CN112516151A - 胆钙化醇的硫酸盐及其用于治疗维生素d3缺乏的用途 - Google Patents
胆钙化醇的硫酸盐及其用于治疗维生素d3缺乏的用途 Download PDFInfo
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- CN112516151A CN112516151A CN202011450425.4A CN202011450425A CN112516151A CN 112516151 A CN112516151 A CN 112516151A CN 202011450425 A CN202011450425 A CN 202011450425A CN 112516151 A CN112516151 A CN 112516151A
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- Prior art keywords
- cholecalciferol
- sulfate
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- aqueous
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Images
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Abstract
胆钙化醇的药学上可接受的硫酸盐用于对抗维生素D3缺乏。也描述了新的胆钙化醇的硫酸盐以及胆钙化醇的药学上可接受的硫酸盐的药物组合物。
Description
本申请是申请日为2016年7月12日、申请号为200680051947.2、发明名称为“胆钙化醇的硫酸盐及其用于治疗维生素D3缺乏的用途”的中国发明专利申请的分案申请。
技术领域
本发明涉及药学上可接受的胆钙化醇的硫酸盐用于在脊椎动物中、特别是人类中对抗维生素D3缺乏的用途,其通过下述施用方法进行:实现至少5%的胆钙化醇的硫酸盐原样(as such)从施用部位供给至人体的全身流体运送系统而不被代谢,涉及新的药学上可接受的胆钙化醇的硫酸盐以及用于上述施用的剂型的药物组合物,其含有药学上可接受的胆钙化醇的硫酸盐。
背景技术
已知世界的大部分人群罹患维生素D3缺乏。在天然条件下,已知维生素D3在人类中通过皮肤暴露于UV辐射由7-脱氢胆甾醇产生,其作为水溶性维生素D3的硫酸盐(胆钙化醇的硫酸盐)。特别是在冬季的月份许多人不能将他们自己充分地暴露于UV辐射,来在皮肤中形成足量的维生素D3的硫酸盐。
胆钙化醇的硫酸盐在母乳中被发现,且还在其它种类的乳液中被发现更少的量。一些其它类型的食品,例如鳕鱼肝油,含有非硫酸化的脂肪-可溶的维生素D3(胆钙化醇)。在膳食补充剂中,还含有维生素D3,作为脂肪-可溶的胆钙化醇。维生素D3的后一种形式在体内并非硫酸化的。
本发明的目的是完成身体的天然胆钙化醇的硫酸盐的供给,所述供给以快速的或者否则以延长的方式进行,无需UV辐射来照射皮肤。
发明内容
相应地,本发明涉及药学上可接受的胆钙化醇的硫酸盐用于在脊椎动物中、特别是人类中对抗维生素D3缺乏的用途,其通过下述施用方法进行:实现至少5%的胆钙化醇的硫酸盐从施用部位原样到达人体的全身流体运送系统而不被代谢。
进一步地,本发明涉及新的药学上可接受的胆钙化醇的硫酸盐,特别是胆钙化醇硫酸镁,胆钙化醇硫酸钙和L-赖氨酸-胆钙化醇硫酸盐。
最后,本发明涉及药物组合物,所述药物组合物包含至少一种胆钙化醇的药学上可接受的硫酸盐和载体(其适于经皮施用或经粘膜施用或真皮内注射(intradermal),皮下注射或肌肉内注射)。
附图说明
图1显示L-赖氨酸胆钙化醇硫酸盐(L-lysine cholecalciferol sulfate)在D4-甲醇中的NMR光谱(200MHz;内标:TMS)。
发明详述
令人惊讶地,发现胆钙化醇的硫酸盐和因而天然形式的维生素D3能够以其不会直接代谢成水-不溶的胆钙化醇或(25OH)-胆钙化醇的方式被供给至身体。淋巴系统能够在体内分布水-可溶的胆钙化醇的硫酸盐(原样)。水-可溶的胆钙化醇的硫酸盐当然也在血液中可溶。然而,在那里它们可以潜在发生快速的,例如酶(促)分解。
