TW202241448A - 含有依匹斯汀(epinastine)或其鹽及硫系抗氧化劑之經皮投與用醫藥組合物 - Google Patents
含有依匹斯汀(epinastine)或其鹽及硫系抗氧化劑之經皮投與用醫藥組合物 Download PDFInfo
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- TW202241448A TW202241448A TW110148511A TW110148511A TW202241448A TW 202241448 A TW202241448 A TW 202241448A TW 110148511 A TW110148511 A TW 110148511A TW 110148511 A TW110148511 A TW 110148511A TW 202241448 A TW202241448 A TW 202241448A
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- Prior art keywords
- pharmaceutical composition
- epinastine
- salt
- acid
- present
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 148
- 150000003839 salts Chemical class 0.000 title claims abstract description 87
- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 title claims abstract description 85
- 229960003449 epinastine Drugs 0.000 title claims abstract description 67
- 239000003963 antioxidant agent Substances 0.000 title claims abstract description 59
- 230000003078 antioxidant effect Effects 0.000 title claims abstract description 39
- 229910052717 sulfur Inorganic materials 0.000 title claims abstract description 29
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 239000011593 sulfur Substances 0.000 title claims abstract description 28
- 239000003921 oil Substances 0.000 claims description 26
- YHMYGUUIMTVXNW-UHFFFAOYSA-N 1,3-dihydrobenzimidazole-2-thione Chemical compound C1=CC=C2NC(S)=NC2=C1 YHMYGUUIMTVXNW-UHFFFAOYSA-N 0.000 claims description 22
- 210000000744 eyelid Anatomy 0.000 claims description 16
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Abstract
本發明提供一種能夠維持眼組織中之有效濃度、且長時間維持穩定性之含有依匹斯汀或其鹽及硫系抗氧化劑之經皮投與用醫藥組合物。
Description
本發明係關於一種含有依匹斯汀或其鹽及硫系抗氧化劑之經皮投與用醫藥組合物(以下亦稱為「本發明之醫藥組合物」)。
醫藥品為了確保有效性及安全性而強制要求嚴格之管理。例如於「與含有新有效成分之醫藥品中製劑之雜質相關之準則」中,為了確保醫藥品之品質,而規定對於在新製劑之製造中或穩定性試驗中所見之分解產物(原料藥之分解產物或原料藥與醫藥品添加物或直接與容器/封蓋系統反應之產物),確定其量之限度值(閾值),若超過該值,則需要確定分解產物之結構、進而確認分解產物之安全性等。因此,於醫藥品之開發中,於其製造中或保存中需要以生成之分解產物不超過閾值之方式管理配方設計及製造步驟。
作為含有依匹斯汀或其鹽之醫藥品,例如作為過敏性結膜炎治療劑,有以依匹斯汀鹽酸鹽作為有效成分之Alesion
( 註冊商標 )滴眼液0.05%,通常以1次1滴、1天4次滴眼之用法、劑量使用(非專利文獻1)。於滴眼液中,就服藥依從性之觀點而言,認為較理想為減少滴眼次數,但若減少滴眼次數,則存在無法維持眼組織中之有效濃度而降低藥效之可能性,為了發揮藥效,需要維持眼組織中之有效濃度。作為維持眼組織中之有效濃度之方法,有增大有效成分之調配濃度之方法,但若增大有效成分之調配濃度,則存在產生副作用之風險提高之可能性。因此,近年來,嘗試藉由選擇滴眼以外之投與方法,而維持眼組織中之有效濃度。
例如專利文獻1中記載有一種眼疾治療用經皮吸收型製劑,其具有於支持體上設置有含有眼疾治療藥之膏體層之結構,用於貼附於包括眼瞼之前表面在內之皮膚表面,將膏體層中之眼疾治療藥實質上不經由全身血流而藉由皮膚透過投與至眼之局部組織。又,關於依匹斯汀或其鹽,亦報告有眼科用經皮吸收型製劑作為滴眼液以外之製劑(專利文獻2)。
[先前技術文獻]
[專利文獻]
[專利文獻1]WO2004/064817
[專利文獻2]WO2007/007851
[非專利文獻]
[非專利文獻1]Alesion
( 註冊商標 )滴眼液0.05%附錄
[發明所欲解決之問題]
於含有依匹斯汀或其鹽之醫藥品中,已知水性滴眼劑中之依匹斯汀或其鹽之穩定性良好,另一方面,於其他劑型、例如經皮吸收型製劑中,長時間維持依匹斯汀或其鹽之穩定性較為困難目前尚屬未知。因此,尚未報告維持經皮吸收型製劑中之依匹斯汀或其鹽之穩定性之方法。
因此,深感興趣之課題在於提供一種能夠維持眼組織中之有效濃度、且長時間維持穩定性之含有依匹斯汀或其鹽作為有效成分之新醫藥組合物。
[解決問題之技術手段]
本發明人等於對含有依匹斯汀或其鹽之新醫藥組合物進行銳意研究之過程中發現,於製備含有依匹斯汀或其鹽之醫藥組合物作為經皮吸收型製劑時,與水性滴眼劑中之穩定性相反,令人驚訝的是依匹斯汀或其鹽之類似物質作為雜質而產生,而難以長時間維持其穩定性。進一步進行了銳意研究,結果發現,藉由在含有依匹斯汀或其鹽之經皮投與用醫藥組合物中添加抗氧化劑、具體而言為硫系抗氧化劑,即便於長期保存下亦可抑制類似物質之產生、增加,而於該醫藥組合物中能夠長時間維持依匹斯汀或其鹽之穩定性,從而完成本發明。
