CN114650828A - 药物组合物 - Google Patents
药物组合物 Download PDFInfo
- Publication number
- CN114650828A CN114650828A CN202080064874.7A CN202080064874A CN114650828A CN 114650828 A CN114650828 A CN 114650828A CN 202080064874 A CN202080064874 A CN 202080064874A CN 114650828 A CN114650828 A CN 114650828A
- Authority
- CN
- China
- Prior art keywords
- sulfate
- nasal
- chondroitin
- polysaccharide
- polysulfated
- 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.)
- Pending
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 20
- 208000000592 Nasal Polyps Diseases 0.000 claims abstract description 101
- 229920001282 polysaccharide Polymers 0.000 claims abstract description 81
- 239000005017 polysaccharide Substances 0.000 claims abstract description 81
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 claims abstract description 53
- 208000016366 nasal cavity polyp Diseases 0.000 claims abstract description 50
- 229940043138 pentosan polysulfate Drugs 0.000 claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- DLGJWSVWTWEWBJ-HGGSSLSASA-N chondroitin Chemical compound CC(O)=N[C@@H]1[C@H](O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@H](O)C=C(C(O)=O)O1 DLGJWSVWTWEWBJ-HGGSSLSASA-N 0.000 claims abstract description 25
- AVJBPWGFOQAPRH-FWMKGIEWSA-L dermatan sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@H](OS([O-])(=O)=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](C([O-])=O)O1 AVJBPWGFOQAPRH-FWMKGIEWSA-L 0.000 claims abstract description 22
- KXCLCNHUUKTANI-RBIYJLQWSA-N keratan Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@H](COS(O)(=O)=O)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@H](O[C@@H](O[C@H]3[C@H]([C@@H](COS(O)(=O)=O)O[C@@H](O)[C@@H]3O)O)[C@H](NC(C)=O)[C@H]2O)COS(O)(=O)=O)O[C@H](COS(O)(=O)=O)[C@@H]1O KXCLCNHUUKTANI-RBIYJLQWSA-N 0.000 claims abstract description 22
- 229920002567 Chondroitin Polymers 0.000 claims abstract description 21
- 229920000288 Keratan sulfate Polymers 0.000 claims abstract description 21
- 229920002971 Heparan sulfate Polymers 0.000 claims abstract description 20
- LUEWUZLMQUOBSB-FSKGGBMCSA-N (2s,3s,4s,5s,6r)-2-[(2r,3s,4r,5r,6s)-6-[(2r,3s,4r,5s,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5s,6r)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-4,5-dihydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@@H](O[C@@H]2[C@H](O[C@@H](OC3[C@H](O[C@@H](O)[C@@H](O)[C@H]3O)CO)[C@@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O LUEWUZLMQUOBSB-FSKGGBMCSA-N 0.000 claims abstract description 19
- 229920002581 Glucomannan Polymers 0.000 claims abstract description 19
- 229940046240 glucomannan Drugs 0.000 claims abstract description 19
- 229960000633 dextran sulfate Drugs 0.000 claims abstract description 18
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 16
- 229920000045 Dermatan sulfate Polymers 0.000 claims abstract description 15
- 229920001202 Inulin Polymers 0.000 claims abstract description 15
- 229940051593 dermatan sulfate Drugs 0.000 claims abstract description 15
- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 claims abstract description 15
- 229940029339 inulin Drugs 0.000 claims abstract description 15
- 230000001603 reducing effect Effects 0.000 claims abstract description 14
