000010489 acacia gum Nutrition 0.000 claims description 2
- 239000000205 acacia gum Substances 0.000 claims description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
- 229920003086 cellulose ether Polymers 0.000 claims description 2
- KXKPYJOVDUMHGS-OSRGNVMNSA-N chondroitin sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](OS(O)(=O)=O)[C@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](C(O)=O)O1 KXKPYJOVDUMHGS-OSRGNVMNSA-N 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 235000010487 tragacanth Nutrition 0.000 claims description 2
- 239000000196 tragacanth Substances 0.000 claims description 2
- 229940116362 tragacanth Drugs 0.000 claims description 2
- 239000000230 xanthan gum Substances 0.000 claims description 2
- 235000010493 xanthan gum Nutrition 0.000 claims description 2
- 229920001285 xanthan gum Polymers 0.000 claims description 2
- 229940082509 xanthan gum Drugs 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims 1
- 241000978776 Senegalia senegal Species 0.000 claims 1
- GSWGDDYIUCWADU-UHFFFAOYSA-N aluminum magnesium oxygen(2-) Chemical compound [O--].[Mg++].[Al+3] GSWGDDYIUCWADU-UHFFFAOYSA-N 0.000 claims 1
- 239000000377 silicon dioxide Substances 0.000 claims 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 33
- 230000007794 irritation Effects 0.000 description 26
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 description 26
- 229960000676 flunisolide Drugs 0.000 description 24
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 239000008213 purified water Substances 0.000 description 19
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
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- 239000000872 buffer Substances 0.000 description 9
- 239000003002 pH adjusting agent Substances 0.000 description 9
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 8
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- 230000000052 comparative effect Effects 0.000 description 7
- 238000011156 evaluation Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
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- 150000001875 compounds Chemical class 0.000 description 6
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- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 5
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- 229910019142 PO4 Inorganic materials 0.000 description 5
- 239000000043 antiallergic agent Substances 0.000 description 5
- 235000015165 citric acid Nutrition 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
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- 239000008363 phosphate buffer Substances 0.000 description 5
- 150000003431 steroids Chemical class 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
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- 239000002253 acid Substances 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 229960000686 benzalkonium chloride Drugs 0.000 description 4
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 4
- 239000004359 castor oil Substances 0.000 description 4
- 235000019438 castor oil Nutrition 0.000 description 4
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- 210000003928 nasal cavity Anatomy 0.000 description 4
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- JVUYWILPYBCNNG-UHFFFAOYSA-N potassium;oxido(oxo)borane Chemical compound [K+].[O-]B=O JVUYWILPYBCNNG-UHFFFAOYSA-N 0.000 description 1
- 229960001309 procaine hydrochloride Drugs 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- 229960003447 pseudoephedrine hydrochloride Drugs 0.000 description 1
- BALXUFOVQVENIU-KXNXZCPBSA-N pseudoephedrine hydrochloride Chemical compound [H+].[Cl-].CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-KXNXZCPBSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- USDOQCCMRDNVAH-UHFFFAOYSA-N sigma-cadinene Natural products C1C=C(C)CC2C(C(C)C)CC=C(C)C21 USDOQCCMRDNVAH-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 235000019721 spearmint oil Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 229950001956 suplatast Drugs 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940116411 terpineol Drugs 0.000 description 1
- 229940021790 tetrahydrozoline hydrochloride Drugs 0.000 description 1
- BJORNXNYWNIWEY-UHFFFAOYSA-N tetrahydrozoline hydrochloride Chemical compound Cl.N1CCN=C1C1C2=CC=CC=C2CCC1 BJORNXNYWNIWEY-UHFFFAOYSA-N 0.000 description 1
- 229960000337 tetryzoline Drugs 0.000 description 1
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 description 1
- 229960000790 thymol Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- CRDAMVZIKSXKFV-UHFFFAOYSA-N trans-Farnesol Natural products CC(C)=CCCC(C)=CCCC(C)=CCO CRDAMVZIKSXKFV-UHFFFAOYSA-N 0.000 description 1
- XMLSXPIVAXONDL-UHFFFAOYSA-N trans-jasmone Natural products CCC=CCC1=C(C)CCC1=O XMLSXPIVAXONDL-UHFFFAOYSA-N 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 239000011576 zinc lactate Substances 0.000 description 1
- 229940050168 zinc lactate Drugs 0.000 description 1
- 235000000193 zinc lactate Nutrition 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- USDOQCCMRDNVAH-KKUMJFAQSA-N β-cadinene Chemical compound C1C=C(C)C[C@H]2[C@H](C(C)C)CC=C(C)[C@@H]21 USDOQCCMRDNVAH-KKUMJFAQSA-N 0.000 description 1
Description
本発明は、刺激の緩和されたステロイド点鼻剤に関する。 The present invention relates to steroid nasal drops with reduced irritation.
近年、花粉、ハウスダストなどを原因物質とするアレルギー性鼻炎患者が急増しており、抗アレルギー剤、ステロイド剤、ロイコトリエン拮抗剤、トロンボキサンA2拮抗剤などを内服あるいは点鼻によって投与する治療が行なわれている。これらの薬物投与は対症療法であり、花粉などの抗原を許容範囲以下まで除去できない環境下では、抗原が患者の身辺に存在する限り症状が現れるため、継続して使用しなければ十分な改善効果が得られない。 In recent years, the number of allergic rhinitis patients caused by pollen, house dust, etc. has been rapidly increasing, and treatments in which antiallergic agents, steroids, leukotriene antagonists, thromboxane A2 antagonists, etc. are administered by oral administration or instillation are performed. It is. Administration of these drugs is a symptomatic treatment. In an environment where antigens such as pollen cannot be removed to an acceptable level or below, symptoms will appear as long as the antigen is present in the patient's area. Cannot be obtained.
現在、汎用されているステロイド化合物としては、フルニソリド、プロピオン酸ベクロメタゾン、プロピオン酸フルチカゾンなどが挙げられ、鼻炎症状に対して優れた薬効を示すことが知られているが、いずれの点鼻剤も投与時における刺激感が問題となっている。特に鼻腔内に炎症症状を呈している場合、鼻粘膜表面が非常に過敏になっていることから、刺激による不快感がさらに増強されるといった副作用が生じるため、点鼻時の刺激感を改善することは非常に重要な課題である。
ステロイド点鼻剤の刺激を緩和する方法としては、プロピレングリコール、ポリエチレングリコール400およびポリソルベート20を含む刺痛のない経鼻投与に適した水性抗炎症ステロイド製剤(特許文献1:特許第2521291号公報)が開示されているが、メントール、クロロブタノールについては言及していない。
Currently used steroidal compounds include flunisolide, beclomethasone propionate, fluticasone propionate, etc., which are known to show excellent medicinal properties against nasal inflammation, but any nasal drops are administered The feeling of irritation at times is a problem. Especially when inflammatory symptoms are present in the nasal cavity, the surface of the nasal mucosa is very sensitive, causing side effects such as further discomfort caused by irritation. This is a very important issue.