具體而言,本發明提供以下。
(1)一種經皮投與用醫藥組合物,其含有依匹斯汀或其鹽及硫系抗氧化劑。
(2)如(1)所記載之醫藥組合物,其中硫系抗氧化劑為選自由半胱胺酸、N-乙醯半胱胺酸、甲硫胺酸、麩胱甘肽、2-巰基苯并咪唑、硫代蘋果酸鈉、硫代甘油、硫代乙醇酸鈉、硫代硫酸鈉、亞硫酸氫鈉及亞硫酸鈉所組成之群中之1種以上。
(3)如(2)所記載之醫藥組合物,其中硫系抗氧化劑為2-巰基苯并咪唑。
(4)如(1)至(3)中任一項所記載之醫藥組合物,其為0.01~5%(w/w)濃度之依匹斯汀或其鹽。
(5)如(1)至(4)中任一項所記載之醫藥組合物,其為軟膏劑、乳霜劑或凝膠劑。
(6)如(5)所記載之醫藥組合物,其為乳霜劑。
(7)如(1)至(6)中任一項所記載之醫藥組合物,其為油包水型乳液。
(8)如(1)至(7)中任一項所記載之醫藥組合物,其係用於眼科。
(9)如(1)至(8)中任一項所記載之醫藥組合物,其中經皮投與為對眼瞼皮膚之投與。
(10)如(1)至(9)中任一項所記載之醫藥組合物,其係用於治療過敏性結膜炎。
(11)如(1)至(10)中任一項所記載之醫藥組合物,其特徵在於:以對患者1天投與1次之方式使用。
(12)一種醫藥組合物,其係含有依匹斯汀或其鹽及硫系抗氧化劑之經皮投與用醫藥組合物,且進而含有選自由烴、蠟、油脂、脂肪族羧酸或其鹽、脂肪酸酯及高級醇所組成之群中之1種以上油成分。
(13)如(12)所記載之醫藥組合物,其進而含有溶劑及/或分散介質。
(14)如(12)或(13)所記載之醫藥組合物,其不含對羥基苯甲酸酯。
進而,本發明提供以下。
(15)如(1)至(14)中任一項所記載之醫藥組合物,其中依匹斯汀或其鹽為依匹斯汀。
(16)如(1)至(14)中任一項所記載之醫藥組合物,其中硫系抗氧化劑為0.01~2%(w/w)。
(17)如(1)至(13)中任一項所記載之醫藥組合物,其不含防腐劑。
(18)一種方法,其係藉由使含有依匹斯汀或其鹽之經皮投與用醫藥組合物含有硫系抗氧化劑,而抑制依匹斯汀或其鹽之類似物質之產生及增加。
(19)一種方法,其係藉由使含有依匹斯汀或其鹽之經皮投與用醫藥組合物含有硫系抗氧化劑,而提高醫藥組合物中之依匹斯汀或其鹽之穩定性。
(20)一種過敏性結膜炎之治療方法,其特徵在於:對需要治療之患者投與治療上之有效量之如(1)至(17)中任一項所記載之醫藥組合物。
(21)一種如(1)至(17)中任一項所記載之醫藥組合物之用途,其係用以製造用於治療過敏性結膜炎之醫藥。
(22)一種經皮投與用醫藥組合物,其含有依匹斯汀或其鹽及抗氧化劑。
再者,上述(1)至(22)之各構成可任意選擇兩者以上加以組合。
[發明之效果]
根據本發明,可提供一種於眼組織中依匹斯汀或其鹽之有效濃度得以維持、進而使醫藥組合物中之依匹斯汀或其鹽長期穩定之含有依匹斯汀或其鹽作為有效成分之經皮投與用醫藥組合物。又,本發明之醫藥組合物作為醫藥品而具有充分之安全性。
以下,對本發明進行詳細說明。
於本發明之醫藥組合物中,所含有之依匹斯汀可為外消旋體,亦可為光學異構物。
於本發明之醫藥組合物中,所含有之依匹斯汀可為鹽,只要為作為醫藥所容許之鹽,則無特別限制。作為鹽,例如可例舉:與無機酸之鹽、與有機酸之鹽等。
作為與無機酸之鹽,可例舉:與鹽酸、氫溴酸、氫碘酸、硝酸、硫酸、磷酸等之鹽。
作為與有機酸之鹽,可例舉:與乙酸、草酸、富馬酸、馬來酸、琥珀酸、蘋果酸、檸檬酸、酒石酸、己二酸、葡萄糖酸、葡庚糖酸、葡萄糖醛酸、對苯二甲酸、甲磺酸、丙胺酸、乳酸、馬尿酸、1,2-乙二磺酸、羥乙磺酸、乳糖酸、油酸、沒食子酸、雙羥萘酸、聚半乳糖醛酸、硬脂酸、鞣酸、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、磺基水楊酸等之鹽。
作為依匹斯汀之鹽,尤佳為一鹽酸鹽(依匹斯汀鹽酸鹽)。
於本發明之醫藥組合物中,所含有之依匹斯汀或其鹽亦可採用水合物或溶劑合物之形態。
於製備本發明之醫藥組合物之情形時,該醫藥組合物中之依匹斯汀之形態可為依匹斯汀之鹽,但為了更高效地提高經皮吸收性,更佳為游離形之依匹斯汀。於本發明之醫藥組合物之製造步驟中,可使用游離形之依匹斯汀製備醫藥組合物,亦可使用依匹斯汀之鹽(例如依匹斯汀鹽酸鹽)與適量之鹼(例如氫氧化鈉),於步驟中進行脫鹽,而使該醫藥組合物中產生游離形之依匹斯汀。
於本發明之醫藥組合物中,依匹斯汀或其鹽之含量只要為對於發揮作為醫藥所需之治療效果而言充分之量,則無特別限制,較佳為0.01~5%(w/w),更佳為0.03~3%(w/w),進而較佳為0.05~1%(w/w),進而更佳為0.05~0.5%(w/w),尤佳為0.1~1%(w/w)。又,依匹斯汀或其鹽之含量亦較佳為0.01%(w/w)、0.03%(w/w)、0.05%(w/w)、0.1%(w/w)、0.2%(w/w)、0.25%(w/w)、0.3%(w/w)、0.4%(w/w)、0.5%(w/w)、0.6%(w/w)、0.7%(w/w)、0.75%(w/w)、0.8%(w/w)、0.9%(w/w)、1%(w/w)、1.5%(w/w)、2%(w/w)、3%(w/w)、5%(w/w)。
再者,於本發明中,「%(w/w)」意指本發明之醫藥組合物100 g中所含之對象成分之質量(g)。於本發明中,於含有依匹斯汀之鹽之情形時,該值為依匹斯汀之鹽之含量。又,於本發明中,於依匹斯汀或其鹽採用水合物或溶劑合物之形態進行調配之情形時,該值為依匹斯汀或其鹽之水合物或溶劑合物之含量。以下,只要無特別說明,則為同樣。
於本發明中,「抗氧化劑」並無特別限定,只要為通常之醫藥品中用作添加劑者即可。作為抗氧化劑,例如可例舉:抗壞血酸、生育酚或其衍生物、沒食子酸丙酯、二丁基羥基甲苯(以下亦稱為「BHT」)、半胱胺酸、N-乙醯半胱胺酸、甲硫胺酸、麩胱甘肽、2-巰基苯并咪唑(以下亦稱為「MBI」)、硫代蘋果酸鈉、硫代甘油、硫代乙醇酸鈉、硫代硫酸鈉、亞硫酸氫鈉、亞硫酸鈉等。本發明中之抗氧化劑較佳為硫系抗氧化劑。於本發明之醫藥組合物中,所含有之抗氧化劑可為鹽之形態,亦可採用水合物或溶劑合物或者鹽之水合物或溶劑合物之形態。又,於所含有之抗氧化劑具有手性中心之情形時,該等可為外消旋體,亦可為光學異構物。
於本發明中,「硫系抗氧化劑」意指於分子內具有硫原子之抗氧化劑,亦稱為硫系氧化防止劑。作為硫系抗氧化劑,例如可例舉:半胱胺酸、N-乙醯半胱胺酸、甲硫胺酸、麩胱甘肽、2-巰基苯并咪唑(MBI)、硫代蘋果酸鈉、硫代甘油、硫代乙醇酸鈉、硫代硫酸鈉、亞硫酸氫鈉、亞硫酸鈉等,亦可為該等之水合物或溶劑合物。尤佳為2-巰基苯并咪唑。
於本發明之醫藥組合物中,亦可一起使用1種或2種以上之硫系抗氧化劑。
