CN112770744A - 丹曲洛林水性制剂及其制备方法 - Google Patents
丹曲洛林水性制剂及其制备方法 Download PDFInfo
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- CN112770744A CN112770744A CN201880097128.0A CN201880097128A CN112770744A CN 112770744 A CN112770744 A CN 112770744A CN 201880097128 A CN201880097128 A CN 201880097128A CN 112770744 A CN112770744 A CN 112770744A
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- China
- Prior art keywords
- dantrolene
- mol
- preparation
- cyclodextrin
- aqueous
- Prior art date
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- OZOMQRBLCMDCEG-CHHVJCJISA-N 1-[(z)-[5-(4-nitrophenyl)furan-2-yl]methylideneamino]imidazolidine-2,4-dione Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(O1)=CC=C1\C=N/N1C(=O)NC(=O)C1 OZOMQRBLCMDCEG-CHHVJCJISA-N 0.000 title claims abstract description 96
- 229960001987 dantrolene Drugs 0.000 title claims abstract description 96
- 238000002360 preparation method Methods 0.000 title claims abstract description 69
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 41
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 14
- 238000009472 formulation Methods 0.000 claims description 13
- 229960003710 dantrolene sodium Drugs 0.000 claims description 9
- LTWQNYPDAUSXBC-CDJGKPBYSA-L dantrolene sodium hemiheptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].C1=CC([N+](=O)[O-])=CC=C1C(O1)=CC=C1\C=N\N1C(=O)[N-]C(=O)C1.C1=CC([N+](=O)[O-])=CC=C1C(O1)=CC=C1\C=N\N1C(=O)[N-]C(=O)C1 LTWQNYPDAUSXBC-CDJGKPBYSA-L 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000003125 aqueous solvent Substances 0.000 claims description 8
- 229920000858 Cyclodextrin Polymers 0.000 claims description 7
- 238000010253 intravenous injection Methods 0.000 claims description 6
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 5
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 claims description 5
