TWI704931B - 含有玻尿酸或其鹽及丙二醇之點眼液 - Google Patents
含有玻尿酸或其鹽及丙二醇之點眼液 Download PDFInfo
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- TWI704931B TWI704931B TW106116311A TW106116311A TWI704931B TW I704931 B TWI704931 B TW I704931B TW 106116311 A TW106116311 A TW 106116311A TW 106116311 A TW106116311 A TW 106116311A TW I704931 B TWI704931 B TW I704931B
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- Taiwan
- Prior art keywords
- concentration
- eye drops
- propylene glycol
- hyaluronic acid
- salt
- Prior art date
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- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 55
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 55
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 53
- 150000003839 salts Chemical class 0.000 title claims abstract description 36
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- 230000003204 osmotic effect Effects 0.000 claims abstract description 29
- 239000003755 preservative agent Substances 0.000 claims abstract description 15
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- 230000002335 preservative effect Effects 0.000 claims abstract description 10
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 11
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- 241000289690 Xenarthra Species 0.000 claims 1
- 229960000686 benzalkonium chloride Drugs 0.000 abstract 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 abstract 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 63
- 229920002385 Sodium hyaluronate Polymers 0.000 description 49
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- 239000013078 crystal Substances 0.000 description 3
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- 125000000217 alkyl group Chemical group 0.000 description 2
- 229910021538 borax Inorganic materials 0.000 description 2