本發明之醫藥組合物除了硫系抗氧化劑以外,可適當調配硫系抗氧化劑以外之抗氧化劑。作為該等抗氧化劑,例如可例舉:抗壞血酸、生育酚或其衍生物、沒食子酸丙酯、二丁基羥基甲苯(BHT)等。
於在本發明之醫藥組合物中調配該等抗氧化劑之情形時,可一起使用1種或2種以上之該抗氧化劑。
於本發明之醫藥組合物中所調配之硫系抗氧化劑之含量以及硫系抗氧化劑及硫系以外之抗氧化劑之含量可根據抗氧化劑之數量或種類等適當調整,例如為0.01~2%(w/w),較佳為0.03~1.5%(w/w),更佳為0.05~1%(w/w),進而較佳為0.05~0.5%(w/w)。
於本發明之醫藥組合物中,於使用2-巰基苯并咪唑作為硫系抗氧化劑之情形時,由於該化合物為難溶於水之化合物,故而其含量較佳為0.5%(w/w)以下。又,為了發揮抗氧化作用,其含量較佳為0.01%(w/w)以上。作為於本發明之醫藥組合物中所調配之2-巰基苯并咪唑之含量,較佳為0.01~0.5%(w/w),更佳為0.03~0.3%(w/w),進而較佳為0.05~0.3%(w/w)。例如,其含量亦可為0.05%(w/w)、0.1%(w/w)、0.15%(w/w)、0.2%(w/w)、0.25%(w/w)或0.3%(w/w)。
本發明之醫藥組合物可局部應用,例如可製備用於眼科、耳鼻科或皮膚科。本發明之醫藥組合物尤佳為眼科用經皮吸收型製劑。
本發明之醫藥組合物之劑型只要為可用作醫藥品者,則無特別限制,例如可例舉:軟膏劑、乳霜劑、凝膠劑、貼附劑(貼劑、敷劑)、噴霧劑(例如泵壓噴霧劑、外用氣溶膠劑)、外用液劑(例如洗劑、擦劑)、外用固體劑(例如外用散劑)等。本發明之醫藥組合物較佳為軟膏劑、乳霜劑、凝膠劑、貼附劑、噴霧劑及外用液劑,更佳為軟膏劑、乳霜劑及凝膠劑,尤佳為乳霜劑。
該等可依照該技術領域中之通常之方法而製造。
於使用本發明之醫藥組合物作為眼科用經皮吸收型製劑之情形時,較佳為將本發明之醫藥組合物投與至眼之附近。「眼之附近」係上眼瞼、下眼瞼等眼瞼及其附近、或眼窩之周圍,亦包括眼瞼皮膚及其附近之皮膚、或眼窩周圍之皮膚。對眼之附近之投與例如包括對上眼瞼、下眼瞼或其兩者之眼瞼皮膚及其附近之塗敷或貼附、或對眼窩周圍之皮膚之塗敷或貼附。再者,眼瞼緣可包括於眼之附近,但由於因眨眼使得投與至眼瞼緣之醫藥組合物之一部分接觸敏感之眼表面導致容易產生眼刺激性之可能性提高,故而更佳為不對眼瞼緣投與。
本發明之醫藥組合物可視需要使用醫藥品之添加劑,例如可添加pH值調節劑、緩衝劑、等張劑、增稠劑、穩定劑、防腐劑、界面活性劑、清涼劑、油成分等。該等可分別單獨使用,又,可適當組合2種以上使用,可調配適量。
於本發明之醫藥組合物中調配pH值調節劑之情形時之pH值調節劑可適當調配能夠用作醫藥品之添加劑之pH值調節劑。作為pH值調節劑,例如為酸或鹼。作為酸,例如可例舉:鹽酸、磷酸、乙酸、檸檬酸、該等之鹽等,作為鹼,例如可例舉:氫氧化鈉、氫氧化鉀、碳酸鈉、碳酸氫鈉等。又,該等亦可為水合物或溶劑合物。
本發明之醫藥組合物之pH值處於作為醫藥品所容許之範圍內即可,例如為4.0~8.5或4.0~8.0之範圍內,較佳為6.0~8.0,更佳為6.5~7.5。尤佳之pH值為6.7~7.3。例如該pH值亦可為6.7、6.8、6.9、7.0、7.1、7.2或7.3。
於本發明之醫藥組合物中調配緩衝劑之情形時之緩衝劑可適當調配能夠用作醫藥品之添加劑之緩衝劑。作為緩衝劑,例如可例舉:磷酸或其鹽、硼酸、硼砂、胺丁三醇、有機酸或其鹽等,亦可為該等之水合物或溶劑合物。
作為磷酸或其鹽,例如可例舉:磷酸、磷酸鈉、磷酸二氫鈉、磷酸氫二鈉、磷酸鉀、磷酸二氫鉀、磷酸氫二鉀等。
作為有機酸,例如可例舉:檸檬酸、乙酸、ε-胺基己酸、葡萄糖酸、富馬酸、乳酸、抗壞血酸、琥珀酸、馬來酸、蘋果酸、胺基酸類等,作為其鹽,例如可例舉:鈉鹽、鉀鹽等。
於本發明之醫藥組合物中調配緩衝劑之情形時之緩衝劑之含量可根據緩衝劑之種類等而適當調整,例如為0.01~5%(w/w),於亦具有緩衝劑以外之作用之情形時不限於此。又,於在本發明之醫藥組合物中調配緩衝劑之情形時,可一起使用1種或2種以上之緩衝劑。
於本發明之醫藥組合物中所調配之磷酸或其鹽及有機酸或其鹽存在具有作為pH值調節劑及緩衝劑之作用之情況。
於本發明之醫藥組合物中調配等張劑之情形時之等張劑可適當調配能夠用作醫藥品之添加劑之等張劑。作為等張劑,例如可例舉:離子性等張劑、非離子性等張劑等。
作為離子性等張劑,例如可例舉:氯化鈉、氯化鉀、氯化鈣、氯化鎂等,亦可為該等之水合物或溶劑合物。
作為非離子性等張劑,例如可例舉:甘油(濃甘油)、丙二醇、1,3-丁二醇、聚乙二醇、山梨醇、甘露醇、海藻糖、麥芽糖、蔗糖、木糖醇等,亦可為該等之水合物或溶劑合物。
於本發明之醫藥組合物中調配等張劑之情形時之等張劑之含量可根據等張劑之種類等而適當調整,例如為0.01~5%(w/w),較佳為0.05~3%(w/w),更佳為0.1~2%(w/w),進而較佳為0.1~1%(w/w),於亦具有等張劑以外之作用之情形時不限於此。又,於在本發明之醫藥組合物中調配等張劑之情形時,可一起使用1種或2種以上之等張劑。
於本發明之醫藥組合物中調配增稠劑之情形時之增稠劑可適當調配能夠用作醫藥品之添加劑之增稠劑。作為增稠劑,例如可例舉:甲基纖維素、乙基纖維素、羥甲基纖維素、羥乙基纖維素、羥丙基纖維素、羥乙基甲基纖維素、羥丙基甲基纖維素、羧甲基纖維素、羧甲基纖維素鈉、乙酸羥丙基甲基纖維素琥珀酸酯、羥丙基甲基纖維素鄰苯二甲酸酯、羧甲基乙基纖維素、乙酸鄰苯二甲酸纖維素、聚乙烯吡咯啶酮、聚乙烯醇、羧基乙烯基聚合物、聚乙二醇、玻尿酸鈉等,亦可為該等之水合物或溶劑合物。
於本發明之醫藥組合物中調配增稠劑之情形時之增稠劑之含量可根據增稠劑之種類等而適當調整,例如為0.01~20%(w/w),較佳為0.1~10%(w/w),更佳為1~10%(w/w),於亦具有增稠劑以外之作用之情形時不限於此。又,若本發明之醫藥組合物之劑型為凝膠劑,則例如亦可含有20%(w/w)以上。又,於在本發明之醫藥組合物中調配增稠劑之情形時,可一起使用1種或2種以上之增稠劑。
於本發明之醫藥組合物中調配穩定劑之情形時之穩定劑可適當調配能夠用作醫藥品之添加劑之穩定劑。作為穩定劑,例如可例舉:乙二胺四乙酸或其鹽、環糊精等,亦可為該等之水合物或溶劑合物。
作為乙二胺四乙酸或其鹽,例如可例舉:乙二胺四乙酸、乙二胺四乙酸二鈉(乙二胺四乙酸鈉)、乙二胺四乙酸四鈉等。
於本發明之水性醫藥組合物中調配穩定劑之情形時之穩定劑之含量可根據穩定劑之種類等而適當調整,例如為0.01~5%(w/w),較佳為0.01~3%(w/w),更佳為0.01~1%(w/w),於亦具有穩定劑以外之作用之情形時不限於此。又,於在本發明之醫藥組合物中調配穩定劑之情形時,可一起使用1種或2種以上之穩定劑。