在本文中,对抗维生素D3缺乏意指预防和治疗维生素D3缺乏。
在本文中,药学上可接受的胆钙化醇的硫酸盐意指这些盐的阳离子对与人体而言决不是有毒的。药学上可接受的阳离子是例如Na,Mg,Ca,Zn,铵,和质子化的氨基酸,例如质子化的赖氨酸。
胆钙化醇的硫酸盐通常在水中或在含水-含醇的混合物中是可溶的。含有无机阳离子的药学上可接受的胆钙化醇的硫酸盐的实例是胆钙化醇硫酸钠,胆钙化醇硫酸镁,胆钙化醇硫酸钙和胆钙化醇硫酸铵。含有有机阳离子的药学上可接受的胆钙化醇的硫酸盐的实例是胆钙化醇硫酸三甲基铵(trimethylammonium cholecalciferol sulfate)和L-赖氨酸胆钙化醇硫酸盐。
如下选择按照本发明的施用方法:使得它实现至少5%施用量的胆钙化醇的硫酸盐从施用部位运送进入人体的全身流体运送系统而不被代谢。取决于施用方法,优选至少10%,15%,20%,25%,30%,35%,40%,45%或50%的所施用的胆钙化醇的硫酸盐从施用部位原样到达人体的全身性的流体运送系统而不经历代谢。
优选地,在至少一种全身流体运送系统(选自血液和淋巴)中,在至少5分钟,优选超过至少10,15,20或甚至30分钟的时间段内,所施用的胆钙化醇的硫酸盐在化学上修饰(代谢)小于70%,优选小于60%,例如50%,40%,30%,20%或甚至小于10%或更小。
人体的全身流体运送系统是例如血液和优选淋巴。
药学上可接受的胆钙化醇的硫酸盐的优选的施用方式是经皮施用或经粘膜施用以及真皮内注射,皮下注射和肌肉内注射,具有延长释放的贮库制剂-注射(包括活性物质)。经口施用(也即供给至胃,例如通过吞咽),静脉内注射和动脉内注射明确地被排除作为施用方式。
所施用的胆钙化醇的硫酸盐的摩尔量一般相应于胆钙化醇的推荐摩尔量。
胆钙化醇的硫酸盐的制备可以如下实现:通过商购的胆钙化醇与吡啶-三氧化硫复合物(complex)在吡啶中反应和随后与三乙胺反应以得到胆钙化醇硫酸三乙铵,其然后通过加入适当的阳离子的饱和的水溶液能够在水溶液中再沉淀,从而形成盐连同这些阳离子。
另选地,胆钙化醇能够与吡啶-三氧化硫复合物在吡啶中反应和然后任选地在适当的缓冲剂存在下,直接与所希望的阳离子反应,以形成所希望的盐。
按照本发明的药物组合物包含适宜的载体或适宜的媒介物。它们还能够包含额外的活性的试剂,例如其它维生素,矿物质和痕量元素以及任意种类的药物。
用于经皮施用的适宜的媒介物或载体是药学领域的技术人员已知的用于这种目的的所有媒介物。这些包含基于脂肪或油的液体或固体媒介物以及基于含水或(are)含水-含醇的媒介物。配制剂能够采用下述形式:软膏剂和油,洗剂,溶液(其适于喷雾),悬浮液和乳液(任意种类),和贴剂(其在媒介物中含有活性物质)。配制剂能够包括渗透促进剂,例如二甲亚砜,乳化剂以及药学常规使用的任意进一步的赋形剂,例如稀释剂,调味剂,增溶剂,润滑剂,助悬剂,粘合剂和防腐剂。
用于经粘膜施用的适宜的配制剂是例如,含水溶液或含醇的-含水溶液(其可以包含进一步的赋形剂),基于脂肪的栓剂,霜剂,凝胶,糊剂,泡沫或喷雾剂和适于阴道施用的子宫脱(pessars)和压塞物(tamponade)以及适于在嘴或舌下施用中的局部施用的固体剂型,包括在调味基质(通常蔗糖和阿拉伯胶或黄蓍胶)中含有活性组分的锭剂(lozenges);软锭,在惰性基质(例如明胶或甘油)含有活性的组分;和口香糖。用于经粘膜施用的配制剂还能够包含渗透促进剂例如二甲亚砜,乳化剂以及药学中常用的任意进一步的赋形剂。
用于肠胃外施用(借助于真皮内注射,皮下注射和肌肉内注射)的液体形式的制剂包括悬浮液,溶液或乳液(在含油或含水媒介物中)。制剂能够包含配制剂赋形剂,例如助悬剂,稳定剂和/或分散剂。另选地,活性组分可以呈粉末形式,在使用前将活性组分与适当的媒介物,像无菌无热原水混合,用于其构建(constitution)。