As a method for alleviating irritation of steroid nasal drops, an aqueous anti-inflammatory steroid preparation containing propylene glycol, polyethylene glycol 400 and polysorbate 20 suitable for nasal administration without tingling (Patent Document 1: Japanese Patent No. 2521291) However, menthol and chlorobutanol are not mentioned.
また、メントールやクロロブタノールによって、非ステロイド性抗アレルギー薬による刺激や刺痛などの不快感を改善することが知られている。具体的には、非ステロイド性抗アレルギー薬として知られているスプラタスト、ペミロラスト、ケトチフェン、レボカバスチンおよびそれらの塩は、その化学的組成から刺激感などの不快な感覚を点鼻又は点眼の際に生じるが、清涼化剤であるメントール、カンフル、ハッカ油、ユーカリ油、ペパーミント油、クロロブタノールおよび乳酸メンチルを配合することにより使用感が改善されることが知られている(特許文献2:特開2002−205942号公報)。また、クロモグリク酸ナトリウムにメントールとクロロブタノールを配合した点眼剤は、眼痛を生じず、目のかゆみを長時間抑える特徴を有することが知られている(特許文献3:特開2002−128671号公報)。しかしこれらはいずれも非ステロイド性抗アレルギー薬の問題点を改善するものであり、フルニソリド等のステロイド化合物に関する検討は全くなされていない。 It is also known that menthol and chlorobutanol can improve discomfort such as irritation and stinging with nonsteroidal antiallergic drugs. Specifically, suplatast, pemirolast, ketotifen, levocabastine and their salts, known as non-steroidal antiallergic drugs, cause unpleasant sensations such as irritation due to their chemical composition during nose drops or eye drops However, it is known that the feeling of use is improved by blending menthol, camphor, mint oil, eucalyptus oil, peppermint oil, chlorobutanol and menthyl lactate which are the refreshing agents (Patent Document 2: JP-A-2002). -205942). Moreover, it is known that an ophthalmic solution containing menthol and chlorobutanol mixed with sodium cromoglycate does not cause eye pain and has a feature of suppressing eye itching for a long time (Patent Document 3: JP 2002-128671 A). Publication). However, these all improve the problems of non-steroidal anti-allergic drugs, and no investigation has been made on steroidal compounds such as flunisolide.
本発明は安全性が高く、鼻腔内への刺激が顕著に改善された点鼻剤を提供することを課題とする。 An object of the present invention is to provide a nasal drop that is highly safe and has significantly improved irritation in the nasal cavity.
本発明者らは、上記の課題を解決するために鋭意研究した結果、フルニソリド、ベクロメタゾンおよびこれらの誘導体の少なくとも1種以上、メントール、カンフル、ボルネオールおよびゲラニオールからなる群より選ばれる1種又は2種以上およびクロロブタノール、リドカイン、ジブカイン、プロカイン、プロカインアミドおよびアミノ安息香酸メチルからなる群より選ばれる1種又は2種以上を配合することにより、投与時の刺激が顕著に緩和されることを知見した。さらに粘稠化剤を配合することによって、さらに使用感の優れた点鼻剤が得られることを知見した。 As a result of intensive studies to solve the above problems, the present inventors have found that at least one or more of flunisolide, beclomethasone and their derivatives, one or two selected from the group consisting of menthol, camphor, borneol and geraniol. It was found that the irritation at the time of administration was remarkably reduced by blending one or two or more selected from the group consisting of the above and chlorobutanol, lidocaine, dibucaine, procaine, procainamide and methyl aminobenzoate. . Furthermore, it discovered that the nasal drop which was further excellent in the usability | use_condition is obtained by mix | blending a thickener.
すなわち、本発明は、以下の(1)〜(4)に示す点鼻剤である。
(1)(A)フルニソリド、ベクロメタゾンおよびこれらの誘導体からなる群より選ばれる1種又は2種以上、(B)メントール、カンフル、ボルネオールおよびゲラニオールからなる群より選ばれる1種又は2種以上、および(C)クロロブタノール、リドカイン、ジブカイン、プロカイン、プロカインアミドおよびアミノ安息香酸メチルからなる群より選ばれる1種又は2種以上を含有する点鼻剤。
(2)さらに粘稠化剤を含有する(1)に記載の点鼻剤。
(3)粘稠化剤が、ポリエチレングリコール、グリセリン、ヒドロキシプロピルセルロースまたはアルギン酸プロピレングリコールの少なくとも1種以上である(1)または(2)に記載の点鼻剤。
(4)pHが4.0〜9.0の範囲にある(1)乃至(3)に記載の点鼻剤。
なお、本明細書中、特に言及しない限り、%はw/v%を意味するものとする。
That is, the present invention is a nasal drop shown in the following (1) to (4).
(1) (A) one or more selected from the group consisting of flunisolide, beclomethasone and derivatives thereof, (B) one or more selected from the group consisting of menthol, camphor, borneol and geraniol, and (C) A nasal drop containing one or more selected from the group consisting of chlorobutanol, lidocaine, dibucaine, procaine, procainamide and methyl aminobenzoate.
(2) The nasal drop according to (1), further containing a thickening agent.
(3) The nasal preparation according to (1) or (2), wherein the thickening agent is at least one of polyethylene glycol, glycerin, hydroxypropyl cellulose, or propylene glycol alginate.
(4) The nasal drop according to any one of (1) to (3), wherein the pH is in the range of 4.0 to 9.0.
In the present specification, unless otherwise specified,% means w / v%.
本発明では、フルニソリド、ベクロメタゾンのいずれか1種以上を含有する点鼻剤に、メントール、カンフル、ボルネオールまたはゲラニオールのいずれか1種以上、クロロブタノール、リドカイン、ジブカイン、プロカイン、プロカインアミドまたはアミノ安息香酸メチルのいずれか1種以上を含有することによって、これらのステロイド化合物によって惹起される鼻粘膜への刺激感を伴う不快感が改善される。さらに、ポリエチレングリコール、グリセリン、ヒドロキシプロピルセルロース、アルギン酸プロピレングリコール等の粘稠化剤を含有させるとこの不快感をさらに軽減することができ、より好適な点鼻剤を得ることができる。 In the present invention, the nasal drops containing any one or more of flunisolide and beclomethasone, one or more of menthol, camphor, borneol or geraniol, chlorobutanol, lidocaine, dibucaine, procaine, procainamide or aminobenzoic acid By containing any one or more of methyl, unpleasant sensation accompanied by irritation to the nasal mucosa caused by these steroid compounds is improved. Furthermore, when a thickening agent such as polyethylene glycol, glycerin, hydroxypropyl cellulose, propylene glycol alginate or the like is contained, this discomfort can be further reduced, and a more suitable nasal agent can be obtained.
