CN108601763A - 含有多佐胺和溴莫尼定的药物组合物 - Google Patents
含有多佐胺和溴莫尼定的药物组合物 Download PDFInfo
- Publication number
- CN108601763A CN108601763A CN201780009996.4A CN201780009996A CN108601763A CN 108601763 A CN108601763 A CN 108601763A CN 201780009996 A CN201780009996 A CN 201780009996A CN 108601763 A CN108601763 A CN 108601763A
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- CN
- China
- Prior art keywords
- salt
- pharmaceutical composition
- preservative
- brimonidine
- dorzolamide
- 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 142
- IAVUPMFITXYVAF-XPUUQOCRSA-N dorzolamide Chemical compound CCN[C@H]1C[C@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 IAVUPMFITXYVAF-XPUUQOCRSA-N 0.000 title claims abstract description 55
- 229960003933 dorzolamide Drugs 0.000 title claims abstract description 53
- XYLJNLCSTIOKRM-UHFFFAOYSA-N Alphagan Chemical compound C1=CC2=NC=CN=C2C(Br)=C1NC1=NCCN1 XYLJNLCSTIOKRM-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 229960003679 brimonidine Drugs 0.000 title claims abstract description 39
- 150000003839 salts Chemical class 0.000 claims abstract description 147
- 239000003755 preservative agent Substances 0.000 claims abstract description 62
- 230000002335 preservative effect Effects 0.000 claims abstract description 61
- 241000894006 Bacteria Species 0.000 claims abstract description 45
- 238000012360 testing method Methods 0.000 claims abstract description 41
- 241000588724 Escherichia coli Species 0.000 claims abstract description 35
- 230000001580 bacterial effect Effects 0.000 claims abstract description 19
- FRXSZNDVFUDTIR-UHFFFAOYSA-N 6-methoxy-1,2,3,4-tetrahydroquinoline Chemical compound N1CCCC2=CC(OC)=CC=C21 FRXSZNDVFUDTIR-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000005260 corrosion Methods 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000011081 inoculation Methods 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims description 40
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- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 24
- 239000004327 boric acid Substances 0.000 claims description 24
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- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 22
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- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
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- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000001509 sodium citrate Substances 0.000 description 4