可以在例如Remington,The Science and Practice of Pharmacy,Ed.Allen,Loyd V.Jr,22nd Edition,Pharmaceutical Press中发现适于本发明使用的施用形式的详细描述。
具体实施方式
实施例1–制备胆钙化醇硫酸三乙铵
在氮气氛下,将6.5ml吡啶加入至1.21g吡啶-三氧化硫复合物(约6.76mmol与SO3复合的(complex)吡啶;Sigma-Aldrich;≥45wt.-%SO3,根据生产商的信息)和1.21g(3.14mmol)胆钙化醇(Sigma-Aldrich)。获得的溶液在58℃密集地搅拌1小时。然后,将0.63ml(0.456g;4.55mmol)三乙胺加入和在58℃继续搅拌另外的20分钟。
然后,在0℃在冰浴中将反应混合物冷却,加入16.5ml冷甲醇-三氯甲烷(10:1vol./vol.)溶液和继续搅拌20分钟。
将溶液过滤通过玻璃釉料和在旋转式蒸发仪上除去溶剂。为了进一步纯化,将残余物用甲醇-三氯甲烷(10:1Vol./Vol.)溶液处理两次和在旋转式蒸发仪上除去溶剂,由此获得1.52g(3.13mmol;99,7%)胆钙化醇硫酸三乙铵。
TLC(硅胶):RF=0.42,在甲醇-三氯甲烷中(1:9vol./vol.)。
实施例2–制备胆钙化醇硫酸铵
将约14ml饱和的乙酸铵溶液加入至1.52g(3.13mmol)胆钙化醇硫酸三乙铵,直到形成胆钙化醇硫酸铵的白色沉淀,在已经被静置过夜后,使用玻璃釉料将其过滤和在高真空下干燥同时通过约15℃的温度的自来水冷却。
收率:1.74g(3.10mmol,99%)。
熔点:104-108℃
实施例3–制备胆钙化醇的硫酸钠
将氯化钠的饱和溶液(约14ml)加入至1.52g(3.13mmol)胆钙化醇硫酸三乙铵,直到形成胆钙化醇硫酸钠的白色沉淀,在已经被静置过夜后,使用玻璃釉料将其过滤和在高真空下干燥同时通过约15℃的温度的自来水冷却。
收率:1.75g(3.10mmol,99%)。
NMR-光谱(NMR-Spektrum)与在L.E.Reeve等人.,The Journal of BiologicalChemistry(1981)Vol.256,Nr.2,p.824中公开的相同。
实施例4–制备胆钙化醇硫酸镁
将氯化镁的饱和溶液(约13ml)加入至1.52g(3.13mmol)胆钙化醇硫酸三乙铵,直到形成胆钙化醇硫酸镁的白色沉淀,在已经被静置过夜后,使用玻璃釉料将其过滤和在高真空下干燥同时通过约15℃的温度的自来水冷却。
收率:1.76g(3.10mmol;99%)。
熔点.:107-110℃(分解)。
实施例5–制备胆钙化醇硫酸钙
将CaCl2·2H2O的饱和的溶液(约13ml)加入至1.52g(3.13mmol)胆钙化醇硫酸三乙铵,直到形成胆钙化醇硫酸钙的白色沉淀,在已经被静置过夜后,使用玻璃釉料将其过滤和在高真空下干燥同时通过约15℃的温度的自来水冷却。
收率:1.81g,(3.10mmol,99%)。
TLC(硅胶):Rf=0.48,在甲醇-三氯甲烷中(1:9Vol./Vol.)
熔点.:97-101℃(分解.)。
实施例6–制备L-赖氨酸胆钙化醇硫酸盐
在氮气氛下,将517.4mg吡啶-三氧化硫复合物(Sigma-Aldrich;≥45Wt.-%SO3,根据生产商的信息)(约2.90mmol与SO3复合的吡啶)和506.3mg(1.32mmol)胆钙化醇(cholecaliferol)(Sigma-Aldrich)溶于4.4ml吡啶和在55℃加热1小时,同时激烈地搅拌。在加入10ml冰-冷却的甲醇-三氯甲烷(1:9Vol/Vol)混合物后,在旋转式蒸发仪上除去溶剂。然后,将在0.5ml磷酸钠缓冲溶液,pH 7.3中的0.29g L-赖氨酸(1.98mmol)加入和搅拌5分钟。然后,将20ml冰-冷却的甲醇-三氯甲烷(1:9vol./vol.)混合物加入同时搅拌,此后在旋转式蒸发仪上反萃取(stripped)混合物。将10ml无水乙醇加入残余物,和将溶液在冷藏器中储存过夜。然后,将乙醇从形成的白色奶油状(creamy)沉淀倾析和干燥残余物,同时通过约15℃的温度的自来水冷却,由此获得标题化合物,作为白色粉末(815mg,(1.30mmol);98.5%)。