本発明に用いるフルニソリド、ベクロメタゾンおよびこれらの誘導体は、公知の化合物であり、公知の方法により合成してもよく市販品として入手することもできる。これらのフルニソリド、ベクロメタゾンおよびこれらの誘導体は、単独で又は2種以上を組み合わせて使用できる。 Flunisolide, beclomethasone and derivatives thereof used in the present invention are known compounds, and may be synthesized by a known method or obtained as a commercial product. These flunisolide, beclomethasone and derivatives thereof can be used alone or in combination of two or more.
本発明に用いるフルニソリドおよびベクロメタゾンそれぞれの誘導体としては、エステル誘導体[例えば、モノカルボン酸エステル(酢酸、トリフルオロ酢酸、プロピオン酸、酪酸、吉草酸、フランカルボン酸、ピバル酸など)、多価カルボン酸エステル(フマル酸、マレイン酸など)、オキシカルボン酸エステル(乳酸、酒石酸、クエン酸、コハク酸、マロン酸など)、有機スルホン酸エステル(メタンスルホン酸、トシル酸エステルなど)など]、エーテル誘導体[例えば、メチルエーテル、エチルエーテル、プロピルエーテル、イソプロピルエーテル、ブチルエーテル、イソブチルエーテルなど]などが例示できる。
また、本発明に用いるフルニソリド、ベクロメタゾンおよびこれらの誘導体は、水和物などの溶媒和物の形態で使用することもできる。
本発明に用いるフルニソリド、ベクロメタゾンおよびこれらの誘導体のうち、特にフルニソリド、フルニソリド1/2水和物、プロピオン酸ベクロメタゾンが好ましい。
As derivatives of flunisolide and beclomethasone used in the present invention, ester derivatives [eg, monocarboxylic acid esters (such as acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, furancarboxylic acid, pivalic acid, etc.), polyvalent carboxylic acids Esters (fumaric acid, maleic acid, etc.), oxycarboxylic acid esters (lactic acid, tartaric acid, citric acid, succinic acid, malonic acid, etc.), organic sulfonic acid esters (methanesulfonic acid, tosylic acid ester, etc.)], ether derivatives [ For example, methyl ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, etc.] can be exemplified.
Flunisolide, beclomethasone and derivatives thereof used in the present invention can also be used in the form of solvates such as hydrates.
Of the flunisolide, beclomethasone and derivatives thereof used in the present invention, flunisolide, flunisolide hemihydrate, and beclomethasone propionate are particularly preferred.
本発明において、フルニソリド、ベクロメタゾンおよびこれらの誘導体は、医薬上、薬理学的に又は生理学的に許容される塩であっても良い。このような塩としては、有機酸塩[例えば、モノカルボン酸塩(酢酸塩、トリフルオロ酢酸塩、酪酸塩、パルミチン酸塩、ステアリン酸塩など)、多価カルボン酸塩(フマル酸塩、マレイン酸塩など)、オキシカルボン酸塩(乳酸塩、酒石酸塩、クエン酸塩、コハク酸塩、マロン酸塩など)、有機スルホン酸塩(メタンスルホン酸塩、トルエンスルホン酸塩、トシル酸塩など)など]、無機酸塩(例えば、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩、リン酸塩など)、有機塩基との塩(例えば、メチルアミン、トリエチルアミン、トリエタノールアミン、モルホリン、ピペラジン、ピロリジン、トリピリジン、ピコリンなどの有機アミンとの塩など)、無機塩基との塩[例えば、アンモニウム塩;アルカリ金属(ナトリウム、カリウムなど)、アルカリ土類金属(カルシウム、マグネシウムなど)、アルミニウムなどの金属との塩など]などが例示できる。 In the present invention, flunisolide, beclomethasone and derivatives thereof may be pharmaceutically, pharmacologically or physiologically acceptable salts. Examples of such salts include organic acid salts [for example, monocarboxylate (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate, maleate). Acid salt), oxycarboxylate (lactate, tartrate, citrate, succinate, malonate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate, etc.) Etc.], inorganic acid salts (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (eg, methylamine, triethylamine, triethanolamine, morpholine, piperazine, Salts with organic amines such as pyrrolidine, tripyridine, picoline), salts with inorganic bases [eg ammonium salts; alkali metals (sodium, potassium, etc.), Alkaline earth metals (calcium, magnesium etc.) and salts with metals such as aluminum or the like].
本発明の点鼻剤中におけるフルニソリドの配合量は、フルニソリドおよびフルニソリド誘導体の総量として、通常0.001〜0.05%、好ましくは0.003〜0.03%、さらに好ましくは0.005〜0.015%である。また、ベクロメタゾンの配合量は、ベクロメタゾンおよびベクロメタゾン誘導体の総量として、通常0.006〜0.3%、好ましくは0.015〜0.15%、さらに好ましくは0.03〜0.1%である。 The blending amount of flunisolide in the nasal drops of the present invention is usually 0.001 to 0.05%, preferably 0.003 to 0.03%, more preferably 0.005 to the total amount of flunisolide and flunisolide derivatives. 0.015%. The amount of beclomethasone is generally 0.006 to 0.3%, preferably 0.015 to 0.15%, and more preferably 0.03 to 0.1% as the total amount of beclomethasone and beclomethasone derivatives. .
本発明の点鼻剤のフルニソリド、ベクロメタゾンおよびそれらの誘導体の、1回当たりの各鼻腔への投与量は、効果を十分に発揮させつつも副作用の発現を回避する観点から、各成分の総量(例えば、フルニソリドおよびフルニソリド誘導体の総量)として、1〜100μgが好ましく、5〜50μgがより好ましく、10〜25μgがさらに好ましい。また、1日当たりの各鼻腔への投与量は10〜1000μgが好ましく、50〜800μgがより好ましく、100〜400μgがさらに好ましいが、これらに限定されるものではない。 The dose of flunasolide, beclomethasone and derivatives thereof of the nasal preparation of the present invention to each nasal cavity per one time is the total amount of each component (from the viewpoint of avoiding the occurrence of side effects while sufficiently exerting the effect) For example, the total amount of flunisolide and flunisolide derivatives) is preferably 1 to 100 μg, more preferably 5 to 50 μg, and even more preferably 10 to 25 μg. Further, the daily dose to each nasal cavity is preferably 10 to 1000 μg, more preferably 50 to 800 μg, and even more preferably 100 to 400 μg, but is not limited thereto.