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Abstract
本發明係一種含有0.03~0.5%(w/v)之濃度的玻尿酸或其鹽及0.1~1.0%(w/v)之濃度的丙二醇之水性點眼液,該點眼液係含有0.001~0.002%(w/v)之濃度的氯化烷基二甲基苄基銨(benzalkonium chloride)作為唯一的防腐劑且含有將該點眼液的滲透壓比設為0.9~1.1之濃度的離子性等滲壓劑(isotonizing agent)之點眼液。
Description
本發明係關於一種水性點眼液,其係含有0.03~0.5%(w/v)之濃度的玻尿酸或其鹽及0.1~1.0%(w/v)之濃度的丙二醇之水性點眼液,該點眼液係含有0.001~0.002%(w/v)之濃度的氯化烷基二甲基苄基銨作為唯一的防腐劑且含有將該點眼液的滲透壓比設為0.9~1.1之濃度的離子性等滲壓劑(isotonizing agent)之水性點眼液。又,本發明亦關於一種方法,其係使含有0.1或0.3%(w/v)之濃度的玻尿酸鈉及作為唯一的防腐劑之氯化烷基二甲基苄基銨之點眼液的保存效力提升的同時,將該點眼液的動黏度設為3.0~4.0或17~30mm2/s且防止該點眼液的滴液之方法;該方法係包含將該點眼液中的濃度成為0.1或0.3%(w/v)之量的玻尿酸鈉、該點眼液中的濃度成為0.001~0.002%(w/v)之量的氯化烷基二甲基苄基銨、該點眼液中的濃度成為0.1~1.0%(w/v)之量的丙二醇、及該點眼液的滲透壓比成為0.9~1.1之量的離子性等滲壓劑混合之步驟(a);將該點眼液的pH調整至6.0~7.0之步驟(b);及填充該點眼液至點眼容器之步驟(c)
之方法。
乾眼症是一種從眼睛乾澀、有異物感的不適程度的症狀開始,一旦惡化就會對日常生活帶來極大的困難之疾病。乾眼症患者數隨著高齡化社會的到來及電腦等視頻顯示終端(VDT;video display terminal)作業的增加而年年增加,據說美國國內的估計患者數為1,000萬人以上,日本國內亦有800萬人以上。
雖然對於乾眼症的病理狀態尚未完全明朗,但已知乾眼症會引起角膜結膜上皮損傷,最終會產生視覺異常。因此,早期且適當地治療因乾眼症造成的角膜結膜上皮損傷是極為重要的。
現在作為乾眼症的治療法,點眼治療是最一般的治療方法,在日本,含有玻尿酸鈉之點眼液被廣泛用於治療乾眼症。
關於含有玻尿酸鈉之點眼液(以下簡稱為「玻尿酸鈉點眼液」),其存在有以經多次使用為目的且可自由地進行蓋子等的開封及再密封之多劑量(multi-dose)型(Hyalein(註冊商標)點眼液0.1%、Hyalein(註冊商標)點眼液0.3%等)、及以單次使用為目的之單一劑量(unit dose)型(Hyalein(註冊商標)Mini點眼液0.1%、Hyalein(註冊商標)Mini點眼液0.3%等)。
多劑量型的玻尿酸鈉點眼液由於進行蓋子的開封及再密封,所以添加氯化烷基二甲基苄基銨作為防腐劑,另一方面,單一劑量型由於是單次使用(用完),
所以不添加防腐劑。
氯化烷基二甲基苄基銨等防腐劑係已被指出有誘發角膜損傷的風險,例如:對於氯化烷基二甲基苄基銨,如Clinical and Experimental Ophthalmology,32,180-184(2004)(非專利文獻1)所揭示,已知有引起濃度依存的角膜上皮損傷的可能性。如前述,乾眼症本來就是伴隨角膜上皮損傷的疾病,因此嚴重的乾眼症患者使用單一劑量型的玻尿酸鈉點眼液。另一方面,從生產成本的問題等來看,對所有乾眼症患者開單一劑量型的玻尿酸鈉點眼液的處方係困難,因此亦考慮藉由使多劑量型的點眼液中的防腐劑濃度減少而將角膜上皮損傷的發生風險減低化。然而,實際上,若使點眼液中的防腐劑濃度減少,則作為多劑量型使用卻無法獲得充分的保存效力,又,藉由伴隨防腐劑的減低化之摻合成分的變化,亦擔心該點眼液的物理化學性質成為與以往的玻尿酸鈉點眼液不同者。
順帶一說,日本特開2004-359629號公報(專利文獻1)、日本特開2009-196903號公報(專利文獻2)、日本特開2009-161454號公報(專利文獻3)已揭示含有玻尿酸鈉、氯化烷基二甲基苄基銨及丙二醇之點眼劑,但完全未揭示該點眼液中的氯化烷基二甲基苄基銨濃度為0.0025%以下,並同時具有充分的保存效力,而且與以往的玻尿酸鈉點眼液具有相同的物理化學性質。
[專利文獻1]日本特開2004-359629號公報