TLC(硅胶):Rf=0.33,在甲醇-三氯甲烷中(1:9Vol./Vol.)。
熔点:168℃(分解)
NMR光谱:参考图1
实施例7–制备D,L-赖氨酸胆钙化醇硫酸盐
D,L-赖氨酸胆钙化醇硫酸盐的制备通过下述来实现:类似于制备L-赖氨酸胆钙化醇硫酸盐的方式,但使用DL-赖氨酸(Sigma.-Aldrich)而不是L-赖氨酸。
在D4-甲醇中的NMR光谱确认结构。
实施例8–在油基中L-赖氨酸胆钙化醇硫酸盐的经皮施用配制剂
将100mg L-赖氨酸胆钙化醇硫酸盐与11.04ml油酸混合,然后将0.83ml二甲亚砜加入和在室温下(21-25℃)通过磁力搅拌器搅拌2天。随后,将10ml甘油三油酸酯和7ml甘油单油酸酯(glycerol momonooleate)(Gattefosse)加入和激烈振摇。在等待直到混合物去泡沫后,获得L-赖氨酸胆钙化醇硫酸盐在油相中几乎完全透明的稳定的溶液。
实施例9–将实施例8的经皮配制剂应用至皮肤
将实施例8中制备的约2ml配制剂应用至受试者的皮肤的薄层中和允许渗透4小时。随后,使用经96%乙醇浸泡的无菌棉垫充分擦拭皮肤。将棉垫用额外的96%乙醇煮沸和挤压的。在旋转式蒸发仪上蒸发乙醇,和将少量的氯仿-甲醇(9:1Vol./Vol.)混合物加入至烧瓶。所述混合物在硅胶上的TLC显示,在皮肤上基本上没有L-赖氨酸胆钙化醇硫酸盐(Rf:0.33)残留。
实施例10–制备含水注射溶液
用于制备2ml注射溶液(其含有对应于10.000IE维生素D3的量的胆钙化醇的硫酸盐)
a)1.5695mg胆钙化醇的硫酸钠用于产生注射溶液A
b)1.6243mg胆钙化醇硫酸钙用于产生注射溶液B和
c)1.970mg L-赖氨酸胆钙化醇硫酸盐用于产生注射溶液C
各自溶于10ml蒸馏水。然后,将89.9028mg氯化钠加入至各溶液以使得它们等渗。
注射溶液B的pH使用0.5N NaOH调节至pH 7。
此后,在氩气氛下,将溶液通过0.22μm膜滤器-灭菌和填充至2ml小瓶。
在本文中所引用的全部文献的公开内容,例如专利,公开的专利申请,在期刊和书籍中所公开的文章,在此通过全文引用的方式并入本说明。
Claims (12)
1.胆钙化醇的药学上可接受的硫酸盐用于在脊椎动物中、特别是人类中对抗维生素D3缺乏的用途,其通过下述施用方法进行:确保至少5%的胆钙化醇的硫酸盐原样从施用部位经过,进入人体的全身流体运送系统而不被代谢。
2.根据权利要求1的用途,其中所述施用方法选自经皮施用和经粘膜施用以及真皮内注射,皮下注射和肌肉内注射,包括持续药物释放贮库制剂注射。
3.根据权利要求1的用途,其中所述胆钙化醇的硫酸盐选自胆钙化醇硫酸钠,胆钙化醇硫酸镁,胆钙化醇硫酸钙,胆钙化醇硫酸铵,胆钙化醇硫酸三甲基铵和/或L-赖氨酸胆钙化醇硫酸盐。
4.根据权利要求2的用途,其中所述胆钙化醇的硫酸盐是L-赖氨酸胆钙化醇硫酸盐。
5.胆钙化醇的药学上可接受的硫酸盐,其排除胆钙化醇硫酸钠,胆钙化醇硫酸铵和胆钙化醇硫酸三甲基铵。
6.根据权利要求5的胆钙化醇的药学上可接受的硫酸盐,其选自胆钙化醇硫酸镁,胆钙化醇硫酸钙和L-赖氨酸胆钙化醇硫酸盐。
7.药物组合物,所述药物组合物包含至少一种胆钙化醇的药学上可接受的硫酸盐和媒介物,所述媒介物适于经皮施用或经粘膜施用或真皮内注射,皮下注射或肌肉内注射,包括持续释放贮库制剂注射。
8.根据权利要求7的药物组合物,其中所述媒介物是基于油的媒介物或基于脂肪的媒介物,所述媒介物适于经皮施用。
9.根据权利要求7的药物组合物,其中所述媒介物是基于含水的媒介物或含水-含醇的媒介物,所述媒介物适于经皮施用。
10.根据权利要求7至9中任一项的药物组合物,所述药物组合物是贴剂的形式。
11.根据权利要求7的药物组合物,其中所述媒介物是基于含水的媒介物或含水-含醇的媒介物,所述媒介物适于经粘膜施用。
12.根据权利要求7的药物组合物,其中所述媒介物是基于含水的媒介物或含水-含醇的媒介物,所述媒介物适于真皮内注射,皮下注射或肌肉内注射。
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