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- 239000001116 FEMA 4028 Substances 0.000 claims description 4
- 239000013011 aqueous formulation Substances 0.000 claims description 4
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 6
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- 238000002835 absorbance Methods 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
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- 150000003863 ammonium salts Chemical class 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
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- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- MEJYDZQQVZJMPP-ULAWRXDQSA-N (3s,3ar,6r,6ar)-3,6-dimethoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan Chemical compound CO[C@H]1CO[C@@H]2[C@H](OC)CO[C@@H]21 MEJYDZQQVZJMPP-ULAWRXDQSA-N 0.000 description 1
- ZFPGARUNNKGOBB-UHFFFAOYSA-N 1-Ethyl-2-pyrrolidinone Chemical compound CCN1CCCC1=O ZFPGARUNNKGOBB-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- 239000005695 Ammonium acetate Substances 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
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- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
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- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 125000005197 alkyl carbonyloxy alkyl group Chemical group 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
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- GUOHRXPYGSKUGT-UHFFFAOYSA-N quinolizinium Chemical class C1=CC=CC2=CC=CC=[N+]21 GUOHRXPYGSKUGT-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- A61K9/08—Solutions
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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Abstract
作为用于迅速且简便地制备丹曲洛林或其药理学上可接受的盐的水性制剂的技术,本发明提供丹曲洛林水性制剂,其包含丹曲洛林或其药理学上可接受的盐、和环糊精衍生物,相对于1摩尔丹曲洛林或其药理学上可接受的盐而言的环糊精衍生物的配合量为0.5摩尔以上且小于2摩尔。