- 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 4
- 235000011083 sodium citrates Nutrition 0.000 description 4
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Abstract
本发明的课题为提供能够充分发挥防腐效果的新型药物组合物,所述药物组合物含有多佐胺或其盐以及溴莫尼定或其盐。本发明涉及的含有多佐胺或其盐以及溴莫尼定或其盐的药物组合物的pH为6.0以上。本发明涉及的药物组合物优选不含防腐剂或以规定量含有防腐剂,规定量优选为下述量:在包含该防腐剂及水的试验试样中,以使大肠杆菌(Escherichia Coli)ATCC 8739的菌液浓度成为105~106cfu/mL范围内的方式接种菌体并均匀混合,在遮光条件下于20~25℃保存试验试样,经过7天后,用微量移液管采集1mL的试验试样,对活菌数进行测定时,使接种时的菌数(B)相对于测定活菌数时的菌数(A)之比(B/A)的常用对数值成为2.0以下的量。
Description
技术领域
本发明涉及含有多佐胺或其盐以及溴莫尼定或其盐的药物组合物。
背景技术
作为碳酸酐酶抑制剂的多佐胺因显示出降眼压作用而在青光眼或高眼压症的治疗中有用,含有多佐胺的制剂作为Trusopt(注册商标)滴眼液已有销售。此外,含有多佐胺和噻吗洛尔的制剂作为Cosopt(注册商标)复方滴眼液已有销售。
此外,作为α2受体激动剂的溴莫尼定也因显示出降眼压作用而在青光眼或高眼压症的治疗中有用,含有溴莫尼定的制剂作为Aiphagan(注册商标)滴眼液已有销售。
另外,对于滴眼液来说,为了防止伴随反复使用而导致的菌类等的繁殖,其需要具有一定水平以上的防腐效力,例如,在上述Trusopt(注册商标)滴眼液、Cosopt(注册商标)复方滴眼液中,作为防腐剂而配合有苯扎氯铵。然而,苯扎氯铵具有细胞毒性,暴露量增加时,存在引起角膜上皮疾病的可能性(非专利文献1),因此也在销售不含苯扎氯铵的Cosopt(注册商标)复方滴眼液。由于该滴眼液不含防腐剂,因此使用一次用尽的单位剂量(unitdose)容器或PFMD(Preservative Free Multi Dose,无防腐剂多次剂量)容器。
从便利性、安全性、制造成本等观点考虑,期望不含苯扎氯铵等防腐剂或其含量低、或者无需利用特殊结构的容器也能够反复使用的新型滴眼液。
现有技术文献
非专利文献
非专利文献1:日本眼科(日本の眼科),58(10),945-950(1987)
发明内容
发明所要解决的课题
本发明的课题是提供一种药物组合物,其含有多佐胺或其盐以及溴莫尼定或其盐,所述药物组合物尽管不含防腐剂或防腐剂的含量少,但仍然能够充分发挥防腐效果。
用于解决课题的手段
本申请的发明人进行了深入研究,结果意外地发现,含有多佐胺或其盐以及溴莫尼定或其盐的药物组合物即使不含苯扎氯铵,但在pH为6.0以上时,仍然能够发挥满足基于第十六版日本药典参考信息“保存效力试验法”的基准“IA类”的充分的防腐效果,从而完成了本发明。具体地,本发明提供以下内容。
(1)药物组合物,其含有多佐胺或其盐以及溴莫尼定或其盐,所述药物组合物不含防腐剂或以规定量含有防腐剂,
所述规定量为通过下述方法进行测定时接种时的菌数(B)相对于测定活菌数时的菌数(A)之比(B/A)的常用对数值为2.0以下时的量,所述方法为:在包含该防腐剂及水的试验试样中,以使大肠杆菌(Escherichia Coli)ATCC 8739的菌液浓度成为105~106cfu/mL范围内的方式接种菌体并均匀混合,在遮光条件下于20~25℃保存所述试验试样,经过7天后,用微量移液管(micropipette)采集1mL的所述试验试样,对活菌数进行测定,
并且,所述药物组合物的pH为6.0以上。
(2)药物组合物,其含有多佐胺或其盐以及溴莫尼定或其盐,所述药物组合物不含苯扎氯铵,且不含除苯扎氯铵以外的防腐剂、或以规定量含有除苯扎氯铵以外的防腐剂,
所述规定量为通过下述方法进行测定时接种时的菌数(B)相对于测定活菌数时的菌数(A)之比(B/A)的常用对数值为2.0以下时的量,所述方法为:在包含该防腐剂及水的试验试样中,以使大肠杆菌(Escherichia Coli)ATCC 8739的菌液浓度成为105~106cfu/mL范围内的方式接种菌体并均匀混合,在遮光条件下于20~25℃保存所述试验试样,经过7天后,用微量移液管采集1mL的所述试验试样,对活菌数进行测定,
并且,所述药物组合物的pH为6.0以上。
(3)如(1)或(2)所述的药物组合物,其含有乙二胺四乙酸或其盐,其中,乙二胺四乙酸或其盐的含量为0.0001~2%(w/v)。
(4)如项(1)~(3)中任一项所述的药物组合物,其含有硼酸或其盐,其中,硼酸或其盐的含量为0.0001~5%(w/v)。
(5)药物组合物,其含有多佐胺或其盐以及溴莫尼定或其盐,所述药物组合物不含除乙二胺四乙酸或其盐以及硼酸或其盐以外的防腐剂、或以规定量含有除乙二胺四乙酸或其盐以及硼酸或其盐以外的防腐剂,
所述规定量为通过下述方法进行测定时接种时的菌数(B)相对于测定活菌数时的菌数(A)之比(B/A)的常用对数值为2.0以下时的量,所述方法为:在包含该防腐剂及水的试验试样中,以使大肠杆菌(Escherichia Coli)ATCC 8739的菌液浓度成为105~106cfu/mL范围内的方式接种菌体并均匀混合,在遮光条件下于20~25℃保存所述试验试样,经过7天后,用微量移液管采集1mL的所述试验试样,对活菌数进行测定,