[專利文獻2]日本特開2009-196903號公報
[專利文獻3]日本特開2009-161454號公報
[非專利文獻1]Clinical and Experimental Ophthalmology, 32, 180-184(2004)
如上所述,探索一種在減少氯化烷基二甲基苄基銨濃度的同時亦具有充分的保存效力而且與以往的玻尿酸鈉點眼液具有相同的物理化學性質之點眼液是一個頗有趣的課題。
本發明人等發現在添加0.002%(w/v)氯化烷基二甲基苄基銨的玻尿酸鈉點眼液中,無法獲得充分的保存效力,另一方面,在添加丙二醇的情況下,即使將氯化烷基二甲基苄基銨濃度減低化至0.001%(w/v),也能獲得充分的保存效力。
另一方面,本發明人等發現一旦玻尿酸鈉點眼液中所添加的丙二醇超過1%(w/v),則將會超過「2010年11月(修正第7版)Hyalein(註冊商標)點眼液0.1%、Hyalein(註冊商標)點眼液0.3%、Hyalein(註冊商標)Mini點眼液0.1%、Hyalein(註冊商標)Mini點眼液0.3%醫藥品interview form(以
下亦稱為「Hyalein interview form」)」中記載之玻尿酸鈉點眼液的動黏度及/或滲透壓比的容許幅度,而達到完成使丙二醇添加量的上限成為1%(w/v)的本發明。
再者,如後面所述,本發明人等發現含丙二醇之玻尿酸鈉點眼液兼具難以滴液而且保護因乾燥角膜上皮細胞之效果。
即,本發明係含有0.03~0.5%(w/v)之濃度的玻尿酸或其鹽及0.1~1.0%(w/v)之濃度的丙二醇之水性點眼液,該點眼液係含有0.001~0.002%(w/v)之濃度的氯化烷基二甲基苄基銨作為唯一的防腐劑且含有將該點眼液的滲透壓比設為0.9~1.1之濃度的離子性等滲壓劑之點眼液(以下簡稱為「本點眼液」)。
又,本發明的其他形態係含有將pH設為6.0~7.0之量的緩衝劑及pH調節劑之本點眼液。
又,本發明的其他形態係含有0.001~0.1%(w/v)之濃度的乙二胺四乙酸鹽(edetate)之本點眼液。
又,本發明的其他形態係玻尿酸或其鹽的濃度為0.1~0.3%(w/v)之本點眼液。
又,本發明的其他形態係丙二醇的濃度為0.25~0.75%(w/v)之本點眼液。
又,本發明的其他形態係氯化烷基二甲基苄基銨的濃度為0.001~0.0015%(w/v)之本點眼液。
又,本發明的其他形態係實質上由0.03~0.5%(w/v)之濃度的玻尿酸或其鹽、0.1~1.0%(w/v)之濃度的丙二醇、0.001~0.002%(w/v)之濃度的氯化烷基二甲
基苄基銨、將點眼液的滲透壓比設為0.9~1.1之濃度的離子性等滲壓劑、將點眼液的pH設為6.0~7.0之量的緩衝劑及pH調節劑、以及0.001~0.1%(w/v)之濃度的乙二胺四乙酸鹽所構成的水性點眼液。
又,本發明的其他形態係實質上由0.1~0.3%(w/v)之濃度的玻尿酸或其鹽、0.25~0.75%(w/v)之濃度的丙二醇、0.001~0.0015%(w/v)之濃度的氯化烷基二甲基苄基銨、將點眼液的滲透壓比設為0.9~1.1之濃度的離子性等滲壓劑、將點眼液的pH設為6.0~7.0之量的緩衝劑及pH調節劑、以及0.001~0.1%(w/v)之濃度的乙二胺四乙酸鹽所構成的水性點眼液。
又,本發明為使含有0.1或0.3%(w/v)之濃度的玻尿酸鈉及作為唯一的防腐劑之氯化烷基二甲基苄基銨之水性點眼液的保存效力提升的同時,將該點眼液的同黏度設為3.0~4.0或17~30mm2/s且防止該點眼液的滴液之方法。本發明亦為包含將該點眼液中的濃度成為0.1或0.3%(w/v)之量的玻尿酸鈉、該點眼液中的濃度成為0.001~0.002%(w/v)之量的氯化烷基二甲基苄基銨、該點眼液中的濃度成為0.1~1.0%(w/v)之量的丙二醇、及該點眼液的滲透壓比成為0.9~1.1之量的離子性等滲壓劑混合之步驟(a);將該點眼液的pH調整為6.0~7.0之步驟(b);及將該點眼液填充至點眼容器之步驟(c)之方法(以下簡單地統稱該等為「本方法」)。
又,在本方法的步驟(a)中,更佳為將該點眼液中的濃度成為0.001~0.1%(w/v)之量的乙二胺四乙酸
鹽混合。
又,在本方法的步驟(a)中,較佳為將該點眼液中的濃度成為0.25~0.75%(w/v)之量的丙二醇混合。
又,在本方法的步驟(a)中,較佳為將該點眼液中的濃度成為0.001~0.0015%(w/v)之量的氯化烷基二甲基苄基銨混合。