Description
技术领域
本发明涉及丹曲洛林水性制剂及其制备方法。
背景技术
恶性高热症是全身麻醉的并发症,是死亡率最高的严重并发症。恶性高热症在具有遗传原因的患者中因使用了挥发性吸入麻醉剂(氟烷等)或肌肉松弛剂(琥珀酰胆碱等)的全身麻醉而发病。恶性高热症的特征症状是肌肉僵硬、心动过速和体温急剧升高。
丹曲洛林(Dantrolene)注射制剂是针对恶性高热症的唯一治疗药。丹曲洛林是肌肉松弛剂之一,通过阻断利阿诺定受体来阻断兴奋从横小管传递至肌质网的过程,从而抑制钙离子从肌质网中游离,引起肌肉松弛。
丹曲洛林注射制剂以使用时制备的方式来使用。对于丹曲洛林而言,制成水性组合物时的贮藏寿命短,因此,将水性组合物干燥而制成粉末,在即将使用之前将其溶解而重新构成来加以使用。对于丹曲洛林注射制剂而言,在将注射用水加入到小瓶中进行振摇并确认到溶液变澄清之后使用。但是,由于丹曲洛林在水中极其难溶,因此存在下述问题:溶解需要大量溶剂并耗费工夫,难以在紧急时迅速地制备。
专利文献1中,尝试了使用环糊精衍生物来改善丹曲洛林的溶解度。专利文献1中记载的丹曲洛林水性组合物是相对于1摩尔丹曲洛林或其药理学上可接受的盐而配合2~30摩尔环糊精衍生物而成的组合物。但另一方面,环糊精衍生物的肾毒性令人担忧。
另外,已知:丹曲洛林在碱溶液中被水解,通过乙内酰脲开环而发生分解,生成开环化合物(5-(对硝基苯基)-2-呋喃甲醛-2-羧甲基-缩氨基脲)。分解随着pH值的增加而加快,且在高温下增强。
专利文献2中,提出了使用碱金属的正盐或氢盐来防止丹曲洛林分解的方案。
有关于本发明,非专利文献1中报道称:丹曲洛林的羟丙基-β-环糊精包合络合物改善了基于口服给药的丹曲洛林的生物利用度。该文献中,于45℃将丹曲洛林和羟丙基-β-环糊精搅拌3小时而使其形成包合络合物,但其中,相对于250mg的丹曲洛林而使用了10g这样大量的羟丙基-β-环糊精(参见154页右栏“2.2Preparation of Da-HP-β-CD complex”)。
现有技术文献
专利文献
专利文献1:国际公开第2017/067980号
专利文献2:日本特开昭53-20413号公报
非专利文献
专利文献1:“Preparation,characterization and in vivo evaluation of aformulation of dantrolene sodium with hydroxypropyl-β-cyclodextrin”,Journalof Pharmaceutical and Biomedical Analysis,2017,Vol.135,p.153-159
发明内容
发明所要解决的课题
本发明的主要目的在于,提供用于迅速且简便地制备丹曲洛林或其药理学上可接受的盐的水性制剂的技术。
用于解决课题的手段
为了解决上述课题,本发明提供以下的[1]-[15]。
[1]丹曲洛林水性制剂,其包含丹曲洛林或其药理学上可接受的盐、和环糊精衍生物,
相对于1摩尔丹曲洛林或其药理学上可接受的盐而言的环糊精衍生物的配合量为0.5摩尔以上且小于2摩尔。
[2]根据[1]所述的丹曲洛林水性制剂,其中,相对于1摩尔丹曲洛林或其药理学上可接受的盐而言的环糊精衍生物的配合量为0.7摩尔以上、1.3摩尔以下。
[3]根据[1]或[2]所述的丹曲洛林水性制剂,其中,前述环糊精衍生物为选自由羟丙基-β-环糊精、β-环糊精及α-环糊精组成的组中的任意一种以上。
[4]根据[1]-[3]中任一项所述的丹曲洛林水性制剂,其为静脉注射用注射制剂。
[5]制备丹曲洛林水性制剂的试剂盒,其包含丹曲洛林或其药理学上可接受的盐、环糊精衍生物和水性溶剂而成,
相对于1摩尔丹曲洛林或其药理学上可接受的盐而言的环糊精衍生物的量为0.5摩尔以上且小于2摩尔。
[6]根据[5]所述的制备丹曲洛林水性制剂的试剂盒,其中,相对于1摩尔丹曲洛林或其药理学上可接受的盐而言的环糊精衍生物的量为0.7摩尔以上、1.3摩尔以下。
[7]根据[5]或[6]所述的制备丹曲洛林水性制剂的试剂盒,其中,前述环糊精衍生物为选自由羟丙基-β-环糊精、β-环糊精及α-环糊精组成的组中的任意一种以上。
[8]根据[5]-[7]中任一项所述的制备丹曲洛林水性制剂的试剂盒,其为制备静脉注射用注射制剂的试剂盒。
