TW201619147A - 水性組成物 - Google Patents
水性組成物 Download PDFInfo
- Publication number
- TW201619147A TW201619147A TW104131861A TW104131861A TW201619147A TW 201619147 A TW201619147 A TW 201619147A TW 104131861 A TW104131861 A TW 104131861A TW 104131861 A TW104131861 A TW 104131861A TW 201619147 A TW201619147 A TW 201619147A
- Authority
- TW
- Taiwan
- Prior art keywords
- aqueous composition
- salt
- solvate
- ribavirin
- quaternary ammonium
- Prior art date
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K33/42—Phosphorus; Compounds thereof
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Ophthalmology & Optometry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本發明所提供的水性組成物係具有優異的防腐效果。
本發明的水性組成物，係含有：下示一般式(1)：
□
[式中，X係表示鹵原子]所示化合物或其鹽或者該等的溶劑合物、與四級銨型界面活性劑。
Description
本發明係關於水性組成物等。
至少含有水作為溶劑的組成物(水性組成物)，因為具有對生物體的刺激少、或可摻合各種成分等優點，而廣泛被利用作為醫藥品或準醫藥品等。
然而，由於含有水因而會有因微生物而容易遭污染的問題。特別係例如點眼劑或點鼻劑、點耳劑等重複使用較多的劑形時，即便填充於例如經滅菌過的容器等之情況，由於在每次使用時水性組成物均會接觸到非無菌的外部空氣，因而增加微生物污染的風險。
所以，大多在水性組成物中摻合防腐劑(殺菌劑)俾使具防腐效果。防腐劑係可使用例如對羥苯甲酸酯類或氯化苄二甲烴銨等四級銨型界面活性劑等。
然而，亦有指出此種防腐劑仍存在有細胞毒性等問題(例如非專利文獻1)，例如當水性組成物使用作為點眼劑的情況會有導致角膜損傷的可能性，因而期待其使用量盡量保留於最低極限。
針對此點，若能確立利用複數種成分組合的協同作用而達優異
防腐效果的水性組成物處方，僅此部分便可降低各種防腐劑單獨的使用量，因而連帶可提供更高安全性的水性組成物。
此處，有報告指出以下構造式：
所示利巴舒滴(Ripasudil)(化學名：4-氟-5-[[(2S)-2-甲基-1,4-二氮雜環庚烷-1-基]磺醯基]異喹啉)、或以下構造式：
所示4-溴-5-[[(2S)-2-甲基-1,4-二氮雜環庚烷-1-基]磺醯基]異喹啉等鹵化異喹啉衍生物，具有Rho激酶抑制作用等藥理作用(例如專利文獻1、2)，可有效使用作為高眼壓症或青光眼等的預防或治療劑(例如專利文獻3)，並可有效使用作為老年性黃斑部病變等眼
底病變的預防或治療劑(例如專利文獻4)，有報告進一步指出亦可有效使用作為點眼劑組成物等水性組成物(例如專利文獻3)。
然而，截至目前為止，關於該等鹵化異喹啉衍生物的防腐效果仍一概未知。
[專利文獻1]日本專利第4212149號公報
[專利文獻2]國際公開第2006/115244號說明書
[專利文獻3]國際公開第2006/068208號說明書
[專利文獻4]日本專利第5557408號公報
[非專利文獻1]Journal of the Eye 8(10)：1599~1603、1991
本發明目的在於提供具優異防腐效果的水性組成物。
緣是，本發明者為解決上述問題經深入鑽研，結果意外發現利巴舒滴等後述一般式(1)所示鹵化異喹啉衍生物具有優異的防腐效果，進一步發現藉由使其與氯化苄二甲烴銨等四級銨型界面活性劑組合，便可獲得明顯提高防腐效果的水性組成物，遂完成本發明。
即，本發明係提供以下<1>~<4>。
<1>一種水性組成物，係含有：下示一般式(1)：
[式中，X係表示鹵原子]