本點眼液雖然在該點眼液中的氯化烷基二甲基苄基銨濃度為0.002%(w/v)以下,但是可藉由含有丙二醇而取得充分的保存效力,另一方面,亦具有作為含有玻尿酸或其鹽之點眼液(以下簡稱為「玻尿酸點眼液」)所能容許的動黏度及滲透壓比。再者,從後述的滴液確認試驗及角膜上皮細胞保護作用確認試驗的結果可清楚得知,本點眼液兼具難以滴液而且保護因乾燥角膜上皮細胞之效果。
第1圖為顯示含丙二醇之玻尿酸鈉點眼液對因乾燥負荷造成的角膜上皮細胞損傷帶來的影響之圖表,縱軸為活細胞活性。
本點眼液係含有0.03~0.5%(w/v)之濃度的玻尿酸或其鹽及0.1~1.0%(w/v)之濃度的丙二醇之水性點眼液,其特徵在於該點眼液係含有0.001~0.002%(w/v)
之濃度的氯化烷基二甲基苄基銨作為唯一的防腐劑,且含有將該點眼液的滲透壓比設為0.9~1.1之濃度的離子性等滲壓劑。此外,在本發明中,「水性點眼液」是指將水作為基劑之點眼液。
本點眼液不但可用於伴隨乾眼症(乾眼症候群)、休格倫氏症候群(Sjogren’s syndrome)、史蒂芬強生症候群(Stevens-Johnson syndrome)等內因性疾病而來的角膜結膜上皮損傷的治療,亦可用於伴隨因術後、藥物性、外傷、戴隱形眼鏡等所造成的外因性疾病而來的角膜結膜上皮損傷的治療。這樣的本點眼液雖然在該點眼液中的氯化烷基二甲基苄基銨濃度為0.002%(w/v)以下,但是藉由含有丙二醇而可取得充分的保存效力,另一方面,亦具有作為玻尿酸點眼液所容許的動黏度及滲透壓比。本點眼液更兼具難以滴液而且保護因乾燥角膜上皮細胞之效果。
本發明中的玻尿酸係下述通式(1)所示的化合物。
[式中,n表示自然數]
作為本發明中的「玻尿酸」,較佳為平均分子量50萬~390萬的玻尿酸,更佳為平均分子量50萬~120萬的玻尿酸。
以玻尿酸的鹽而言,只要是作為醫藥所容許的鹽,則沒有特殊的限制,可列舉和鹽酸、氫溴酸、氫碘酸、硝酸、硫酸、磷酸等無機酸的鹽;和醋酸、富馬酸、馬來酸、琥珀酸、檸檬酸、酒石酸、己二酸、葡萄糖酸、葡萄糖庚醣酸(glucoheptonic acid)、葡萄糖醛酸、對苯二甲酸、甲磺酸、乳酸、馬尿酸、1,2-乙二磺酸、2-羥乙磺酸、乳糖醛酸、油酸、羥萘酸(pamoate)、聚半乳糖醛酸、硬脂酸、單寧酸、三氟甲磺酸、苯磺酸、對甲苯磺酸、硫酸月桂酯、硫酸甲酯、萘磺酸、磺柳酸等有機酸的鹽;和溴甲烷、碘甲烷等的四級銨鹽;和溴離子、氯離子、碘離子等鹵素離子的鹽;和鋰、鈉、鉀等鹼金屬的鹽;和鈣、鎂等鹼土金屬的鹽;和鐵、鋅等的金屬鹽;和氨的鹽;和三乙二胺(triethylene diamine)、2-胺乙醇、2,2-亞胺基雙(乙醇)、1-去氧-1-(甲胺基)-2-D-山梨醇、2-胺基-2-(羥甲基)-1,3-丙二醇、普羅卡因、N,N-雙(苯甲基)-1,2-乙二胺等有機胺的鹽等。
作為本發明中的「玻尿酸的鹽」,較佳為下述通式(2)所示的鈉鹽(以下亦稱為「玻尿酸鈉」)。
[式中,m表示自然數]
本發明中的「玻尿酸或其鹽」亦可採取水合物或溶劑合物的形態。
在幾何異構物或光學異構物存在於玻尿酸時,該異構物或該等的鹽亦包含在本發明的範圍內。又,在質子互變異構性存在於玻尿酸時,該互變異構物或該等的鹽亦包含在本發明的範圍內。
當同質多晶形性(crystal polymorphism)及同質多晶形性群組(同質多晶形性系統)存在於玻尿酸或其鹽、水合物或溶劑合物時,該等的同質多晶形體及同質多晶形性群組(同質多晶形性系統)亦包含在本發明的範圍內。在此,同質多晶形性群組(同質多晶形性系統)是指藉由該等晶體的製造、結晶、保存等的條件及狀態(再者,本狀態亦包含經製劑化的狀態),結晶形變化時的各階段中的各個結晶形及其過程全體。
「玻尿酸或其鹽」可依照有機合成化學的領域中一般的方法來製造,亦可依照日本特開平1-115902號公報所記載的方法來製造。又,本發明之「玻尿酸或
其鹽」亦可使用Sigma公司等所販售者,例如:「玻尿酸鈉」係由Sigma公司所販售(目錄編號:H5388)。
本點眼液亦可含有「玻尿酸或其鹽」以外的有效成分,較佳為含有「玻尿酸或其鹽」作為唯一的有效成分。
本點眼液中「玻尿酸或其鹽」的濃度為0.03~0.5%(w/v),較佳為0.1~0.3%(w/v),更佳為0.1%(w/v)或0.3%(w/v)。