[9]丹曲洛林水性制剂的制备方法,其包括:于40℃以上、45℃以下使丹曲洛林或其药理学上可接受的盐、和环糊精衍生物溶解于水性溶剂中的步骤,其中,相对于1摩尔丹曲洛林或其药理学上可接受的盐而言的环糊精衍生物的量为0.5摩尔以上且小于2摩尔。
[10]根据[9]所述的制备方法,其中,在前述步骤中,制剂的pH被制备为9.0-10.5。
[11]根据[10]所述的制备方法,其中,在前述步骤中,制剂的pH被制备为9.3-10.0。
[12]根据[9]-[11]中任一项所述的制备方法,其中,相对于1摩尔丹曲洛林或其药理学上可接受的盐而言的环糊精衍生物的量为0.7摩尔以上、1.3摩尔以下。
[13]根据[9]-[12]所述的制备方法,其中,前述环糊精衍生物为选自由羟丙基-β-环糊精、β-环糊精及α-环糊精组成的组中的任意一种以上。
[14]根据[9]-[13]中任一项所述的制备方法,其中,丹曲洛林水性制剂为静脉注射用注射制剂。
[15]丹曲洛林静脉注射用注射制剂的制备方法,其包括:于40℃以上、45℃以下使丹曲洛林钠、和羟丙基-β-环糊精溶解于水中而得到pH为9.0-10.0的制剂的步骤,其中,相对于1摩尔丹曲洛林钠而言的羟丙基-β-环糊精的量为0.73摩尔以上、1.31摩尔以下。
发明的效果
本发明的主要目的在于,提供用于迅速且简便地制备丹曲洛林或其药理学上可接受的盐的水性制剂的技术。
具体实施方式
以下,针对用于实施本发明的优选方式进行说明。需要说明的是,以下所说明的实施方式表示本发明的代表性的实施方式的一例,本发明的范围并不由此被解释得很窄。
本发明涉及的丹曲洛林水性制剂包含丹曲洛林或其药理学上可接受的盐、和环糊精衍生物,相对于1摩尔丹曲洛林或其药理学上可接受的盐而言的环糊精衍生物的配合量为0.5摩尔以上且小于2摩尔。
另外,本发明涉及的制备丹曲洛林水性制剂的试剂盒包含丹曲洛林或其药理学上可接受的盐、环糊精衍生物和任选的水性溶剂而成,相对于1摩尔丹曲洛林或其药理学上可接受的盐而言的环糊精衍生物的量为0.5摩尔以上且小于2摩尔。
丹曲洛林的结构示于以下。
[化学式1]
丹曲洛林的药理学上可接受的盐可以为选自由碱金属盐、碱土金属盐、铵盐、烷基铵盐、聚烷基铵盐、芳基铵盐、取代或未取代喹嗪鎓(quinolizinium)盐、及取代或未取代吡啶鎓盐组成的组中的任意一种以上的盐。
丹曲洛林的药理学上可接受的盐优选为钠盐、钾盐、铵盐、钙盐、镁盐,特别优选为钠盐。
水性溶剂为水、或者生理学上可接受的溶剂与水的混合物,优选为水。
作为生理学上可接受的溶剂,可举出C1-6醇(特别是乙醇)、聚乙二醇、丙二醇、甘油、二甲基乙酰胺、二甲基异山梨醇、二甲基亚砜、1-甲基-2-2吡咯烷酮及1-乙基-2-吡咯烷酮。
需要说明的是,水性溶剂不是本发明涉及的试剂盒的必需构成要素,也可以与试剂盒分开地被制备者获取。
环糊精是具有疏水性中心空洞和亲水性外表面的环状(α-1,4)键合低聚糖。
环糊精衍生物是在环糊精中导入选自由烷基、羟烷基、羧烷基、磺基烷基、烷基羰基氧基烷基、烷氧羰基烷基及羟基-(单或多)烷基组成的组中的取代基而成的。
环糊精衍生物可以为选自由羟丙基-β-环糊精、β-环糊精及α-环糊精组成的组中的任意一种以上。其中,特别优选为羟丙基-β-环糊精。
丹曲洛林或其药理学上可接受的盐在水性制剂中的配合量为0.1-10mg/ml、优选为0.2-7.0mg/ml、更优选为0.3-4.0mg/ml。
另外,丹曲洛林或其药理学上可接受的盐在水性制剂中的配合量为0.25-25.0mM、更优选为0.50-17.50mM、更优选为0.75-10.0mM。
环糊精衍生物在水性制剂中的配合量为3.4-13.7mg/ml、优选为5-9.5mg/ml。
另外,环糊精衍生物在水性制剂中的配合量为25-99mM、优选为36-69mM。
相对于1摩尔丹曲洛林或其药理学上可接受的盐而言的环糊精衍生物的配合量设为0.5摩尔以上且小于2摩尔,优选设为0.7摩尔以上、1.3摩尔以下。
后述的试验例1中,可知:通过相对于1摩尔丹曲洛林或其药理学上可接受的盐而配合约0.7摩尔以上的环糊精衍生物,从而可得到良好的丹曲洛林的溶解度和制剂的浊度。环糊精衍生物被疑有肾毒性,因此,其配合量优选设为实现良好的丹曲洛林的溶解度和制剂的浊度所必需的最小限度。因此,相对于1摩尔丹曲洛林或其药理学上可接受的盐而言的环糊精衍生物的配合量优选为0.7摩尔以上、1.3摩尔以下。