- 239000004480 active ingredient Substances 0.000 claims abstract description 8
- HEBKCHPVOIAQTA-NGQZWQHPSA-N d-xylitol Chemical compound OC[C@H](O)C(O)[C@H](O)CO HEBKCHPVOIAQTA-NGQZWQHPSA-N 0.000 claims abstract description 8
- 150000004676 glycans Chemical class 0.000 claims abstract 5
- 201000009890 sinusitis Diseases 0.000 claims description 30
- 230000002327 eosinophilic effect Effects 0.000 claims description 28
- 208000027157 chronic rhinosinusitis Diseases 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 11
- 206010009137 Chronic sinusitis Diseases 0.000 claims description 9
- 238000009472 formulation Methods 0.000 claims description 6
- 229920001287 Chondroitin sulfate Polymers 0.000 abstract description 40
- 229940059329 chondroitin sulfate Drugs 0.000 abstract description 37
- 238000000034 method Methods 0.000 abstract description 26
- 150000004804 polysaccharides Chemical class 0.000 description 76
- -1 pentosan polysulfate Chemical compound 0.000 description 43
- 229920002683 Glycosaminoglycan Polymers 0.000 description 36
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 29
- 229920001499 Heparinoid Polymers 0.000 description 27
- 239000002554 heparinoid Substances 0.000 description 27
- 239000000243 solution Substances 0.000 description 26
- 239000003814 drug Substances 0.000 description 24
- 239000007923 nasal drop Substances 0.000 description 24
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 19
- 150000002772 monosaccharides Chemical class 0.000 description 18
- 230000009467 reduction Effects 0.000 description 17
- 229940079593 drug Drugs 0.000 description 16
- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 15
- 235000014113 dietary fatty acids Nutrition 0.000 description 15
- 239000000194 fatty acid Substances 0.000 description 15
- 229930195729 fatty acid Natural products 0.000 description 15
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 14
- 229940025770 heparinoids Drugs 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- 229940100662 nasal drops Drugs 0.000 description 13
- 229940061706 sulfated mucopolysaccharides Drugs 0.000 description 13
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 12
- 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 description 12
- 239000000126 substance Substances 0.000 description 12
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 11
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 239000000654 additive Substances 0.000 description 11
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 11
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
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- 239000002253 acid Substances 0.000 description 9
- 230000008859 change Effects 0.000 description 9
- 150000002016 disaccharides Chemical class 0.000 description 9
- 238000011534 incubation Methods 0.000 description 9
- 230000001180 sulfating effect Effects 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 8
- 239000002202 Polyethylene glycol Substances 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- AEMOLEFTQBMNLQ-CLQWQSTFSA-N l-iduronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@@H](O)[C@@H]1O AEMOLEFTQBMNLQ-CLQWQSTFSA-N 0.000 description 8