本発明に用いるメントールまたはカンフルは日本薬局方に記載されている化合物であり、ボルネオールまたはゲラニオールは医薬品添加物事典に記載されている化合物であって、市販品として入手することができる。また、メントール、カンフル、ボルネオールおよびゲラニオールは天然物由来または合成品であっても良く、d体、l体、dl体のいずれであっても良い。さらに、植物から単離精製せず、ハッカ油、スペアミント油、ペパーミント油、ミント油といったメントール、カンフル、ボルネオールおよびゲラニオールを含有する精油として使用しても良い。
本発明の点鼻剤中におけるメントール、カンフル、ボルネオールおよびゲラニオールの配合量は、各成分の総量として、0.0001〜0.5%が好ましく、0.001〜0.1%がより好ましく、0.003〜0.05%がさらに好ましい。
Menthol or camphor used in the present invention is a compound described in the Japanese Pharmacopoeia, and borneol or geraniol is a compound described in the Pharmaceutical Additives Dictionary and can be obtained as a commercial product. In addition, menthol, camphor, borneol and geraniol may be derived from natural products or synthetic products, and may be any of d-form, l-form and dl-form. Furthermore, it may be used as an essential oil containing menthol, camphor, borneol and geraniol such as mint oil, spearmint oil, peppermint oil and mint oil without isolation and purification from plants.
The blending amount of menthol, camphor, borneol and geraniol in the nasal drops of the present invention is preferably 0.0001 to 0.5%, more preferably 0.001 to 0.1% as the total amount of each component, 0 0.003 to 0.05% is more preferable.
本発明に用いるクロロブタノール、リドカイン、ジブカイン、プロカイン、プロカインアミドおよびアミノ安息香酸メチルは、日本薬局方に記載されている化合物であって、公知の方法により合成してもよく市販品としても入手することができる。
本発明において、リドカイン、ジブカイン、プロカイン、プロカインアミドおよびアミノ安息香酸メチルは、医薬上、薬理学的に又は生理学的に許容される塩であっても良い。このような塩としては、無機酸塩(例えば、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩、リン酸塩など)などが例示でき、好ましくは塩酸塩、硫酸塩、硝酸塩であり、特に好ましくは塩酸塩であり、具体的には塩酸リドカイン等が挙げられる。
本発明の点鼻剤中におけるクロロブタノール、リドカイン、ジブカイン、プロカイン、プロカインアミドおよびアミノ安息香酸メチルの配合量は、0.01〜5.0%が好ましく、0.05〜1%がより好ましく、0.1〜0.5%がさらに好ましい。
Chlorobutanol, lidocaine, dibucaine, procaine, procainamide and methyl aminobenzoate used in the present invention are compounds described in the Japanese Pharmacopoeia, and may be synthesized by known methods or obtained as commercial products. be able to.
In the present invention, lidocaine, dibucaine, procaine, procainamide and methyl aminobenzoate may be pharmaceutically, pharmacologically or physiologically acceptable salts. Examples of such salts include inorganic acid salts (for example, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), preferably hydrochloride, sulfate, nitrate, Hydrochloride is preferable, and specific examples include lidocaine hydrochloride.
The amount of chlorobutanol, lidocaine, dibucaine, procaine, procainamide and methyl aminobenzoate in the nasal drops of the present invention is preferably 0.01 to 5.0%, more preferably 0.05 to 1%. 0.1 to 0.5% is more preferable.
本発明の点鼻剤に対し、粘稠化剤を配合すると、フルニソリドおよびベクロメタゾンの鼻粘膜への刺激をさらに改善し、かつ点鼻後の液ダレを防止できることから、より好ましい点鼻剤を提供することができる。粘稠化剤としては、ポリエチレングリコール、ポリオキシエチレングリコール、ポリビニルアルコール、ポリビニルピロリドン、カルボキシビニルポリマー、セルロース誘導体(ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、メチルセルロース、エチルセルロース、ヒドロキシプロピルメチルセルロースなどのセルロースエーテル類又はこれらの塩など)、アルギン酸プロピレングリコール、アラビアゴム末、カルメロースナトリウム、キサンタンガム、グリセリン、ケイ酸マグネシウムアルミニウム、コンドロイチン硫酸ナトリウム、シクロデキストリン、トラガント末など、マクロゴール4000などが例示でき、ポリエチレングリコール、ポリオキシエチレングリコール、ヒドロキシプロピルセルロース、アルギン酸プロピレングリコール、グリセリンなどが好ましい。
本発明の点鼻剤中における粘稠化剤の配合量は、0.001〜20%が好ましく、0.005〜18%がより好ましく、0.01〜15%がさらに好ましい。
When a thickening agent is added to the nasal drop of the present invention, flunisolide and beclomethasone can further improve irritation to the nasal mucosa and prevent dripping after nasal drop, thus providing a more preferable nasal drop. can do. Examples of thickening agents include polyethylene glycol, polyoxyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, cellulose derivatives (cellulose ethers such as hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose or the like. Salt, etc.), propylene glycol alginate, gum arabic powder, carmellose sodium, xanthan gum, glycerin, magnesium aluminum silicate, sodium chondroitin sulfate, cyclodextrin, tragacanth powder, macrogol 4000, etc., polyethylene glycol, polyoxyethylene Glycol, hydroxypropylcellulose, alginic acid B propylene glycol, and glycerin are preferable.
0.001 to 20% is preferable, as for the compounding quantity of the thickener in the nasal drop of this invention, 0.005 to 18% is more preferable, and 0.01 to 15% is further more preferable.
本発明の点鼻剤は、滴下式、塗布式、スプレー式等の種々の形態をとることができる。また、スプレー式の場合には、容器に付属されたポンプを手動で動かして液剤を噴出する機構のある手動ポンプ式点鼻剤、圧縮ガス(空気や酸素、窒素、炭酸や、混合ガス)等の噴射剤を容器内に充填しておいて容器に付属して設けた弁を動かして液剤を自動噴出する機構のあるエアゾール式点鼻剤なども含む。 The nasal drops of the present invention can take various forms such as a drop type, a coating type, and a spray type. In the case of the spray type, manual pump type nasal drops with a mechanism for ejecting liquid by manually moving the pump attached to the container, compressed gas (air, oxygen, nitrogen, carbonic acid, mixed gas), etc. In addition, an aerosol type nasal spray having a mechanism in which a liquid agent is automatically ejected by moving a valve attached to the container and filling the container with the propellant is automatically included.