所述乙二胺四乙酸或其盐的含量为0.0001~2%(w/v),
所述硼酸或其盐的含量为0.0001~5%(w/v),
所述药物组合物的pH为6.0以上。
(6)药物组合物,其含有多佐胺或其盐以及溴莫尼定或其盐,所述药物组合物不含除乙二胺四乙酸或其盐以及硼酸或其盐以外的防腐剂,
所述乙二胺四乙酸或其盐的含量为0.0001~2%(w/v),
所述硼酸或其盐的含量为0.0001~5%(w/v),
所述药物组合物的pH为6.0以上。
(7)如(3)、(5)或(6)所述的药物组合物,其中,乙二胺四乙酸或其盐的含量为0.005~0.05%(w/v)。
(8)如(4)~(7)中任一项所述的药物组合物,其中,硼酸或其盐的含量为0.001~1%(w/v)。
(9)如(1)~(8)中任一项所述的药物组合物,其中,多佐胺或其盐为多佐胺盐酸盐。
(10)如(1)~(9)中任一项所述的药物组合物,其中,溴莫尼定或其盐为溴莫尼定酒石酸盐。
(11)如(1)~(10)中任一项所述的药物组合物,其中,多佐胺或其盐的含量为0.1-5%(w/v)。
(12)如(11)所述的药物组合物,其中,多佐胺或其盐的含量为1%(w/v)或2%(w/v)。
(13)如(1)~(12)中任一项所述的药物组合物,其中,溴莫尼定或其盐的含量为0.01-2%(w/v)。
(14)如(13)所述的药物组合物,其中,溴莫尼定或其盐的含量为0.1%(w/v)或0.15%(w/v)。
(15)如(1)~(14)中任一项所述的药物组合物,其pH为6.0~8.0。
(16)如(1)~(15)中任一项所述的药物组合物,其用于青光眼或高眼压症的治疗。
(17)如(1)~(16)中任一项所述的药物组合物,其被装入多次剂量(Multi-dose)型容器中。
(18)制品,其具备多次剂量型容器、和(1)~(17)中任一项所述的药物组合物。
(19)(1)~(17)中任一项所述的药物组合物在制造用于治疗青光眼或高眼压症的药剂中的应用。
(20)提高防腐效力的方法,其通过使药物组合物中含有多佐胺或其盐来提高防腐效力,
所述药物组合物含有溴莫尼定或其盐,且不含防腐剂或以规定量含有防腐剂,所述药物组合物的pH为6.0以上,
所述规定量为通过下述方法进行测定时接种时的菌数(B)相对于测定活菌数时的菌数(A)之比(B/A)的常用对数值为2.0以下时的量,所述方法为:在包含该防腐剂及水的试验试样中,以使大肠杆菌(Escherichia Coli)ATCC 8739的菌液浓度成为105~106cfu/mL范围内的方式接种菌体并均匀混合,在遮光条件下于20~25℃保存所述试验试样,经过7天后,用微量移液管采集1mL的所述试验试样,对活菌数进行测定。
(21)通过在使含有溴莫尼定或其盐、pH为6.0以上的药物组合物中含有多佐胺或其盐来提高防腐效力的方法,其中,
对于含有所述多佐胺或其盐之前的药物组合物,以使大肠杆菌(EscherichiaColi)ATCC 8739的菌液浓度成为105~106cfu/mL范围内的方式对所述药物组合物接种菌体并均匀混合,在遮光条件下于20~25℃保存所述药物组合物,经过7天后,用微量移液管采集1mL的所述药物组合物,对活菌数进行测定,接种时的菌数(B)相对于测定活菌数时的菌数(A)之比(B/A)的常用对数值为2.0以下。
需要说明的是,对于上述(1)至(19)的各构成而言,可任意选择两项以上进行组合。
发明效果
根据本发明,提供含有多佐胺或其盐以及溴莫尼定或其盐的药物组合物,所述药物组合物尽管不含防腐剂、或防腐剂的含量低,但仍然能够充分发挥防腐效果。
具体实施方式
以下,对本发明进行详细说明。
本发明的药物组合物中含有的多佐胺是以化学名(4S,6S)-4-乙基氨基-6-甲基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-磺酰胺-7,7-二氧化物((4S,6S)-4-Ethylamino-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide)表示的化合物。
本发明的药物组合物中含有的溴莫尼定是由化学名5-溴-N-(4,5-二氢-1H-咪唑-2-基)喹喔啉-6-胺(5-Bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxaline-6-amine)表示的化合物。
本发明的药物组合物中含有的多佐胺及溴莫尼定可以是盐,只要是作为药物被允许的盐则没有特别限制。作为盐可以举出与无机酸形成的盐、与有机酸形成的盐、季铵盐、与卤素离子形成的盐、与碱金属形成的盐、与碱土金属形成的盐、金属盐、与有机胺形成的盐等。
作为与无机酸形成的盐,可举出与盐酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸等形成的盐。
作为与有机酸形成的盐,可举出与乙酸、草酸、富马酸、马来酸、琥珀酸、苹果酸、柠檬酸、酒石酸、己二酸、葡糖酸、葡庚糖酸、葡糖醛酸、对苯二甲酸、甲磺酸、丙氨酸、乳酸、马尿酸、1,2-乙二磺酸、羟乙基磺酸、乳糖酸、油酸、没食子酸、亚甲基双羟萘酸(pamoicacid)、多聚半乳糖醛酸、硬脂酸、鞣酸、三氟甲磺酸、苯磺酸、对甲苯磺酸、硫酸月桂酯、硫酸甲酯、萘磺酸、磺基水杨酸等形成的盐。
作为季铵盐,可列举与溴代甲烷、碘代甲烷等形成的盐。
作为与卤素离子形成的盐,可举出与氯化物离子、溴化物离子、碘化物离子等形成的盐。
作为与碱金属形成的盐,可举出与锂、钠、钾等形成的盐。
作为与碱土金属形成的盐,可举出与钙、镁等形成的盐。