- 210000003928 nasal cavity Anatomy 0.000 description 8
- 229920001223 polyethylene glycol Polymers 0.000 description 8
- 235000000346 sugar Nutrition 0.000 description 8
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 description 7
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 7
- SRBFZHDQGSBBOR-HWQSCIPKSA-N L-arabinopyranose Chemical compound O[C@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-HWQSCIPKSA-N 0.000 description 7
- OVRNDRQMDRJTHS-KEWYIRBNSA-N N-acetyl-D-galactosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-KEWYIRBNSA-N 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
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- FPJHWYCPAOPVIV-VOZMEZHOSA-N (2R,3S,4R,5R,6R)-6-[(2R,3R,4R,5R,6R)-5-acetamido-2-(hydroxymethyl)-6-methoxy-3-sulfooxyoxan-4-yl]oxy-4,5-dihydroxy-3-methoxyoxane-2-carboxylic acid Polymers CO[C@@H]1O[C@H](CO)[C@H](OS(O)(=O)=O)[C@H](O[C@@H]2O[C@H]([C@@H](OC)[C@H](O)[C@H]2O)C(O)=O)[C@H]1NC(C)=O FPJHWYCPAOPVIV-VOZMEZHOSA-N 0.000 description 6
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- RSLNRVYIRDVHLY-UHFFFAOYSA-N Tulobuterol hydrochloride Chemical compound [Cl-].CC(C)(C)[NH2+]CC(O)C1=CC=CC=C1Cl RSLNRVYIRDVHLY-UHFFFAOYSA-N 0.000 description 3
- BNPSSFBOAGDEEL-UHFFFAOYSA-N albuterol sulfate Chemical compound OS(O)(=O)=O.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 BNPSSFBOAGDEEL-UHFFFAOYSA-N 0.000 description 3
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Abstract
本发明涉及:鼻息肉缩小剂、药物组合物、鼻息肉缩小方法、或鼻息肉的预防/治疗方法,所述鼻息肉缩小剂以选自多硫酸化硫酸软骨素、硫酸软骨素、硫酸皮肤素、硫酸角质素、硫酸乙酰肝素、硫酸葡聚糖、多硫酸戊聚糖(PPS)、软骨素、葡甘露聚糖、菊粉和木寡糖的多糖或其盐为有效成分。根据本发明,可提供有效且安全的鼻息肉缩小剂。
Description
技术领域
本发明涉及:包含用作鼻息肉缩小剂的规定的多糖的药物组合物、或使用了规定的多糖的处置鼻息肉的方法等。
背景技术
鼻息肉也称为鼻息肉病(Nasal polyps),其是在粘膜固有层发生下垂性水肿(坠积性水肿,dependent edema)的部位(通常是上颌窦开口部的周围)形成的鼻粘膜的肉质增殖。该疾病经常合并慢性鼻窦炎,使慢性鼻窦炎的鼻塞症状加重,是鼻病的主要疾病之一(MSD manual professional版、https://www.msdmanuals.com/ ja-jp)。
关于鼻息肉的成因,认为有血管通透性亢进所引起的水肿、粘膜固有层脱垂、细胞外基质的蓄积等各种成因,而且还报道了与各种细胞因子或生长因子的关联。作为生长因子,报道了血管内皮生长因子或来自血小板的生长因子与鼻息肉的关联(非专利文献1:川崎医学会杂志 35(1):39-50, 2009)。
慢性鼻窦炎会持续3个月以上的鼻塞、鼻漏、后鼻漏、咳嗽等呼吸***症状,作为其成因,有病毒性或细菌性、真菌性、过敏性、或病情不明的嗜酸性粒细胞性等,此外还有因鼻腔形态的不同或生活环境、遗传等因素的影响,形成包括鼻息肉形成的复杂病情(非专利文献2:日本耳鼻咽喉科学会会报 2018、121, 1118-1120)。
慢性鼻窦炎中,伴有鼻息肉的疾病有嗜酸性粒细胞性鼻窦炎和非嗜酸性粒细胞性鼻窦炎。其中,嗜酸性粒细胞性鼻窦炎是指定的顽症(顽固性疾病),因两侧的多发性鼻息肉和粘稠的鼻涕而显示高度的鼻塞和嗅觉障碍,是成人发病的难治性鼻窦炎。在该疾病的治疗中,抗菌药无效,仅对类固醇的内服有反应。由于鼻腔内充满鼻息肉,所以会通过鼻窦手术取出鼻息肉,但存在立即复发的问题。
作为针对鼻息肉的药物疗法,报道了使用局部性类固醇药物、全身性类固醇药物、抗白介素4等的单克隆抗体或拮抗剂(专利文献1:日本专利6463351)、干扰素(专利文献2:日本特开平09-104636)、阿司匹林粉末(专利文献3:日本特开平10-203988)和/或透明质酸(非专利文献3:Indian Journal of Otolaryngology and Head & Neck Surgery 67(3):299-307, 2015年9月)等。
另一方面,报道了具有抗凝作用的肝素在大鼠鼻粘膜炎症模型中显著地抑制粘液产生或嗜中性粒细胞浸润(非专利文献4:耳鼻免疫アレルギー(耳鼻免疫过敏) 29(3):221-227, 2011),但对由嗜酸性粒细胞性鼻窦炎患者采集的鼻息肉没有显示缩小效果(非专利文献5:Allergology International 66(2017) 594-602)。
现有技术文献
专利文献
专利文献1:日本专利6463351;
专利文献2:日本特开平09-104636;
专利文献3:日本特开平10-203988;
非专利文献
非专利文献1:川崎医学会杂志 35(1):39-50, 2009;
非专利文献2:日本耳鼻咽喉科学会会报 2018、121, 1118-1120;
非专利文献3:Indian Journal of Otolaryngology and Head & Neck Surgery67(3): 299-307, 2015年9月;
非专利文献4:耳鼻免疫アレルギー 29(3): 221-227, 2011;
非专利文献5:Allergology International 66(2017) 594-602。
发明内容
发明所要解决的课题
本发明提供:对鼻息肉显示优异的缩小效果且安全的鼻息肉缩小剂或处置鼻息肉的方法。
用于解决课题的手段
本发明人深入研究的结果,发现规定的多糖、特别是作为硫酸化多糖之一的类肝素(heparinoid)或多硫酸戊聚糖(PPS)显著地缩小鼻息肉,从而完成了本发明。