於本發明之醫藥組合物中調配防腐劑之情形時之防腐劑可適當調配能夠用作醫藥品之添加劑之防腐劑,例如可例舉:氯化苄烷銨、溴化苄烷銨、苄索氯銨、葡萄糖酸洛赫西定、鹽酸洛赫西定、對羥基苯甲酸酯、亞氯酸鈉、苯氧基乙醇、瑞香草酚、山梨酸或氯丁醇等。
作為對羥基苯甲酸酯,可例舉:對羥基苯甲酸甲酯、對羥基苯甲酸乙酯、對羥基苯甲酸丙酯等。
於本發明之醫藥組合物中調配防腐劑之情形時之防腐劑之含量可根據防腐劑之種類等而適當調整,例如為0.001~1%(w/w)。又,於在本發明之醫藥組合物中調配防腐劑之情形時,可一起使用1種或2種以上之防腐劑。
於本發明之醫藥組合物即便不含防腐劑亦可發揮醫藥品所要求之防腐效能之情形時,較佳為不調配防腐劑,例如較佳為不調配對羥基苯甲酸酯。醫藥品所要求之防腐效能例如按照日本藥典第十七修訂版中各製劑區分確定判定基準,各製劑只要滿足該判定基準,則認為具有防腐效能。再者,依匹斯汀或其鹽根據調配濃度而發揮防腐效能,因此本發明之醫藥組合物根據該製劑之種類,即便不調配防腐劑,亦可發揮所需之防腐效能。所需之防腐效能例如係指適配於日本藥典第十七修訂版所記載之防腐效能試驗法。又,藉由不含防腐劑,可降低經皮投與本發明之醫藥組合物之情形時之刺激性。
於本發明之醫藥組合物中調配界面活性劑之情形時之界面活性劑可適當調配能夠用作醫藥品之添加劑之界面活性劑。作為界面活性劑,例如可例舉:陽離子性界面活性劑、陰離子性界面活性劑、非離子性界面活性劑等。
作為陽離子性界面活性劑,例如可例舉:烷基胺鹽、烷基胺聚氧乙烯加成物、脂肪酸三乙醇胺單酯鹽、醯基胺基乙基二乙胺鹽、脂肪酸多胺縮合物、烷基咪唑啉、1-醯基胺基乙基-2-烷基咪唑啉、1-羥基乙基-2-烷基咪唑啉等。
作為陰離子性界面活性劑,例如可例舉:烷基苯磺酸鈉、十二烷基硫酸鈉、卵磷脂等磷脂質等。
作為非離子性界面活性劑,例如可例舉:硬脂酸聚烴氧40等聚氧乙烯脂肪酸酯;山梨醇酐硬脂酸酯等山梨醇酐脂肪酸酯;聚山梨糖醇酯80等聚氧乙烯山梨醇酐脂肪酸酯;聚氧乙烯氫化蓖麻油60等聚氧乙烯氫化蓖麻油;聚烴氧35蓖麻油等聚烴氧蓖麻油;聚氧乙烯(20)聚氧丙烯(20)等聚氧乙烯聚氧丙烯二醇;聚氧乙烯(20)聚氧丙烯(4)鯨蠟基醚等聚氧乙烯聚氧丙烯鯨蠟基醚;聚氧乙烯鯨蠟基醚;聚氧乙烯月桂醚;聚氧乙烯山萮醚;月桂酸甘油酯、月桂酸聚甘油酯、棕櫚酸甘油酯、棕櫚酸聚甘油酯、硬脂酸甘油酯(單硬脂酸甘油酯)、硬脂酸聚甘油酯、油酸甘油酯(單油酸甘油酯)、油酸聚甘油酯、亞麻油酸甘油酯、亞麻油酸聚甘油酯、次亞麻油酸甘油酯、次亞麻油酸聚甘油酯、蓖麻油酸甘油酯、蓖麻油酸聚甘油酯、縮合蓖麻油酸聚甘油酯(亦稱為聚蓖麻油酸聚甘油酯、縮合蓖麻醇酸聚甘油酯或聚蓖麻醇酸聚甘油酯)等甘油脂肪酸酯;蔗糖硬脂酸酯等蔗糖脂肪酸酯等。
於本發明之醫藥組合物中調配界面活性劑之情形時之界面活性劑之含量可根據界面活性劑之種類等而適當調整,例如為0.1~20%(w/w),較佳為0.5~10%(w/w),更佳為1~5%(w/w),於亦具有界面活性劑以外之作用之情形時不限於此。又,於在本發明之醫藥組合物中調配界面活性劑之情形時,可一起使用1種或2種以上之界面活性劑,又,亦可以2種以上界面活性劑之混合物之形式使用。
界面活性劑藉由該等分子之親水性部分與親油性部分之平衡而被賦予特性,具有親水性-親油性平衡(HLB)數。HLB伴隨親水性之增加而增加,即便成分名相同,亦存在因製造公司導致HLB不同之情況。
關於在本發明之醫藥組合物中調配界面活性劑之情形時之界面活性劑之HLB,只要可作為塗敷投與用之製劑而製備,則無特別限制,例如為1~20,較佳為1.0~10.0,更佳為2.0~8.0,進而較佳為3.0~6.0。
於本發明之醫藥組合物中調配清涼劑之情形時之清涼劑可適當調配能夠用作醫藥品之添加劑之清涼劑。作為清涼劑,例如可例舉:類萜、含有類萜之精油等。
作為類萜,例如可例舉:薄荷腦、樟腦、龍腦、香葉草醇、橙花醇、桉樹腦、香茅醇、香旱芹酮、大茴香腦、丁香油酚、檸檬烯、沈香醇、乙酸沈香酯等,可為d體、l體及dl體之任一者。
作為含有類萜之精油,例如可例舉:桉葉油、香柑油、胡椒薄荷油、茴香油、玫瑰油、桂皮油、綠薄荷油、樟腦油、涼薄荷、薄荷油等。
於本發明之醫藥組合物中調配清涼劑之情形時之清涼劑之含量可根據清涼劑之種類等而適當調整,例如為0.001~1%(w/w)。又,於在本發明之醫藥組合物中調配清涼劑之情形時,可一起使用1種或2種以上之清涼劑。
於本發明之醫藥組合物中調配油成分之情形時之油成分之含量可適當調配能夠用作醫藥品之添加劑之油成分。作為油成分,例如可例舉:烴、蠟、油脂、脂肪族羧酸或其鹽、脂肪酸酯、中長鏈三酸甘油酯(MCT)、高級醇等。
作為烴,例如可例舉:凡士林、白凡士林、液態石蠟(輕質液態石蠟、重質液態石蠟)、固態石蠟(石蠟)、角鯊烯、角鯊烷、地蠟、微晶蠟等,亦可為該等之混合物,例如可例舉石蠟與微晶蠟之混合物等。
作為蠟,例如可例舉:蜂蠟、白蜂蠟、羊毛脂等。
作為油脂,例如可例舉:橄欖油、蓖麻油、芝麻油、大豆油等。
作為脂肪族羧酸,例如可例舉:丁酸、戊酸、己酸等短鏈脂肪酸類;辛酸、癸酸等中鏈脂肪酸類;月桂酸、肉豆蔻酸、棕櫚酸、硬脂酸、山萮酸、油酸、亞麻油酸、次亞麻油酸、蓖麻油酸(蓖麻醇酸)、花生四烯酸等長鏈脂肪酸類;琥珀酸、戊二酸、己二酸、癸二酸等脂肪族二羧酸類等,亦包括分支之脂肪族羧酸。作為脂肪族羧酸之鹽,例如可例舉該等之鈉鹽等。
於本發明中,脂肪酸酯係指脂肪族羧酸之羧基與醇進行酯鍵結而成之化合物。作為可與脂肪族羧酸之羧基進行酯鍵結之醇,例如可例舉:甲醇、乙醇、正丙醇、正丁醇、正戊醇、正己醇、正庚醇、正辛醇、異丙醇、異丁醇、第二丁醇、異戊醇等一元醇;乙二醇、二乙二醇、丙二醇、丁二醇、甘油等多元醇;二聚乙二醇、聚乙二醇、二丙二醇、聚丙二醇、二甘油、三甘油、聚甘油等多元醇之多聚體(聚合物)等。例如可例舉:月桂酸聚乙二醇、肉豆蔻酸異丙酯、肉豆蔻酸辛酯、棕櫚酸乙二醇酯、聚乙二醇硬脂酸酯、油酸異丙酯、亞麻油酸丙二醇酯、次亞麻油酸乙酯、蓖麻油酸(蓖麻醇酸)乙二醇酯、己二酸二異丙酯等。於脂肪族酯具有2個以上酯鍵之情形時,構成該酯鍵之醇可相同亦可不同。
作為高級醇,例如可例舉:月桂醇、肉豆蔻醇、棕櫚醇(鯨蠟醇)、硬脂醇、山萮醇、油醇、亞麻醇、次亞麻醇、辛基十二烷醇等。
於本發明之醫藥組合物中調配油成分之情形時之油成分之含量可根據油成分之種類等而適當調整,例如為0.1~50%(w/w),較佳為1~40%(w/w),更佳為10~30%(w/w),若本發明之醫藥組合物之劑型為軟膏劑,則例如可包含50%(w/w)以上。又,於在本發明之醫藥組合物中調配油成分之情形時,可一起使用1種或2種以上之油成分。
於在本發明之醫藥組合物中所調配之油成分具有作為界面活性劑之作用之情形時,亦可將油成分改稱為界面活性劑。