前述「玻尿酸或其鹽的濃度」是指「玻尿酸(自由體)」及「玻尿酸的鹽」的濃度的兩者,例如:「0.1%(w/v)玻尿酸或其鹽」是指點眼液中的「玻尿酸(自由體)」的濃度為0.1%(w/v)之情形與「玻尿酸的鹽」的濃度為0.1%(w/v)之情形的兩者。
本點眼液中「丙二醇」的濃度為0.1~1.0%(w/v),較佳為0.25~0.75%(w/v)。
氯化烷基二甲基苄基銨係下述通式(3)所示之化合物。
[式中,R表示碳數8~18的烷基。]
較佳作為本發明之「氯化烷基二甲基苄基銨」係在上述通式(3)中,R係表示為「C12H25」者(以下亦稱為「氯化烷基二甲基苄基銨(C12)」)。
本點眼液中「氯化烷基二甲基苄基銨」的濃度為0.001~0.002%(w/v),較佳為0.001~0.0015%(w/v)。
在本發明中,「含有氯化烷基二甲基苄基銨作為唯一的防腐劑」是指本點眼液含有氯化烷基二甲基苄基銨,另一方面是指本點眼液未含有陽性皂(benzethonium chloride)、葡萄糖酸氯己定(chlorhexidine gluconate)、對羥苯甲酸酯(paraben)類、山梨酸及其鹽、氯丁醇、硼酸、硼砂以及亞氯酸鹽的任一者。
在本發明中,「含有使點眼液的滲透壓比為0.9~1.1之濃度的離子性等滲壓劑」是指除了丙二醇等,更添加離子性等滲壓劑至本點眼液,藉此將本點眼液的滲透壓比調整至「0.9~1.1」的範圍。再者,本點眼液的滲透壓比係可使用自動滲透壓分析裝置而容易地進行測定。
本發明所使用的離子性等滲壓劑是指氯化鈉、氯化鉀、氯化鈣、氯化鎂等的離子性等滲壓劑。
本點眼液較佳為含有將該點眼液的pH設為6.0~7.0之量的緩衝劑及pH調節劑。在本發明中,「含有將點眼液的pH設為6.0~7.0之量的緩衝劑及pH調節劑」是指藉由添加緩衝劑及pH調節劑至本點眼液,而將本點眼液的pH調整至「6.0~7.0」的範圍,只要是將本點眼液的pH調整至該範圍,緩衝劑及pH調節劑的添加量(濃度)則沒有特別的限制。
作為本發明中的「緩衝劑」的具體例,可列舉磷酸鈉、磷酸氫鈉、磷酸二氫鈉、醋酸鈉、ε-胺己酸
等,特佳為ε-胺己酸。惟硼酸及硼砂並未包含在本發明中的「緩衝劑」內。
作為本發明中的「pH調節劑」,只要是可調節本點眼液的pH,則沒有特別的限制,以具體例而言,可列舉稀鹽酸、氫氧化鈉等。
本點眼液具有與以往的玻尿酸鈉點眼液相同程度的動黏度,例如本點眼液中的玻尿酸或其鹽的濃度為0.1%(w/v)時,其動黏度係在Hyalein(註冊商標)點眼液0.1%或Hyalein(註冊商標)Mini點眼液0.1%醫藥品interview form所記載的「3.0~4.0mm2/s」範圍內。又,本點眼液中的玻尿酸或其鹽的濃度為0.3%(w/v)時,其動黏度係在Hyalein(註冊商標)點眼液0.3%或Hyalein(註冊商標)Mini點眼液0.3%醫藥品interview form所記載的「17~30mm2/s」範圍內。
本點眼液較佳為含有0.001~0.1%(w/v)之濃度的乙二胺四乙酸鹽。在此,本發明中的「乙二胺四乙酸鹽」是指乙二胺四乙酸一鈉、乙二胺四乙酸二鈉、乙二胺四乙酸三鈉、乙二胺四乙酸四鈉等的乙二胺四乙酸(乙二胺四醋酸)的鹽及該等的水合物。較佳作為本發明之「乙二胺四乙酸鹽」者係乙二胺四乙酸二鈉二水合物(以下亦稱為「乙二胺四乙酸鈉水合物」)。
本點眼液中,可因應必要而添加製藥學上可容許的添加劑,本點眼液較佳為所包含為未指定的添加劑,未含有對本點眼液的效果帶來影響者,更佳為未含有所包含為未指定的添加劑。
本發明提供一種實質上由0.03~0.5%(w/v)之濃度的玻尿酸或其鹽、0.1~1.0%(w/v)之濃度的丙二醇、0.001~0.002%(w/v)之濃度的氯化烷基二甲基苄基銨、點眼液的滲透壓比設為0.9~1.1之濃度的離子性等滲壓劑、將點眼液的pH設為6.0~7.0之量的緩衝劑及pH調節劑、以及0.001~0.1%(w/v)之濃度的乙二胺四乙酸鹽而成的水性點眼液作為上述之本點眼液的較佳形態。在本形態的水性點眼液中,較佳為玻尿酸或其鹽的濃度為0.1~0.3%(w/v)、丙二醇的濃度為0.25~0.75%(w/v)、氯化烷基二甲基苄基銨的濃度為0.001~0.0015%(w/v)。
在本方法中,「使保存效力提升」是指對於含有0.002%(w/v)以下之濃度的氯化烷基二甲基苄基銨之玻尿酸鈉點眼液,不使防腐劑的添加量增大,而使該點眼液通過規定的保存效力試驗(例如:第十五版日本藥典之保存效力試驗)。