即,本发明如下。
(1) 鼻息肉缩小剂,其以选自多硫酸化硫酸软骨素、硫酸软骨素、硫酸皮肤素、硫酸角质素、硫酸乙酰肝素、硫酸葡聚糖、多硫酸戊聚糖、软骨素、葡甘露聚糖、菊粉和木寡糖的多糖或其盐为有效成分。
(1a) (1)所述的鼻息肉缩小剂,其中,上述多糖或其盐选自多硫酸化硫酸软骨素、硫酸软骨素、硫酸角质素、硫酸乙酰肝素、硫酸葡聚糖、多硫酸戊聚糖、软骨素、葡甘露聚糖和菊粉。
(1b) 鼻息肉缩小剂,其以硫酸化多糖或其盐为有效成分。
(1c) (1b)所述的鼻息肉缩小剂,其中,上述硫酸化多糖或其盐选自多硫酸化硫酸软骨素、硫酸软骨素、硫酸角质素、硫酸乙酰肝素、硫酸葡聚糖和多硫酸戊聚糖。
(2) (1b)所述的鼻息肉缩小剂,其中,上述硫酸化多糖由选自D-半乳糖胺、D-葡萄糖醛酸、L-艾杜糖醛酸、D-葡萄糖、D-半乳糖、D-木糖和L-***糖的单糖构成,上述单糖可被部分乙酰化。
(3) (1b)或(2)所述的鼻息肉缩小剂,其中,上述硫酸化多糖为多硫酸化硫酸软骨素、多硫酸化硫酸皮肤素或多硫酸戊聚糖。
(4) (1)~(3)中任一项所述的鼻息肉缩小剂,该鼻息肉缩小剂进行鼻腔内给药。
(5) 药物组合物,其用于缩小慢性鼻窦炎患者的鼻息肉,包含选自多硫酸化硫酸软骨素、硫酸软骨素、硫酸皮肤素、硫酸角质素、硫酸乙酰肝素、硫酸葡聚糖、多硫酸戊聚糖、软骨素、葡甘露聚糖、菊粉和木寡糖的多糖或其盐。
(5a) (5)所述的药物组合物,其中,上述多糖选自多硫酸化硫酸软骨素、硫酸软骨素、硫酸角质素、硫酸乙酰肝素、硫酸葡聚糖、多硫酸戊聚糖、软骨素、葡甘露聚糖和菊粉。
(5b) 药物组合物,其包含用于缩小慢性鼻窦炎患者的鼻息肉的硫酸化多糖或其盐。
(6) (5b)所述的药物组合物,其中,上述硫酸化多糖由选自D-半乳糖胺、D-葡萄糖醛酸、L-艾杜糖醛酸、D-葡萄糖、D-半乳糖、D-木糖和L-***糖的单糖构成,上述单糖可被部分乙酰化。
(7) (5b)或(6)所述的药物组合物,其中,上述硫酸化多糖为多硫酸化硫酸软骨素、多硫酸化硫酸皮肤素或多硫酸戊聚糖。
(8) (5)~(7)中任一项所述的药物组合物,其中,上述慢性鼻窦炎患者为嗜酸性粒细胞性鼻窦炎或非嗜酸性粒细胞性鼻窦炎患者。
(9) (5)~(8)中任一项所述的药物组合物,其中,上述慢性鼻窦炎患者为嗜酸性粒细胞性鼻窦炎患者。
(10) 鼻腔内给药制剂,其包含(5)~(9)中任一项所述的药物组合物。
(11) 处置鼻息肉的方法,该方法通过对需要治疗鼻息肉的患者给予有效量的选自多硫酸化硫酸软骨素、硫酸软骨素、硫酸皮肤素、硫酸角质素、硫酸乙酰肝素、硫酸葡聚糖、多硫酸戊聚糖、软骨素、葡甘露聚糖、菊粉和木寡糖的多糖或其盐来进行。
(12) (11)所述的方法,其中,上述多糖或其盐选自多硫酸化硫酸软骨素、硫酸软骨素、硫酸角质素、硫酸乙酰肝素、硫酸葡聚糖、多硫酸戊聚糖、软骨素、葡甘露聚糖和菊粉。
(13) 鼻息肉的缩小方法,该方法包括:对需要治疗鼻息肉的患者给予有效量的硫酸化多糖或其盐。
(14) (13)所述的方法,其中,上述硫酸化多糖或其盐选自多硫酸化硫酸软骨素、硫酸软骨素、硫酸角质素、硫酸乙酰肝素、硫酸葡聚糖和多硫酸戊聚糖。
(15) (13)所述的方法,其中,上述硫酸化多糖由选自D-半乳糖胺、D-葡萄糖醛酸、L-艾杜糖醛酸、D-葡萄糖、D-半乳糖、D-木糖和L-***糖的单糖构成,上述单糖被部分乙酰化。
(16) (13)所述的方法,其中,上述硫酸化多糖为多硫酸化硫酸软骨素、多硫酸化硫酸皮肤素或多硫酸戊聚糖。
(17) (11)所述的方法,其中,上述患者患有鼻窦炎。
(18) (11)所述的方法,其中,上述患者患有嗜酸性粒细胞性鼻窦炎或非嗜酸性粒细胞性鼻窦炎的慢性鼻窦炎。
(19) (11)所述的方法,其中,上述患者患有嗜酸性粒细胞性鼻窦炎。
(20) (11)所述的方法,该方法是进行鼻腔内给药。
发明效果
规定的多糖、特别是类肝素或多硫酸戊聚糖等硫酸化多糖在低用量下可用作有效且安全的鼻息肉缩小剂。
附图说明
[图1]显示在类肝素的各剂量(0.3、30和3000μg/mL)下的鼻息肉重量的变化。
[图2]显示在类肝素的各剂量(0.003、0.03、0.3和30μg/mL)下的鼻息肉重量的变化。
[图3]显示在0.003μg/mL的多硫酸戊聚糖(PPS)下的鼻息肉重量的变化。
具体实施方式
以下,详细地说明本发明。
本发明中使用的多糖为:选自硫酸软骨素、软骨素、硫酸皮肤素、硫酸角质素、硫酸乙酰肝素和多硫酸化硫酸软骨素等多硫酸化粘多糖的硫酸化粘多糖;在硫酸化粘多糖中进一步包含有硫酸葡聚糖和多硫酸戊聚糖的硫酸化多糖;以及选自葡甘露聚糖、菊粉和木寡糖的多糖。优选为选自多硫酸化硫酸软骨素、硫酸软骨素、硫酸角质素、硫酸乙酰肝素、硫酸葡聚糖、多硫酸戊聚糖、软骨素、葡甘露聚糖和菊粉的多糖。
本发明中的硫酸化多糖由选自D-葡萄糖胺、D-半乳糖胺、D-葡萄糖醛酸、L-艾杜糖醛酸、D-半乳糖醛酸、D-葡萄糖、D-半乳糖、D-木糖和L-***糖的单糖构成,这些单糖可被部分乙酰化,在以该单糖的1种或2种以上为重复单元的多糖中具有硫酸基。本发明中使用的硫酸化多糖在每1分子的单糖中硫酸基为平均0.55~4分子、优选为平均0.6~2.9分子、更优选为平均0.7~2分子。
另外,本发明中使用的硫酸化多糖的硫酸基含量优选通过日本药典外药品标准2002的“类肝素(heparinoid)”中规定的定量法测得的有机硫酸基含量为10~70w/w%,更优选为具有10~65w/w%的有机硫酸基含量的硫酸化多糖。
优选所构成的主要单糖选自D-半乳糖胺、D-葡萄糖醛酸、L-艾杜糖醛酸、D-葡萄糖、D-半乳糖、D-木糖和L-***糖,该单糖是可被部分乙酰化的硫酸化多糖。更优选为由选自D-半乳糖胺、D-葡萄糖醛酸、D-葡萄糖、D-半乳糖、D-木糖和L-***糖的单糖构成的硫酸化多糖。
需要说明的是,作为被部分乙酰化的单糖,例如作为天然存在的单糖,可列举:乙酰葡萄糖、N-乙酰葡萄糖胺、乙酰半乳糖、N-乙酰半乳糖胺、乙酰木糖等。
本发明中使用的硫酸化多糖或其盐的重均分子量为1000~10000000左右、优选为4000~1000000左右。
本说明书中使用的重均分子量在存在Ni个具有Mi的分子量的高分子的情况下是指以下的算式所表示的值:
重均分子量(Mw) = Σ(Ni·Mi 2)/Σ(Ni·Mi)。
重均分子量是指通过凝胶渗透色谱法(GPC)测定而得的值。重均分子量例如是以茁霉多糖(pullulan,普鲁兰多糖)或聚乙二醇为标准物质通过GPC测定而得的茁霉多糖或聚乙二醇换算的重均分子量。重均分子量的测定例如可通过高效液相色谱法(Waters或岛津制作所)进行,柱可使用Ohpak SB-804和SB-803 (均由昭和电工(株)制造)。作为流动相,可使用乙酸铵水溶液或氯化钠水溶液等水系溶剂,流速可设为1.0mL/分钟。在检测方法中可使用差示折射率。
本发明中使用的各种硫酸化多糖通过以下的方法而得到。
硫酸化多糖通过对由可被部分乙酰化的单糖构成的多糖进行硫酸化反应并引入硫酸基而得到。
硫酸化反应如下进行:相对于1g的原料多糖,准备10~30mL冰冷的溶剂,向其中加入相对于1g原料多糖为2~6倍的硫酸化剂,在该溶液中加入1g原料多糖,在0℃~100℃下使其反应1~10小时,进行硫酸化。作为所使用的溶剂,可使用吡啶、N,N-二甲基甲酰胺、N,N-二烷基丙烯酰胺等,作为硫酸化剂,可使用氯磺酸、三乙胺-三氧化硫络盐等。
本发明中使用的由可被部分乙酰化的单糖构成的硫酸化多糖优选该硫酸化多糖的构成糖的0%~60% (摩尔比)被N-乙酰化或O-乙酰化。