於本發明之醫藥組合物中所調配之油成分亦可作為用以提高醫藥組合物中所含之其他成分之溶解性的溶解劑(助溶劑)。於本發明之醫藥組合物中所調配之油成分例如亦可作為用以提高依匹斯汀或其鹽、硫系抗氧化劑之溶解性之溶解劑而使用。
本發明之醫藥組合物可進而包含溶劑及/或分散介質。包含溶劑及/或分散介質之本發明之醫藥組合物可為構成成分全部溶解或一部分懸浮,又,亦可為乳液或半固體狀之形態。作為溶劑及/或分散介質之例,並無限定,可例舉:水、乙醇、多元醇(例如甘油(glycerol)、丙二醇、1,3-丁二醇、液體聚乙二醇、聚乙二醇等)等。
於本發明之醫藥組合物中調配溶劑及/或分散介質之情形時之溶劑及/或分散介質之含量可根據該等之種類等而適當調整,例如相對於醫藥組合物之總重量,較佳為10%(w/v)以上,更佳為30%(w/v)以上。又,於在本發明之醫藥組合物中調配溶劑及/或分散介質之情形時,溶劑及/或分散介質可使用1種或一起使用2種以上。
於以乳液之形式使用本發明之醫藥組合物之情形時,本發明之醫藥組合物可為水包油型乳液(將水相製成連續相而包含水相與分散之油性液滴之乳液),亦可為油包水型乳液(將油相製成連續相而包含油與分散之水性液滴之乳液)。本發明之醫藥組合物較佳為油包水型乳液。
油性液滴或水性液滴之平均尺寸例如為20~3000 nm,較佳為50~2000 nm,更佳為100~1000 nm,進而較佳為200~800 nm。
本發明之醫藥組合物可依照該技術領域中通用之通常之方法而製造。例如除了有效成分及硫系抗氧化劑以外,可混合穩定劑、防腐劑、界面活性劑、油成分等添加劑及水等溶劑或分散介質而製造。又,可視需要依照該技術領域中所通用之通常之滅菌方法而製造為無菌製劑。作為滅菌方法,只要為製造步驟中能夠使用之方法,則無特別限制,例如為高壓蒸汽滅菌、過濾滅菌、乾熱滅菌、電子束(EB)滅菌、γ射線滅菌、環氧乙烷氣體(EOG)滅菌、過氧化氫氣體滅菌。
本發明之醫藥組合物只要無特別說明,則亦可包含依匹斯汀或其鹽以外之醫藥活性成分。例如於本發明之醫藥組合物為眼科用醫藥組合物之情形時,可包含依匹斯汀或其鹽以外之用於滴眼劑之其他醫藥活性成分。作為其他醫藥活性成分,例如可例舉:抗炎症劑、抗菌劑、抗病毒劑、維生素劑、血管收縮劑、擴瞳劑、縮瞳劑、降眼壓劑、乾眼症治療劑、局部麻醉劑等。又,本發明之醫藥組合物可包含依匹斯汀或其鹽作為唯一之有效成分。
於使用本發明之醫藥組合物作為眼科用醫藥組合物之情形時,尤其可用作過敏性結膜炎之治療劑。於本發明中,「過敏性結膜炎之治療」包括過敏性結膜炎及其症狀之所有治療(例如改善、減輕、進展之抑制等)及其預防。
於使用本發明之醫藥組合物作為耳鼻用醫藥組合物之情形時,尤其可用作過敏性鼻炎之治療劑。於本發明中,「過敏性鼻炎之治療」包括過敏性鼻炎及其症狀之所有治療(例如改善、減輕、進展之抑制等)及其預防。
於使用本發明之醫藥組合物作為皮膚科用醫藥組合物之情形時,尤其可用作接觸皮膚炎、濕疹皮膚炎、異位性皮膚炎、蕁麻疹等過敏性皮膚炎之治療劑。於本發明中,「過敏性皮膚炎之治療」包括過敏性皮膚炎及其症狀之所有治療(例如改善、減輕、進展之抑制等)及其預防。
於本發明中,「患者」不限於人類,亦意指其他動物、例如犬、貓、馬等。患者較佳為哺乳動物,更佳為人類。於本發明中,「治療上之有效量」係指與未治療對象相比帶來疾病及其症狀之治療效果之量、或帶來疾病及其症狀之進展之延遲的量等。
於投與本發明之醫藥組合物之情形時,只要對於發揮所需之藥效而言充分,則用法劑量並無特別限制,可為1天投與1~4次,較佳為1天投與1~2次,更佳為1天投與1次。
於使用本發明之醫藥組合物作為軟膏劑、乳霜劑或凝膠劑之情形時,其投與量只要對於發揮所需之藥效而言充分,則無特別限制,又,亦依所含有之有效成分之含量或患者而不同。例如若為乳霜劑,則例如於成人之情形時,可每次經皮投與適量,具體而言經皮投與1 mg~5 g、較佳為5 mg~1 g、更佳為10 mg~500 mg、尤佳為20 mg~100 mg。例如其投與量為30 mg。作為投與之一例,於使用本發明之醫藥組合物作為眼科用醫藥組合物之情形時,患者自身用手指取適量、例如20~40 mg醫藥組合物,以各大約一半之方式對單眼之上眼瞼皮膚及下眼瞼皮膚分配並分別塗敷,對於另一單眼亦同樣塗敷。再者,於實際之使用中,可不稱量醫藥組合物,而以單眼每次之上述投與量為標準,由患者自身以估量取出醫藥組合物而使用。又,亦取決於收容本發明之醫藥組合物之容器之尺寸或形狀,但作為投與量之標準,可以於成人之食指指尖至第1關節載置藥劑之量作為1FTU(1指尖單位),例如取出0.5FTU或1FTU而使用。
塗敷於皮膚之情形時之施用時間較佳為0.5~24小時,更佳為2~12小時,進而較佳為4~8小時。於經過施用時間後,即便去除醫藥組合物,於皮膚組織中亦滯留有充分量之有效成分,由於其緩釋,可期待藥效之持續。作為用法之一例,於就寢前將本發明之醫藥組合物投與至眼瞼皮膚,於起床後去除,藉此即便白天不投與,亦可期待治療及預防過敏性結膜炎之效果之持續。
於使用本發明之醫藥組合物作為軟膏劑、乳霜劑或凝膠劑之情形時,所收容之容器並無特別限制,可收容於管、瓶、罐等任一者中。容器之材質並無特別限制,可為:聚乙烯(PE)製、聚丙烯(PP)製、聚對苯二甲酸乙二酯(PET)製、聚對苯二甲酸丁二酯(PBT)製、聚丙烯-聚乙烯共聚物製、聚氯乙烯製、丙烯酸樹脂製、聚苯乙烯製、聚環狀烯烴共聚物製等樹脂製容器;鋁等金屬製容器;將樹脂、紙、鋁箔等複數種材料貼合並加工而成之層壓容器。又,若樹脂製容器之材質例如為聚乙烯,則聚乙烯根據其密度而分類,可使用低密度聚乙烯(LDPE)製、直鏈狀低密度聚乙烯(LLDPE)製、中密度聚乙烯(MDPE)製、高密度聚乙烯(HDPE)製等容器。
本發明之醫藥組合物於戴有硬性隱形眼鏡時或戴有軟性隱形眼鏡時均可使用。
本發明之醫藥組合物可抑制依匹斯汀或其鹽之類似物質之產生及增加。於本發明中,「類似物質」係指依匹斯汀或其鹽之原料藥之雜質及依匹斯汀或其鹽之分解產物。
[實施例]
以下,示出製劑例及各試驗之結果,但該等係為了更好地理解本發明,並不對本發明之範圍進行限定。
製劑例以下示出本發明之代表性之製劑例。再者,於下述製劑例中,各成分之調配量為製劑100 g中之含量。又,「%(w/w)」意指製劑100 g中之各成分之含量(g)。
[製劑例1]油包水型乳液
依匹斯汀 1.0 g
角鯊烷 5.0 g
輕質液態石蠟 5.0 g
地蠟 3.0 g
白凡士林 10.0 g
白蜂蠟 1.0 g
甘油脂肪酸酯 5.0 g
對羥基苯甲酸丙酯 0.1 g
對羥基苯甲酸甲酯 0.1 g
2-巰基苯并咪唑 0.1 g
乙二胺四乙酸鈉水合物 0.5 g
濃甘油 15.0 g
精製水 適量
[製劑例2]油包水型乳液
依匹斯汀鹽酸鹽 2.0 g
鯨蠟醇 0.5 g
白凡士林 8.0 g
肉豆蔻酸異丙酯 4.0 g
