TWI745313B - 鼻黏膜投與用醫藥組成物 - Google Patents
鼻黏膜投與用醫藥組成物 Download PDFInfo
- Publication number
- TWI745313B TWI745313B TW105135103A TW105135103A TWI745313B TW I745313 B TWI745313 B TW I745313B TW 105135103 A TW105135103 A TW 105135103A TW 105135103 A TW105135103 A TW 105135103A TW I745313 B TWI745313 B TW I745313B
- Authority
- TW
- Taiwan
- Prior art keywords
- oxytocin
- pharmaceutical composition
- nasal
- mucosal administration
- viscosity
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 47
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 claims abstract description 75
- 101800000989 Oxytocin Proteins 0.000 claims abstract description 74
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 claims abstract description 68
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Abstract
本發明係以提供一種屬胜肽激素之催產素或者其酸加成鹽或該等之衍生物之從鼻黏膜的吸收性高,且在安全性方面之疑慮較少的滴鼻劑為目的。本發明為一種鼻黏膜投與用醫藥組成物,其特徵為包含催產素或者其酸加成鹽或該等之衍生物、及羧基乙烯基聚合物,且滲透壓比低於1。
Description
本發明係有關於一種鼻黏膜投與用醫藥組成物,尤其係有關於一種含有催產素或者其酸加成鹽或該等之衍生物作為有效成分的鼻黏膜投與用醫藥組成物。
催產素是一種在腦的下視丘神經核合成,由腦垂腺的神經末梢所分泌之由9個胺基酸構成的胜肽激素。催產素係向來廣為人知之激素,就其作用,經發現有乳汁分泌促進效果,而予以作成滴鼻劑(製品名:Syntocinon)使用。
近年來,有人報導若滴鼻投與催產素,可增加對該投與者的可靠性,從而越來越多人嘗試予以開發作為改善社會性行動的治療藥。若為以促進乳汁分泌為目的之滴鼻劑時,係為暫時性投與,且催產素的投與量亦為少量;相對於此,若為以改善社會性行動為目的之滴鼻劑時,則為長時間之投與,並有可能要投與更多量的催產素,由此而言,便企望開發出一種催產素從鼻黏膜的吸收性高,且在安全性方面顧慮較少的滴鼻劑。
迄今作為提升催產素之經黏膜的吸收性的方法,在專利文獻1中提出一種使用妥美丁或其鹽作為吸收促進劑的方法。於其實施例中,透過使用妥美丁鈉作為吸收促進劑,顯示出從直腸黏膜的吸收性之提升,但未顯示從鼻黏膜的吸收性之改善效果。又,將包含如妥美丁鈉之吸收促進劑的製劑經長時間投與至鼻黏膜時,仍無法免除在安全性方面的疑慮,像是對於對鼻黏膜的刺激性或對組織細胞的損傷的疑慮。