在本发明中,硫酸化多糖可以以生理学上可接受的盐的形式使用,作为生理学上可接受的盐,可列举:钠盐、钾盐等碱金属盐;钙盐等碱土金属盐;以及镁盐等,也包括它们的多种盐。
本发明中的硫酸化多糖可列举:硫酸化粘多糖、硫酸葡聚糖和多硫酸戊聚糖等。优选为多硫酸化硫酸软骨素、硫酸软骨素、软骨素、硫酸皮肤素、硫酸角质素、硫酸乙酰肝素、硫酸葡聚糖和多硫酸戊聚糖。
在本申请说明书中,硫酸软骨素、软骨素、硫酸皮肤素、硫酸角质素和硫酸乙酰肝素、以及多硫酸化硫酸软骨素等多硫酸化粘多糖被分类为硫酸化粘多糖。
另外,葡甘露聚糖、菊粉和木寡糖被分类为不符合上述的多糖。
“粘多糖”是指具有由己糖胺和糖醛酸或半乳糖构成的二糖的重复单元作为基本结构的长链氨基糖。
“硫酸化粘多糖”是指具有硫酸基的粘多糖。本发明的硫酸化粘多糖还包括:糖链中具有硫酸基的来自天然的粘多糖、进一步对粘多糖或天然的硫酸化粘多糖进行化学修饰而得的物质。
“多硫酸化粘多糖”是硫酸化粘多糖中在糖链中具有更多的硫酸基的物质,除了来自天然的多硫酸化粘多糖,还包括对粘多糖或天然的硫酸化粘多糖进一步进行化学硫酸化而得的物质。
以下,对硫酸化粘多糖的例子进行说明,其整体结构根据这些硫酸化粘多糖所形成的蛋白多糖的种类、这些硫酸化粘多糖所存在的动物种、组织、发育阶段等具有多态性。即,来自天然的粘多糖或硫酸化粘多糖有时还在作为这些硫酸化粘多糖的基本结构的以下说明的结构中进一步接受修饰、或者其一部分具有除基本结构以外的结构或糖。本发明中使用的这些各硫酸化粘多糖还包括这样的变体。
“己糖胺”广义是指己糖的羟基被氨基取代而得的化合物,具体而言,可列举:D-葡萄糖胺、D-半乳糖胺等。
另外,“糖醛酸”广义是指醛糖的伯醇被氧化成为羧基而得的物质,具体而言,可列举:D-葡萄糖醛酸、L-艾杜糖醛酸、D-半乳糖醛酸等来自天然的糖醛酸。
“硫酸软骨素”是由动物的粘质性分泌液或软骨组织等分离的物质。根据构成糖和硫酸基的键合位置,有硫酸软骨素A和硫酸软骨素C、D、E等,但在本申请说明书中,硫酸软骨素A和硫酸软骨素C被分类为硫酸化粘多糖,而硫酸软骨素D和E是还被分类为多硫酸化粘多糖的硫酸化粘多糖。
硫酸软骨素A (4-硫酸软骨素)具有在4位具有硫酸基的N-乙酰-D-半乳糖胺(GalNAc)和D-葡萄糖醛酸(GlcA)的二糖的重复结构作为基本结构。
硫酸软骨素C (6-硫酸软骨素)具有在6位具有硫酸基的GalNAc和GlcA的二糖的重复结构作为基本结构。
优选为硫酸软骨素A和C。
另外,也可使用对硫酸软骨素进行重均分子量为10万以下、优选1万~5万的低分子化而得的低分子硫酸软骨素。低分子硫酸软骨素通过使用软骨素酶或硫酸软骨素裂合酶等酶来降解天然的硫酸软骨素而得到。
“硫酸皮肤素”由艾杜糖醛酸(IdoUA)和GalNAc的重复二糖构成,以在GalNAc的4位具有硫酸基的结构作为基本结构。有时还被称为硫酸软骨素B。
“硫酸角质素”由半乳糖(Gal)和N-乙酰-D-葡萄糖胺(GlcNAc)分别通过β(1→4)和β(1→3)键交替键合而得的重复二糖构成,GlcNAc的6位总是以硫酸化而得的结构作为基本结构。
“硫酸乙酰肝素”是以D-葡萄糖胺、D-葡萄糖醛酸、L-艾杜糖醛酸为构成糖的多糖的N-乙酰基、N-硫酸、O-硫酸取代物。
“软骨素”以GalNAc和GlcA的重复二糖作为基本结构,是硫酸基特别少(通常,每个二糖单元为0.7分子以下)的粘多糖。除牛角膜等天然来源以外,也可将硫酸软骨素进行化学脱硫酸化而得到。
本发明中使用的硫酸化粘多糖优选为具有由N-乙酰-D-半乳糖胺或N-乙酰-D-葡萄糖胺和糖醛酸或半乳糖构成的二糖的重复单元的硫酸化粘多糖,更优选为硫酸软骨素、硫酸皮肤素、硫酸角质素和硫酸乙酰肝素。
另外,本发明中使用的硫酸化粘多糖类还包括将硫酸软骨素、硫酸皮肤素、硫酸角质素等进一步硫酸化而得的多硫酸化粘多糖。
对本发明的硫酸化粘多糖所具有的硫酸基的数量没有特别限定,每个单糖通常以平均0.55~4分子、优选平均0.6~2.9分子、更优选平均0.7~2分子的比例具有硫酸基。
本发明中使用的硫酸化粘多糖或其盐的分子量根据多糖的种类而不同,没有限定,其平均分子量以重均分子量计为10000~1000000左右、希望为10000~50000左右。
本发明的硫酸化粘多糖对其来源没有特别限定,作为更适合的硫酸化粘多糖,例如可列举:通过对上述的来自天然的粘多糖人为地施行硫酸化处理进行硫酸化而形成的硫酸化粘多糖。
“多硫酸化粘多糖”是指上述硫酸化粘多糖中更多的硫酸基被取代而得的粘多糖,具体而言,可列举:多硫酸化硫酸软骨素、多硫酸化硫酸皮肤素等。优选为多硫酸化硫酸软骨素。
作为向硫酸软骨素A或C等硫酸化粘多糖中进一步引入硫酸基而得到多硫酸化粘多糖的方法,可列举:已知的方法、例如在硫酸化剂的存在下、在适当的溶剂中加热使其反应的方法。作为硫酸化剂,只要是可达到多硫酸化目的的物质即可,没有特别限定,优选使用硫酸酐与吡啶或三乙胺等的络合物。硫酸化剂的使用比例可依据所期望的硫酸化粘多糖的硫酸化率(或硫含量)和反应条件任意选择,通常以相对于1重量份所多硫酸化的硫酸化粘多糖为2~10重量份的比例使用。作为溶剂,例如可列举:二甲基甲酰胺等亲质子性溶剂。对反应温度、反应时间没有特别限定,只要可达到所期望的硫酸化率即可,例如在40~90℃下反应30分钟~20天左右。
如上操作而生成的多硫酸化粘多糖可通过各种修饰多糖中常用的纯化操作进行纯化。例如可列举:中和、基于透析的脱盐、回收通过添加有机溶剂而生成的沉淀的操作、基于冷冻干燥的回收操作等。
本发明中,多硫酸化粘多糖可以以生理学上可接受的盐的形式使用,作为生理学上可接受的盐,可列举:钠盐、钾盐等碱金属盐;钙盐等碱土金属盐;以及镁盐等,还包括它们的多种盐。
“多硫酸化硫酸软骨素”是指每一个由D-乙酰半乳糖胺和D-葡萄糖醛酸构成的二糖单元包含2~4分子左右、优选2~3分子左右的硫酸基的聚合物。
作为多硫酸化硫酸软骨素,例如可列举:硫酸软骨素D、硫酸软骨素E、日本药典外药品标准中记载的类肝素。优选为日本药典外药品标准中记载的类肝素。
多硫酸化硫酸软骨素除了硫酸软骨素D和硫酸软骨素E等由天然得到的物质以外,例如还可通过使软骨素、硫酸软骨素(A、C、D、E)等软骨素成分与氯硫酸、浓硫酸、三氧化硫-吡啶络合物等硫酸化剂反应的已知方法容易地制造。
作为优选的多硫酸化硫酸软骨素,可示例日本药典外药品成分标准中记载的类肝素。
具体而言,是物理化学性质显示下述值的多硫酸化硫酸软骨素:
a) 硫酸基含量:25.8~37.3%;
b) 极限粘度:0.09~0.18。
多硫酸化硫酸软骨素可以以来自硫酸残基的游离酸的形式使用,但通常使用碱盐。
作为该碱盐,可列举:钠盐、钾盐等碱金属盐;钙盐等碱土金属盐;以及镁盐等。
硫酸软骨素D由鲨鱼软骨等分离,具有类似于硫酸软骨素C的结构,其基本结构除了在GalNAc的6位还在GlcA的2或3位具有硫酸基。
硫酸软骨素E (4,6-硫酸软骨素)由枪乌贼软骨等分离,具有类似于硫酸软骨素C的结构,其基本结构在GalNAc的4位和6位具有硫酸基。
“多硫酸化硫酸皮肤素”是指通过向具有由N-乙酰半乳糖胺和L-艾杜糖醛酸构成的重复糖单元的天然硫酸化粘多糖即硫酸皮肤素中化学引入硫酸基而合成的物质和天然存在的多硫酸皮肤素、或者通过向其中化学引入硫酸基而合成的物质。
对所引入的硫酸基的数量没有特别限定,例如可列举:每个重复糖单元多于1个、最多4个、优选1.3~4个、更优选2~4个。另外,本发明的多硫酸化硫酸皮肤素的重均分子量例如为1000~数万左右。
以下,对用于本发明的上述以外的硫酸化多糖进行说明。