所示化合物或其鹽或者該等的溶劑合物、與四級銨型界面活性劑。
<2>一種賦予水性組成物防腐效果之方法，係包括有摻合上述一般式(1)所示化合物或其鹽或者該等的溶劑合物、與四級銨型界面活性劑的步驟。
<3>一種組合，係為賦予水性組成物防腐效果而使用的上述一般式(1)所示化合物或其鹽或者該等的溶劑合物、與四級銨型界面活性劑之組合。
<4>一種組合之使用，係用於賦予水性組成物防腐效果的上述一般式(1)所示化合物或其鹽或者該等的溶劑合物、與四級銨型界面活性劑的組合之使用。
根據本發明，可提供具有優異防腐效果、且保存安定性優異的
水性組成物。
本說明書並不因該等而受任何限定，例如揭示以下態樣發明。
[1]一種水性組成物，係含有：下示一般式(1)：
[式中，X係表示鹵原子]
所示化合物或其鹽或者該等的溶劑合物、與四級銨型界面活性劑。
[2]如[1]所記載的水性組成物，其中，上述一般式(1)所示化合物係利巴舒滴。
[3]如[1]或[2]所記載的水性組成物，其中，上述四級銨型界面活性劑係從氯化苄二甲烴銨及氯化本索寧(benzethonium chloride)所構成群組中選擇1種以上。
[4]如[1]~[3]中任一項所記載的水性組成物，其中，上述一般式(1)所示化合物係利巴舒滴，且四級銨型界面活性劑係氯化苄二甲烴銨。
[5]如[1]~[4]中任一項所記載的水性組成物，係點眼劑或眼軟膏劑。
[6]如[1]~[5]中任一項所記載的水性組成物(用於抑制慢性進行性腎衰竭的醫藥及膜製劑除外)，係未含有磷酸、硼酸及該等的鹽、碳酸酐酶抑制藥、α 1阻斷藥、以及尼普洛爾(Nipradilol)。
[7]一種賦予水性組成物防腐效果之方法，係包括有：將上述一般式(1)所示化合物或其鹽或者該等的溶劑合物、與四級銨型界面活性劑，摻合於水性組成物中的步驟。
[8]如[7]所記載的方法，其中，上述一般式(1)所示化合物係利巴舒滴。
[9]如[7]或[8]所記載的方法，其中，上述四級銨型界面活性劑係從氯化苄二甲烴銨及氯化本索寧所構成之群組中選擇1種以上。
[10]如[7]~[9]中任一項所記載的方法，其中，上述一般式(1)所示化合物係利巴舒滴，且四級銨型界面活性劑係氯化苄二甲烴銨。
[11]如[7]~[10]中任一項所記載的方法，其中，上述水性組成物係點眼劑或眼軟膏劑。
[12]如[7]~[11]中任一項所記載的方法，其中，上述水性組成物(用於抑制慢性進行性腎衰竭的醫藥及膜製劑除外)係未含有磷酸、硼酸及該等的鹽、碳酸酐酶抑制藥、α 1阻斷藥、及尼普洛爾。
[13]如[1]~[5]中任一項所記載的水性組成物，其中，更進一步含有從：α 1受體阻斷藥、α 2受體作用藥、β阻斷藥、碳酸酐酶
抑制劑、前列腺素F2 α衍生物、交感神經作用藥、副交感神經作用藥、鈣拮抗劑、及膽酯脢抑制劑所構成之群組中選擇1種以上。
[14]如[1]~[5]中任一項所記載的水性組成物，其中，更進一步含有從拉坦前列腺素(Latanoprost)、尼普洛爾、多佐胺(Dorzolamide)、布林佐胺(Brinzolamide)、及噻嗎洛爾(Timolol)、以及該等的鹽所構成之群組中選擇1種以上。
[15]如[7]~[11]中任一項所記載的方法，其中，水性組成物係更進一步含有從α 1受體阻斷藥、α 2受體作用藥、β阻斷藥、碳酸酐酶抑制劑、前列腺素F2 α衍生物、交感神經作用藥、副交感神經作用藥、鈣拮抗劑、及膽酯脢抑制劑所構成之群組中選擇1種以上。
[16]如[7]~[11]中任一項所記載的方法，其中，水性組成物係更進一步含有從拉坦前列腺素、尼普洛爾、多佐胺、布林佐胺及噻嗎洛爾、以及該等的鹽所構成之群組中選擇1種以上。
以下，首先針對「水性組成物」相關態樣的發明，詳細說明其文中用語的意義等。
上述一般式(1)中，鹵原子係可列舉：氟原子、氯原子、溴原子等。上述一般式(1)中，鹵原子較佳係氟原子、溴原子，更佳係氟原子。
再者，上述一般式(1)中，構成經取代甲基的高哌環之碳原子係非對稱碳。所以，會生成立體異構，但一般式(1)所示化合物亦涵
蓋任何立體異構物，亦可為單一的立體異構物，亦可為各種立體異構物的任意比例混合物。上述一般式(1)所示化合物較佳係絕對組態為S組態的化合物。
上述一般式(1)所示化合物的鹽，只要在藥學上容許的鹽之前提下，其餘並無特別的限定，具體而言，可列舉例如：鹽酸鹽、硫酸鹽、硝酸鹽、氫氟酸鹽、氫溴酸鹽等無機酸鹽；醋酸鹽、酒石酸鹽、乳酸鹽、檸檬酸鹽、反丁烯二酸鹽、順丁烯二酸鹽、琥珀酸鹽、甲磺酸鹽、乙磺酸鹽、苯磺酸鹽、甲苯磺酸鹽、萘磺酸鹽、樟腦磺酸鹽等有機酸鹽等，較佳係鹽酸鹽。
