CN104080478A - 非水性液体组合物 - Google Patents
非水性液体组合物 Download PDFInfo
- Publication number
- CN104080478A CN104080478A CN201380007257.3A CN201380007257A CN104080478A CN 104080478 A CN104080478 A CN 104080478A CN 201380007257 A CN201380007257 A CN 201380007257A CN 104080478 A CN104080478 A CN 104080478A
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- CN
- China
- Prior art keywords
- aqueous liquid
- dopc
- liquid compositions
- tocopherol
- scope
- 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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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
一种非水性液体组合物,是含有药物、二油酰磷脂酰胆碱、生育酚及有机溶剂的药物溶解型的非水性液体组合物,其中,二油酰磷脂酰胆碱与生育酚的配合浓度比在75/25~25/75的范围内,二油酰磷脂酰胆碱的配合浓度在15~85%(w/w)的范围内,生育酚的配合浓度在15~85%(w/w)的范围内,所述非水性液体组合物通过接触水、磷酸缓冲液、体液、泪液或玻璃体液而相变化为非片状液晶。
Description
技术领域
本发明涉及含有药物、二油酰磷脂酰胆碱、生育酚及有机溶剂的药物溶解型的非水性液体组合物、以及含有该非水性液体组合物的注射剂、眼科用制剂。
背景技术
二油酰磷脂酰胆碱(以下,“DOPC”)是具有2个油酸、甘油、磷酸及胆碱复合而成的结构的两亲性物质。作为两亲性物质,除DOPC之外,例如,还已知二油酰磷脂酰甘油(以下,“DOPG”)、二油酰磷脂酰乙醇胺(以下,“DOPE”)、磷脂酰胆碱(以下,“PC”)、大豆卵磷脂(以下,“SPC”)、单油酸甘油酯(以下,“GMO”)等。
另一方面,要求开发将药物给予至机体时长期滞留在给予部位(例如,玻璃体等)附近、具有持续释放药物的作用的贮库制剂(depotpreparations)。例如,国际公开第2006/131730号(专利文献1)公开了含有SPC和二油酸甘油酯(以下,“GDO”)的贮库制剂,另外,国际公开第2005/117830号(专利文献2)公开了含有PC和GDO的贮库制剂、含有PC和生育酚(以下,“VE”)的贮库制剂。但是,专利文献1、2中公开的贮库制剂若以向玻璃体等机体给予为前提则在机体内的药物的缓释性不充分,另外,在机体内也可能膨润。
专利文献1:国际公开第2006/131730号
专利文献2:国际公开第2005/117830号
发明内容
本发明是为了解决上述课题而完成的,其目的在于,以通过利用作为两亲性物质的DOPC的特性来探索下述非水性制剂作为课题,所述非水性制剂在给予前是液体状态,但给予后在机体内成为贮库(液晶状态),具有药物缓释作用。
本发明人等发现含有药物、DOPC、VE及有机溶剂、并且使DOPC与VE的配合浓度比在特定范围的非水性液体组合物为具有粘性的液体,但若接触到磷酸缓冲液、玻璃体液等则形成非片状液晶,结果在机体内长期持续释放药物,从而完成了本发明。即,本发明如下所述。
(1)一种非水性液体组合物,是含有药物、DOPC、VE及有机溶剂的药物溶解型的非水性液体组合物,其中,
1)上述DOPC与上述VE的配合浓度比在75/25~25/75的范围内,
2)上述DOPC的配合浓度在15~85%(w/w)的范围内,
3)上述VE的配合浓度在15~85%(w/w)的范围内,
4)所述非水性液体组合物通过接触水、磷酸缓冲液、体液、泪液或玻璃体液而相变化为非片状液晶。