“硫酸葡聚糖”是由葡萄糖单元构成的多糖即葡聚糖的聚阴离子衍生物,所述葡萄糖单元由葡萄糖进行α(1→6)键合而得的直链和从α(1→3)键的支链开始通常1000至数千Da至数十万Da这样的长度的链构成,C2~C4位以及末端基的C1位和C6位的一部分被硫酸化。
“多硫酸戊聚糖”是半合成硫酸化多糖,包含以D-木糖和/或L-***糖为构成单糖的多价阴离子性多糖的混合物。多硫酸戊聚糖通过由木本、例如山毛榉得到的多糖(例如木聚糖)的化学硫酸化而生成。通常,认为其是在木聚糖链上键合有作为侧链的O-甲基葡萄糖醛酸而得的物质的多硫酸化物。
多硫酸戊聚糖可以以生理学上可接受的盐的形式使用,作为生理学上可接受的盐,可列举:钠盐、钾盐等碱金属盐;钙盐等碱土金属盐;以及镁盐。特别优选的盐为多硫酸戊聚糖钠。
对多硫酸戊聚糖没有特别限定,优选使用重均分子量为1000~30000的多硫酸戊聚糖,更优选为2000~10000,进一步优选使用4000~6500的多硫酸戊聚糖。
以下,对硫酸化多糖以外的多糖的具体例子进行说明。
“葡甘露聚糖”主要由葡萄糖和甘露糖构成,两者进行β(1→4)键合而形成主链,一部分具有由β(1→3)键或β(1→6)键形成的支链结构。
“菊粉”是由2~140个分子的具有末端葡萄糖的果糖进行β(2→1)键合而得的物质。
“木寡糖”是木聚糖的水解物,是具有2~7个左右的木糖进行β(1→4)键合而得的结构的寡糖。还包括来自作为原料的木聚糖且具有4-O-甲基葡萄糖醛酸侧链、***呋喃糖基侧链等的木寡糖。
上述多糖可以以生理学上可接受的盐的形式使用,作为生理学上可接受的盐,可列举:钠盐、钾盐等碱金属盐;钙盐等碱土金属盐;以及镁盐等,还包括它们的多种盐。
上述多糖可由动物或植物组织、链球菌属微生物等微生物、动物细胞或植物细胞的培养物提取、回收。另外,也可使用市售品。
根据本发明,可提供对缩小鼻息肉有效的药物,该药物包含上述规定的多糖、优选规定的硫酸化多糖作为有效成分。
另外,由于本发明的药物具有鼻息肉的缩小效果,因此还可期待改善呈现鼻息肉的疾病、具体而言包括嗜酸性粒细胞性鼻窦炎或非嗜酸性粒细胞性鼻窦炎的慢性鼻窦炎、或过敏性鼻炎等的症状。
另外,本发明的另一方案提供处置鼻息肉的方法、缩小鼻息肉的方法、或鼻息肉的预防或治疗方法,这些方法通过对需要治疗鼻息肉的患者给予本发明中使用的规定的多糖来进行。
鼻息肉也称为鼻息肉病(Nasal polyps),其是在粘膜固有层发生下垂性水肿的部位(通常是上颌窦开口部的周围)形成的鼻粘膜的肉质增殖。需要治疗鼻息肉的患者是伴有鼻息肉的疾病、具体而言是鼻窦炎的患者、优选为患有慢性鼻窦炎的患者。慢性鼻窦炎包括嗜酸性粒细胞性鼻窦炎和非嗜酸性粒细胞性鼻窦炎。
处置鼻息肉包括:改善由鼻息肉引起的鼻塞等症状、缩小鼻息肉、或治疗鼻息肉、即缩小鼻息肉和改善鼻塞等症状。
改善由鼻息肉引起的鼻塞等症状是指,虽然在鼻息肉的数量或大小上未见减少,但与用于本发明的多糖的非给药组相比,鼻塞等临床症状有所改善。
鼻息肉的缩小是指发现鼻息肉的数量减少或大小(每1个鼻息肉的面积或重量)缩小的至少1种情形。
在液体制剂的情况下,用于本发明的多糖的浓度优选3×10 -7~30w/v%左右、更优选0.003~10w/v%左右。
用于本发明的多糖被用作鼻腔内给药制剂,其通过鼻腔内给药而送达至呈现鼻息肉的鼻腔内。
鼻腔内给药制剂是以鼻腔内给药为目的的药物形式,具体而言是液体制剂、悬浮剂、粉末剂、固体制剂或半固体制剂。悬浮剂是含有分散在液体介质中的固体颗粒的液体制剂。
作为鼻腔内给药制剂的优选剂型,可列举:滴鼻剂。
滴鼻剂是对鼻腔或鼻粘膜给药的制剂,分为滴鼻液体制剂和滴鼻粉末剂。滴鼻剂可根据需要使用喷雾泵等具有适当的喷雾量的均匀性的喷雾用器具进行喷雾吸入。通过使用可调节喷雾量的喷雾用器具,可调节滴鼻剂的给药量。
滴鼻液体制剂是对鼻腔给药的液态、或在使用时溶解或在使用时悬浮而进行使用的固体滴鼻剂,通常可通过将有效成分直接或加入溶剂或其他适当的添加剂,进行溶解或悬浮,根据需要进行过滤来制造。或者,可使用适当的溶解液或悬浮用液,在使用时溶解或在使用时悬浮而进行使用。根据需要,可在滴鼻液体制剂中加入助溶剂、等渗剂、缓冲剂或pH调节剂等。另外,在悬浮剂的情况下,为了得到有效成分均匀的状态,根据需要可加入分散剂或稳定剂等。
作为滴鼻液体制剂的给药方式,例如可列举:喷雾式滴鼻剂、鼻气溶胶或鼻雾化器。喷雾式滴鼻剂通常含有溶解或悬浮于未加压分配器中的溶液或混合物中的多糖。喷雾式滴鼻剂具有以下优点:送达器件小型、简便、且使用方法简便,可准确量取25~200μL的送达给药量。在喷雾式滴鼻剂中可使用含有多糖的液体或悬浮剂。另一鼻腔内方式为鼻气溶胶。鼻气溶胶由于过剩的压力而分配药剂,通过阀门进行释放。在喷雾式滴鼻剂中,药剂通过微量泵筒(micro pump bucket)被强制地分配,但小瓶的压力与大气压相同。鼻气溶胶具有与喷雾同样的优点。
鼻雾化器是使用通过超声波将药剂形成细雾状而释放的仪器的给药方式。
在将滴鼻液体制剂填充至多次给药容器的情况下,根据需要,加入足以阻止微生物生长的量的适当的保存剂(防腐剂)。用于滴鼻液体制剂的容器通常为气密容器。
滴鼻粉末剂是对鼻腔给药的微粉状滴鼻剂,通常可将有效成分制成适度微细的颗粒,如果需要则与适当的添加剂混合、并进行均匀化来制造。用于滴鼻粉末剂的容器通常是密闭容器。根据需要赋予防湿性。
除滴鼻剂以外,还可将本发明的药物制成软膏剂、硬膏剂、霜剂、凝胶剂等固体、半固体或应用于鼻粘膜的高粘性的液体制剂或悬浮剂,从而通过涂布在鼻腔内等进行给药。
这些滴鼻剂、软膏剂、硬膏剂、霜剂、凝胶剂等剂型是将用于本发明的多糖和药学上可接受的添加剂一起调制成各种剂型。
作为用于本发明的药物的药学上可接受的添加剂,可列举:该领域中通常使用的添加剂、即如下所示的药剂用赋形剂或药剂用载体等,适当使用这些添加剂,通过通常所采用的方法,可调制适合于各自的给药形式的药物组合物。
作为用于本发明的药物的药学上可接受的添加剂,只要是该领域中通常使用的添加剂即可,没有特别限定,例如可列举:基质、助溶剂、赋形剂、分散剂、乳化剂、增稠剂、等渗剂、缓冲剂、pH调节剂、稳定剂、螯合剂、保存剂、抗氧化剂、吸收促进剂、保湿剂、填充剂、交联剂、清凉剂和覆膜剂,适当使用这些添加剂,通过通常所采用的方法,可调制适合于各自的给药形式的药物组合物。
作为用于本发明的药物的基质,可列举:疏水性基质、亲水性基质和水。
对疏水性基质没有特别限定,可使用高级烃、油脂类、蜡类、脂肪酸、高级醇和脂肪酸酯类等。作为高级烃,例如可列举:角鲨烷、合成石蜡、液体石蜡、白色凡士林和微晶蜡等。作为油脂类,例如可列举:芝麻油、玉米油、橄榄油和可可脂等。作为蜡类,例如可列举:蜂蜡、白蜂蜡、羊毛脂、还原羊毛脂和地蜡等。作为脂肪酸,例如可列举:硬脂酸和油酸等。作为高级醇,例如可列举:羊毛脂醇、肉豆蔻醇、鲸蜡醇、硬脂醇、鲸蜡硬脂醇和胆固醇等。作为脂肪酸酯类,例如可列举:肉豆蔻酸异丙酯、肉豆蔻酸硬脂酯和中链脂肪酸三甘油酯等。
作为亲水性基质,例如可列举:乙醇、丙醇、异丙醇、丁醇、异丁醇、丙二醇、聚乙二醇(polyethylene glycol)和聚乙烯二醇(macrogol)等。
对助溶剂没有特别限定,例如可列举:丙二醇、D-甘露醇、苯甲酸苄酯、乙醇、异丙醇、三乙醇胺、碳酸钠和柠檬酸钠等。
在本发明的药物为滴鼻粉末剂的情况下,根据需要使用赋形剂作为添加剂。
对赋形剂没有特别限定,例如可列举:赤藓糖醇、麦芽糖醇、甘露醇、山梨醇、木糖醇和乳糖醇等糖醇;精制糖(white sugar)、乳糖、还原麦芽糖糖稀、粉末还原麦芽糖糖稀、葡萄糖和麦芽糖等糖类;玉米淀粉、结晶纤维素、磷酸一氢钙、磷酸氢钙、无水磷酸氢钙、轻质硅酸酐、含水二氧化硅以及二氧化硅等。
在本发明的药物为悬浮剂的情况下,根据需要使用分散剂作为添加剂。