作为金属盐,可举出与铁、锌等形成的盐。
作为与有机胺形成的盐,可举出与三乙二胺、2-氨基乙醇、2,2-亚氨基双(乙醇)、1-脱氧-1-(甲基氨基)-2-D-山梨糖醇、2-氨基-2-(羟基甲基)-1,3-丙二醇、普鲁卡因、N,N-双(苯基甲基)-1,2-乙二胺等形成的盐。
作为多佐胺的盐,特别优选一盐酸盐(多佐胺盐酸盐)。作为溴莫尼定的盐,特别优选一酒石酸盐(溴莫尼定酒石酸盐),最优选一(2R,3R)酒石酸盐。
本发明的药物组合物中含有的多佐胺、溴莫尼定及它们的盐可以是水合物或溶剂合物的形态。
本发明的药物组合物中含有的多佐胺或其盐的含量只要是对于发挥所期望的药效及防腐效力而言充分的量则没有特别限制,优选为0.1~5%(w/v),更优选为0.2~3%(w/v),进一步优选为0.5~2%(w/v),更进一步优选为0.7~1.2%(w/v),特别优选为1%(w/v)。最优选为1%(w/v)或2%(w/v)。需要说明的是,在本发明的药物组合物中含有多佐胺的盐的情况下,上述值是换算为游离多佐胺后的含量。并且,“%(w/v)”是指100mL的本发明的药物组合物中所含有的对象成分(此处指多佐胺)的质量(g)。以下,只要没有特别说明则同样。
本发明的药物组合物中含有的溴莫尼定或其盐的含量只要是对于发挥所期望的药效而言充分的量则没有特别限制,优选为0.01~2%(w/v),更优选为0.02~1%(w/v),进一步优选为0.05~0.5%(w/v),特别优选为0.07~0.2%(w/v),最优选为0.1%(w/v)或0.15%(w/v)。需要说明的是,在本发明的药物组合物中含有溴莫尼定的盐的情况下,上述值是换算为游离溴莫尼定后的含量。
从治疗效果及防腐效果的观点考虑,相对于溴莫尼定或其盐的含量而言,多佐胺或其盐的含量优选为1~30倍,更优选为3~25倍,进一步优选为5倍~20倍。
由于本发明的药物组合物能够发挥充分的防腐效果,因此可以不含防腐剂或以规定量含有防腐剂。在此,所谓“规定量”是指例如单独使用时不发挥防腐效果的量,具体而言,可以是以下述方法进行测定时接种时的菌数(B)相对于测定活菌数时的菌数(A)之比(B/A)的常用对数值为2.0以下(优选为1.5以下,更优选为1.2以下,进一步优选为1.0以下,特别优选为0.8以下,最优选为0.7以下)时的量,所述方法为:在包含防腐剂及水的试验试样中,以使大肠杆菌(Escherichia Coli)ATCC 8739的菌液浓度成为105~106cfu/mL范围内的方式接种菌体并均匀混合,在遮光条件下于20~25℃保存试验试样,经过7天后,用微量移液管采集1mL的试验试样,对活菌数进行测定。特别地,在本发明的药物组合物中,作为防腐剂的苯扎氯铵的含量小或不含苯扎氯铵是令人期望的。
本发明的药物组合物中,在含有苯扎氯铵的情况下,优选以规定量含有苯扎氯铵。在此,所述“规定量”是指例如单独情况下不发挥防腐效果的量,具体而言,可以是以下述方法进行测定时接种时的菌数(B)相对于测定活菌数时的菌数(A)之比(B/A)的常用对数值为2.0以下(优选为1.5以下、更优选为1.2以下、进一步优选为1.0以下、特别优选为0.8以下、最优选为0.7以下)时的量,所述方法为:在包含苯扎氯铵及水的试验试样中,以使大肠杆菌(Escherichia Coli)ATCC 8739的菌液浓度成为105~106cfu/mL范围内的方式接种菌体并均匀混合,在遮光条件下于20~25℃保存试验试样,经过7天后,用微量移液管采集1mL的试验试样,对活菌数进行测定。更具体地,苯扎氯铵优选为0.001%(w/v)以下,更优选为0.0007%(w/v)以下,进一步优选为0.0005%(w/v)以下,更进一步优选为0.0003%(w/v)以下,特别优选为0.0001%(w/v)以下,最优选实质上不含有苯扎氯铵。
并且,对于作为除苯扎氯铵以外的防腐剂使用的季铵盐而言,期望季铵盐的含量小或不含季铵盐。作为除苯扎氯铵以外的季铵盐的实例,可举出苯扎溴铵、苄索氯铵、十二烷基二甲基苄基溴化铵(benzododecinium bromide)等。本发明的药物组合物中含有除苯扎氯铵以外的季铵盐的情况下,优选以规定量含有该季铵盐。此处,所述“规定量”是指例如单独使用时不发挥防腐效果的量,具体而言,可以是以下述方法进行测定时接种时的菌数(B)相对于测定活菌数时的菌数(A)之比(B/A)的常用对数值为2.0以下(优选为1.5以下,更优选为1.2以下,进一步优选为1.0以下,特别优选为0.8以下,最优选为0.7以下)时的量,所述方法为:在包含所述防腐剂(除苯扎氯铵以外的季铵盐)及水的试验试样中,以使大肠杆菌(Escherichia Coli)ATCC 8739的菌液浓度成为105~106cfu/mL范围内的方式接种菌体并均匀混合,在遮光条件下于20~25℃保存试验试样,经过7天后,用微量移液管采集1mL的试验试样,对活菌数进行测定。更具体而言,对于除苯扎氯铵以外的季铵盐而言,尽管因种类的不同而不同,但优选不含有例如0.01%(w/v)以上(含量低于0.01%(w/v)),更优选不含有0.005%(w/v)以上,进一步优选不含有0.001%(w/v)以上,更进一步优选不含有0.0005%(w/v)以上,特别优选不含有0.0001%(w/v)以上,最优选实质上不含有除苯扎氯铵以外的季铵盐。