作為提升胜肽或蛋白性藥物而非催產素其本身從鼻黏膜之吸收性的方法,除上述妥美丁以外,尚有各種膽汁酸、各種螯合劑、各種界面活性劑、各種脂肪酸、皂素等的配醣體、殼聚糖等的糖類、各種環糊精、各種磷脂質等極多種吸收促進劑之報導(非專利文獻1、非專利文獻2)。又,也有人提出利用滲透壓、pH或者黏度等製劑之物性的調整或各種聚合物基劑的方法(專利文獻2~4)。
例如,在專利文獻2中揭示,對於屬胜肽激素的分泌素,予以作成滲透壓比提高至1~5的滴鼻劑,可改善吸收性。又,其中揭示,同一分泌素,在氯化鈉濃度為0.46M的水溶液(滲透壓比3)中,吸收性達最大(非專利文獻3)。又,在專利文獻3中揭示,對於似胰島素生長因子I,予以作成含有羧基乙烯基聚合物的滴鼻用液劑,可促進吸收。與此相反,在非專利文獻4中揭示,透過以聚乙二醇為基劑,可迅速發生尼非待平的吸收,但若
為羧基乙烯基聚合物時則較低。此外,屬上述催產素滴鼻劑之市售品的Syntocinon中不含羧基乙烯基聚合物。再者,在專利文獻4中揭示,對於屬胜肽激素的抑鈣激素,予以作成包含結晶纖維素作為水不溶性及/或水難溶性物質,且使滲透壓(重量滲透濃度)成為60mOsm以下的滴鼻劑,可改善吸收性。另一方面,屬上述催產素滴鼻劑之市售品的Syntocinon的重量滲透濃度高達629mOsm(滲透壓比2)。
利用滲透壓或聚合物基劑的方法,可望降低經長時間投與時對鼻黏膜的刺激性或對細胞組織的損傷,在安全性方面較為理想;然,一般就胜肽而言,因其分子量較大而從鼻黏膜穿出之穿透性較低,而且,隨其種類的不同,如上述所報導,滲透壓或聚合物基劑的效果也不同;因此,能否應用迄今所提出的這些方法來達到催產素從鼻黏膜的吸收性之提升尚且不明。
〔專利文獻1〕日本專利第3705620號公報
〔專利文獻2〕日本特開昭60-123426號公報
〔專利文獻3〕日本專利第2734554號公報
〔專利文獻4〕日本專利第5142420號公報
〔非專利文獻1〕Indian Journal of Pharmaceutical Sciences.,1996,58(1),pp1-8
〔非專利文獻2〕DDT Vol.7,No.18 September 2002,pp 967-975
〔非專利文獻3〕Chem.Pharm.Bull.37(12)3359-3362(1989)
〔非專利文獻4〕Chem.Pharm.Bull.35,304-1(1987)
本發明目的在於開發出一種催產素或者其酸加成鹽或該等之衍生物之從鼻黏膜的吸收性高,且在安全性方面之疑慮較少的滴鼻劑。
本案發明人等為達成上述課題而致力進行研究的結果發現,藉由調成在含有催產素或者其酸加成鹽或該等之衍生物的水性製劑中,以包含羧基乙烯基聚合物,且滲透壓比低於1為特徵的鼻黏膜投與用醫藥組成物,可達成前述本發明之目的,終至完成本發明。
亦即,本發明為一種鼻黏膜投與用醫藥組成物,其特徵為包含催產素或者其酸加成鹽或該等之衍生物、及羧基乙烯基聚合物,且滲透壓比低於1。
又,本發明較佳進一步包含鹽類,且黏度為100~10000mPa‧s,更佳為1500~2800mPa‧s。
再者,本發明較佳為重量滲透濃度為0~200mOsm。
再者,本發明較佳為相對於鼻黏膜投與用醫藥組成物,含有0.1~2.0重量%的羧基乙烯基聚合物。
再者,本發明較佳為相對於鼻黏膜投與用醫藥組成物,含有0.01~20mM的鹽類。