(2)一种非水性液体组合物,是含有药物、DOPC、VE及有机溶剂的药物溶解型的非水性液体组合物,其中,
1)上述DOPC与上述VE的配合浓度比在70/30~30/70的范围内,
2)上述DOPC的配合浓度在20~80%(w/w)的范围内,
3)上述VE的配合浓度在20~80%(w/w)的范围内,
4)所述非水性液体组合物通过接触水、磷酸缓冲液、体液、泪液或玻璃体液而相变化为非片状液晶。
(3)如(1)或(2)所述的非水性液体组合物,其中,上述有机溶剂为乙醇、苯甲醇、聚乙二醇或二甲基乙酰胺。
(4)一种注射剂,含有(1)~(3)所述的非水性液体组合物。
(5)一种眼科用制剂,含有(1)~(3)所述的非水性液体组合物。
关于本发明的非水性液体组合物,如由后述的相特性试验(phasebehavior test)、以及体外及体内的药物释放特性试验所表明的那样,具有下述特性:若接触磷酸缓冲液、玻璃体液等则相变为非片状液晶,形成硬的贮库,结果长时间稳定地缓释药物。由此,本发明的非水性液体组合物在向机体给予前是操作容易的液体,但给予后相变为非片状液晶,由此可期待发挥优异的药物缓释效果。进而,如后述使用了各种两亲性物质的膨润性试验的结果所示,确认到即使将使用了DOPC作为两亲性物质的本发明的非水性液体组合物给予至例如玻璃体内,4个月以上在水中也不膨润,因此,也不会发生伴随着膨润的视野障碍、视力下降等副作用。
具体实施方式
本发明的非水性液体组合物中的药物没有特别限定,期望为在由DOPC、VE及有机溶剂形成的非水性液体中溶解的药物。作为优选药物,例如,可举出氢化可的松、氟羟脱氢皮质醇、氟轻松、地塞米松等甾族化合物、异丙基乌诺前列酮等前列腺素、环孢菌素、雷帕霉素等免疫抑制剂、吲哚美辛、溴芬酸等非甾族化合物性抗炎剂、帕唑帕尼、SU5416、瓦他拉尼(valatinib)、兰尼单抗(ranibizumab)、贝伐单抗(bevacizumab)等血管生成抑制剂、日本特开2006-96739号公报、日本特开2011-37844号公报、日本特开2005-232149号公报、日本特开2006-273851号公报、日本特开2006-306861号公报、日本特开2008-266294号公报等中记载的VEGF抑制剂、日本特开2007-230993号公报、日本特开2008-074829号公报、日本特开2008-143889号公报、日本特开2008-143890号公报、日本特开2008-143891号公报、日本特开2009-007344号公报、日本特开2009-084274号公报等中记载的具有糖皮质激素受体结合活性的化合物、RU24858等选择性糖皮质激素受体激动剂、氟尿嘧啶等抗癌剂、托法替尼等詹纳斯激酶抑制剂(Janus kinase inhibitor)、鲁伯斯塔(ruboxistaurin mesylate)等蛋白激酶抑制剂等。
关于本发明的非水性液体组合物中药物的配合浓度,由于根据药物种类的不同而不同,因此没有特别限定,但优选在0.1~60%(w/w)的范围内,较优选在0.1~10%(w/w)的范围内,特别优选在0.2~8%(w/w)的范围内。
本发明的非水性液体组合物中的DOPC是两亲性物质,其配合浓度在15~85%(w/w)的范围内,优选在20~80%(w/w)的范围内。
本发明的非水性液体组合物中的VE是指α-生育酚(维生素E)、β-生育酚、γ-生育酚,也可以为生育酚乙酸酯、生育酚烟酸酯、生育酚琥珀酸酯等生育酚衍生物。本发明的非水性液体组合物中的VE的配合浓度在15~85%(w/w)的范围内,优选在20~80%(w/w)的范围内。
本发明的非水性液体组合物中的DOPC与VE的配合浓度比在75/25~25/75的范围,优选在70/30~30/70的范围内,较优选在70/30~35/65的范围内。由后述相特性试验的结果确认到,若将DOPC与VE的配合浓度比设定在上述范围内,则为具有粘性的液体,但通过接触磷酸缓冲液、玻璃体液而相变为非片状液晶,形成硬的贮库。此处,所谓“非片状液晶”,是指处于液体与固体中间的液晶状态中、不形成片状结构(层状结构)的形态的液晶,可举出反六方液晶(H2)、反立方液晶(Q2)等。是否相变为非片状液晶,可利用偏光显微镜进行观察,基于以下确认:例如,在反六方液晶的情况下,由于显示双折射性,因此成为各向异性的条纹图案或者几何图案,另外,在反立方液晶的情况下,由于不显示双折射性,因此成为暗视野。另外,确认到本发明的非水性液体组合物在后述的体外的药物释放特性试验的结果中具有70天以上稳定缓释药物的特性,在后述体内的药物释放特性试验的结果中具有12周(84天)稳定缓释药物的特性,作为贮库制剂有用。由此,本发明的非水性液体组合物的稳定的药物缓释特性,是通过将DOPC与VE的配合浓度比设定在上述范围内才能够实现的效果。