通过在上述配合比率范围内在丹曲洛林或其药理学上可接受的盐中添加环糊精衍生物,从而可以使丹曲洛林的溶解度提高并且得到澄清的制剂。因此,根据本发明涉及的丹曲洛林水性制剂及制备其的试剂盒,对于在恶性高热症的临床中迅速且简便地提供丹曲洛林静脉注射用注射制剂是有效的。
丹曲洛林水性制剂及制备其的试剂盒可以包含pH调节剂、渗透压调节剂及/或表面活性剂。
pH调节剂选自由柠檬酸盐、碳酸盐、磷酸盐、精氨酸、赖氨酸、葡甲胺、氨丁三醇、组氨酸及它们的混合物组成的组中。pH调节剂以适于将制剂的pH调节并维持在上述范围内的量来使用。
渗透压调节剂选自由具有2~10个碳原子的脂肪族多羟基烷醇及它们的混合物组成的组中,所述具有2~10个碳原子的脂肪族多羟基烷醇选自由甘露醇、果糖、葡萄糖、葡糖酸内酯、葡糖酸盐、蔗糖、乳糖、海藻糖、右旋糖、葡聚糖、羟乙基淀粉组成的组中。其中,特别优选甘露醇。pH调节剂以适于将制剂的渗透压调节并维持为约1(相对于生理盐水的比)的量来使用。
作为表面活性剂,没有特别限定,可示例出PEG-40氢化蓖麻油(NIKKOL HCO-40,Nikko Chemicals Co.,Ltd.)、PEG-50氢化蓖麻油(NIKKOL HCO-50,Nikko Chemicals Co.,Ltd.)、PEG-60氢化蓖麻油(NIKKOL HCO-60,Nikko Chemicals Co.,Ltd.)、聚山梨酯20(NIKKOL TL-10,Nikko Chemicals Co.,Ltd.)、聚乙二醇(MACROGOL 400,三洋化成工业株式会社)、聚氧乙烯脂肪酸单酯(IONET MO-400或MS-400,三洋化成工业株式会社)及单硬脂酸甘油酯(TG-C,三洋化成工业株式会社)。
制备丹曲洛林水性制剂的试剂盒可以通过在收容于小瓶等容器中的丹曲洛林或其药理学上可接受的盐和环糊精衍生物中加入水性溶剂而使其溶解从而重新构成为丹曲洛林水性制剂。
溶解时的温度优选设为40℃以上、45℃以下。通过将溶解温度设定为上述范围,从而可以进一步提高丹曲洛林的溶解度并且得到更澄清的制剂(试验例2)。因此,与通常的室温下的溶解相比,存在下述可能性:抑制相对于丹曲洛林或其药理学上可接受的盐而言的环糊精衍生物的配合量,同时可以达成良好的丹曲洛林的溶解度和制剂的浊度。
需要说明的是,若超过上述温度范围,则存在因丹曲洛林的水解而导致的杂质的生成被增强之忧。
溶解后的制剂的pH被制备为9.0-10.5,优选被制备为9.3-10.0。通过将制剂的pH设定为上述范围,从而能够维持丹曲洛林的良好的溶解度,同时还能够抑制杂质的生成(试验例3)。
实施例
[试验例1:丹曲洛林与环糊精衍生物的摩尔比对丹曲洛林的溶解度和制剂的浊度带来的影响的研究]
将丹曲洛林钠20mg(50mM)、羟丙基-β-环糊精(HPβCD)及甘露醇800mg溶解于45℃的水10ml中,并搅拌15分钟,从而进行制剂化。
使HPβCD的添加摩尔量变化,并测定丹曲洛林的溶解度和制剂的浊度。
丹曲洛林的溶解度的测定如下所述地进行。
分取1mL样品,并利用0.22μm的过滤器进行过滤后,利用纯水稀释至0.02μg/mL。利用紫外可见分光光度计测定稀释液的吸光度(390nm)。基于预先制作的校正曲线,由所测定的吸光度算出溶解度。
对于制剂的浊度而言,将5mL样品投入到小瓶中,并利用浊度计进行测定。
将结果示于“表1”。
[表1]
可知:通过相对于1摩尔丹曲洛林钠而添加0.73摩尔以上的HPβCD,从而可得到良好的丹曲洛林的溶解度和制剂的浊度。
[试验例2:溶解温度对丹曲洛林的溶解度和制剂的浊度带来的影响的研究]
将丹曲洛林钠20mg、HPβCD75mg及甘露醇800mg溶解于水10ml中,并搅拌15分钟,从而进行制剂化。
使溶解温度变化,并与试验例1同样地操作来测定丹曲洛林的溶解度和制剂的浊度。
将结果示于“表2”。
[表2]
溶解温度(℃) | 溶解度(mg/mL) | 浊度(NTU) |
45 | 2.11 | 3 |
40 | 2.03 | 60 |
35 | 1.99 | 459 |
溶解温度在35℃时,制剂的浊度不良。可知:通过将溶解温度设为40℃(优选45℃),从而可得到良好的丹曲洛林的溶解度和制剂的浊度。
[试验例3:制备时的pH对丹曲洛林的溶解度以及制剂的浊度及杂质浓度带来的影响的研究]