本発明の点鼻剤は、鼻腔粘膜に適用した場合に不快な刺激を生じにくくするために、pHを調整することができ、通常4.0〜9.0、好ましくは、4.0〜7.5、より好ましくは4.5〜7.0、特に好ましくは4.5〜6.5である。pH調整剤としては、ホウ酸、ホウ砂、リン酸、酢酸、プロピオン酸、シュウ酸、グルコン酸、フマル酸、乳酸、クエン酸、コハク酸、酒石酸、リンゴ酸、グルコノラクトン、酢酸アンモニウム、塩酸、硫酸、ポリリン酸、炭酸カリウム、炭酸水素ナトリウム、炭酸ナトリウム、炭酸水素アンモニウム、リン酸水素カリウム、乳酸ナトリウム、クエン酸ナトリウム、水酸化カリウム、水酸化ナトリウム、モノエタノールアミン、トリエタノールアミン、ジイソプロパノールアミン、トリイソプロパノールアミンなどが例示できる。
また、本発明の点鼻剤のpH調整は緩衝剤を用いてもよい。緩衝剤としては、公知のホウ酸緩衝剤、リン酸緩衝剤、炭酸緩衝剤、クエン酸緩衝剤、酢酸緩衝剤、グッド緩衝剤などが挙げられ、好ましくは、グッド緩衝剤、ホウ酸緩衝剤、リン酸緩衝剤、炭酸緩衝剤またはクエン酸緩衝剤、特に好ましくは、グッド緩衝剤、ホウ酸緩衝剤、リン酸緩衝剤またはクエン酸緩衝剤である。「グッド緩衝剤」とは、緩衝能を有する双性イオン構造のアミノエタンスルホン酸誘導体及びアミノプロパンスルホン酸誘導体の総称であり、グッドらにより考案された緩衝剤である。グッド緩衝剤としては、MES、MOPS(3−モルホリノプロパンスルホン酸)、PIPES、HEPES(2−[4−(2−ヒドロキシエチル)−1−ピペラジニル]エタンスルホン酸)、BES、TESなどが挙げられる。ホウ酸緩衝剤としては、ホウ酸、ホウ酸アルカリ金属塩、ホウ酸アルカリ土類金属塩などのホウ酸塩、ホウ酸及びホウ酸塩の組み合わせなどが挙げられる。リン酸緩衝剤としては、リン酸、リン酸アルカリ金属塩、リン酸アルカリ土類金属塩などのリン酸塩、リン酸及びリン酸塩の組み合わせなどが挙げられる。クエン酸緩衝剤としては、クエン酸、クエン酸アルカリ金属塩、クエン酸アルカリ土類金属塩などのクエン酸塩、クエン酸及びクエン酸塩の組み合わせなどが挙げられる。また、ホウ酸緩衝剤、リン酸緩衝剤又はクエン酸緩衝剤として、ホウ酸塩、リン酸塩又はクエン酸塩の水和物を用いてもよい。より具体的には、ホウ酸又はその塩(ホウ酸ナトリウム、テトラホウ酸カリウム、メタホウ酸カリウムなど)、リン酸又はその塩(リン酸水素ナトリウム、リン酸二水素ナトリウム、リン酸二水素カリウムなど)、炭酸又はその塩(炭酸水素ナトリウム、炭酸ナトリウムなど)、クエン酸またはその塩(クエン酸一ナトリウム、クエン酸三ナトリウムなど)などが挙げられる。
When applied to the nasal mucosa, the nasal drops of the present invention can be adjusted in pH so that unpleasant irritation is less likely to occur, and is usually 4.0 to 9.0, preferably 4.0 to 7 0.5, more preferably 4.5 to 7.0, and particularly preferably 4.5 to 6.5. As pH adjusters, boric acid, borax, phosphoric acid, acetic acid, propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, citric acid, succinic acid, tartaric acid, malic acid, gluconolactone, ammonium acetate, hydrochloric acid , Sulfuric acid, polyphosphoric acid, potassium carbonate, sodium bicarbonate, sodium carbonate, ammonium bicarbonate, potassium hydrogen phosphate, sodium lactate, sodium citrate, potassium hydroxide, sodium hydroxide, monoethanolamine, triethanolamine, diisopropanol Examples thereof include amines and triisopropanolamine.
Moreover, you may use a buffer agent for pH adjustment of the nasal drop of this invention. Examples of the buffer include known borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, Good buffer, etc., preferably Good buffer, borate buffer, Phosphate buffer, carbonate buffer or citrate buffer, particularly preferably Good buffer, borate buffer, phosphate buffer or citrate buffer. “Good buffering agent” is a general term for aminoethanesulfonic acid derivatives and aminopropanesulfonic acid derivatives having a zwitterionic structure having buffering ability, and is a buffering agent devised by Good et al. Good buffering agents include MES, MOPS (3-morpholinopropanesulfonic acid), PIPES, HEPES (2- [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid), BES, TES and the like. . Examples of the boric acid buffer include boric acid, boric acid salts such as alkali metal borate salts and alkaline earth metal borate salts, and combinations of boric acid and boric acid salts. Examples of the phosphate buffer include phosphates such as phosphoric acid, alkali metal phosphates, and alkaline earth metal phosphates, and combinations of phosphoric acid and phosphates. Examples of the citrate buffer include citrates such as citric acid, alkali metal citrate salts, and alkaline earth metal citrate salts, and combinations of citric acid and citrate salts. Further, borate, phosphate or citrate hydrate may be used as borate buffer, phosphate buffer or citrate buffer. More specifically, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, etc.), phosphoric acid or a salt thereof (sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.) , Carbonic acid or a salt thereof (sodium hydrogencarbonate, sodium carbonate, etc.), citric acid or a salt thereof (monosodium citrate, trisodium citrate, etc.).
さらに、本発明の点鼻剤には、本発明の効果を妨げない範囲で、必要に応じて点鼻剤に用いられる有効成分、防腐剤、非イオン性界面活性剤、香料等を1種又は2種以上組み合わせて用いることができる。 Furthermore, the nasal drops of the present invention include one or more active ingredients, preservatives, nonionic surfactants, fragrances and the like used in the nasal drops as needed, as long as the effects of the present invention are not hindered. Two or more types can be used in combination.