在本方法中,「防止滴液」是指在填充玻尿酸鈉點眼液至點眼容器後進行點眼操作時,與未含有丙二醇之玻尿酸鈉點眼液進行比較,使點眼液從點眼容器的頂端沿著外部流下的現象(滴液)的發生頻率減低。
在本方法的步驟(a)中,亦可混合玻尿酸鈉、氯化烷基二甲基苄基銨、丙二醇及離子性等滲壓劑以外的成分,特佳為混合玻尿酸鈉點眼液中的濃度成為0.001~0.1%(w/v)之量的乙二胺四乙酸鹽。
本方法的步驟(b)是指添加緩衝劑及pH調節劑至玻尿酸鈉點眼液後,將其pH調整至「6.0~7.0」的
範圍。若可將玻尿酸鈉點眼液的pH調整至該範圍,則緩衝劑及pH調節劑的添加量(濃度)沒有特別的限制。
在本方法的步驟(c)中,一般而言,填充玻尿酸鈉點眼液之點眼容器若是作為點眼容器所使用的容器,則沒有特別的限制,但特佳為聚乙烯製點眼容器。
在本方法中,亦可包含步驟(a)、(b)及(c)以外的步驟。
以下表示保存效力試驗、動黏度測定試驗、滴液確認試驗及角膜上皮細胞保護作用確認試驗的結果、以及製劑例,惟此等之例係用於更加理解本發明而非限定本發明的範圍。
[保存效力試驗]
為了確認丙二醇對玻尿酸點眼液的保存效力造成的影響,進行保存效力試驗。
(試料製備)
<比較處方1、2>
將玻尿酸鈉0.3g、氯化鈉0.7g、氯化鉀0.15g、ε-胺己酸0.2g、乙二胺四乙酸鈉水合物0.01g及氯化烷基二甲基苄基銨(C12)0.0025g溶解於水中並使其成為100mL,將添加稀鹽酸及/或氫氧化鈉而成為pH6.0者設為比較處方1,將成為pH7.0者設為比較處方2。
<比較處方3、4>
除了使氯化烷基二甲基苄基銨(C12)的添加量為0.002g之點以外,係與上述比較處方1及2同樣地進行而
製備。
<處方1>
將玻尿酸鈉0.3g、氯化鈉0.7g、丙二醇0.25g、ε-胺己酸0.2g、乙二胺四乙酸鈉水合物0.01g及氯化烷基二甲基苄基銨(C12)0.001g溶解於水中並使其成為100mL,添加稀鹽酸及/或氫氧化鈉使其成為pH6.0。
<處方2>
除了使玻尿酸鈉的添加量為0.1g、使氯化烷基二甲基苄基銨(C12)的添加量為0.0012g之點以外,係與上述處方1同樣地進行而製備。
(試驗方法)
保存效力試驗係依據第十五版日本藥典(以下簡稱為「日本藥典」)之保存效力試驗法來進行,在本試驗中,使用Esherichia Coli(E.coli)、Pseudormonas aeruginosa(P.aeruginosa)、Staphylococcus aureus(S.aureus)、Candida al bicans(C.albicans)及Aspergillus niger(A.niger)作為試驗菌。
(試驗結果)
將試驗結果顯示在表1,表1中,「N.D.」表示未檢測出菌。
(考察)
如表1所示,玻尿酸鈉點眼液在0.0025%(w/v)氯化烷基二甲基苄基銨存在下所容許的pH範圍內(pH6.0及7.0)中,滿足「日本藥典參考資訊保存效力試驗分類IA」的判定基準,在0.002%(w/v)氯化烷基二甲基苄基銨存在
下pH6.0中未滿足相同判定基準,不具有充分的保存效力係變得顯而易見。接著,在0.25%(w/v)丙二醇存在下,經評價保存效力變得更弱的pH6.0的保存效力,在0.1%(w/v)玻尿酸鈉點眼液中,在氯化烷基二甲基苄基銨濃度0.0012%(w/v)下滿足「日本藥典參考資訊保存效力試驗分類IA」的判定基準,又,在0.3%(w/v)玻尿酸鈉點眼液中,即使在氯化烷基二甲基苄基銨濃度0.001%(w/v)下亦滿足相同基準,各自具有充分的保存效力系變得明顯。從以上顯示,在玻尿酸點眼液中,藉由添加丙二醇,即使將氯化烷基二甲基苄基銨濃度設為0.002%(w/v)以下,亦可取得充分的保存效力。
[動黏度測定試驗]
為了確認將摻合丙二醇之玻尿酸點眼液的滲透壓比調整至0.9~1.1時的該點眼液的動黏度,進行動黏度測定試驗。
(試料製備)
<比較處方>
將玻尿酸鈉0.3g、ε-胺己酸0.2g、氯化鈉0.8g、氯化烷基二甲基苄基銨(C12)0.0015g及乙二胺四乙酸鈉水合物0.01g溶解於水中並使其成為100mL,將添加稀鹽酸及/或氫氧化鈉而成為pH6.5、滲透壓比1.0者設為比較處方。
<處方1~5>
除了適當變化氯化鈉與丙二醇的添加量將滲透壓比調整至1.0的點(參照表2)以外,係與上述比較處方同樣地進行而製備。
(試驗方法)