再者，上述一般式(1)所示化合物或其鹽，亦可為水合物或醇合物等溶劑合物，較佳係水合物。
上述一般式(1)所示化合物或其鹽或者該等的溶劑合物，具體而言，可列舉例如：利巴舒滴(化學名：4-氟-5-[[(2S)-2-甲基-1,4-二氮雜環庚烷-1-基]磺醯基]異喹啉)或其鹽或者該等的溶劑合物；4-溴-5-[[(2S)-2-甲基-1,4-二氮雜環庚烷-1-基]磺醯基]異喹啉或其鹽或者該等的溶劑合物等。
上述一般式(1)所示化合物或其鹽或者該等的溶劑合物，較佳係利巴舒滴或其鹽或者該等的溶劑合物、4-溴-5-[[(2S)-2-甲基-1,4-二氮雜環庚烷-1-基]磺醯基]異喹啉或其鹽或者該等的溶劑合物，更佳
係利巴舒滴或其鹽或者該等的溶劑合物，特佳係利巴舒滴或其鹽酸鹽或者該等的水合物，最佳係以下結構式：
所示利巴舒滴鹽酸鹽水合物(利巴舒滴一鹽酸鹽二水合物)。
上述一般式(1)所示化合物或其鹽或者該等的溶劑合物係屬於公知，可利用公知方法製造。具體而言，例如利巴舒滴或其鹽或者該等的溶劑合物係可利用國際公開第1999/020620號說明書、國際公開第2006/057397號說明書所記載方法等進行製造。又，4-溴-5-[[(2S)-2-甲基-1,4-二氮雜環庚烷-1-基]磺醯基]異喹啉或其鹽或者該等的溶劑合物係可利用國際公開第2006/115244號說明書所記載方法等進行製造。
水性組成物中的上述一般式(1)所示化合物或其鹽或者該等的溶劑合物之含有量並無特別的限定，只要配合適用疾病或患者的性別、年齡、症狀等進行適當檢討決定便可，從獲得優異防腐效果的觀點，相對於水性組成物總容量，依一般式(1)所示化合物的自由體換算，較佳係含有0.01~10w/v%、更佳係含有0.02~8w/v%、特佳係含有0.04~6w/v%。尤其是當一般式(1)所示化合物係使用利巴舒滴
的情況，從獲得優異防腐效果的觀點，相對於水性組成物總容量，利巴舒滴或其鹽或者該等的溶劑合物依自由體換算，較佳係含有0.05~5w/v%、更佳係含有0.1~3w/v%、特佳係含有0.1~2w/v%。
「四級銨型界面活性劑」係可列舉已知之作為防腐劑的氯化苄二甲烴銨、氯化本索寧等。四級銨型界面活性劑從獲得優異防腐效果的觀點，較佳係氯化苄二甲烴銨。
另外，四級銨型界面活性劑係屬於公知，可利用公知方法製造，亦可使用市售物。
水性組成物中的四級銨型界面活性劑含有量並無特別的限定，只要經適當檢討之後再行決定便可，但從獲得優異防腐效果的觀點，相對於水性組成物總容量，較佳係含有0.00005~0.02w/v%、更佳係含有0.00025~0.01w/v%、特佳係含有0.00025~0.004w/v%。其中，當四級銨型界面活性劑係使用氯化苄二甲烴銨的情況，從獲得優異防腐效果的觀點，相對於水性組成物總容量，較佳係含有0.0001~0.01w/v%、更佳係含有0.0005~0.005w/v%、特佳係含有0.0005~0.002w/v%。
如後述試驗例所記載，藉由上述一般式(1)所示化合物或其鹽或者該等的溶劑合物、與四級銨型界面活性劑的組合，利用協同作用便可發揮更明顯提高之防腐效果。所以，例如可降低氯化苄二甲烴銨等四級銨型界面活性劑的使用量，亦能形成更高安全性的水性組成物。
該組合從利用協同作用造成增強防腐效果的觀點，特佳係利巴舒滴或其鹽或者該等的溶劑合物、與氯化苄二甲烴銨的組合。
水性組成物中的上述一般式(1)所示化合物或其鹽或者該等的溶劑合物、與四級銨型界面活性劑的含有質量比率並無特別的限定，從獲得優異防腐效果的觀點，相對於上述一般式(1)所示化合物或其鹽或者該等的溶劑合物以自由體計1質量份，四級銨型界面活性劑較佳係含有0.0001~0.4質量份、更佳係含有0.001~0.04質量份、特佳係含有0.00125~0.015質量份。
特別係當一般式(1)所示化合物或其鹽或者該等的溶劑合物係使用利巴舒滴或其鹽或者該等的溶劑合物，而四級銨型界面活性劑係使用氯化苄二甲烴銨的情況，從獲得優異防腐效果的觀點，相對於利巴舒滴或其鹽或者該等的溶劑合物依自由體計1質量份，氯化苄二甲烴銨較佳係含有0.0002~0.2質量份、更佳係含有0.002~0.02質量份、特佳係含有0.0025~0.01質量份。