根據本發明,可獲得一種催產素從鼻黏膜的吸收性高,且在安全性方面之疑慮較少的滴鼻劑。
第1圖為表示各實施例及比較例中的兔子血漿中催產素濃度之時間變化的圖表。
就本發明中的醫藥組成物,僅不含羧基乙烯基聚合物,且降低包含催產素或者其酸加成鹽或該等之衍生物的水性組成物的重量滲透濃度,並無法獲得催產素或者其酸加成鹽或該等之衍生物之顯著的吸收性提升。又,僅對使滲透壓比為1(等張)或更高的水性組成物添加羧基乙烯基聚合物,也無法獲得催產素或者其酸加成鹽或該等之衍生物之顯著的吸收性提升。亦即,在包含催產素或者其酸加成鹽或該等之衍生物的水性組成物中,透過包含羧基乙
烯基聚合物,並使滲透壓比低於1,才可達到顯著的吸收性提升。
本發明中,作為有效成分的催產素係Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly之胺基酸序列的胜肽。就催產素而言,亦可為其酸加成鹽,作為代表性之酸加成鹽,可舉出乙酸鹽,但不限定於此。作為催產素衍生物,可舉出去氨縮宮素(demoxytocin)、卡貝縮宮素(carbetocin)及該等之酸加成鹽或附加有多糖或聚乙二醇作為連結子的衍生物等,但不限定於此。又,本發明中的催產素或者其酸加成鹽或該等之衍生物的含量,可依據治療之對象疾病、對象患者的症狀或年齡等治療目的來決定,無法一概而論;作為一例,相對於製劑,可取0.001~1.0重量%,較佳為0.004~0.4重量%。
本發明之組成物的滲透壓比係低於1。本發明中所稱滲透壓比,係指本發明之組成物的重量滲透濃度相對於生理食鹽液(氯化鈉0.900g/水100mL)的重量滲透濃度之286mOsm的比,係視為等張性之尺度。生理食鹽液的重量滲透濃度為與待投與部位之生物體之黏膜組織的一般重量滲透濃度大致相同的重量滲透濃度,而生物體之黏膜組織的重量滲透濃度會有變動,本發明中,等張(本發明中所稱「等張」,係指與生物體之黏膜組織的重量滲透濃度相等的重量滲透濃度)係指286mOsm±5%,亦即272mOsm~300mOsm,特別是於此範圍內滲透壓比係視為1。本發明之組成物的重量滲透濃度較佳為0~
200mOsm,更佳為0~150mOsm,再者以0~100mOsm、0~70mOsm、0~50mOsm、0~30mOsm、0~10mOsm之順序為更佳。此外,本發明中的重量滲透濃度係採用凝固點下降法所算出的質量重量滲透濃度(mol/kg),而在到至少1000mOsm左右的稀薄濃度區域,數值上可視為等同於容量滲透濃度(mol/L),因此,將單位以容量滲透濃度表示,數值亦相同。又,於本發明中有將重量滲透濃度記載為滲透壓。
為調節本發明中的滲透壓,可使用滲透壓調節劑。作為具體的滲透壓調節劑,只要為水溶性者則不特別限制,可舉出葡萄糖、果糖、麥芽糖等的糖類、甘油等的醇類、D-山梨糖醇、D-甘露糖醇、木糖醇等的糖醇類、氯化鈉等的鹽類等。此等可單獨或以1種或2種以上的混合系統使用。
本發明中,羧基乙烯基聚合物係以丙烯酸為主要單元結構的親水性聚合物,只要可溶於水或發生膨潤、增黏則不特別限制,可部分經過交聯,又,也可為包含其他單元結構的共聚物。羧基含量,在羧基乙烯基聚合物中較佳為50%~75%。又,較佳為在0.5重量%水溶液中的黏度(25℃、pH7.3~pH7.8)為20,000~50,000者。具體而言可舉出Lubrizol公司之Carbopol(註冊商標)910、934、934P、940、941、971PNF、974PNF等,其中Carbopol(註冊商標)934、934P、974PNF因增黏效果較高而更佳,具同樣特長之其他公司的羧基乙烯基聚合物亦同樣地