本发明的药物组合物中,也期望除季铵盐以外的防腐剂的含量小或不含除季铵盐以外的防腐剂。作为除季铵盐以外的防腐剂,可举出山梨酸、山梨酸钾、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、氯丁醇、氯己定、硼酸或其盐、乙二胺四乙酸或其盐等。本发明的药物组合物中含有除季铵盐以外的防腐剂的情况下,优选以规定量含有该防腐剂。此处,所谓“规定量”是指例如单独使用时发挥防腐效果的量,具体而言,可以是以下述方法进行测定时接种时的菌数(B)相对于测定活菌数时的菌数(A)之比(B/A)的常用对数值为2.0以下(优选为1.5以下、更优选为1.2以下、进一步优选为1.0以下、特别优选为0.8以下、最优选为0.7以下)时的量,所述方法为:在包含所述防腐剂(除季铵盐以外的防腐剂)及水的试验试样中,以使大肠杆菌(Escherichia Coli)ATCC 8739的菌液浓度成为105~106cfu/mL范围内的方式接种菌体并均匀混合,在遮光条件下于20~25℃保存试验试样,经过7天后,用微量移液管采集1mL的试验试样,对活菌数进行测定。更具体而言,尽管因为种类的不同而不同,但除季铵盐以外的防腐剂(特别是硼酸及其盐的情况下)优选为5%(w/v)以下,更优选为3%(w/v)以下,进一步优选为1%(w/v)以下,更进一步优选不含有0.5%(w/v)以上(含量低于0.5%(w/v)),特别优选不含有0.10%(w/v)以上(含量低于0.10%(w/v)),进一步优选不含有0.05%(w/v)以上,更进一步优选不含有0.01%(w/v)以上,进而优选不含有0.005%(w/v)以上,特别优选不含有0.001%(w/v)以上,最优选实质上不含有除季铵盐以外的防腐剂。作为硼酸的盐的例子,可举出硼砂、硼酸钠、硼酸钾等。需要说明的是,在本发明的药物组合物中含有硼酸的盐的情况下,上述值是换算为游离硼酸后的含量。另外,虽然乙二胺四乙酸或其盐多被作为稳定剂而添加至药物组合物中,但它们具有防腐效果也是已知的,在本发明的药物组合物中含有乙二胺四乙酸或其盐的情况下,其含量以总量计优选为大于0%(w/v)(0.0001%以上、0.0005%以上、0.001%以上、0.002%以上、0.003%以上、0.005%以上、0.007%以上等)且为2%(w/v)以下,更优选为1%(w/v)以下,进一步优选为0.5%(w/v)以下,更进一步优选为0.3%(w/v)以下,进而优选为0.1%(w/v)以下,特别优选为0.07%(w/v)以下,最优选为0.05%(w/v)以下。作为乙二胺四乙酸的盐的例子,可举出乙二胺四乙酸一钠、乙二胺四乙酸二钠、乙二胺四乙酸四钠、柠檬酸钠等,优选乙二胺四乙酸二钠,特别优选乙二胺四乙酸二钠二水合物。特别地,本发明的药物组合物优选不含除硼酸及其盐、以及乙二胺四乙酸及其盐以外的防腐剂。需要说明的是,在本发明的药物组合物中含有乙二胺四乙酸的盐或其水合物的情况下,上述值为基于乙二胺四乙酸的盐或其水合物的质量计算得到的含量。本发明中的防腐剂是指在药物组合物中标示为防腐剂的成分,不包括本发明的药物组合物中的多佐胺或其盐这样的、虽然发挥防腐效果但未被标示为防腐剂的成分。
本发明的药物组合物中,可根据需要使用添加剂,作为添加剂,可添加表面活性剂、缓冲剂、等渗剂、稳定剂、抗氧化剂、高分子量聚合物等。
本发明的药物组合物中,可配合能用作药品添加物的表面活性剂,例如阳离子性表面活性剂、阴离子性表面活性剂、非离子性表面活性剂。
作为阴离子性表面活性剂的例子,可举出磷脂等,作为磷脂,可举出卵磷脂等。
作为阳离子性表面活性剂的例子,可举出烷基胺盐、烷基胺聚氧乙烯加成物、脂肪酸三乙醇胺单酯盐、酰基氨基乙基二乙胺盐、脂肪酸多胺缩合物、烷基咪唑啉、1-酰基氨基乙基-2-烷基咪唑啉、1-羟乙基-2-烷基咪唑啉等。
作为非离子性表面活性剂的例子,可举出聚氧乙烯脂肪酸酯、聚氧乙烯山梨糖醇酐脂肪酸酯、聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、聚氧乙烯聚氧丙烯二醇、蔗糖脂肪酸酯、维生素E TPGS等。
作为聚氧乙烯脂肪酸酯,可举出硬脂酸-40-聚烃氧基酯等。
作为聚氧乙烯山梨糖醇酐脂肪酸酯,可举出聚山梨醇酯(polysorbate)80、聚山梨醇酯60、聚山梨醇酯40、聚氧乙烯山梨糖醇酐单月桂酸酯、聚氧乙烯山梨糖醇酐三油酸酯、聚山梨醇酯65等。
作为聚氧乙烯氢化蓖麻油,可使用氧化乙烯的聚合数不同的各种聚氧乙烯氢化蓖麻油,氧化乙烯的聚合数优选为10~100,更优选为20~80,特别优选为40~70,最优选为60。作为聚氧乙烯氢化蓖麻油的具体例,可举出聚氧乙烯氢化蓖麻油10、聚氧乙烯氢化蓖麻油40、聚氧乙烯氢化蓖麻油50、聚氧乙烯氢化蓖麻油60等。
作为聚氧乙烯蓖麻油,可使用氧化乙烯的聚合数不同的各种聚氧乙烯蓖麻油,氧化乙烯的聚合数优选为5~100,更优选为20~50,特别优选为30~40,最优选为35。作为聚氧乙烯蓖麻油的具体例,可举出聚氧乙烯(5)蓖麻油、聚氧乙烯(9)蓖麻油、聚氧乙烯(15)蓖麻油、聚氧乙烯(35)蓖麻油、聚氧乙烯(40)蓖麻油等。
作为聚氧乙烯聚氧丙烯二醇,可举出聚氧乙烯(160)聚氧丙烯(30)二醇、聚氧乙烯(42)聚氧丙烯(67)二醇、聚氧乙烯(54)聚氧丙烯(39)二醇、聚氧乙烯(196)聚氧丙烯(67)二醇、聚氧乙烯(20)聚氧丙烯(20)二醇等。
作为蔗糖脂肪酸酯,可举出蔗糖硬脂酸酯等。
维生素E TPGS也称为生育酚聚乙二醇1000琥珀酸酯。
在本发明的使用防腐剂的药物组合物中配合表面活性剂的情况下,表面活性剂的含量可根据表面活性剂的种类等适当调节,优选为0.001~10%(w/v),更优选为0.01~5%(w/v),进一步优选为0.1~3%(w/v),最优选为0.2~2%(w/v)。
本发明的药物组合物中,可配合能用作药品添加物的缓冲剂。作为缓冲剂的例子,可举出磷酸或其盐、柠檬酸或其盐、乙酸或其盐、碳酸或其盐、酒石酸或其盐、ε-氨基己酸、氨丁三醇等。