Hyalein interview form的4頁中已記載0.3%(w/v)玻尿酸鈉點眼液的滲透壓比及動黏度的容許幅度各自為「0.9~1.1」及「17~30mm2/s」,於是使用丙二醇及離子性等滲壓劑將玻尿酸鈉點眼液的滲透壓比調整為「0.9~1.1」後,測定該點眼液的動黏度。再者,動黏度測定試驗係依據「日本藥典一般試驗法黏度測定法第1法毛細管黏度計法」,測定測定溫度30℃中的動黏度。又,滲透壓比係依據「日本藥典一般試驗法滲透壓測定法」,使用自動滲透壓分析裝置(ARKRAY公司製)進行測定。
(結果)
將結果顯示於表2。
(考察)
由表2可明顯得知,當丙二醇的摻合濃度為1%(w/v)以下時,0.3%(w/v)玻尿酸鈉點眼液的動黏度會在容許範圍內(17~30mm2/s),另一方面,在這以上的濃度時,則
表示超出動黏度的容許範圍。又,根據上述結果,若丙二醇的摻合濃度為1%(w/v)以下,則推測0.1%(w/v)玻尿酸鈉點眼液的動黏度亦在容許範圍內(3.0~4.0mm2/s)。根據上述,摻合丙二醇至玻尿酸點眼液時,顯示有將其摻合濃度設為1.0%(w/v)以下之必要性。
[滴液確認試驗]
為了確認丙二醇對玻尿酸點眼液的滴液帶來的影響,進行滴液確認試驗。
(試劑製備)
‧未含有丙二醇之處方
使用市售的「Hyalein(註冊商標)點眼液0.1%」。
‧含有丙二醇之處方
將玻尿酸鈉(0.1g)、緩衝劑(ε-胺己酸)、氯化鈉、丙二醇、氯化烷基二甲基苄基銨(C12)及乙二胺四乙酸鈉水合物溶解於水中並使其成為100mL(滲透壓比:0.9~1.1),添加稀鹽酸及/或氫氧化鈉使其成為pH6.5。
(試驗方法)
填充未含有丙二醇之處方或含有丙二醇之處方5mL至聚乙烯製點眼容器,健康的人5名實施6次於點眼時進行相同的操作。每次操作時,評估滴液(點眼液從點眼容器的頂端沿著外部流下的現象)是否產生。
(結果)
將結果表示於表3。
(考察)
由表3可明顯得知,相對於在未含有丙二醇之處方中有滴液的情形,在含有丙二醇之處方中完全未觀察到滴液。從以上顯示在本點眼液中,相較於以往未摻合丙二醇的玻尿酸點眼液,已改善滴液性。
[角膜上皮細胞保護作用確認試驗]
為了探討研究含有丙二醇之玻尿酸點眼液對因乾燥負荷造成的角膜上皮細胞損傷帶來的影響,進行角膜上皮細胞保護作用確認試驗。
(試驗方法)
將SV40-不死化人類角膜上皮細胞(SV40-immortalized human corneal epithelial cell):(HCE-T:理化學研究所、BioResource Center、Cell No.:RCB2280)接種於96孔盤(1×104細胞/孔),在SHEM培養基中培養1天。翌日,將培養基與含有0.25%(w/v)丙二醇、0.03%(w/v)玻尿酸鈉或0.25%(w/v)丙二醇及0.03%(w/v)玻尿酸鈉之D-MEM/F12培養基交換後,培養前述角膜上皮細胞1小時(以下各自稱為「丙二醇單獨群組」、「玻尿酸單獨群組
」或「丙二醇/玻尿酸併用群組」)。再者,與不含有試驗物質之D-MEM/F12培養基交換後,將培養前述角膜上皮細胞1小時的群組作為「基劑群組」。培養後,將各群組的培養基與不含有試驗物質之D-MEM/F12培養基交換後,進行乾燥負荷7.5分鐘。負荷後,使用細胞增生分析套組(Cell Proliferation Assay Kit)(Promega公司製、型錄編號:G3580)來測定活細胞活性(相當於490nm的吸光度)。
(結果)
將試驗結果顯示於第1圖。
(考察)
由第1圖可清楚得知,因乾燥負荷所造成的角膜上皮細胞的活細胞活性的降低(參照基劑群組)係在丙二醇或玻尿酸的單獨處置中無法充分地被抑制(參照丙二醇單獨群組、玻尿酸單獨群組)。另一方面,在丙二醇/玻尿酸鈉併用群組中,驚人的是確認有可有意地抑制該活細胞活性的降低。根據以上的結果,含有丙二醇之玻尿酸點眼液被認為具有保護因乾燥角膜上皮細胞的作用。
[製劑例]
列舉製劑例以進一步具體說明本發明的藥劑,然而本發明並不僅限於此等製劑例。
(處方例1)
可藉由將玻尿酸鈉及其以外的上述成分加入至滅菌純化水,並將該等充分混合,而製備為pH6.0~7.0、滲透壓比0.9~1.1的0.1%(w/v)玻尿酸鈉點眼液。
(處方例2)
可藉由將玻尿酸鈉及其以外的上述成分加入至滅菌純化水,並將該等充分混合,而製備為pH6.0~7.0、滲透壓比0.9~1.1的0.3%(w/v)玻尿酸鈉點眼液。
本發明的玻尿酸點眼液雖然在該點眼液中的