為較佳者。
又,本發明中的羧基乙烯基聚合物的含量,可於由滴鼻投與器噴霧的範圍內任意地設定,相對於製劑較佳為0.1~2.0重量%,更佳為0.2~1.0重量%,再者以0.3~1.0重量%、0.3%~0.6重量%之順序為更佳。
進而,在包含催產素或者其酸加成鹽或該等之衍生物、以及羧基乙烯基聚合物,且使滲透壓比低於1的水性組成物中,為了進一步提高有效成分從鼻黏膜的吸收性,較佳的是黏度為100~10000mPa‧s。若黏度未達100mPa‧s,不易獲得催產素從鼻黏膜的吸收性提升之充分的效果;黏度超過10000mPa‧s則藉由滴鼻投與器投與時的擠出壓力會變高,難以用手進行噴霧,且噴霧時的液滴粒徑會變大,而不易均勻地噴霧,因而不佳。
本發明中的黏度係調整於由滴鼻投與器噴霧的範圍,較佳的是以鹽類調整於100~10000mPa‧s,更佳為200~10000mPa‧s,更佳為100~5000mPa‧s,再更佳為500~5000mPa‧s,再者以1000~3000mPa‧s、1500~2800mPa‧s、1800~2500mPa‧s之順序為更佳。作為本發明中供調整黏度的鹽類,只要為水溶性者不特別限制,可舉出例如氯化鈉、氯化鉀、氯化鈣、氯化鎂、氯化鋅、碳酸鉀、硫酸鎂、磷酸氫鈉等的無機鹽、或檸檬酸鈉、乙二胺四乙酸鈉、山梨酸鉀、精胺酸鹽酸鹽、離胺酸鹽酸鹽、天冬胺酸鈉、天冬胺酸鎂、辛酸鈉、葡萄糖酸鈉、葡萄糖酸鈉、麩胺酸鈉、琥珀酸鈉、乙酸鈉、乙酸鈣、酒石
酸鈉、蘋果酸鈉等的有機鹽等。鹽類可添加一種以上。就黏度而言,對於透過含有前述之羧基乙烯基聚合物所賦予的黏度,會因鹽類的添加而降低,可根據鹽類的種類及其添加量調整成目標之特定黏度。黏度的調整不限於鹽類的添加,亦可以攪拌等來進行調整。
又,本發明中的鹽類的含量,可於含有羧基乙烯基聚合物之水溶液的黏度經調整於100~10000mPa‧s等的較佳範圍的範圍內任意地設定。又,鹽類可於添加羧基乙烯基聚合物之際,預先以鹽類添加,也可同時添加,亦可於羧基乙烯基聚合物添加後再添加。再者,酸性物質及鹼性物質之鹽類可個別添加。鹽類的添加量,相對於組成物,較佳添加0.01~20mM,更佳添加0.1~4mM。
本發明中的pH,較佳為pH2.5~pH7.5,更佳為pH3.0~pH6.0,特佳為pH3.5~pH5.0。又,作為pH調節劑,只要是呈水溶性並可將pH調節於上述範圍者則不特別限制,具體而言,可舉出例如氫氧化鈉、精胺酸、鹽酸、檸檬酸、硼酸、酒石酸、碳酸、磷酸及該等之鹽等。此等可單獨或以1種或2種以上的混合系統使用。
又,亦可對本發明中的鼻黏膜投與用醫藥組成物,視需求添加向來周知的保存劑。例如,可舉出對羥基苯甲酸甲酯、對羥基苯甲酸乙酯、對羥基苯甲酸丙酯、對羥基苯甲酸丁酯、氯化苄烷銨、山梨酸鉀、乙二胺四乙酸鈉、氯丁醇、苯氧乙醇、苯甲酸鈉等,較佳為,可為對羥基苯甲酸甲酯、對羥基苯甲酸丙酯等的對羥基苯甲酸酯
(paraben)類。此等可單獨或以1種或2種以上的混合系統使用。
更且,亦可對本發明之組成物視需求添加向來周知之穩定化劑、抗氧化劑或矯味藥等。具體而言,可舉出例如檸檬酸、檸檬酸鈉、乙二胺四乙酸鈉、異抗壞血酸鈉等的穩定化劑、抗壞血酸、生育酚等的抗氧化劑、薄荷醇等的矯味藥。此等可單獨或以1種或2種以上的混合系統使用。