本說明書中，所謂「水性組成物」係指至少含有水的組成物，其性狀係可列舉液狀(溶液或懸浮液)、半固態狀(軟膏)。另外，組成物中的水係可使用例如：淨化水、注射用水、無菌淨化水(sterile purified water)等。
水性組成物中所含水的含有量並無特別的限定，較佳係5質量%以上、更佳係20質量%以上、進而更佳係50質量%以上、特佳係90質量%以上、最佳係90~99.8質量%。
水性組成物係例如可依照第十六修訂日本藥典製劑總則等所記載的公知方法，形成各種劑形。劑形並無特別的限定，可列舉：注射劑、吸入液劑、點眼劑、眼軟膏劑、點耳劑、點鼻液劑、灌腸劑、外用液劑、噴霧劑、軟膏劑、凝膠劑、口服液劑、糖漿劑等。劑形從有利於利用一般式(1)所示化合物的藥理作用觀點，較佳係眼疾病用劑，具體而言，較佳係點眼劑、眼軟膏劑，更佳係點眼劑。
水性組成物係除上述之外，亦可配合劑形含有醫藥品或準醫藥品等所利用的添加物。此種添加物係例如：無機鹽類、等滲壓劑、螯合劑、安定化劑、pH調節劑、四級銨型界面活性劑，此外尚可列舉：防腐劑、抗氧化劑、黏稠化劑、界面活性劑、可溶化劑、懸浮劑、清涼劑、分散劑、保存劑、油性基劑、乳劑性基劑、水溶性基劑等。
此種添加物具體而言，可例示例如：抗壞血酸、天冬胺酸鉀、亞硫酸氫鈉、海藻酸、苯甲酸鈉、苯甲酸苄酯、ε-胺基己酸(aminocaproic acid)、小茴香油、乙醇、乙烯‧醋酸乙烯酯共聚合體、伸乙二胺四乙酸鈉、伸乙二胺四乙酸四鈉、氯化鉀、氯化鈣水合物、氯化鈉、氯化鎂、鹽酸、鹽酸烷基二胺乙基甘胺酸溶液、羧乙烯聚合物、乾燥亞硫酸鈉、乾燥碳酸鈉、d-樟腦、d1-樟腦、木糖醇、檸檬酸水合物、檸檬酸鈉水合物、甘油、葡糖酸、L-麩胺酸、L-麩胺酸鈉、肌酸內醯胺、葡萄糖酸洛赫西定液(chlorhexidine gluconate)、氯丁醇(chlorbutanol)、結晶磷酸二氫鈉、香葉草醇(geraniol)、軟骨素硫酸鈉、醋酸、醋酸鉀、醋酸鈉水合物、氧化鈦、結冷膠、二丁基羥基甲苯、溴化鉀、酒石酸、氫氧化鈉、聚氧乙烯硬脂酸酯45、
純化羊毛脂(purified lanolin)、D-山梨糖醇、山梨糖醇液、山梨酸、山梨酸鉀、牛磺酸、碳酸氫鈉、碳酸鈉水合物、硫代硫酸鈉水合物、硫柳汞(thimerosal)、四丁酚醛(tyloxapol)、脫氫醋酸鈉、氨丁三醇(trometamol)、濃甘油、濃縮混合生育酚、白色凡士林、薄荷水、薄荷油、對羥苯甲酸乙酯、對羥苯甲酸丁酯、對羥苯甲酸丙酯、對羥苯甲酸甲酯、玻尿酸鈉、人血清白蛋白、羥乙基纖維素、羥丙基纖維素、羥丙基甲基纖維素、冰醋酸、焦亞硫酸鈉、苯乙醇(phenylethyl alcohol)、葡萄糖、丙二醇、佛手柑油(bergamot oil)、苄醇、硼砂、硼酸、聚維酮(povidone)、聚氧乙烯(200)聚氧丙烯二醇(70)、聚苯乙烯磺酸鈉、聚山梨酸酯80、聚氧乙烯硬化蓖麻油60、聚乙烯醇(部分皂化物)、d-冰片、聚乙烯二醇4000、聚乙烯二醇6000、D-己六醇、檸檬酸酐、無水磷酸一氫鈉、無水磷酸二氫鈉、甲磺酸、甲基纖維素、1-薄荷醇、單乙醇胺、單硬脂酸鋁、單硬脂酸聚乙二醇、猷加利油、碘化鉀、硫酸、硫酸氧喹啉、流動石蠟、龍腦、磷酸、磷酸氫鈉水合物、磷酸二氫鉀、磷酸二氫鈉、磷酸二氫鈉一水合物、蘋果酸、凡士林等。
添加物較佳係例如：氯化鉀、氯化鈣水合物、氯化鈉、氯化鎂、甘油、醋酸、醋酸鉀、醋酸鈉水合物、酒石酸、氫氧化鈉、碳酸氫鈉、碳酸鈉水合物、濃甘油、羥乙基纖維素、羥丙基纖維素、羥丙基甲基纖維素、硼砂、硼酸、聚維酮、聚山梨酸酯80、聚氧乙烯硬化蓖麻油、單硬脂酸聚乙二醇、聚乙烯醇(部分皂化物)、聚乙烯二醇4000、聚乙烯二醇6000、檸檬酸酐、無水磷酸一氫鈉、無水磷酸二氫鈉、甲基纖維素、單乙醇胺、磷酸、磷酸氫鈉水合物、磷酸
二氫鉀、磷酸二氫鈉、磷酸二氫鈉一水合物、玻尿酸鈉、葡萄糖、1-薄荷醇等。
水性組成物係除上述之外，配合適用疾病等，亦可更進一步含有其他的藥效成分。