作为本发明的非水性液体组合物中使用的有机溶剂,优选药物中允许的有机溶剂,例如,可举出乙醇等低级醇、丙二醇、甘油等多元醇、PEG400等聚乙二醇、苯甲醇、二甲基乙酰胺(DMA)、二甲基亚砜(DMSO)等。其中,优选乙醇、苯甲醇、聚乙二醇或二甲基乙酰胺。
本发明的非水性液体组合物中的有机溶剂的配合浓度没有特别限定,优选在1~50%(w/w)的范围内,较优选在3~30%(w/w)的范围内。
本发明的非水性液体组合物期望非口服给予,作为给予剂型,例如,可举出溶液剂(liquid medicine)、注射剂等,它们可使用通用的技术制成制剂。例如,若为溶液剂、注射剂等,则根据需要可使用聚氧乙烯山梨醇酐单油酸酯、硬脂酸-40-聚烃氧基酯、聚氧乙烯氢化蓖麻油等表面活性剂、依地酸钠等稳定剂、苯扎氯铵、对羟基苯甲酸酯等防腐剂等进行制备。本发明的非水性液体组合物能够以含有其的注射剂、眼科用制剂等的形式进行利用。
以下示出各种试验结果及制剂例,这些例子用于更好地理解本发明,不限定本发明的范围。
〔1〕相特性试验
在改变二油酰磷脂酰胆碱(DOPC)与生育酚(VE)的配合浓度比而得的组合物中添加磷酸缓冲液,研究相特性。
(实验操作)
在DOPC中加入甲醇并溶解使得成为500mg/mL,另外,在VE中加入甲醇并溶解使得成为500mg/mL。将制备得到的DOPC溶液及VE溶液按照下述表1所示的比例分别混合后,在氮气流下除去甲醇,在减压下保存24小时以上。保存后,在该组合物中加入磷酸缓冲液(pH7.4)进行混合,使用偏光显微镜(LICA公司制LEICA DMLB)确认其外观及相特性。需要说明的是,每次加入5%(w/w)磷酸缓冲液直至DOPC/VE中的磷酸缓冲液浓度变为45%(w/w)。
(结果)
将添加磷酸缓冲液后的外观及相特性示于表1。
[表1]
※1:Q2表示反立方液晶。
※2:H2表示反六方液晶。
(讨论)
表1表明,关于包含在本发明中的组合物4~8,由于形成非片状液晶Q2或H2,因此若给予至机体内则形成贮库。相对于此,关于不包含在本发明中的组合物1~3及9~11,由于未形成液晶,因此认为即使给予至机体内也不形成贮库。
〔2〕制剂例1~6及比较例1~4
(1)制剂例1
在20mg的氢化可的松(HC)中加入约980mg的乙醇(EtOH),加热至60℃搅拌至溶解(2%HC溶液)。将该50mg的2%HC溶液加入到225mg的DOPC中,加热至70℃一边搅拌一边溶解。溶解后,加入225mg的VE,再次加热至70℃搅拌至溶解,制备含有0.2%HC的DOPC制剂。
(2)制剂例2
使用20mg的醋酸氟羟脱氢皮质醇(TA)代替HC,除此之外,与制剂例1同样地操作,制备含有0.2%TA的DOPC制剂。
(3)制剂例3
使用20mg的醋酸氟轻松(FA)代替HC,除此之外,与制剂例1同样地操作,制备含有0.2%FA的DOPC制剂。
(4)制剂例4
在50mg的FA中加入约200mg的苯甲醇(BzOH),加热至60℃搅拌至溶解(20%FA溶液)。将该100mg的20%FA溶液加入至200mg的DOPC中,加热至70℃一边搅拌一边溶解。溶解后,加入200mg的VE,再次加热至70℃搅拌至溶解,制备含有4%FA的DOPC制剂。
(5)制剂例5
将6mg的氟尿嘧啶(5-FU)加入到294mg的聚乙二醇(PEG)400中,加热至70℃搅拌至溶解(2%5-FU溶液)。将该50mg的2%5-FU溶液加入到225mg的DOPC中,加热至70℃一边搅拌一边溶解。溶解后,加入225mg的VE,再次加热至70℃搅拌至溶解,制备含有0.2%5-FU的DOPC制剂。
(6)制剂例6