本發明中的滴鼻劑由於含有催產素或者其酸加成鹽或該等之衍生物作為有效成分,透過投與本發明中的滴鼻劑,對例如泛自閉症障礙、精神分裂症、X染色體易裂症、反應性依附障礙、肥胖症等的疾病之預防或治療係屬有效。
本發明之組成物可例如藉由使催產素或者其酸加成鹽或該等之衍生物溶解於水,對其添加另外使羧基乙烯基聚合物溶解水所調製而成的羧基乙烯基聚合物水溶液,並進一步添加氫氧化鈉水溶液而調成所要的pH來製造。
以下根據實施例來說明本發明,惟本發明不受此等所限定。此外,實施例中,份係指重量份,%係指重量%。
取催產素乙酸鹽0.054g(以催產素計為0.048g)至玻
璃容器中,添加純水30g使其溶解。其次添加1%羧基乙烯基聚合物水溶液40g。添加2.40mL的0.1M氫氧化鈉溶液使其以pH計量測為pH4.0後,添加純水使總量達100g,調製成鼻黏膜投與用水性醫藥組成物。重量滲透濃度係使用滲透壓分析裝置(ARKRAY公司,OM-6060)進行測定,黏度則使用E型黏度計(東機產業公司,TVE-25),於25℃進行測定。將調製之醫藥組成物的成分表、pH、重量滲透濃度、黏度示於表1。又,將調製之鼻黏膜投與用水性醫藥組成物100μL以市售滴鼻液劑用投與器對兔子(日本白種,公,體重約3kg)的單側鼻腔進行噴霧。在投與前、投與後5分鐘、10分鐘、15分鐘、20分鐘、30分鐘、45分鐘、60分鐘後自耳靜脈抽血約1mL,以LC-MS/MS法定量血漿中催產素濃度。將至噴霧60分後為止的血漿中催產素濃度曲線示於第1圖、將由時間-濃度曲線求得之AUC0-60min.的平均值及標準差(兔子5或6隻)示於表1。此外,本案中AUC0-60min.為0至60分鐘之時間-濃度曲線下的面積。
取純水85g至玻璃容器中,一面以攪拌器攪拌一面添加催產素乙酸鹽0.054g(以催產素計為0.048g)、羧基乙烯基聚合物0.50g使其溶解後,添加3.00mL的0.1M氫氧化鈉溶液使其以pH計量測為pH4.0後,添加供調整黏度用的生理食鹽水0.60mL,其次添加純水使總量達100g,
調製成鼻黏膜投與用水性醫藥組成物。與實施例1同樣地測定重量滲透濃度、黏度。將調製之醫藥組成物的成分表、pH、重量滲透濃度、黏度示於表1。將調製之鼻黏膜投與用水性醫藥組成物與實施例1同樣地對兔子的單側鼻腔進行噴霧,並隨時間經過進行抽血。將由血漿中催產素濃度測定求得的血漿中催產素濃度曲線示於第1圖、將AUC0-60min.示於表1。
取純水95.55g至玻璃容器中,一面以攪拌器攪拌一面添加催產素乙酸鹽0.054g(以催產素計為0.048g)、羧基乙烯基聚合物0.50g使其溶解後,添加供調整黏度用的生理食鹽水0.60mL,並進一步添加3.30mL的0.1M氫氧化鈉溶液使pH成為4.0,調製成鼻黏膜投與用水性醫藥組成物。與實施例1同樣地測定重量滲透濃度、黏度。將調製之醫藥組成物的成分表、pH、重量滲透濃度、黏度示於表1。將調製之鼻黏膜投與用水性醫藥組成物與實施例1同樣地對兔子的單側鼻腔進行噴霧,並隨時間經過進行抽血。將由血漿中催產素濃度測定求得的血漿中催產素濃度曲線示於第1圖、將AUC0-60min.示於表1。
除供調整黏度用的生理食鹽水取2.30mL、供調整pH用的0.1M氫氧化鈉溶液取3.30mL以外,係與實施例2