有効成分:エピネフリン、エフェドリン、テトラヒドロゾリン、ナファゾリン、フェニレフリン、メチルエフェドリン、シュードエフェドリンなどの血管収縮剤、イプロヘプチン、ジフェンヒドラミン、クロルフェニラミンなどの抗ヒスタミン剤、アクリノール、セチルピリジニウム、ベンザルコニウム、ベンゼトニウム、クロルヘキシジンなどの殺菌剤、グリチルレチン酸、グリチルリチン酸、サリチル酸メチル、サリチル酸グリコール、アラントイン、アズレン、アズレンスルホン酸、グアイアズレン、トラネキサム酸、ε−アミノカプロン酸、ベルベリン、リゾチーム、甘草などの消炎剤、亜鉛華、乳酸亜鉛、硫酸亜鉛などの収斂剤、インドメタシン、イブプロフェン、イブプロフェンピコノール、ブフェキサマク、フルフェナム酸ブチル、ベンダザック、ピロキシカム、ケトプロフェン、フェルビナク、紫根、セイヨウトチノキ、およびこれらの塩など Active ingredients: Vasoconstrictors such as epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine, pseudoephedrine, antihistamines such as iproheptin, diphenhydramine, chlorpheniramine, acrinol, cetylpyridinium, benzalkonium, benzethonium, chlorhexidine Agents, glycyrrhetinic acid, glycyrrhizic acid, methyl salicylate, glycol salicylate, allantoin, azulene, azulenesulfonic acid, guaiazulene, tranexamic acid, ε-aminocaproic acid, berberine, lysozyme, licorice and other anti-inflammatory agents, zinc white, zinc lactate, zinc sulfate Astringents such as indomethacin, ibuprofen, ibuprofen piconol, bufexamac, flufenamic acid Le, bendazac, piroxicam, ketoprofen, felbinac, lithospermi radix, horse chestnut, and the like salts thereof
防腐剤:安息香酸ナトリウム、パラオキシ安息香酸エステル、ソルビン酸カリウム、フェノキシエタノール、ヘキサンジオール、ホウ酸、ホウ砂など Preservatives: sodium benzoate, paraoxybenzoate ester, potassium sorbate, phenoxyethanol, hexanediol, boric acid, borax, etc.
非イオン性界面活性剤:ポリオキシエチレン(POE)−ポリオキシプロピレン(POP)ブロックコポリマー(例えば、ポロクサマー407、ポロクサマー235、ポロクサマー188、ポロキサミンなど);モノラウリン酸POE(20)ソルビタン(ポリソルベート20)、モノオレイン酸POE(20)ソルビタン(ポリソルベート80)などのPOEソルビタン脂肪酸エステル類;POE(60)ヒマシ油、POE(60)硬化ヒマシ油などのPOEヒマシ油又は硬化ヒマシ油;POE(9)ラウリルエーテルなどのPOEアルキルエーテル類;POE(20)POP(4)セチルエーテルなどのPOE・POPアルキルエーテル類;POE(10)ノニルフェニルエーテルなどのPOEアルキルフェニルエーテル類など Nonionic surfactant: polyoxyethylene (POE) -polyoxypropylene (POP) block copolymer (eg, poloxamer 407, poloxamer 235, poloxamer 188, poloxamine, etc.); monolauric acid POE (20) sorbitan (polysorbate 20), POE sorbitan fatty acid esters such as monooleic acid POE (20) sorbitan (polysorbate 80); POE castor oil such as POE (60) castor oil, POE (60) hydrogenated castor oil or hydrogenated castor oil; POE (9) lauryl ether POE alkyl ethers such as POE (20) POP (4) POE alkyl ethers such as POP (4) cetyl ether; POE alkyl phenyl ethers such as POE (10) nonyl phenyl ether
香料:テルピネオール、カジネン、アネソール、フェランドレン、サフロール、オイゲノール、リナロール、シンナムアルデヒド、シトロネロール、リモネン、ネロール、エストラゴール、パチョリアルコール、チモール、ベンジルアセテート、リナリルアセテート、ジャスモン、インドール、ミントラクトン、ピペリトン、オクタノール、ミルテノール、カルバクロール、エチルフラン、オシメン、シネオール、ファルネソール、グアイオール、サンタロール、クミンアルデヒド、セドロール、サンタロール、ツヨプセン、グロブロール、セドレン、エピグロブロール、精油など Fragrance: Terpineol, Cadinene, Anesol, Ferrandrene, Safrole, Eugenol, Linalol, Cinnamaldehyde, Citronellol, Limonene, Nerol, Estragole, Patchoulialcohol, Thymol, Benzyl acetate, Linalyl acetate, Jasmon, Indole, Mintlactone, Piperidone, Octanol , Miltenol, Carvacrol, Ethylfuran, Ocymen, Cineol, Farnesol, Guaiol, Santalol, Cuminaldehyde, Cedrol, Santalol, Tsuyopsen, Globulol, Cedrene, Epiglobulol, Essential Oil, etc.
本発明の点鼻剤の製造方法は、特に制限されるものではなく公知の方法によって製造することができる。例えば、上記各成分を、常法により水または温水中、必要に応じて油性基剤中に、溶解・懸濁させた後、pHや浸透圧などを適宜調整して液剤を製し、さらに必要に応じて無菌ろ過を行い、点鼻用容器に充填して製造することができる。 The method for producing the nasal drops of the present invention is not particularly limited and can be produced by a known method. For example, after dissolving and suspending each of the above components in water or warm water in a conventional manner in an oily base as necessary, adjusting the pH, osmotic pressure, etc., to prepare a liquid, and further necessary Aseptic filtration can be performed according to the above, and a nasal container can be filled and manufactured.
以下、実施例および比較例を示し、本発明を具体的に説明するが、本発明は下記の実施例に制限されるものではない。 EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.
実施例1
フルニソリド1/2水和物 0.0255g
l−メントール 0.03g
クロロブタノール 0.2g
ポリエチレングリコール 10g
塩化ベンザルコニウム 0.01g
プロピレングリコール 20g
ポリソルベート80 0.2g
pH調製剤 適量
精製水 適量
100ml
上記の各成分を秤量し適当量の精製水に溶解し、pHを5.5に調整した後、点鼻容器に充填して点鼻剤を得た。
Example 1
Flunisolide 1/2 hydrate 0.0255g
l-Menthol 0.03g
Chlorobutanol 0.2g
Polyethylene glycol 10g
Benzalkonium chloride 0.01g
20g propylene glycol
Polysorbate 80 0.2g
pH adjuster
Purified water
100ml
Each of the above components was weighed and dissolved in an appropriate amount of purified water, adjusted to pH 5.5, and then filled into a nasal drop container to obtain a nasal drop.
実施例2
フルニソリド 0.02g
l−メントール 0.02g
クロロブタノール 0.3g
リドカイン 0.1g
グリセリン 5g
塩化ベンザルコニウム 0.01g
プロピレングリコール 10g
ポリソルベート80 0.1g
pH調製剤 適量
精製水 適量
100ml
上記の各成分を秤量し適当量の精製水に溶解し、pHを5.5に調整した後、点鼻容器に充填して点鼻剤を得た。
Example 2
Flunisolide 0.02g
l-Menthol 0.02g
Chlorobutanol 0.3g
Lidocaine 0.1g
Glycerin 5g
Benzalkonium chloride 0.01g
10g of propylene glycol
Polysorbate 80 0.1g
pH adjuster
Purified water
100ml
Each of the above components was weighed and dissolved in an appropriate amount of purified water, adjusted to pH 5.5, and then filled into a nasal drop container to obtain a nasal drop.