此種藥效成分係可列舉例如：含有鹽酸布那唑嗪(bunazosin hydrochloride)等布那唑嗪(bunazosin)或其鹽或者該等的溶劑合物之α 1受體阻斷藥；含有酒石酸溴莫尼定(brimonidine tartrate)等溴莫尼定或其鹽或者該等的溶劑合物、阿可樂定(apraclonidine)或其鹽或者該等的溶劑合物的α 2受體作用藥；含有鹽酸卡特洛(carteolol hydrochloride)等卡特洛(carteolol)或其鹽或者該等的溶劑合物、尼普洛爾或其鹽或者該等的溶劑合物、噻嗎洛爾順丁烯二酸鹽等噻嗎洛爾(Timolol)或其鹽或者該等的溶劑合物、鹽酸貝特舒洛(betaxolol hydrochloride)等貝特舒洛(betaxolol hydrochloride)或其鹽或者該等的溶劑合物、鹽酸萘丁諾(levobunolol hydrochloride)等萘丁諾或其鹽或者該等的溶劑合物、苯呋洛爾(befunolol)或其鹽或者該等的溶劑合物、美替洛爾(metipranolol)或其鹽或者該等的溶劑合物之β阻斷藥；含有鹽酸多佐胺(Dorzolamide Hydrochloride)等多佐胺(Dorzolamide)或其鹽或者該等的溶劑合物、布林佐胺(Brinzolamide)或其鹽或者該等的溶劑合物、乙醯偶氮胺或其鹽或者該等的溶劑合物、雙氯非那胺(dichlorphenamide)或其鹽或者該等的溶劑合物、醋甲唑胺(methazolamide)或其鹽或者該等的溶劑合物之碳酸酐酶抑制劑；含有烏諾前列酮異丙酯(isopropyl unoprostone)或其鹽或者該等的溶劑合物、他氟前列腺素(tafluprost)或其鹽或者該等的溶劑合物、曲
伏前列腺素(travoprost)或其鹽或者該等的溶劑合物、比馬前列腺素(bimatoprost)或其鹽或者該等的溶劑合物、拉坦前列腺素或其鹽或者該等的溶劑合物、氯前列烯醇(cloprostenol)或其鹽或者該等的溶劑合物、氟前列醇(fluprostenol)或其鹽或者該等的溶劑合物之前列腺素F2 α衍生物；含有鹽酸地匹福林(dipivefrine hydrochloride)等地匹福林(dipivefrine)或其鹽或者該等的溶劑合物、腎上腺素、腎上腺素硼酸鹽、鹽酸腎上腺素(epinephrine hydrochloride)等腎上腺素或其鹽或者該等的溶劑合物之交感神經作用藥；含有溴地斯的明(distigmine bromide)或其鹽或者該等的溶劑合物、毛果芸香、鹽酸毛果芸香(pilocarpine hydrochloride)、毛果芸香硝酸鹽等毛果芸香或其鹽或者該等的溶劑合物、碳醯膽(carbachol)或其鹽或者該等的溶劑合物之副交感神經作用藥；含有鹽酸洛美利嗪(lomerizine hydrochloride)等洛美利嗪(lomerizine)或其鹽或者該等的溶劑合物之鈣拮抗藥；含有諸如：地美卡林(demecarium)或其鹽或者該等的溶劑合物、膽硫磷酯(echothiophate)或其鹽或者該等的溶劑合物、毒扁豆(physostigmine)或其鹽或者該等的溶劑合物之膽脂抑制劑等，可摻合該等中之1種或2種以上。
其他的藥效成分較佳係從拉坦前列腺素、尼普洛爾、多佐胺、布林佐胺及噻嗎洛爾、以及該等的鹽所構成之群組中選擇1種以上。
水性組成物的pH並無特別的限定，較佳係4~9、更佳係4.5~8、特佳係5~7。又，對生理食鹽水的滲透壓比並無特別的限定，較佳係0.6~3、更佳係0.6~2。
水性組成物從保存安定性、攜帶性等觀點，較佳係收容於容器中。容器的形態係在可收容水性組成物之前提下，其餘並無特別的限定，只要配合劑形等再行適當選擇、設定便可。此種容器的形態，具體而言，可列舉例如：注射劑用容器、吸入劑用容器、噴霧劑用容器、瓶狀容器、管狀容器、點眼劑用容器、點鼻劑用容器、點耳劑用容器、袋狀容器等。又，該等容器亦可更進一步利用箱、袋等包裝。
容器的材質(材料)並無特別的限定，只要配合容器的形態再行適當選擇便可。具體而言，可列舉例如：玻璃、塑膠、纖維素、紙漿、橡膠、金屬等。從加工性、可壓擠性或耐久性的觀點，較佳係塑膠製。塑膠製容器的樹脂較佳係熱可塑性樹脂，可列舉例如：低密度聚乙烯(含直鏈狀低密度聚乙烯在內)、高密度聚乙烯、中密度聚乙烯、聚丙烯、環狀聚烯烴等聚烯烴系樹脂；聚對苯二甲酸乙二酯、聚對苯二甲酸丁二酯、聚萘二甲酸乙二酯、聚萘二甲酸丁二酯、聚(對苯二甲酸-1,4-環己二甲酯)等聚酯系樹脂；聚苯醚系樹脂；聚碳酸酯系樹脂；聚碸系樹脂；聚醯胺系樹脂；聚氯乙烯樹脂；苯乙烯系樹脂等，亦可為該等的混合體(聚合物摻合物)。
由於水性組成物係含有具優異藥理作用的上述一般式(1)所示化合物，因而可適當利用作為醫藥品等。此情況，適用的疾病並無特別的限定，只要配合上述一般式(1)所示化合物所具有的藥理作用等再行適當選擇便可。