聚山梨糖醇酯80 0.5 g
對羥基苯甲酸丙酯 0.05 g
對羥基苯甲酸甲酯 0.03 g
二丁基羥基甲苯 0.2 g
2-巰基苯并咪唑 0.05 g
丙二醇 5.0 g
氫氧化鈉 適量
精製水 適量
[製劑例3]油包水型乳液
依匹斯汀鹽酸鹽 3.0 g
鯨蠟醇 2.0 g
角鯊烷 10.0 g
甘油脂肪酸酯 4.0 g
聚氧乙烯氫化蓖麻油 0.5 g
2-巰基苯并咪唑 0.3 g
辛基十二烷醇 5.0 g
乙二胺四乙酸鈉水合物 0.5 g
濃甘油 10.0 g
氫氧化鈉 適量
精製水 適量
[製劑例4]水包油型乳液
依匹斯汀鹽酸鹽 1.0 g
角鯊烷 10.0 g
單硬脂酸甘油酯 4.0 g
聚氧乙烯山萮醚 4.0 g
聚氧乙烯氫化蓖麻油 1.0 g
鯨蠟醇 5.0 g
硬脂醇 2.5 g
2-巰基苯并咪唑 0.1 g
己二酸二異丙酯 4.0 g
1,3-丁二醇 5.0 g
檸檬酸鈉 適量
氫氧化鈉 適量
精製水 適量
進而,將製劑例5~36示於表1~4。
[表1]
成分[%(w/w)] | 製劑例 | |||||||
5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | |
依匹斯汀鹽酸鹽 | 0.05 | 0.05 | 0.05 | 0.05 | 0.05 | 0.05 | 0.05 | 0.05 |
白凡士林 | 10 | 5.0 | 5.0 | 8.0 | 5.0 | 8.0 | 8.0 | 5.0 |
輕質液態石蠟 | 8.0 | 10 | 5.0 | 8.0 | 8.0 | 8.0 | 5.0 | 5.0 |
角鯊烷 | 8.0 | 5.0 | 10 | 8.0 | 8.0 | 5.0 | 4.0 | 5.0 |
石蠟與微晶蠟之混合物 | 4.0 | 4.0 | 4.5 | 2.5 | 3.0 | 5.0 | 4.5 | 3.0 |
白蜂蠟 | 1.0 | 1.0 | 0.5 | 1.5 | 1.0 | 0.5 | 1.5 | 1.5 |
甘油脂肪酸酯 | 5.5 | 4.5 | 4.5 | 4.5 | 4.0 | 4.0 | 4.0 | 5.0 |
2-巰基苯并咪唑 | 0.1 | 0.05 | 0.05 | 0.05 | 0.05 | 0.1 | 0.1 | 0.05 |
乙二胺四乙酸鈉水合物 | 0.05 | 0.75 | 0.75 | 0.05 | 0.03 | 0.75 | 0.05 | 0.1 |
濃甘油 | 8.0 | 10 | 11 | 12 | 13 | 14 | 14 | 15 |
氯化鈉 | 0.5 | 0.5 | 0.45 | 0.4 | 0.35 | 0.3 | 0.25 | 0.5 |
氫氧化鈉 | 適量 | |||||||
精製水 | 適量 |
[表2]
成分[%(w/w)] | 製劑例 | |||||||
13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | |
依匹斯汀鹽酸鹽 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 |
白凡士林 | 10 | 5.0 | 5.0 | - | - | 8.0 | 10 | 15 |
輕質液態石蠟 | - | 10 | 5.0 | 5.0 | 5.0 | 8.0 | 8.0 | - |
角鯊烷 | 10 | - | 8.0 | 5.0 | 5.0 | - | 5.0 | 2.0 |
羊毛脂 | - | - | - | 15 | 10 | 5.0 | - | - |
石蠟與微晶蠟之混合物 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 |
白蜂蠟 | - | - | - | 1.0 | - | - | - | 5.0 |
甘油脂肪酸酯 | - | 5.0 | - | - | - | - | - | 5.0 |
聚乙二醇硬脂酸酯 | 8.0 | - | - | - | - | 6.0 | 4.0 | |
單油酸甘油酯 | - | - | 8.0 | 4.0 | 4.0 | - | - | - |
2-巰基苯并咪唑 | 0.05 | 0.05 | 0.05 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 |
辛基十二烷醇 | 5.0 | 5.0 | - | - | - | 8.0 | 8.0 | 3.0 |
鯨蠟醇 | - | - | 7.5 | 7.5 | - | - | - | 3.0 |
乙二胺四乙酸鈉水合物 | - | 0.05 | 0.05 | 0.05 | 0.05 | 0.05 | - | - |
濃甘油 | 8.0 | 10 | - | 12 | - | 15 | - | - |
丙二醇 | - | - | 10 | - | 12 | - | 15 | 15 |
氯化鈉 | 0.5 | 0.5 | 1.0 | 0.3 | 1.0 | - | - | 0.8 |
氫氧化鈉 | 適量 | |||||||
精製水 | 適量 |
[表3]
成分[%(w/w)] | 製劑例 | |||||||
21 | 22 | 23 | 24 | 25 | 26 | 27 | 28 | |
依匹斯汀鹽酸鹽 | 1.0 | 1.0 | 1.0 | 1.0 | 0.5 | 0.5 | 0.5 | 0.5 |
白凡士林 | 10 | 15 | 5.0 | 10 | 5.0 | 10 | 8.0 | 8.0 |
輕質液態石蠟 | 5.0 | - | 10 | - | 5.0 | 5.0 | 8.0 | 5.0 |
角鯊烷 | 8.0 | 5.0 | 5.0 | 10 | 5.0 | - | 8.0 | 5.0 |
地蠟 | 1.0 | 1.0 | - | 1.0 | - | - | 1.0 | 2.0 |
甘油脂肪酸酯 | - | - | 5.0 | - | - | 2.0 | 4.0 | - |
聚氧乙烯氫化蓖麻油60 | 5.0 | - | - | 5.0 | - | - | 3.0 | - |
聚山梨糖醇酯80 | - | 5.0 | - | - | 5.0 | - | - | - |
中長鏈三酸甘油酯 | - | - | - | 10 | 10 | 15 | - | 10 |
2-巰基苯并咪唑 | 0.05 | 0.05 | 0.05 | 0.1 | 0.1 | 0.05 | 0.05 | 0.05 |
聚氧乙烯鯨蠟基醚 | - | - | 3.0 | 3.0 | 3.0 | 3.0 | - | - |
鯨蠟醇 | 8.0 | 8.0 | 8.0 | 8.0 | 8.0 | - | - | - |