作为磷酸盐,可举出磷酸钠、磷酸二氢钠、磷酸氢二钠、磷酸钾、磷酸二氢钾、磷酸氢二钾等,作为柠檬酸盐,可举出柠檬酸钠、柠檬酸二钠等,作为乙酸盐,可举出乙酸钠、乙酸钾等,作为碳酸盐,可举出碳酸钠、碳酸氢钠等,作为酒石酸盐,可举出酒石酸钠、酒石酸钾等。优选柠檬酸或其盐,特别优选柠檬酸钠。
在本发明的药物组合物中配合缓冲剂的情况下,缓冲剂的含量可根据缓冲剂的种类等适当调节,优选为0.001~10%(w/v),更优选为0.01~5%(w/v),进一步优选为0.1~3%(w/v),最优选为0.2~2%(w/v)。
在本发明的药物组合物中,可适当配合能用作药品添加物的等渗剂。作为等渗剂的实例,可举出离子型等渗剂、非离子型等渗剂等。作为离子型等渗剂,可举出氯化钠、氯化钾、氯化钙、氯化镁等,优选氯化钠。作为非离子型等渗剂,可举出甘油、丙二醇、山梨糖醇、甘露糖醇等,优选甘露糖醇。在本发明的药物组合物中配合等渗剂的情况下,等渗剂的含量可根据等渗剂的种类等适当调节,优选为0.01~10%(w/v),更优选为0.02~7%(w/v),进一步优选为0.1~5%(w/v),特别优选为0.5~4%(w/v),最优选为0.8~3%(w/v)。
本发明的药物组合物中,可适当配合能用作药品添加物的稳定剂。作为稳定剂的实例,可举出乙二胺四乙酸、乙二胺四乙酸一钠、乙二胺四乙酸二钠、乙二胺四乙酸四钠、柠檬酸钠等,优选为乙二胺四乙酸二钠,特别优选为乙二胺四乙酸二钠二水合物。在本发明的药物组合物中配合稳定剂的情况下,稳定剂的含量可根据稳定剂的种类等适当调节,优选为0.0001~2%(w/v),更优选为0.0005~1%(w/v),进一步优选为0.001~0.5%(w/v),更进一步优选为0.002~0.3%(w/v),进而优选为0.003~0.1%(w/v),特别优选为0.005~0.07%(w/v),最优选为0.007~0.05%(w/v)。
本发明的药物组合物中,可适当配合能用作药品添加物的抗氧化剂。作为抗氧化剂的例子,可举出抗坏血酸、生育酚、二丁基羟基甲苯、丁基羟基苯甲醚、异抗坏血酸钠、没食子酸丙酯、亚硫酸钠等。在本发明的药物组合物中配合抗氧化剂的情况下,抗氧化剂的含量可根据抗氧化剂的种类等适当调节,优选为0.0001~1%(w/v),更优选为0.0005~0.1%(w/v),进一步优选为0.001~0.02%(w/v),最优选为0.005~0.010%(w/v)。
本发明的药物组合物中,可适当配合能用作药品添加物的高分子量聚合物。作为高分子量聚合物的例子,可举出甲基纤维素、乙基纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟乙基甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素乙酸酯琥珀酸酯、羟丙基甲基纤维素邻苯二甲酸酯、羧甲基乙基纤维素、乙酸邻苯二甲酸纤维素、聚乙烯吡咯烷酮、聚乙烯醇、羧基乙烯基聚合物、聚乙二醇等,优选羟乙基纤维素。在本发明的药物组合物中配合高分子量聚合物的情况下,高分子量聚合物的含量可根据高分子量聚合物的种类等适当调节,优选为0.001~5%(w/v),更优选为0.01~3%(w/v),进一步优选为0.1~2%(w/v),最优选为0.2~1%(w/v)。
本发明的药物组合物中,可适当配合能用作药品添加物的pH调节剂。作为pH调节剂的例子,可举出盐酸、磷酸、柠檬酸、乙酸、氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠等。
本发明的药物组合物中,羟乙基纤维素(作为高分子聚合物)、甘露糖醇(作为等渗剂)、柠檬酸或其盐(作为缓冲剂)被组合含有是特别优选的。由此,本发明的药物组合物能够迅速地杀菌。这种情况下,在本发明的药物组合物中配合各成分时的各成分的含量优选羟乙基纤维素为0.001~5%(w/v)、甘露糖醇为0.01~10%(w/v)、柠檬酸或其盐为0.001~10%(w/v),更优选羟乙基纤维素为0.01~3%(w/v)、甘露糖醇为0.02~7%(w/v)、柠檬酸或其盐为0.01~5%(w/v),进一步优选羟乙基纤维素为0.1~2%(w/v)、甘露糖醇为0.1~5%(w/v)、柠檬酸或其盐为0.1~3%(w/v),最优选羟乙基纤维素为0.2~1%(w/v)、甘露糖醇为0.8~3%(w/v)、柠檬酸或其盐为0.2~2%(w/v)。
本发明的药物组合物的pH为6.0以上,从多佐胺及溴莫尼定的溶解性及稳定性的观点考虑,作为pH的上限,优选为8.0,更优选为7.5,进一步优选为7.0,最优选为6.8。作为pH的范围,优选为6.0~8.0,更优选为6.0~7.5,进一步优选为6.0~7.0,最优选为6.0~6.8。
本发明的药物组合物可装入单位剂量(unit dose)型容器、多次剂量(multidose)型容器中,优选装入多次剂量型容器中。单位剂量型容器为一次用尽的容器,多次剂量型容器是指以多次使用为目的而使得盖等能够自由开闭的容器。也可装入具有防倒流功能等用于发挥防腐效果的特殊结构的PFMD(Preservative Free Multi Dose,无防腐剂多次剂量)容器中。容器的材质并没有特别限制,可使用例如聚乙烯(PE)制、聚丙烯(PP)制、聚对苯二甲酸乙二醇酯(PET)制等的容器。
本发明的药物组合物的剂型只要是能作为药品使用的剂型则没有特别限制,特别优选为滴眼剂,可按照本技术领域中的常规方法进行制造。
本发明的药物组合物作为青光眼或高眼压症的治疗剂有用。
在给予本发明的药物组合物的情况下,只要对于发挥所期望的药效而言是充分的,则对于用法用量没有特别限制,优选每次1~3滴、每天滴眼1~3次,更优选每次1~2滴、每天滴眼1~2次,最优选每次1滴、每天滴眼2次。