对分散剂没有特别限定,例如可列举:甲基纤维素、羧甲基纤维素钠和羟丙基甲基纤维素等纤维素类;聚乙烯醇、聚乙烯吡咯烷酮和羧基乙烯基聚合物等合成高分子化合物;聚氧乙烯烷基醚、聚氧乙烯聚丙烯烷基醚、脱水山梨糖醇脂肪酸酯、聚氧乙烯脱水山梨糖醇脂肪酸酯、甘油脂肪酸酯、聚甘油脂肪酸酯、聚氧乙烯甘油脂肪酸酯、聚乙二醇脂肪酸酯、蔗糖脂肪酸酯、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油和聚氧乙烯聚氧丙烯聚合物等非离子性表面活性剂;烷基甜菜碱、烷基酰胺甜菜碱、烷基磺基甜菜碱和咪唑啉等两性表面活性剂;以及饱和高级脂肪酸盐、烷基磺酸盐、烷基醚磺酸盐和聚氧乙烯烷基醚磷酸盐等阴离子性表面活性剂等。
作为乳化剂,可列举:阳离子性表面活性剂、阴离子性表面活性剂、两性离子性表面活性剂和非离子性表面活性剂等。
对阳离子性表面活性剂没有特别限定,例如可列举:十六烷基三甲基氯化铵、十二烷基二甲基苄基氯化铵、四丁基氯化铵和双十八烷基二甲基氯化铵等。
对阴离子性表面活性剂没有特别限定,例如可列举:烷基苯磺酸钠、十二烷基硫酸钠、椰油醇乙氧基硫酸钠、α-烯烃磺酸钠和乳化鲸蜡硬脂醇等。
对非离子性表面活性剂没有特别限定,例如可列举:聚氧乙烯烷基醚、聚氧乙烯烷基酚醚、聚氧乙烯脱水山梨糖醇脂肪酸酯、聚氧乙烯氢化蓖麻油、聚氧乙烯硬脂酸酯、甘油脂肪酸酯和二甘油脂肪酸酯等。
对两性表面活性剂没有特别限定,例如可列举:N-烷基-N,N-二甲基铵甜菜碱和咪唑啉型两性表面活性剂等。
上述表面活性剂可单独或组合使用。
对增稠剂没有特别限定,例如可列举:海藻酸钠、明胶、甲基纤维素、羧基乙烯基聚合物、羧甲基纤维素和聚丙烯酸钠等。
对等渗剂没有特别限定,例如可列举:山梨醇、葡萄糖和甘露醇等糖类;甘油、聚乙二醇和丙二醇等多元醇;以及氯化钠和氯化钾等无机盐等。
对缓冲剂没有特别限定,例如可列举:硼酸、硼砂、磷酸一氢钠、磷酸二氢钠、柠檬酸、柠檬酸钠、柠檬酸二氢钠和柠檬酸二钠等。
对pH调节剂没有特别限定,例如可列举:二异丙醇胺、三异丙醇胺、三乙醇胺、氢氧化钾、氢氧化钠、柠檬酸钠、磷酸、酒石酸、dl-苹果酸和冰醋酸等。
对稳定剂没有特别限定,例如可列举:依地酸钠、油酸钠、酪蛋白和酪蛋白钠盐等。
对螯合剂没有特别限定,例如可列举:依地酸、草酸、柠檬酸、焦磷酸、六偏磷酸、葡萄糖酸和它们的盐等。
对保存剂没有特别限定,例如可列举:苯扎氯铵(benzalkonium chloride)、苯佐氯铵(benzoxonium chloride)、苯扎溴铵(benzododecinium bromide)、苄索氯铵(benzethonium chloride)、氯化十六烷基吡啶鎓(cetylpyridinium chloride)和溴化十六烷基三甲铵(cetrimide)等季铵盐;苯甲酸及其盐、4-羟基苯甲酸甲酯和4-羟基苯甲酸丙酯等4-羟基苯甲酸的C1-C7烷基酯及其盐;二葡萄糖酸氯己定(chlorhexidinedigluconate)、醋酸氯己定(chlorhexidine acetate)和氯化氯己定(chlorhexidinechloride)等氯己定及其鼻内可接受的盐;2-苯基乙醇、2-苯氧乙醇、氯丁醇以及山梨酸。
作为保存剂,优选鼻内可接受的保存剂。
对抗氧化剂没有特别限定,例如可列举:多元酚、抗坏血酸、叔丁基氢醌、丁基羟基茴香醚、丁基羟基甲苯、L-半胱氨酸盐酸盐、亚硫酸氢钠、以及α-生育酚及其衍生物。
对吸收促进剂没有特别限定,例如可列举:己二酸二异丙酯、卵磷脂、角鲨烷、角鲨烯、l-薄荷醇、聚乙二醇、肉豆蔻酸异丙酯、二甲基亚砜、薄荷油、桉树油、d-柠檬烯和dl-柠檬烯等。
对保湿剂没有特别限定,例如可列举:甘油、丙二醇和1,3-丁二醇等。
对填充剂没有特别限定,例如可列举:高岭土、二氧化钛和氧化锌等。
对交联剂没有特别限定,例如可列举:乙醛、二甲基酮和硫酸铝等。
对清凉剂没有特别限定,例如可列举:l-薄荷醇、dl-樟脑、d-冰片、茴香油、薄荷油和薄荷水等。
含有本发明的药物的滴鼻液体制剂可包含鼻内可接受的覆膜剂。若添加覆膜剂,则通过抑制水分流失以更长地维持鼻粘膜的良好的水合水平,可增强本发明的组合物的保湿效果和无痛化效果。
对覆膜剂没有特别限定,例如可列举:羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素、羟乙基甲基纤维素和羧甲基纤维素钠等在水中呈溶解性或溶胀性的纤维素材料;聚乙烯吡咯烷酮(聚维酮)以及交联聚乙烯吡咯烷酮(交联聚维酮)。
本发明的药物根据患者的年龄、体重、性別、鼻息肉的程度(量、范围)等而不同,没有特别限定,应用量根据鼻息肉的程度而不同。
每天以5×10-11~1g对鼻腔内应用1次~数次。
需要说明的是,由于慢性鼻窦炎、特别是嗜酸性粒细胞性鼻窦炎的病情与哮喘密切相关,所以对于并发哮喘的慢性鼻窦炎患者,还可将本发明的药物与哮喘治疗药并用进行给药。
作为哮喘治疗药,例如可列举:以下的药剂。
吸入类固醇药物或鼻喷雾用类固醇药物:倍氯米松丙酸酯(beclomethasonepropionate)、氟替卡松丙酸酯(fluticasone propionate)、布***(budesonide)、环索奈德(ciclesonide)、莫美他松呋喃甲酸酯(mometasone furan carboxylate)等;
吸入类固醇药物与长效作用型β2激动剂的复方药:与昔萘酸沙美特罗(salmeterol xinafoate)的联合用药、与富马酸福莫特罗水合物(formoterol fumaratehydrate)的联合用药;
茶碱缓释制剂:Theodur (茶碱缓释片)、Theolong、Slo-bid (无水茶碱长效制剂)、Uniphyl、Unicon、Neophyllin、Theodrip等;
短效作用性茶碱药:Neophyllin、Theocolin、Monophylline、Asthmolysin-D/M、Asthphyllin、Albina栓剂等;
长效作用性β2激动剂:吸入剂(LABA)/Serevent、贴剂/Hokunalin带、口服药/Meptin、Spiropent、Hokunalin、Berachin、Atock、Broncholin等;
短效作用性β2激动剂(SABA):吸入剂/Airomir、Sultanol、Meptin Air、Berotec气溶胶等、口服药/Venetlin、Alotec、Inolin、LEANOL、麻黄碱、Isopal P等;
白三烯拮抗剂(受体拮抗剂):Onon、Accolate、Singulair、Kipres等;
Th2细胞因子抑制剂:IPD等;
组胺H1受体拮抗剂:Zesulan、Nipolazin、Zaditen、Celtect、Alesion等;
介质释放抑制剂:Intal、Rizaben、Solfa、Romet、Ketas、Alegysal、Pemilaston、Tazanol、Tazalest等;
血栓烷A2抑制剂:Vega、Domenan等;
血栓烷A2拮抗剂:Bronica、Baynas等;
口服类固醇药物:***、***龙、美卓乐(Medrol,甲基强的松龙)、临得隆(rinderon)、立可通(ledercort)、地卡特隆(Decadron)、Corson、***、帕拉米松等;
免疫抑制药:环孢素(cyclosporine)等;
白介素4R (IL-4R)抑制剂:度普利尤单抗(dupilumab)等;
碘制剂:Jolethin (沃丽汀)等。