実施例3
フルニソリド 0.0125g
l−メントール 0.01g
クロロブタノール 0.1g
アルギン酸プロピレングリコール 0.1g
塩酸ナファゾリン 0.05g
塩化ベンゼトニウム 0.01g
プロピレングリコール 15g
ポリソルベート80 0.1g
pH調製剤 適量
精製水 適量
100ml
上記の各成分を秤量し適当量の精製水に溶解し、pHを5.5に調整した後、点鼻容器に充填して点鼻剤を得た。
Example 3
Flunisolide 0.0125g
l-Menthol 0.01g
Chlorobutanol 0.1g
Propylene glycol alginate 0.1g
Naphazoline hydrochloride 0.05g
Benzethonium chloride 0.01g
15g propylene glycol
Polysorbate 80 0.1g
pH adjuster
Purified water
100ml
Each of the above components was weighed and dissolved in an appropriate amount of purified water, adjusted to pH 5.5, and then filled into a nasal drop container to obtain a nasal drop.
実施例4
フルニソリド 0.0125g
d−カンフル 0.01g
塩酸ジブカイン 0.5g
アルギン酸プロピレングリコール 0.1g
塩酸テトラヒドロゾリン 0.05g
塩化セチルピリジニウム 0.025g
プロピレングリコール 15g
ポリソルベート80 0.1g
pH調製剤 適量
精製水 適量
100ml
上記の各成分を秤量し適当量の精製水に溶解し、pHを5.5に調整した後、点鼻容器に充填して点鼻剤を得た。
Example 4
Flunisolide 0.0125g
d-Camphor 0.01g
Dibucaine hydrochloride 0.5g
Propylene glycol alginate 0.1g
Tetrahydrozoline hydrochloride 0.05g
Cetylpyridinium chloride 0.025g
15g propylene glycol
Polysorbate 80 0.1g
pH adjuster
Purified water
100ml
Each of the above components was weighed and dissolved in an appropriate amount of purified water, adjusted to pH 5.5, and then filled into a nasal drop container to obtain a nasal drop.
実施例5
フルニソリド 0.0125g
d−ボルネオール 0.03g
塩酸プロカイン 0.5g
アルギン酸プロピレングリコール 0.1g
塩酸シュードエフェドリン 0.03g
アクリノール 0.05g
プロピレングリコール 15g
ポリソルベート80 0.1g
pH調製剤 適量
精製水 適量
100ml
上記の各成分を秤量し適当量の精製水に溶解し、pHを5.5に調整した後、点鼻容器に充填して点鼻剤を得た。
Example 5
Flunisolide 0.0125g
d-borneol 0.03g
Procaine hydrochloride 0.5g
Propylene glycol alginate 0.1g
Pseudoephedrine hydrochloride 0.03g
Acrinol 0.05g
15g propylene glycol
Polysorbate 80 0.1g
pH adjuster
Purified water
100ml
Each of the above components was weighed and dissolved in an appropriate amount of purified water, adjusted to pH 5.5, and then filled into a nasal drop container to obtain a nasal drop.
実施例6
プロピオン酸ベクロメタゾン 0.05g
プロピオン酸フルチカゾン 0.026g
l−メントール 0.03g
クロロブタノール 0.2g
ヒドロキシプロピルセルロース 0.1g
塩化ベンザルコニウム 0.01g
プロピレングリコール 10g
ポリソルベート80 0.1g
pH調製剤 適量
精製水 適量
100ml
上記の各成分を秤量し適当量の精製水に溶解し、pHを6.0に調整した後、点鼻容器に充填して点鼻剤を得た。
Example 6
0.05 g beclomethasone propionate
Fluticasone propionate 0.026g
l-Menthol 0.03g
Chlorobutanol 0.2g
Hydroxypropylcellulose 0.1g
Benzalkonium chloride 0.01g
10g of propylene glycol
Polysorbate 80 0.1g
pH adjuster
Purified water
100ml
Each of the above components was weighed and dissolved in an appropriate amount of purified water, adjusted to pH 6.0, and then filled into a nasal drop container to obtain a nasal drop.
実施例7
フルニソリド 0.0063g
プロピオン酸フルチカゾン 0.013g
dl−カンフル 0.01g
塩酸リドカイン 0.3g
ヒドロキシプロピルセルロース 0.1g
塩化ベンザルコニウム 0.01g
プロピレングリコール 10g
ポリソルベート80 0.1g
pH調製剤 適量
精製水 適量
100ml
上記の各成分を秤量し適当量の精製水に溶解し、pHを6.0に調整した後、点鼻容器に充填して点鼻剤を得た。
Example 7
Flunisolide 0.0063g
Fluticasone propionate 0.013g
dl-Camphor 0.01g
Lidocaine hydrochloride 0.3g
Hydroxypropylcellulose 0.1g
Benzalkonium chloride 0.01g
10g of propylene glycol
Polysorbate 80 0.1g
pH adjuster
Purified water
100ml
Each of the above components was weighed and dissolved in an appropriate amount of purified water, adjusted to pH 6.0, and then filled into a nasal drop container to obtain a nasal drop.
実施例8
プロピオン酸ベクロメタゾン 0.1g
l−メントール 0.01g
クロロブタノール 0.1g
アルギン酸プロピレングリコール 0.1g
塩化ベンゼトニウム 0.01g
プロピレングリコール 8g
ポリソルベート80 0.2g
pH調製剤 適量
精製水 適量
100ml
上記の各成分を秤量し適当量の精製水に溶解し、pHを6.0に調整した後、点鼻容器に充填して点鼻剤を得た。
Example 8
0.1 g of beclomethasone propionate
l-Menthol 0.01g
Chlorobutanol 0.1g
Propylene glycol alginate 0.1g
Benzethonium chloride 0.01g
8g propylene glycol
Polysorbate 80 0.2g
pH adjuster
Purified water
100ml
Each of the above components was weighed and dissolved in an appropriate amount of purified water, adjusted to pH 6.0, and then filled into a nasal drop container to obtain a nasal drop.
実施例9
プロピオン酸ベクロメタゾン 0.1g
dl−カンフル 0.01g
リドカイン 0.5g
アルギン酸プロピレングリコール 0.1g
塩化ベンゼトニウム 0.01g
プロピレングリコール 8g
ポリソルベート80 0.2g
pH調製剤 適量
精製水 適量
100ml
上記の各成分を秤量し適当量の精製水に溶解し、pHを6.0に調整した後、点鼻容器に充填して点鼻剤を得た。
Example 9
0.1 g of beclomethasone propionate
dl-Camphor 0.01g
Lidocaine 0.5g
Propylene glycol alginate 0.1g
Benzethonium chloride 0.01g
8g propylene glycol
Polysorbate 80 0.2g
pH adjuster
Purified water
100ml
Each of the above components was weighed and dissolved in an appropriate amount of purified water, adjusted to pH 6.0, and then filled into a nasal drop container to obtain a nasal drop.