具體而言，例如根據一般式(1)所示化合物具有的Rho激酶抑制作用或降低眼壓作用，可利用作為高眼壓症或青光眼的預防或治療劑。此處，青光眼更詳言之，係可列舉例如：原發性開角型青光眼(POAG；open angle primary glaucoma)、正常眼壓性青光眼(NTG：Normal Tension Glaucoma)、分泌過多性青光眼(hypersecretion glaucoma)、急性閉角型青光眼(acute angle closure glaucoma)、慢性閉角型青光眼(chronic angle closure glaucoma)、高原型虹膜症候群(plateau iris syndrome)、混合型青光眼(mixed glaucoma)、類固醇性青光眼(steroid glaucoma)、水晶體的囊膜性青光眼(capsular glaucoma)、色素性青光眼(pigmentary glaucoma)、澱粉樣蛋白青光眼(amyloid,amyloidotic glaucoma)、新生血管性青光眼(neovascular glaucoma；NVG)、惡性青光眼(malignant glaucoma)等。
再者，如日本專利第5557408號公報所揭示，可利用作為眼底病變的預防或治療劑。(眼底病變主要係在視網膜及/或脈絡膜顯現的病變，具體而言，可列舉例如：因高血壓與動脈硬化衍生的眼底變化；視網膜中央動脈阻塞症、視網膜中央靜脈阻塞症(central retinal vein occlusion)或視網膜分支靜脈阻塞症(branch retinal vein occlusion)等視網膜靜脈阻塞症；糖尿病視網膜病變、糖尿病黃斑部水腫、糖尿病黃斑部病變(diabetic maculopathy)、伊爾斯氏病(Eales disease)、柯氏症(Coats disease)等先天性視網膜血管異常；馮希伯氏症(von Hippel disease，視網膜血管瘤病)、無脈症(pulseless disease)；黃斑部病變(中心性漿液性脈絡視網膜病變(central serous chorioretinopathy)、黃斑囊樣水腫(cystoid macular edema)、老年性黃斑部病變(age related macular degeneration)、黃斑部裂孔(macular
hole)、近視性黃斑部退化(myopic macular degeneration)、視網膜玻璃體界面黃斑部病變、藥物毒性黃斑部病變、遺傳性黃斑部病變(hereditary macular degeneration)等)；(裂孔性、牽引性、滲出性等)視網膜剝離、視網膜色素變性症(pigmentary degeneration of the retina)、早產兒視網膜病變(ROP：Retinopathy of prematurity)等)。更佳係可利用作為糖尿病視網膜病變、糖尿病黃斑部水腫(DME：Diabetic Macular Edema)或老年性黃斑部病變的預防或治療劑。
接著，針對「賦予防腐效果之方法」的態樣發明進行說明。
所謂「賦予防腐效果之方法」係指賦予水性組成物具防腐效果的方法。賦予防腐效果之方法中，防腐效果係就評價對象的防腐力，經與上述一般式(1)所示化合物或其鹽或者該等的溶劑合物、及四級銨型界面活性劑等二成分均未摻合的情況進行比較，若防腐力較優異便判定具效果，無論其效果程度。
具體而言，例如依照第十六修訂日本藥典參考資訊「保存效力試驗法」，使用細菌(例如：綠膿桿菌(Pseudomonas aeruginosa)、金黃色葡萄球菌(Staphylococcus aureus)、大腸菌(Escherichia coli))、或真菌(例如：白色念珠菌(Candida albieans)]的情況，經與上述一般式(1)所示化合物或其鹽或者該等的溶劑合物、及四級銨型界面活性劑等二成分均未摻合的對照(只要將已知無具防腐效果的淨化水使用作為對照便可)進行比較，若任一種以上微生物種在任意日數中可確認到生菌數較少的話，便判定具有防腐效果，此情況
確認對水性組成物賦予防腐效果。
另外，賦予防腐效果之方法中的其他各用語意義、各種成分摻合量等，均係與上述<<水性組成物相關態樣的發明>>中所說明者同樣。
其次，列舉實施例針對本發明進行更進一步說明，惟本發明並不受該等的任何限定。另外，以下實施例、試驗例等之中，利巴舒滴一鹽酸鹽二水合物係例如利用國際公開第2006/057397號說明書所記載方法便可製造。