将6mg的5-FU加入到294mg的PEG400中,加热至70℃搅拌至溶解(2%5-FU溶液)。将该50mg的2%5-FU溶液加入到180mg的DOPC中,加热至70℃一边搅拌一边溶解。溶解后,加入270mg的生育酚,再次加热至70℃搅拌至溶解,制备含有0.2%5-FU的DOPC制剂。
(7)比较例1
在20mg的TA中加入约980mg的EtOH,加热至60℃搅拌至溶解(2%TA溶液)。将该50mg的2%TA溶液加入到225mg的大豆卵磷脂(SPC)中,加热至70℃一边搅拌一边溶解。溶解后,加入225mg的VE,再次加热至70℃搅拌至溶解,制备含有0.2%TA的SPC制剂。
(8)比较例2
将比较例1中制备的50mg的2%TA溶液加入到90mg的SPC中,加热至70℃一边搅拌一边溶解。溶解后,加入90mg的二油酸甘油酯(GDO),再次加热至70℃搅拌至溶解,制备含有0.2%TA的SPC制剂。
(9)比较例3
在40℃下加热单油酸甘油酯(GMO)并溶解。溶解后,将比较例1中制备的50mg的2%TA溶液加入到225mg的GMO中,加热至40℃一边搅拌一边溶解。溶解后,加入225mg的VE,再次加热至40℃搅拌至溶解,制备含有0.2%TA的GMO制剂。
(10)比较例4
在40℃下加热GMO并溶解。溶解后,将比较例1中制备的50mg的2%TA溶液加入到450mg的GMO中,加热至约40℃,一边搅拌一边溶解,制备含有0.2%TA的GMO制剂。
〔3〕制剂例1~6及比较例1~4中得到的各制剂的相特性试验
(实验操作)
将在上述项目〔2〕中分别制备的制剂例1~6及比较例1~4的各溶液20mg投入到2mL的0.1M磷酸缓冲液(pH7.4)中,在37℃下孵育。所有制剂在投入到磷酸缓冲液中后,均形成了硬的贮库。1天后,使用偏光显微镜评价生成的贮库的相特性。
(制剂例1~6的结果)
将制剂例1~6的相特性示于表2。需要说明的是,表2的各成分的数值表示%(w/w)。
[表2]
(比较例1~4的结果)
将比较例1~4的相特性示于表3。需要说明的是,表3的各成分表示%(w/w)。
[表3]
〔4〕制剂例7~34及所述制剂的相特性试验
进行与制剂例1~6相同的实验操作,制备下述表4所示的组成的各制剂(制剂例7~34),评价它们的相特性。关于它们的结果也示于表4。需要说明的是,表4的各成分的数值表示%(w/w)。
[表4]
※3:PG表示丙二醇。
※4:DSP表示地塞米松磷酸酯。
(讨论)
表4表明制剂例7~34均形成非片状液晶Q2或H2。
〔5〕制剂例1~6及比较例1~4中得到的各制剂的体外药物释放特性试验
(实验操作)
将制剂例1~6及比较例1~4中制备的各溶液20mg投入到2mL的0.1M磷酸缓冲液(pH7.4)中,在37℃下孵育。所有制剂在投入到磷酸缓冲液中后,均形成硬的贮库。经时地回收磷酸缓冲液,使用UPLC测定磷酸缓冲液中的药物浓度。
(结果)
将各制剂的体外药物释放特性示于表5。需要说明的是,表5中的累积药物释放率(%)是各3例的平均值,“ND”表示检测限以下。
[表5]
(讨论)
由表5可知,关于DOPC制剂(制剂例1~6),4种药物均持续释放药物70天以上,因此认为与SPC制剂(比较例1、2)及GMO制剂(比较例3、4)相比,发挥优异的药物缓释效果。
〔6〕体内药物释放特性试验
(实验操作)
在醋酸氟羟脱氢皮质醇(TA)80mg中,加入720mg的二甲基乙酰胺(DMA),搅拌至溶解(10%TA溶液)。在该10%TA溶液中加入1600mg DOPC及1600mg生育酚,加热至65℃搅拌至溶解,制备含有10%TA的DOPC制剂(制剂例35),评价投入到磷酸缓冲液后的相特性。表6中表示制剂例35的相特性。需要说明的是,表6的各成分的数值为%(w/w)。
[表6]
接着,将50μL制剂例35使用26gauge针给予至日本白色家兔(雄)的玻璃体中(N=4)。经时地从家兔采集房水、玻璃体、及脉络膜,使用LC-MS/MS测定药物浓度。制剂例35的药物浓度的测定结果示于表7。
[表7]
(讨论)
该制剂(制剂例35)在玻璃体注射后,历经12周(84天)维持一定以上的醋酸氟羟脱氢皮质醇浓度,因此预测长时间持续药物缓释效果。
〔7〕由各种两亲性物质和VE得到的各组合物的相特性和膨润性
(实验操作)