氯化烷基二甲基苄基銨濃度為0.002%(w/v)以下,但是可藉由含有丙二醇而取得充分的保存效力,另一方面,亦具有作為玻尿酸點眼液所容許的滲透壓比及動黏度。再者,由於本發明的玻尿酸點眼液兼具難以滴液而且保護因乾燥角膜上皮細胞之效果,期待成為可更有效地治療乾眼症的點眼液。
Claims (7)
- 一種點眼液,其係含有0.03~0.5%(w/v)之濃度的玻尿酸或其鹽及0.1~1.0%(w/v)之濃度的丙二醇之水性點眼液,該點眼液係含有0.001~0.0015%(w/v)之濃度的氯化烷基二甲基苄基銨作為唯一的防腐劑且含有將該點眼液的滲透壓比設為0.9~1.1之濃度的離子性等滲壓劑(isotonizing agent)。
- 如請求項1之點眼液,其係含有將該點眼液的pH設為6.0~7.0之量的緩衝劑及pH調節劑。
- 如請求項1或2之點眼液,其係含有0.001~0.1%(w/v)之濃度的乙二胺四乙酸鹽(edentate)。
- 如請求項1之點眼液,其中玻尿酸或其鹽的濃度為0.1~0.3%(w/v)。
- 如請求項1之點眼液,其中丙二醇的濃度為0.25~0.75%(w/v)。
- 一種水性點眼液,其係實質上由0.03~0.5%(w/v)之濃度的玻尿酸或其鹽、0.1~1.0%(w/v)之濃度的丙二醇、0.001~0.0015%(w/v)之濃度的氯化烷基二甲基苄基銨、將點眼液的滲透壓比設為0.9~1.1之濃度的離子性等滲壓劑、將點眼液的pH設為6.0~7.0之量的緩衝劑及pH調節劑、以及0.001~0.1%(w/v)之濃度的乙二胺四乙酸鹽所構成。
- 如請求項6之點眼液,其中玻尿酸或其鹽的濃度為0.1~0.3%(w/v),丙二醇的濃度為0.25~0.75%(w/v)。
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CN1486188A (zh) * | 2000-11-08 | 2004-03-31 | ʵ | 改进的含有单糖类作为防腐增强剂的眼科和隐形眼镜用溶液 |
JP2003002837A (ja) * | 2001-06-21 | 2003-01-08 | Lion Corp | 水性外用剤組成物及び液体組成物の白濁防止方法 |
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MX2013015273A (es) | 2014-04-14 |
EP2684560A4 (en) | 2014-08-06 |
CN103608000B (zh) | 2016-05-11 |
BR112013033060A2 (pt) | 2017-01-24 |
AU2017203905A1 (en) | 2017-06-29 |
KR20140041586A (ko) | 2014-04-04 |
CA2839822A1 (en) | 2012-12-27 |
EA025078B1 (ru) | 2016-11-30 |
AU2017203905B2 (en) | 2019-07-11 |
TW201309306A (zh) | 2013-03-01 |
JP2013028599A (ja) | 2013-02-07 |
EP2684560A1 (en) | 2014-01-15 |
NZ618822A (en) | 2015-07-31 |
WO2012176865A1 (ja) | 2012-12-27 |
KR101906631B1 (ko) | 2018-10-10 |
TW201742620A (zh) | 2017-12-16 |
EA201490127A1 (ru) | 2014-04-30 |
SG10201605080VA (en) | 2016-08-30 |
HK1190089A1 (zh) | 2014-06-27 |
JP5981783B2 (ja) | 2016-08-31 |
MY176112A (en) | 2020-07-24 |
US20140088039A1 (en) | 2014-03-27 |
AU2012274367A1 (en) | 2014-01-23 |
MX345216B (es) | 2017-01-18 |
CN103608000A (zh) | 2014-02-26 |
GEP20166459B (en) | 2016-04-11 |
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