為確認利巴舒滴對微生物(細菌及真菌)有無發育抑制活性，便使用綠膿桿菌(Pseudomonas aeruginosa)作為細菌、使用白色念珠菌(Candida albicans)作為真菌，並實施以下的試驗。
將綠膿桿菌(Pseudomonas aeruginosa)NBRC 13275株接種於大豆分解蛋白質-乾酪素培養基(Merck公司)，於30~35℃下培養20~22小時。經培養後，利用氯化鈉-蛋白腖緩衝液(buffered sodium chloride peptone solution)(pH7.0)稀釋至成為1000CFU/mL以下，便獲得試驗菌懸浮液。
將利巴舒滴一鹽酸鹽二水合物2g溶解於270mL磷酸緩衝液
(pH7.2)中，獲得試料稀釋液。
在試料稀釋液50mL中混合試驗菌懸浮液0.5mL，獲得試料樣品(另外，將在磷酸緩衝液(pH7.2)50mL中混合試驗菌懸浮液0.5mL者，設為對照樣品)。
經30分鐘以上之後，依照薄膜過濾器法，使用纖維素混合酯性過濾器(Millipore公司)過濾各種樣品，將菌體回收於過濾器上之後，利用磷酸緩衝液(pH7.2)100mL洗淨過濾器。所獲得過濾器放置於大豆分解蛋白質-乾酪素瓊脂培養基(Merck公司)上，於30~35℃下培養3日。
經培養後，計數所形成的菌落數(另外，試驗實施2次，獲得其平均值)。又，從所獲得菌落數，依照下式計算出發育抑制率(%)。
[數1]發育抑制率(%)=|(對照樣品的菌落數-試料樣品的菌落數)|/對照樣品的菌落數×100
將Candida albicans NBRC 1594株接種於薩氏葡萄糖液體培養基(Merck公司)，於20~25℃下培養44~46小時。然後，利用氯化鈉-蛋白腖緩衝液(pH7.0)稀釋至成為1000CFU/mL以下，獲得試驗菌懸浮液。使用所獲得試驗菌懸浮液，施行與上述對綠膿桿菌所進行試驗同樣的操作，將菌體回收於過濾器上。所獲得過濾器放置於薩氏葡萄糖瓊脂培養基(Merck公司)上，於20~25℃下培養5日。
經培養後，計數所形成的菌落數(另外，試驗實施2次，獲得
其平均值)。又，計算出發育抑制率(%)。
將結果示於表1。
由表1所記載的結果，確認到利巴舒滴對綠膿桿菌與白色念珠菌均同樣具有發育抑制活性。
由以上的試驗結果得知，以利巴舒滴所代表的一般式(1)所示化合物或其鹽或者該等的溶劑合物，對細菌及真菌具有防腐效果。
為確認利用利巴舒滴與苄二甲烴銨的組合，有無增強對微生物(細菌及真菌)的防腐效果，便使用綠膿桿菌(Pseudomonas aeruginosa)作為細菌、使用白色念珠菌(Candida albicans)作為真菌，並實施以下試驗。
另外，已知氯化苄二甲烴銨的有效濃度係0.002~0.01%，若為0.001%便無法呈現充分的殺菌活性(南山堂股份有限公司1984年出版『點眼劑』、第76~83頁)。所以，本試驗便藉由使用該量的氯化苄二甲烴銨，確認有無利巴舒滴與苄二甲烴銨(benzalkonium)的協同作用(相乘作用)。
將Pseudomonas aeruginosa NBRC 13275株接種於大豆分解蛋白質-乾酪素瓊脂培養基(Merck公司)，於30~35℃下培養18~24小時。然後，使培養菌體浮游於0.1%氯化鈉-蛋白腖緩衝液(日本製藥公司)中，調整成為每1mL的菌體約108個的狀態，獲得試驗菌懸浮液。
對依照下述方法所調製的各種製劑樣品15mL，接種試驗菌懸浮液0.1mL之後，填充於經滅菌過的聚丙烯製點眼劑用容器(容量：20mL)中，在20~25℃、遮光條件下保存14日。
經保存後，各種製劑樣品依序利用卵磷脂‧聚山梨酸酯80添加大豆分解蛋白質-乾酪素培養基(日本製藥公司)、調製每次稀釋10倍的稀釋系列，再依照瓊脂平板混釋法，混釋於卵磷脂‧聚山梨酸酯80添加大豆分解蛋白質-乾酪素瓊脂培養基(日本製藥公司)中，於30~35℃下培養5日。
經培養後，從所形成菌落數與稀釋倍數，計算出各種製劑樣品1mL中的生菌數。
將Candida albicans NBRC 1594株接種於薩氏葡萄糖瓊脂培養基(Merck公司)，於20~25℃下培養40~48小時。然後，使培養菌體浮游於0.1%氯化鈉-蛋白腖緩衝液(日本製藥公司)中，調整成為每1mL的菌體約108個的狀態，獲得試驗菌懸浮液。使用所獲得試驗菌懸浮液，施行與上述對綠膿桿菌所進行試驗同樣的操作，保存經接種試驗菌懸浮液的各種製劑樣品。