另外,也可将本发明的药物与血管收缩药并用进行给药。作为血管收缩药,例如可列举:盐酸萘甲唑啉(naphazoline hydrochloride)、盐酸四氢唑啉(tetrahydrozolinehydrochloride)、盐酸去氧肾上腺素(phenylephrine hydrochloride)、盐酸肾上腺素(epinephrine hydrochloride)、dl-盐酸甲基麻黄碱(dl-methylephedrinehydrochloride)、硝酸四氢唑啉(tetrahydrozoline nitrate)、硝酸萘甲唑啉(naphazoline nitrate)和肾上腺素(epinephrine)。
实施例
以下,根据实施例,进一步详细地说明本发明。需要说明的是,本发明并不限于下述实施例。
[实施例1] 类肝素对嗜酸性粒细胞性鼻窦炎患者的鼻息肉的鼻息肉缩小作用
将减压干燥后的类肝素(有机硫酸基为25.8~37.3%w/w、D-葡萄糖醛酸为19.0~24.0%w/w、Maruho株式会社)溶解于生理盐水,制作了类肝素溶液(0.3、30和3000μg/mL)。将由嗜酸性粒细胞性鼻窦炎患者摘取的鼻息肉样本细切成约5mm见方,擦去水分,测定了重量。将各样本转移至12孔板中,添加1mL的生理盐水或各浓度的类肝素溶液,在37°C下培养了约24小时。从板中取出样本,擦去水分,测定了重量。以培养前后的样本重量之差作为鼻息肉缩小作用的指标进行评价。另外,图1的生理盐水组和各浓度的类肝素溶液组的病例数为6例。
培养前后的样本重量的变化见图1。图1中的*和**表示根据配对t检验在培养前后的鼻息肉重量上的显著差异(*p<0.05、**p<0.01)。通过与生理盐水进行培养,没有看到鼻息肉重量的显著变化,相对于此,通过与类肝素溶液(0.3、30和3000μg/mL)进行培养,鼻息肉重量显著减少,由此暗示了:类肝素具有鼻息肉缩小作用。
[实施例2] 类肝素对嗜酸性粒细胞性鼻窦炎患者的鼻息肉的鼻息肉缩小作用
利用与实施例1同样的方法,评价了0.003、0.03、0.3和30μg/mL类肝素溶液的鼻息肉缩小作用。另外,图2的生理盐水组和各浓度的类肝素溶液组的病例数为6例。
培养前后的样本重量的变化见图2。图2中的**表示通过配对t检验在培养前后的鼻息肉重量上的显著差异(**p<0.01)。通过与生理盐水进行培养,没有看到鼻息肉重量的显著变化,相对于此,通过与类肝素溶液(0.003、0.03、0.3和30μg/mL)进行培养,鼻息肉重量显著减少,由此暗示了:类肝素具有鼻息肉缩小作用。
[实施例3] 多硫酸戊聚糖(PPS)对嗜酸性粒细胞性鼻窦炎患者的鼻息肉的鼻息肉缩小作用
利用与实施例1同样的方法,调制PPS溶液(0.003μg/mL),评价了鼻息肉缩小作用。使用Molclone Labs公司制造的多硫酸戊聚糖钠(重均分子量为4000~6500、硫含量为13.0~20.0%w/w、葡萄糖醛酸含量为2.5~4.0%w/w)作为PPS。另外,图3的生理盐水组和PPS溶液组的病例数为6例。
培养前后的样本重量的变化见图3。通过与生理盐水进行培养,几乎没有看到鼻息肉重量的减少,相对于此,通过与PPS溶液(0.003μg/mL)进行培养,鼻息肉重量大幅减少,由此暗示了:PPS具有嗜酸性粒细胞性鼻窦炎患者的鼻息肉缩小作用。
[实施例4] 各多糖对嗜酸性粒细胞性鼻窦炎患者的鼻息肉的鼻息肉缩小作用
利用与实施例1同样的方法,调制下述的11种多糖溶液(除葡甘露聚糖以外分别为300μg/mL、葡甘露聚糖为30μg/mL),评价了鼻息肉缩小作用。另外,表1~4的生理盐水组和各多糖溶液组的病例数为1例。
・软骨素(软骨素钠、重均分子量为42,351、硫酸基含量为2.6%、Maruho株式会社制造);
・低分子硫酸软骨素(低分子硫酸软骨素钠、重均分子量为11,500、硫酸基含量为8.9%、Maruho株式会社制造);
・硫酸软骨素A (硫酸软骨素A钠、株式会社PG Research制造);
・硫酸皮肤素(硫酸皮肤素钠、东京化成工业株式会社制造);
・硫酸软骨素C (硫酸软骨素C钠、株式会社PG Research制造);
・葡甘露聚糖(Propol A、清水化学株式会社制造);
・硫酸葡聚糖(硫酸葡聚糖钠500,000、富士胶片和光纯药株式会社制造);
・硫酸角质素(硫酸角质素钠、株式会社PG Research制造);
・菊粉(东京化成工业株式会社制造);
・硫酸乙酰肝素(Toronto Research Chemicals,Inc.制造);
・木寡糖(木六糖、Megazyme制造)。
软骨素通过利用与日本特开平07-062001同样的方法对硫酸软骨素钠(Bioiberica公司制造)进行脱硫酸化来合成。低分子硫酸软骨素通过在酸性条件下将硫酸软骨素钠(Bioiberica公司制造)水解来合成。其他多糖使用所记载的市售品。
培养前后的样本重量的变化见表1~4。通过与生理盐水进行培养,几乎没有看到鼻息肉重量的减少,相对于此,通过与11种多糖溶液(除葡甘露聚糖以外分别为300μg/mL、葡甘露聚糖为30μg/mL)进行培养,鼻息肉重量大幅减少,由此暗示了:11种多糖具有嗜酸性粒细胞性鼻窦炎患者的鼻息肉缩小作用。
[表1]
[表2]
[表3]
[表4]
[实施例5] 类肝素和PPS对非嗜酸性粒细胞鼻窦炎患者的鼻息肉的鼻息肉缩小作用
利用与实施例1同样的方法,调制类肝素溶液和PPS溶液(分别为0.03、0.3、30和300μg/mL),评价了对由非嗜酸性粒细胞性鼻窦炎患者摘取的鼻息肉样本的鼻息肉缩小作用。需要说明的是,类肝素和PPS使用与实施例1和实施例3中使用的物质相同的物质。另外,表5的生理盐水组、类肝素溶液和PPS溶液组的病例数为1例。
培养前后的样本重量的变化见表5。通过与生理盐水进行培养,没有看到鼻息肉重量的减少,相对于此,通过与类肝素溶液和PPS溶液(分别为0.03、0.3、30和300μg/mL)进行培养,鼻息肉重量大幅减少,由此暗示了:类肝素和PPS对非嗜酸性粒细胞鼻窦炎患者的鼻息肉也具有缩小作用。
[表5]
产业实用性
包含作为硫酸化多糖的类肝素的某种多糖对鼻息肉以低剂量显示显著的效果,因此包含硫酸化多糖的规定的多糖可作为鼻息肉缩小剂用于伴有鼻息肉的慢性鼻窦炎患者的治疗或预防。
Claims (8)
1.鼻息肉缩小剂,其以选自多硫酸化硫酸软骨素、硫酸软骨素、硫酸皮肤素、硫酸角质素、硫酸乙酰肝素、硫酸葡聚糖、多硫酸戊聚糖、软骨素、葡甘露聚糖、菊粉和木寡糖的多糖或其盐为有效成分。
2.权利要求1所述的鼻息肉缩小剂,其中,上述多糖选自多硫酸化硫酸软骨素、硫酸软骨素、硫酸角质素、硫酸乙酰肝素、硫酸葡聚糖、多硫酸戊聚糖、软骨素、葡甘露聚糖和菊粉。
3.权利要求1或2所述的鼻息肉缩小剂,该鼻息肉缩小剂进行鼻腔内给药。
4.药物组合物,其用于缩小慢性鼻窦炎患者的鼻息肉,包含选自多硫酸化硫酸软骨素、硫酸软骨素、硫酸皮肤素、硫酸角质素、硫酸乙酰肝素、硫酸葡聚糖、多硫酸戊聚糖、软骨素、葡甘露聚糖、菊粉和木寡糖的多糖或其盐。
5.权利要求4所述的药物组合物,其中,上述多糖选自多硫酸化硫酸软骨素、硫酸软骨素、硫酸角质素、硫酸乙酰肝素、硫酸葡聚糖、多硫酸戊聚糖、软骨素、葡甘露聚糖和菊粉。
6.权利要求4或5所述的药物组合物,其中,上述慢性鼻窦炎患者为嗜酸性粒细胞性鼻窦炎或非嗜酸性粒细胞性鼻窦炎患者。
7.权利要求4~6中任一项所述的药物组合物,其中,上述慢性鼻窦炎患者为嗜酸性粒细胞性鼻窦炎患者。
8.鼻腔内给药制剂,其包含权利要求4~7中任一项所述的药物组合物。
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