同樣地調製成鼻黏膜投與用水性醫藥組成物。與實施例1同樣地測定滲透壓。黏度係使用B型黏度計(Brookfield公司,LVDV-II+)於25℃進行測定。將調製之醫藥組成物的成分表、pH、重量滲透濃度、黏度示於表1。又,將調製之鼻黏膜投與用水性醫藥組成物與實施例1同樣地對兔子的單側鼻腔進行噴霧,並隨時間經過進行抽血。將由血漿中催產素濃度測定求得的血漿中催產素濃度曲線示於第1圖、將AUC0-60min.示於表1。
對Syntocinon(製品名)以催產素濃度成為0.048%的方式添加催產素乙酸鹽而調製成醫藥組成物。與實施例1同樣地測定調製之鼻黏膜投與用水性醫藥組成物的pH、重量滲透濃度。將調製之醫藥組成物的pH、重量滲透濃度示於表1。又,將調製之鼻黏膜投與用水性醫藥組成物與實施例1同樣地對兔子的單側鼻腔進行噴霧,並隨時間經過進行抽血。將由血漿中催產素濃度測定求得的血漿中催產素濃度曲線示於第1圖、將AUC0-60min.示於表1。
取純水140g至玻璃容器中,一面以攪拌器攪拌一面添加0.1%氯化苄烷銨水溶液20g、純水20g、催產素乙酸鹽0.108g使其溶解後,添加1.0mL的0.1M鹽酸使其以pH計量測為pH4.0後,添加純水使總量達200g,調製成
鼻黏膜投與用水性醫藥組成物。與實施例4同樣地測定重量滲透濃度、黏度。將調製之醫藥組成物的成分表、pH、重量滲透濃度、黏度示於表1。又,將調製之鼻黏膜投與用水性醫藥組成物與實施例1同樣地對兔子的單側鼻腔進行噴霧,並隨時間經過進行抽血。將由血漿中催產素濃度測定求得的血漿中催產素濃度曲線示於第1圖、將AUC0-60min.示於表1。
取純水90g至玻璃容器中,一面以攪拌器攪拌一面添加羧基乙烯基聚合物0.26g使其溶解後,添加山梨糖醇4.80g、催產素乙酸鹽0.054g使其溶解後,添加0.70mL的0.1M氫氧化鈉溶液使其以pH計量測為pH4.0後,添加純水使總量達100g,調製成鼻黏膜投與用水性醫藥組成物。與實施例4同樣地測定重量滲透濃度、黏度。將調製之醫藥組成物的成分表、pH、重量滲透濃度、黏度示於表1。又,將調製之鼻黏膜投與用水性醫藥組成物與實施例1同樣地對兔子的單側鼻腔進行噴霧,並隨時間經過進行抽血。將由血漿中催產素濃度測定求得的血漿中催產素濃度曲線示於第1圖、將AUC0-60min.示於表1。
如實施例1所示,使用羧基乙烯基聚合物,且滲透壓比調整成低於1的組成物,相對於僅有屬催產素滴鼻劑唯一市售品之Syntocinon(製品名)的催產素濃度調整成與實施例相同的組成物(比較例1),顯示出實際顯著高達7倍的經鼻吸收性。又,如實施例2~4所示,使用羧基
乙烯基聚合物、滲透壓比低於1,且以鹽類將黏度調整成1917、2492、106mPa‧s的組成物,顯示出較高的經鼻吸收性。實施例2及3其AUC(0-60min.)特別高;而就以鹽類將黏度調整成1500~2800mPa‧s的組成物,顯示出經鼻吸收性提升效果特別高。另一方面,如比較例1所示,對Syntocinon(製品名)添加催產素使催產素濃度與實施例相同所調製而成的組成物,為低經鼻吸收性。又,如比較例2所示,未使用羧基乙烯基聚合物,僅使滲透壓比低於1的組成物,無法獲得高經鼻吸收性。又,如比較例3所示,使用羧基乙烯基聚合物且滲透壓比調整成接近等張的組成物,無法獲得高經鼻吸收性。