硬脂醇 | - | - | - | - | - | 5.0 | 5.0 | 5.0 |
乙二胺四乙酸鈉水合物 | 0.03 | 0.03 | 0.05 | 0.05 | 0.03 | 0.03 | 0.05 | 0.05 |
濃甘油 | 15 | 15 | - | - | - | - | 12 | 12 |
聚乙二醇400 | - | - | 20 | 20 | 15 | 15 | - | - |
檸檬酸鈉水合物 | 1.0 | 1.0 | 0.5 | 0.5 | 1.0 | 1.0 | 0.5 | 0.5 |
氫氧化鈉 | 適量 | |||||||
精製水 | 適量 |
[表4]
成分[%(w/w)] | 製劑例 | |||||||
29 | 30 | 31 | 32 | 33 | 34 | 35 | 36 | |
依匹斯汀鹽酸鹽 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 |
白凡士林 | 10 | 5.0 | 5.0 | 8.0 | 5.0 | 8.0 | 8.0 | 5.0 |
輕質液態石蠟 | 8.0 | 10 | 5.0 | 8.0 | 8.0 | 8.0 | 5.0 | 5.0 |
角鯊烷 | 8.0 | 5.0 | 10 | 8.0 | 8.0 | 5.0 | 4.0 | 5.0 |
石蠟與微晶蠟之混合物 | 3.0 | 4.0 | 4.5 | 2.5 | 3.0 | 5.0 | 4.5 | 4.0 |
白蜂蠟 | 1.5 | 1.0 | 0.5 | 1.5 | 1.0 | 0.5 | 1.5 | 1.0 |
甘油脂肪酸酯 | 5.0 | 4.5 | 4.5 | 4.5 | 4.0 | 4.0 | 4.0 | 5.5 |
2-巰基苯并咪唑 | 0.05 | 0.05 | 0.05 | 0.05 | 0.05 | 0.1 | 0.1 | 0.1 |
乙二胺四乙酸鈉水合物 | 0.1 | 0.75 | 0.75 | 0.05 | 0.03 | 0.75 | 0.05 | 0.05 |
濃甘油 | 8.0 | 10 | 11 | 12 | 13 | 14 | 14 | 15 |
氯化鈉 | 0.5 | 0.5 | 0.45 | 0.4 | 0.35 | 0.3 | 0.25 | 0.25 |
氫氧化鈉 | 適量 | |||||||
精製水 | 適量 |
實施例1.依匹斯汀或其鹽之穩定性試驗(1)
(1)試驗順序
使用通用之方法,將作為有效成分之依匹斯汀鹽酸鹽、油性基劑、各抗氧化劑、氫氧化鈉及精製水混合,製備試驗製劑1~4。又,除了不含抗氧化劑以外,使用與試驗製劑1~4同樣之方法製備試驗製劑5。將所製備之試驗製劑1~5分別於溫度60℃之保存庫中保存1週。將剛製備製劑後與保存1週後之類似物質之含量於以下所記載之分析條件進行定量,將含量加以比較。
<分析條件>
管柱:於內徑4.6 mm、長度15 cm之不鏽鋼管中填充5 μm之液相層析用十八烷基二氧化矽化矽膠
流動相:利用流動相A(包含磷酸二氫鉀、1-戊磺酸鈉、甲醇、磷酸緩衝液之水溶液)與流動相B(乙腈-甲醇混液)之濃度梯度
流速:0.7 mL/min
檢測器:紫外吸光光度計(測定波長:220 nm)
管柱溫度:50℃附近之一定溫度
試驗製劑1~5之添加成分如表5所述。再者,表5中之「油性基劑」分別包含適量角鯊烷、硬脂醇、鯨蠟醇、單硬脂酸甘油酯、聚氧乙烯氫化蓖麻油100、聚氧乙烯山萮醚20、聚氧乙烯(20)聚氧丙烯(4)鯨蠟基醚、己二酸二異丙酯、對羥基苯甲酸丙酯,油性基劑中之比率於試驗製劑1~5中無差異。又,氫氧化鈉及精製水設為包含適於依匹斯汀鹽酸鹽之溶解與中和之量。
[表5]
成分[%(w/w)] | 試驗製劑 | |||||
1 | 2 | 3 | 4 | 5 | ||
依匹斯汀鹽酸鹽 | 2.6 | 2.6 | ||||
油性基劑 | 80.1 | 80.5 | ||||
抗氧化劑 | BHT | 0.5 | - | - | - | - |
生育酚乙酸酯 | - | 0.5 | - | - | - | |
沒食子酸丙酯 | - | - | 0.5 | - | - | |
MBI | - | - | - | 0.5 | - | |
氫氧化鈉及精製水 | 16.8 | 16.9 |
(2)試驗結果及探討
將主要之類似物質之含量示於表6。可知關於製備並保存1週後之類似物質之量,相對保持時間(RRT)為0.142之類似物質於不含抗氧化劑之試驗製劑5中增加,又,於各含有抗氧化劑之試驗製劑1~3中亦增加。另一方面,可知僅於抗氧化劑為2-巰基苯并咪唑之試驗製劑4之情形時能夠抑制類似物質之量之增加。又,可知RRT為1.035之類似物質於不含抗氧化劑之試驗製劑5、含有生育酚乙酸酯作為抗氧化劑之試驗製劑2及含有沒食子酸丙酯之試驗製劑3中增加,另一方面,含有二丁基羥基甲苯之試驗製劑1及含有2-巰基苯并咪唑之試驗製劑4能夠抑制類似物質之量之增加。
[表6]
類似物質[%] | 測定時 | 試驗製劑 | ||||
1 | 2 | 3 | 4 | 5 | ||
RRT 0.142 | 剛製備後 | 0.16 | 0.27 | 0.40 | 0.10 | 0.24 |
1週後 | 0.25 | 0.42 | 0.92 | 0.11 | 0.54 | |
RRT 1.035 | 剛製備後 | 0.05 | 1.15 | 0.13 | 0.01 | 0.06 |
1週後 | 0.05 | 7.33 | 0.31 | 0.07 | 0.17 |
2.依匹斯汀或其鹽之穩定性試驗(2)
(1)試驗順序
使用通用之方法,將作為有效成分之依匹斯汀鹽酸鹽、基劑、各抗氧化劑、氫氧化鈉、氯化鈉及精製水加以混合,製備作為油包水型乳液之試驗製劑6~9。又,除了不含抗氧化劑以外,使用與試驗製劑6~9同樣之方法製備作為油包水型乳液之試驗製劑10。將所製備之試驗製劑6~10於溫度40℃、濕度75%之保存庫中保存1個月。於與上述「1.依匹斯汀或其鹽之穩定性試驗(1)」同樣之分析條件下對剛製備製劑後與保存1個月後之類似物質之含量進行定量,將含量加以比較。
試驗製劑6~10之添加成分如表7所述。再者,表7中之「基劑」分別包含適量角鯊烷、白凡士林、輕質液態石蠟、地蠟、白蜂蠟、濃甘油、辛基十二烷醇、甘油脂肪酸酯、對羥基苯甲酸甲酯、對羥基苯甲酸丙酯、乙二胺四乙酸鈉水合物,基劑中之比率於試驗製劑6~10中無差異。
[表7]
成分[%(w/w)] | 試驗製劑 | |||||
6 | 7 | 8 | 9 | 10 | ||
依匹斯汀鹽酸鹽 | 0.5 | |||||
基劑 | 42.2 | |||||
抗氧化劑 | BHT | 0.1 | 0.2 | - | 0.2 | - |