經保存後，各種製劑樣品依序利用卵磷脂‧聚山梨酸酯80添加大豆分解蛋白質-乾酪素培養基(日本製藥公司)、調製每次稀釋10倍的稀釋系列，再依照瓊脂平板混釋法，混釋於卵磷脂‧聚山梨酸酯80添加薩氏葡萄糖瓊脂培養基(日本製藥公司)中，於20~25℃下培養5日
經培養後，從所形成菌落數與稀釋倍數，計算出各種製劑樣品1mL中的生菌數。
另外，製劑樣品係使用單獨含有利巴舒滴的製劑樣品、與含有利巴舒滴及苄二甲烴銨的製劑樣品等2種。
調製每100mL中，含有：利巴舒滴一鹽酸鹽二水合物0.4896g(依利巴舒滴的自由體計係0.4g)、無水磷酸二氫鈉0.4g、甘油2.136g、氫氧化鈉適量(pH6.0)、及無菌淨化水(其餘)的水性組成物，經施行過濾器滅菌便獲得製劑樣品。
調製每100mL中，含有：利巴舒滴一鹽酸鹽二水合物0.4896g(依利巴舒滴的自由體計係0.4g)、氯化苄二甲烴銨0.001g(0.001w/v%)、無水磷酸二氫鈉0.4g、甘油2.136g、氫氧化鈉適量(pH6.0)、及無菌淨化水(其餘)的水性組成物，經施行過濾器滅菌便獲得製劑樣品。
將結果示於表2。另外，接種菌數係從接種時的試驗菌懸浮液
中之生菌數，換算樣品1mL中的生菌數。
由表2所記載的結果，藉由使不會呈現充分殺菌活性之量的氯化苄二甲烴銨與利巴舒滴組合，相較於利巴舒滴單獨之下，綠膿桿菌的生菌數減少至未滿1/38000，且念珠菌生菌數減少至1/475。
由以上的試驗結果得知，藉由使以利巴舒滴所代表的一般式(1)所示化合物或其鹽或者該等的溶劑合物、與以苄二甲烴銨所代表的四級銨型界面活性劑組合，便可相乘地增強防腐效果，即便在四級銨型界面活性劑單獨的情況下不會呈現防腐效果的量，仍可達優異的防腐效果。
除取代綠膿桿菌(Pseudomonas aeruginosa)，改為使用金黃色葡萄球菌(Staphylococcus aureus：NBRC 13276株)作為細菌之外，其餘均依照與試驗例2同樣的方法實施試驗。
將結果示於表3。
[表3]
由表3所記載的結果，藉由使不會呈現充分殺菌活性之量的氯化苄二甲烴銨與利巴舒滴組合，相較於利巴舒滴單獨之下，金黃色葡萄球菌的生菌數減少至未滿1/20。
[試驗例4]利用利巴舒滴與苄二甲烴銨的組合所造成防腐效果增強之確認 其三
除取代綠膿桿菌(Pseudomonas aeruginosa)，改為使用大腸菌(Escherichia coli：NBRC 3972株)作為細菌，並將保存期間設為28日之外，其餘均依照與試驗例2同樣的方法實施試驗。
將結果示於表4。
由表4所記載的結果，藉由使不會呈現充分殺菌活性之量的氯化苄二甲烴銨與利巴舒滴組合，相較於利巴舒滴單獨之下，大腸菌的生菌數減少至未滿1/140000。
由表3及表4所記載的結果得知，組合利巴舒滴與苄二甲烴銨，不僅綠膿桿菌或念珠菌，就連廣範圍微生物均可確認發育抑制
活性增強。
由以上的試驗結果得知，藉由以利巴舒滴所代表的一般式(1)所示化合物或其鹽或者該等的溶劑合物、與以苄二甲烴銨所代表的四級銨型界面活性劑之組合，對廣範圍微生物均可確認優異的防腐效果增強。
依照常法可製造含有表5~表7所記載成分及分量(水性組成物每100mL的量(g))的點眼劑。
在製造例1~27中，取代氯化苄二甲烴銨，改為使用同量的氯化本索寧，依照常法可製造製造例28~54的點眼劑。
在製造例1~54中，取代利巴舒滴一鹽酸鹽二水合物，改為使用同量的4-溴-5-[[(2S)-2-甲基-1,4-二氮雜環庚烷-1-基]磺醯基]異喹啉，依照常法可製造製造例55~108的點眼劑。
根據本發明，可提供含有具優異藥理作用的上述一般式(1)所示化合物，且防腐效果優異、保存安定性良好的水性組成物，可適用於醫藥品產業等。
Claims (8)
- 一種水性組成物，係含有：下示一般式(1)：
- 如請求項1之水性組成物，其中，一般式(1)所示化合物係利巴舒滴(Ripasudil)。
- 如請求項1之水性組成物，其中，四級銨型界面活性劑係氯化苄二甲烴銨。
- 如請求項1至3中任一項之水性組成物，係點眼劑。
- 一種賦予水性組成物防腐效果之方法，係包括有摻合：下示一般式(1)
- 如請求項5之方法，其中，一般式(1)所示化合物係利巴舒滴。
- 如請求項5之方法，其中，四級銨型界面活性劑係氯化苄二甲烴銨。
- 如請求項5至7中任一項之方法，其中，水性組成物係點眼劑。
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