本发明的药物组合物可用于接触透镜(contact lenses)(佩戴者)的用途。适用的接触透镜的种类没有特别限制,具体而言,可举出硬性接触透镜、软性接触透镜等,也可以是透氧性接触透镜。作为软性接触透镜,可举出含水软性接触透镜、非含水软性接触透镜、(非离子性)硅水凝胶软性接触透镜等。
上述的本发明的药物组合物的详细说明也适用于具备本发明的药物组合物和多次剂量型容器(容纳药物组合物)的制品、本发明的药物组合物在制造用于治疗青光眼或高眼压症的药物中的应用、及提高防腐效力的方法。
本发明的提高防腐效力的方法优选为通过使含有溴莫尼定或其盐、被装入多次剂量型容器中的药物组合物(特别是pH为6.0以上的药物组合物)中进一步含有多佐胺或其盐来提高防腐效力的方法。
本发明的提高防腐效力的方法优选为通过使不含防腐剂或以规定量含有防腐剂、pH为6.0以上、被装入多次剂量型容器中的药物组合物中进一步含有多佐胺或其盐来提高防腐效力的方法。此处,本发明的提高防腐效力的方法中的“防腐剂”、“规定量”,可以与上述在本发明中的防腐剂及本发明的药物组合物中所说明的内容相同。特别地,本发明的提高防腐效力的方法优选为通过使下述药物组合物中进一步含有多佐胺或其盐来提高防腐效力的方法,所述药物组合物不含苯扎氯铵,且不含硼酸或其盐、或者硼酸或其盐的含量低于0.001%(w/v),所述药物组合物的pH为6.0以上且被装入多次剂量型容器中。
本发明的提高防腐效力的方法中,对于含有多佐胺或其盐之前的药物组合物,以使大肠杆菌(Escherichia Coli)ATCC 8739的菌液浓度成为105~106cfu/mL范围内的方式对该药物组合物接种菌体并均匀混合,在遮光条件下于20~25℃保存药物组合物,经过7天后,用微量移液管采集1mL的药物组合物,对活菌数进行测定,接种时的菌数(B)相对于测定活菌数时的菌数(A)之比(B/A)的常用对数值优选为2.0以下,更优选为1.5以下,进一步优选为1.0以下。
本发明的提高防腐效力的方法中,在使药物组合物含有上述多佐胺或其盐之后,以使大肠杆菌(Escherichia Coli)ATCC 8739的菌液浓度成为105~106cfu/mL范围内的方式对该药物组合物接种菌体并均匀混合,在遮光条件下于20~25℃保存药物组合物,经过7天后,用微量移液管采集1mL的药物组合物,对活菌数进行测定,接种时的菌数(B)相对于测定活菌数时的菌数(A)之比(B/A)的常用对数值优选为2.5以上,更优选为3.0以上,进一步优选为3.5以上,更进一步优选为4.0以上。或者,本发明的提高防腐效力的方法中,含有上述多佐胺或其盐之后的药物组合物优选满足基于第十六版日本药典参考信息“保存效力试验法”的基准“IA类”。
实施例
以下示出制剂例及防腐效力试验的结果,但其是为了更好地理解本发明,并不限定本发明的范围。
制剂例
以下示出本发明的代表性制剂例。需要说明的是,下述制剂例中各成分的配合量为1mL制剂中的含量。
制剂例1(多次剂量型容器中)
制剂例2(多次剂量型容器中)
需要说明的是,可通过适当调节前述制剂例1及2中的多佐胺、溴莫尼定及添加剂的种类、配合量来获得所期望的组合物。
防腐效力试验(1)
1.受试制剂的制备
将多佐胺盐酸盐(1g)、溴莫尼定酒石酸盐(0.1g)、柠檬酸钠水合物(0.294g)、硼酸(0.7g)、D-甘露糖醇(2.0g)、乙二胺四乙酸二钠二水合物(0.05g)溶解于水中,进行过滤灭菌,将所得溶液用pH调节剂调节为pH6.5后,加水使总量为100mL,由此制备实施例1的制剂。除了改变pH值以外,以与实施例1的制备方法相同的方法制备比较例1的制剂。
2.试验方法
使用以下菌株作为接种菌。
细菌:
大肠杆菌,Escherichia Coli ATCC 8739(也称为E.coli)
绿脓杆菌,Pseudomonas aeruginosa ATCC 9027(也称为P.aeruginosa)
金黄色葡萄球菌,Staphylococcus aureus ATCC 6538(也称为S.aureus)
酵母菌及霉菌类:
白色念珠菌,Candida albicans ATCC 10231(也称为C.albicans)
巴西曲霉,Aspergillus brasiliensis ATCC 16404(也称为A.brasiliensis)
以使包含各制剂的试验试样中的菌液浓度成为105~106个/mL(5种菌种均如此)的方式将接种菌液接种于试验试样中。具体而言,以成为107~108cfu/mL的方式制备接种菌液,以使该接种菌液成为105~106cfu/mL的方式将各接种菌液接种于包含实施例1及比较例1的制剂的试验试样中并均匀混合,制成试样。将这些试样在遮光条件下于20~25℃保存,在各采样点(sampling point)(7天后、14天后或28天后)用微量移液管从各试样中采集1mL,对活菌数进行测定。在各采样点进行打开试样溶液的盖实施采样、然后闭合盖的操作。
3.试验结果及讨论
试验结果示于表1。表1的试验结果以接种时的菌数(B)相对于测定活菌数时的菌数(A)之比(B/A)的常用对数值表示,例如在为“1”时,表示检测时的活菌数减少至接种菌数的10%。另外,对是否符合基于第十六版日本药典参考信息“保存效力试验法”的基准“IA类”的基准进行了判定。
表1
如表1所示,含有多佐胺盐酸盐及溴莫尼定酒石酸盐的制剂中,pH为6.5的实施例1的制剂对所有菌体均显示出较强的防腐效果,符合基于第十六版日本药典参考信息“保存效力试验法”的基准“IA类”的基准,而pH为5.8的比较例1的制剂不符合该标准。
Claims (21)
1.药物组合物,其含有多佐胺或其盐以及溴莫尼定或其盐,所述药物组合物不含防腐剂或以规定量含有防腐剂,