MBI | - | - | 0.05 | 0.05 | - | |
氫氧化鈉、氯化鈉及精製水 | 適量 |
(2)試驗結果及探討
將總類似物質之量及RRT為1.064之類似物質之量示於表8。可知關於製備並保存1個月後之類似物質之量,RRT為1.064之類似物質於不含抗氧化劑之試驗製劑10中增加,又,於含有二丁基羥基甲苯作為抗氧化劑之試驗製劑6及試驗製劑7中,不論二丁基羥基甲苯之濃度如何,均表現出增加傾向。另一方面,可知僅含有2-巰基苯并咪唑之試驗製劑8及試驗製劑9抑制類似物質之量之增加。又,可知試驗製劑8及試驗製劑9亦抑制總類似物質之量之增加。
[表8]
類似物質[%] | 試驗製劑 | |||||
6 | 7 | 8 | 9 | 10 | ||
總類似物質 | 剛製備後 | 0.17 | 0.14 | 0.19 | 0.11 | 0.24 |
1個月後 | 0.55 | 0.54 | 0.45 | 0.40 | 0.74 | |
RRT 1.064 | 剛製備後 | 0.10 | 0.08 | 0.05 | 0.04 | 0.17 |
1個月後 | 0.27 | 0.25 | 0.10 | 0.09 | 0.42 |
3.長期穩定性試驗
(1)試驗順序
製備上述「2.依匹斯汀或其鹽之穩定性試驗(2)」所記載之試驗製劑8及試驗製劑10,於溫度40℃、濕度75%之保存庫中保存6個月。於與上述「1.依匹斯汀或其鹽之穩定性試驗(1)」同樣之分析條件下對剛製備製劑後與保存6個月後之類似物質之含量進行定量,將含量加以比較。
(2)試驗結果及探討
將總類似物質之量及RRT為1.05之類似物質之量示於表9。可知關於製備並保存6個月後之類似物質之量,RRT為1.05之類似物質於不含抗氧化劑之試驗製劑10中增加,另一方面,於含有2-巰基苯并咪唑之試驗製劑8中,抑制類似物質之量之增加。又,可知試驗製劑8與試驗製劑10相比,亦抑制總類似物質之量之增加。
[表9]
類似物質[%] | 試驗製劑 | ||
8 | 10 | ||
總類似物質 | 剛製備後 | 0.10 | 0.30 |
6個月後 | 0.87 | 1.67 | |
RRT 1.05 | 剛製備後 | <0.05 | 0.12 |
6個月後 | 0.17 | 0.49 |
4.依匹斯汀或其鹽之穩定性試驗(3)
(1)試驗順序
使用通用之方法,將作為有效成分之依匹斯汀鹽酸鹽、基劑、各抗氧化劑、氫氧化鈉、氯化鈉及精製水加以混合,製備作為油包水型乳液之試驗製劑11~15。將所製備之試驗製劑11~15於溫度60℃之保存庫中保存4週。於與上述「1.依匹斯汀或其鹽之穩定性試驗(1)」同樣之分析條件下對剛製備製劑後與保存4週後之類似物質之含量進行定量,將含量加以比較。
試驗製劑11~14之添加成分如表10所述。又,試驗製劑15之添加成分以上文所述之專利文獻2(WO2007/007851)為參考,而如表11所述。
[表10]
成分[%(w/w)] | 試驗製劑 | ||||
11 | 12 | 13 | 14 | ||
依匹斯汀鹽酸鹽 | 0.5 | ||||
基劑 | 輕質液態石蠟 | 8.0 | |||
角鯊烷 | 5.0 | ||||
白凡士林 | 5.0 | ||||
石蠟與微晶蠟之混合物 | 3.0 | ||||
白蜂蠟 | 1.0 | ||||
甘油脂肪酸酯 | 4.0 | ||||
辛基十二烷醇 | 3.0 | ||||
濃甘油 | 13.0 | ||||
抗氧化劑 | MBI | 0.2 | - | - | - |
L-半胱胺酸鹽酸鹽水合物 | - | 0.2 | - | - | |
L-甲硫胺酸 | - | - | 0.2 | - | |
生育酚(維生素E) | - | - | - | 0.2 | |
氫氧化鈉 | 適量 | ||||
氯化鈉 | 適量 | ||||
精製水 | 適量 |
[表11]
成分[%(w/w)] | 試驗製劑 | |
15 | ||
依匹斯汀鹽酸鹽 | 0.5 | |
基劑 | 白凡士林 | 10.0 |
鯨蠟醇 | 3.0 | |
硬脂酸 | 2.0 | |
肉豆蔻酸異丙酯 | 40 | |
聚山梨糖醇酯80 | 5.0 | |
丙二醇 | 5.0 | |
甲基對羥基苯甲酸酯 | 0.2 | |
丙基對羥基苯甲酸酯 | 0.02 | |
抗氧化劑 | 抗壞血酸(維生素C) | 1.0 |
精製水 | 適量 |
(2)試驗結果及探討
將總類似物質之量示於表12。可知作為抗氧化劑而調配有生育酚(維生素E)之試驗製劑14及調配有抗壞血酸(維生素C)之試驗製劑15於保存4週後之總類似物質之量大幅增加,相對於此,調配有硫系抗氧化劑之試驗製劑11~13有抑制保存4週後之總類似物質之量之增加的傾向。
[表12]
[產業上之可利用性]
總類似物質[%] | 試驗製劑 | ||||
11 | 12 | 13 | 14 | 15 | |
剛製備後 | 0 | 0.08 | 0.07 | 2.29 | 2.20 |
4週後 | 2.28 | 1.35 | 2.05 | 19.15 | 6.47 |
本發明提供一種能夠維持眼組織中之有效濃度、且長時間維持穩定性之含有依匹斯汀或其鹽作為有效成分之經皮投與用醫藥組合物。
Claims (14)
- 一種經皮投與用醫藥組合物,其含有依匹斯汀或其鹽及硫系抗氧化劑。
- 如請求項1之醫藥組合物,其中硫系抗氧化劑為選自由半胱胺酸、N-乙醯半胱胺酸、甲硫胺酸、麩胱甘肽、2-巰基苯并咪唑、硫代蘋果酸鈉、硫代甘油、硫代乙醇酸鈉、硫代硫酸鈉、亞硫酸氫鈉及亞硫酸鈉所組成之群中之1種以上。
- 如請求項2之醫藥組合物,其中硫系抗氧化劑為2-巰基苯并咪唑。
- 如請求項1至3中任一項之醫藥組合物,其為0.01~5%(w/w)濃度之依匹斯汀或其鹽。
- 如請求項1至4中任一項之醫藥組合物,其為軟膏劑、乳霜劑或凝膠劑。
- 如請求項5之醫藥組合物,其為乳霜劑。
- 如請求項1至6中任一項之醫藥組合物,其為油包水型乳液。
- 如請求項1至7中任一項之醫藥組合物,其係用於眼科。
- 如請求項1至8中任一項之醫藥組合物,其中經皮投與為對眼瞼皮膚之投與。
- 如請求項1至9中任一項之醫藥組合物,其係用於治療過敏性結膜炎。
- 如請求項1至10中任一項之醫藥組合物,其係以對患者1天投與1次之方式使用。
- 一種醫藥組合物,其係含有依匹斯汀或其鹽及硫系抗氧化劑之經皮投與用醫藥組合物,且進而含有選自由烴、蠟、油脂、脂肪族羧酸或其鹽、脂肪酸酯及高級醇所組成之群中之1種以上油成分。
- 如請求項12之醫藥組合物,其進而含有溶劑及/或分散介質。
- 如請求項12或13之醫藥組合物,其不含對羥基苯甲酸酯。
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