取0.036%對羥基苯甲酸甲酯/0.018%對羥基苯甲酸丙酯溶液83.55g至玻璃容器中,一面以攪拌器攪拌一面添加催產素乙酸鹽0.282g(以催產素計為0.248g)、羧基乙烯基聚合物0.60g使其溶解後,添加3.2mL的0.1M氫氧化鈉溶液使其以pH計量測為pH4.0,其次添加純水使總量達100g,調製成鼻黏膜投與用水性醫藥組成物。與實施例1同樣地測定重量滲透濃度、黏度。將調製之醫藥組成物的成分表、pH、重量滲透濃度、黏度示於表2。又,將調製之鼻黏膜投與用水性醫藥組成物100μL以市售滴鼻液劑用投與器對兔子(日本白種,公,體重約3kg,20隻)的單側鼻腔進行噴霧。於投與後0.5、1、2、4、8小
時後由大池採取約0.5mL的腦脊髓液(CSF),以LC-MS/MS法定量CSF中的催產素濃度。
取0.036%對羥基苯甲酸甲酯/0.018%對羥基苯甲酸丙酯溶液83.87g至玻璃容器中,一面以攪拌器攪拌一面添加催產素乙酸鹽0.283g(以催產素計為0.249g)、羧基乙烯基聚合物0.60g使其溶解後,添加供調整黏度用的生理食鹽水0.8mL,並添加3.9mL的0.1M氫氧化鈉溶液使其以pH計量測為pH4.0後,其次添加純水使總量達100g,調製成鼻黏膜投與用水性醫藥組成物。與實施例1同樣地測定重量滲透濃度、黏度。將調製之醫藥組成物的成分表、pH、重量滲透濃度、黏度示於表2。將調製之鼻黏膜投與用水性醫藥組成物與實施例5同樣地對兔子(日本白種,公,體重約3kg,20隻)的單側鼻腔進行噴霧,並由大池隨時間經過採取CSF,以LC-MS/MS法定量CSF中的催產素濃度。
如實施例5所示,使用羧基乙烯基聚合物,且滲透壓比調整成低於1的組成物,其經鼻投與後之催產素在腦脊髓液(CSF)中的濃度的半衰期為1.8小時,為血中濃度的半衰期的2倍以上。又,如實施例6所示,使用羧基乙烯基聚合物、滲透壓比低於1,且以鹽類調整黏度的組成物,其經鼻投與後之催產素在腦脊髓液(CSF)中濃度的半衰期為2.3小時,為血中濃度的半衰期的2倍以上。亦即,此顯示出經長時間仍能以高水準維持催產素在CSF中的濃度之CSF中的濃度持續性。此外,比較例1之製劑,催產素在CSF中的濃度在大部分的個體中為未達測定靈敏度。
由此顯示,在包含催產素或者其酸加成鹽或該等之衍生物的水性組成物中,藉由包含羧基乙烯基聚合物,且使滲透壓比低於1,可達成顯著之催產素向腦脊髓液的可轉移性與腦脊髓液中催產素濃度的持續性。根據本發明,可獲得能長時間以高濃度維持催產素在腦脊髓液中的濃度之滴鼻劑。
本發明之鼻黏膜投與用醫藥組成物係含有催產素或者其酸加成鹽或該等之衍生物作為有效成分,可作為催產素從鼻黏膜的吸收性高,且在安全面之疑慮較少的滴鼻劑使用。
Claims (6)
- 一種鼻黏膜投與用醫藥組成物,其特徵為包含催產素或者其酸加成鹽,或於催產素或者其酸加成鹽附加有多糖或聚乙二醇作為連結子的化合物、及羧基乙烯基聚合物,且重量滲透濃度為2~200mOsm。
- 如請求項1之鼻黏膜投與用醫藥組成物,其重量滲透濃度為2~100mOsm。
- 如請求項1之鼻黏膜投與用醫藥組成物,其係進一步包含水溶性之鹽類,且黏度為100~10000mPa‧s。
- 如請求項3之鼻黏膜投與用醫藥組成物,其黏度為1500~2800mPa‧s。
- 如請求項1~4中任一項之鼻黏膜投與用醫藥組成物,其中相對於鼻黏膜投與用醫藥組成物,含有0.1~2.0重量%的羧基乙烯基聚合物。
- 如請求項1~4中任一項之鼻黏膜投與用醫藥組成物,其中相對於鼻黏膜投與用醫藥組成物,含有0.01~20mM的鹽類。
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