如下述表8所示,作为两亲性物质,取DOPC、DOPG、DOPE及SPC各90mg,加入10mg的EtOH及90mg的VE。在约70℃下加热后,搅拌溶解。溶解后,将各组合物0.1mL投入到2mL的水中,在37℃下孵育。所有的组合物在投入水中后形成硬的贮库。1天后,使用偏光显微镜评价生成的贮库的相特性。另外,还评价贮库在水中是否膨润。结果,所有的组合物均形成由非片状液晶形成的硬的贮库,但未确认到含有DOPC的组合物在水中膨润,而确认到含有DOPG、DOPE或SPC的组合物在水中的膨润。需要说明的是,表8的各成分的数值表示%(w/w)。
[表8]
(讨论)
将在水中膨润的制剂(组合物)给予至玻璃体内时,存在引起患者的视野障碍或视力下降的可能性,因此DOPC制剂适合给予至玻璃体、体液。
Claims (6)
1.一种非水性液体组合物,是含有药物、二油酰磷脂酰胆碱、生育酚及有机溶剂的药物溶解型的非水性液体组合物,其中,
1)所述二油酰磷脂酰胆碱与所述生育酚的配合浓度比在75/25~25/75的范围内,
2)所述二油酰磷脂酰胆碱的配合浓度在15~85%(w/w)的范围内,
3)所述生育酚的配合浓度在15~85%(w/w)的范围内,
4)所述非水性液体组合物通过接触水、磷酸缓冲液、体液、泪液或玻璃体液而相变化为非片状液晶。
2.一种非水性液体组合物,是含有药物、二油酰磷脂酰胆碱、生育酚及有机溶剂的药物溶解型的非水性液体组合物,其中,
1)所述二油酰磷脂酰胆碱与所述生育酚的配合浓度比在70/30~30/70的范围内,
2)所述二油酰磷脂酰胆碱的配合浓度在20~80%(w/w)的范围内,
3)所述生育酚的配合浓度在20~80%(w/w)的范围内,
4)所述非水性液体组合物通过接触水、磷酸缓冲液、体液、泪液或玻璃体液而相变化为非片状液晶。
3.如权利要求1所述的非水性液体组合物,其中,
所述有机溶剂为乙醇、苯甲醇、聚乙二醇或二甲基乙酰胺。
4.如权利要求2所述的非水性液体组合物,其中,所述有机溶剂为乙醇、苯甲醇、聚乙二醇或二甲基乙酰胺。
5.一种注射剂,含有权利要求1~4中任一项所述的非水性液体组合物。
6.一种眼科用制剂,含有权利要求1~4中任一项所述的非水性液体组合物。
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- 2013-01-30 JP JP2013015164A patent/JP2013177372A/ja active Pending
- 2013-01-30 US US14/375,251 patent/US20150011518A1/en not_active Abandoned
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- 2013-01-30 CA CA 2861261 patent/CA2861261A1/en not_active Abandoned
- 2013-01-30 EP EP13744346.1A patent/EP2810657B1/en not_active Not-in-force
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IN2014DN06911A (zh) | 2015-05-15 |
CA2861261A1 (en) | 2013-08-08 |
EP2810657A4 (en) | 2015-07-29 |
TW201336526A (zh) | 2013-09-16 |
PH12014501689A1 (en) | 2014-10-20 |
SG11201404230QA (en) | 2014-10-30 |
EP2810657B1 (en) | 2016-09-21 |
WO2013115201A1 (ja) | 2013-08-08 |
KR20150000874A (ko) | 2015-01-05 |
EA201491453A1 (ru) | 2014-12-30 |
SG10201606271RA (en) | 2016-09-29 |
US20150011518A1 (en) | 2015-01-08 |
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