試験例1 刺激感の評価
表1に記載の処方に従い、各成分を精製水に溶解しpH調整後、全量を100mLとし、点鼻スプレー容器に充填し点鼻剤を調製した。これを6人のパネラーに1回100μlを点鼻し、点鼻直後に感じる刺激感を評価した。評価は下記4段階評価基準に従って採点してもらい、その平均値をスコアとして算出した。
3:非常に痛い、2:痛い、1:わずかに痛い、0:痛みがない
結果を表1に示す。
Test Example 1 Evaluation of irritation According to the formulation described in Table 1, each component was dissolved in purified water and adjusted to pH, and the total amount was adjusted to 100 mL and filled into a nasal spray container to prepare a nasal drop. 100 μl of this was sprayed once to 6 panelists, and the feeling of irritation immediately after nasal drop was evaluated. Evaluation was scored according to the following four-level evaluation criteria, and the average value was calculated as a score.
3: Very painful, 2: Painful, 1: Slightly painful, 0: Painless results are shown in Table 1.
比較例1、2から、フルニソリドは非常に刺激感が強く、比較例3からクロロブタノールを配合するとその刺激は多少緩和されることがわかる。また、比較例4から、メントールのみを配合すると刺激感はさらに強くなったが、ステロイドにクロロブタノールとメントールを同時に配合した実施例10は、驚くべきことに刺激の程度が比較例1と同程度にまで抑制された。
したがって、ステロイド化合物は単独では使用感に問題があり、メントールの単独配合ではより刺激を増大させるなど、非ステロイド性抗アレルギー剤とは異なる挙動を示すことが明らかになった。
From Comparative Examples 1 and 2, flunisolide is very irritating, and from Comparative Example 3 it can be seen that the irritation is moderated somewhat when chlorobutanol is added. Moreover, from the comparative example 4, when irritation | stimulation was mix | blended only with menthol, the irritation | stimulation became still stronger, but the degree of irritation | stimulation of Example 10 which mix | blended chlorobutanol and menthol simultaneously with the steroid was comparable as the comparative example 1. It was suppressed to.
Therefore, it has been clarified that the steroid compound alone has a problem in the feeling of use, and the menthol compound alone exhibits a behavior different from that of the nonsteroidal antiallergic agent, such as increasing irritation.
試験例2 刺激感の評価:粘稠化剤の影響
実施例10に各種粘稠化剤を配合した場合の刺激感について、さらに評価を行った。表2に記載の処方に従い、試験例1と同様に点鼻剤を調製し、これを6人のパネラーに1回100μlを点鼻し、試験例1と同様の基準にて評価した。さらに刺激の持続する時間についても測定し、6人の平均値を平均持続時間として算出した。結果を表2に示す。
Test Example 2 Evaluation of irritation: Effect of thickening agent The irritation feeling when various thickening agents were added to Example 10 was further evaluated. In accordance with the formulation described in Table 2, nasal drops were prepared in the same manner as in Test Example 1, and 100 μl was sprayed once on 6 panelists, and evaluated according to the same criteria as in Test Example 1. Furthermore, the duration of stimulation was also measured, and the average value of 6 people was calculated as the average duration. The results are shown in Table 2.
実施例11、12から、ポリエチレングリコール、グリセリンを配合した場合は、刺激のスコアは変化しなかったが刺激の持続時間は短くなり、実施例10より使用感のよい点鼻剤との評価を得た。また、実施例13、14から、ヒドロキシプロピルセルロース、アルギン酸プロピレングリコールを配合した場合は、刺激が完全に消失し、非常に使用感に優れた点鼻剤との評価を得た。 From Examples 11 and 12, when polyethylene glycol and glycerin were blended, the irritation score did not change, but the irritation duration was shortened, and the evaluation as a nasal spray with a better feeling of use than in Example 10 was obtained. It was. Further, from Examples 13 and 14, when hydroxypropylcellulose and propylene glycol alginate were blended, the irritation disappeared completely, and the evaluation was made as a nasal preparation with excellent usability.
試験例3 刺激感の評価
表3に記載の処方に従い、試験例1と同様に点鼻剤を調製し、これを6人のパネラーに1回100μlを点鼻し、試験例1と同様の基準にて評価した。
また、刺激の持続する時間についても測定し、6人の平均値を平均持続時間として算出した。
結果を表3に示す。
Test Example 3 Evaluation of irritation According to the formulation described in Table 3, a nasal drop was prepared in the same manner as in Test Example 1, and 100 μl was dripped once into 6 panelists. Evaluated.
In addition, the duration of stimulation was also measured, and the average value of 6 people was calculated as the average duration.
The results are shown in Table 3.
比較例5、6から、プロピオン酸ベクロメタゾンはフルニソリドよりもさらに非常に刺激感が強く、比較例7、8からリドカインまたはメントール、カンフルを配合するとその刺激は多少緩和されることがわかる。一方、ステロイドにリドカインとメントール、カンフルを同時に配合した実施例15は、驚くべきことに刺激が消失していた。
また、プロピオン酸ベクロメタゾンには独特のにおいがあるが、メントール、カンフルを配合することで、製剤のにおいについても改善することができた。
From Comparative Examples 5 and 6, it can be seen that beclomethasone propionate is much more irritating than flunisolide, and from Comparative Examples 7 and 8, the addition of lidocaine, menthol or camphor reduces the irritation somewhat. On the other hand, in Example 15, in which lidocaine, menthol, and camphor were simultaneously added to the steroid, the irritation was surprisingly lost.
In addition, beclomethasone propionate has a unique odor, but the odor of the preparation could be improved by adding menthol and camphor.
以上の結果から、特定のステロイド化合物を含有する点鼻剤の投与時に生じる刺激感を、クロロブタノール、リドカインまたはジブカインなど、およびメントールまたはカンフルなどを配合することで緩和できることを知見した。
さらに、ポリエチレングリコール、グリセリン、ヒドロキシプロピルセルロース、アルギン酸プロピレングリコールなどの粘稠化剤を配合することにより、より使用感の良い点鼻剤が得られることが確認された。
From the above results, it was found that the irritating sensation produced upon administration of a nasal preparation containing a specific steroid compound can be alleviated by adding chlorobutanol, lidocaine or dibucaine, and menthol or camphor.
Furthermore, it was confirmed that a nasal agent having a better feeling of use can be obtained by blending a thickening agent such as polyethylene glycol, glycerin, hydroxypropyl cellulose, propylene glycol alginate, and the like.
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