所述规定量为通过下述方法进行测定时接种时的菌数(B)相对于测定活菌数时的菌数(A)之比(B/A)的常用对数值为2.0以下时的量,所述方法为:在包含所述防腐剂及水的试验试样中,以使大肠杆菌(Escherichia Coli)ATCC 8739的菌液浓度成为105~106cfu/mL范围内的方式接种菌体并均匀混合,在遮光条件下于20~25℃保存所述试验试样,经过7天后,用微量移液管采集1mL的所述试验试样对活菌数进行测定,
并且,所述药物组合物的pH为6.0以上。
2.药物组合物,其含有多佐胺或其盐以及溴莫尼定或其盐,所述药物组合物不含苯扎氯铵,并且也不含除苯扎氯铵以外的防腐剂、或以规定量含有除苯扎氯铵以外的防腐剂,
所述规定量为通过下述方法进行测定时接种时的菌数(B)相对于测定活菌数时的菌数(A)之比(B/A)的常用对数值为2.0以下时的量,所述方法为:在包含所述防腐剂及水的试验试样中,以使大肠杆菌(Escherichia Coli)ATCC 8739的菌液浓度成为105~106cfu/mL范围内的方式接种菌体并均匀混合,在遮光条件下于20~25℃保存所述试验试样,经过7天后,用微量移液管采集1mL的所述试验试样,对活菌数进行测定,
并且,所述药物组合物的pH为6.0以上。
3.如权利要求1或2所述的药物组合物,其含有乙二胺四乙酸或其盐,其中,乙二胺四乙酸或其盐的含量为0.0001~2%(w/v)。
4.如权利要求1~3中任一项所述的药物组合物,其含有硼酸或其盐,其中,硼酸或其盐的含量为0.0001~5%(w/v)。
5.药物组合物,其含有多佐胺或其盐以及溴莫尼定或其盐,所述药物组合物不含除乙二胺四乙酸或其盐以及硼酸或其盐以外的防腐剂、或以规定量含有除乙二胺四乙酸或其盐以及硼酸或其盐以外的防腐剂,
所述规定量为通过下述方法进行测定时接种时的菌数(B)相对于测定活菌数时的菌数(A)之比(B/A)的常用对数值为2.0以下时的量,所述方法为:在包含该防腐剂及水的试验试样中,以使大肠杆菌(Escherichia Coli)ATCC 8739的菌液浓度成为105~106cfu/mL范围内的方式接种菌体并均匀混合,在遮光条件下于20~25℃保存所述试验试样,经过7天后,用微量移液管采集1mL的所述试验试样,对活菌数进行测定,
所述乙二胺四乙酸或其盐的含量为0.0001~2%(w/v),
所述硼酸或其盐的含量为0.0001~5%(w/v),
所述药物组合物的pH为6.0以上。
6.药物组合物,其含有多佐胺或其盐以及溴莫尼定或其盐,所述药物组合物不含除乙二胺四乙酸或其盐以及硼酸或其盐以外的防腐剂,
所述乙二胺四乙酸或其盐的含量为0.0001~2%(w/v),
所述硼酸或其盐的含量为0.0001~5%(w/v),
所述药物组合物的pH为6.0以上。
7.如权利要求3、5或6所述的药物组合物,其中,乙二胺四乙酸或其盐的含量为0.005~0.05%(w/v)。
8.如权利要求4~7中任一项所述的药物组合物,其中,硼酸或其盐的含量为0.001~1%(w/v)。
9.如权利要求1~8中任一项所述的药物组合物,其中,多佐胺或其盐为多佐胺盐酸盐。
10.如权利要求1~9中任一项所述的药物组合物,其中,溴莫尼定或其盐为溴莫尼定酒石酸盐。
11.如权利要求1~10中任一项所述的药物组合物,其中,多佐胺或其盐的含量为0.1-5%(w/v)。
12.如权利要求11所述的药物组合物,其中,多佐胺或其盐的含量为1%(w/v)或2%(w/v)。
13.如权利要求1~12中任一项所述的药物组合物,其中,溴莫尼定或其盐的含量为0.01-2%(w/v)。
14.如权利要求13所述的药物组合物,其中,溴莫尼定或其盐的含量为0.1%(w/v)或0.15%(w/v)。
15.如权利要求1~14中任一项所述的药物组合物,其pH为6.0~8.0。
16.如权利要求1~15中任一项所述的药物组合物,其用于青光眼或高眼压症的治疗。
17.如权利要求1~16中任一项所述的药物组合物,其被装入多次剂量型容器中。
18.制品,其具备多次剂量型容器、和权利要求1~17中任一项所述的药物组合物。
19.权利要求1~17中任一项所述的药物组合物在制造用于治疗青光眼或高眼压症的药剂中的应用。
20.提高防腐效力的方法,其通过使药物组合物中含有多佐胺或其盐来提高防腐效力,
所述药物组合物含有溴莫尼定或其盐,且不含防腐剂或以规定量含有防腐剂,所述药物组合物的pH为6.0以上,
所述规定量为通过下述方法进行测定时接种时的菌数(B)相对于测定活菌数时的菌数(A)之比(B/A)的常用对数值为2.0以下时的量,所述方法为:在包含该防腐剂及水的试验试样中,以使大肠杆菌(Escherichia Coli)ATCC 8739的菌液浓度成为105~106cfu/mL范围内的方式接种菌体并均匀混合,在遮光条件下于20~25℃保存所述试验试样,经过7天后,用微量移液管采集1mL的所述试验试样,对活菌数进行测定。
21.通过在含有溴莫尼定或其盐、pH为6.0以上的药物组合物中含有多佐胺或其盐来提高防腐效力的方法,其中,
对于含有所述多佐胺或其盐之前的药物组合物,以使大肠杆菌(Escherichia Coli)ATCC 8739的菌液浓度成为105~106cfu/mL范围内的方式对所述药物组合物接种菌体并均匀混合,在遮光条件下于20~25℃保存所述药物组合物,经过7天后,用微量移液管采集1mL的所述药物组合物,对活菌数进行测定,接种时的菌数(B)相对于测定活菌数时的菌数(A)之比(B/A)的常用对数值为2.0以下。
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