于室温将丹曲洛林钠20mg、HPβCD200mg及甘露醇800mg溶解于水10ml中,并搅拌24小时,从而进行制剂化。
通过改变制备时所维持的水的pH范围,从而使制备后的制剂的pH变化,与试验例1同样地操作来测定丹曲洛林的溶解度。
将结果示于“表3”。
[表3]
制备后的pH | 溶解度(mg/mL) |
7.0 | 0.07 |
8.0 | 0.31 |
9.0 | 1.95 |
10.0 | 1.95 |
接下来,将丹曲洛林钠20mg、HPβCD75mg及甘露醇800mg溶解于水10ml中,并搅拌约30~50秒,从而进行制剂化。
通过改变制备时所维持的水的pH范围,从而使制备后的制剂的pH变化,测定制剂的浊度及杂质浓度。与试验例1同样地操作来测定制剂的浊度。
杂质(5-(对硝基苯基)-2-呋喃甲醛-2-羧甲基-缩氨基脲:F-524)是由丹曲洛林原体通过经时变化而生成的分解物。F-524的浓度的测定使用液相色谱仪在以下条件下进行。
柱:ZORBAX ODS,4.6mm×150mm,5μm
稀释液:60%乙腈
缓冲液:乙酸铵缓冲液,pH4.5±0.1
流动相A:缓冲液840mL、乙腈560mL及乙酸49mL的混合液
流动相B:乙腈350mL与纯水150mL的混合液
梯度条件:示于“表4”。
[表4]
时间(分钟) | 流动相A(%) | 流动相B(%) |
0-17 | 100 | 0 |
17-17.1 | 100->0 | 0->100 |
17.1-22 | 0 | 100 |
22-22.1 | 0->100 | 100->0 |
22.1-29 | 100 | 0 |
将结果示于“表5”。
[表5]
制备时的pH | 浊度(NTU) | 杂质浓度(%) |
9.3 | 274 | 0.44 |
9.4 | 59 | 0.41 |
9.5 | 48 | 0.40 |
9.6 | 36 | 0.43 |
9.7 | 20 | 0.41 |
由“表3”所示的溶解度的结果可知:制剂的pH优选被制备为9.0以上。另外,由“表5”所示的结果可预测:若pH低,则浊度变高,随着pH变高,杂质浓度上升。由这些结果认为制剂的pH优选为9.3-10.0左右。
Claims (8)
1.丹曲洛林水性制剂,其包含丹曲洛林或其药理学上可接受的盐、和环糊精衍生物,
相对于1摩尔丹曲洛林或其药理学上可接受的盐而言的环糊精衍生物的配合量为0.5摩尔以上且小于2摩尔。
2.根据权利要求1所述的丹曲洛林水性制剂,其中,相对于1摩尔丹曲洛林或其药理学上可接受的盐而言的环糊精衍生物的配合量为0.7摩尔以上且1.3摩尔以下。
3.根据权利要求1或2所述的丹曲洛林水性制剂,其中,所述环糊精衍生物为选自由羟丙基-β-环糊精、β-环糊精及α-环糊精组成的组中的任意一种以上。
4.制备丹曲洛林水性制剂的试剂盒,其包含丹曲洛林或其药理学上可接受的盐、环糊精衍生物和水性溶剂而成,
相对于1摩尔丹曲洛林或其药理学上可接受的盐而言的环糊精衍生物的量为0.5摩尔以上且小于2摩尔。
5.丹曲洛林水性制剂的制备方法,其包括:于40℃以上且45℃以下使丹曲洛林或其药理学上可接受的盐、和环糊精衍生物溶解于水性溶剂中的步骤,其中,相对于1摩尔丹曲洛林或其药理学上可接受的盐而言的环糊精衍生物的量为0.5摩尔以上且小于2摩尔。
6.根据权利要求5所述的制备方法,其中,在所述步骤中,制剂的pH被制备为9.0-10.5。
7.根据权利要求6所述的制备方法,其中,在所述步骤中,制剂的pH被制备为9.3-10.0。
8.丹曲洛林静脉注射用注射制剂的制备方法,其包括:于40℃以上且45℃以下使丹曲洛林钠、和羟丙基-β-环糊精溶解于水中而得到pH为9.0-10.0的制剂的步骤,其中,相对于1摩尔丹曲洛林钠而言的羟丙基-β-环糊精的量为0.73摩尔以上且1.31摩尔以下。
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CN108366963A (zh) * | 2015-10-20 | 2018-08-03 | B.布劳恩梅尔松根股份公司 | 包含丹曲林的水性组合物 |
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CN108366963A (zh) * | 2015-10-20 | 2018-08-03 | B.布劳恩梅尔松根股份公司 | 包含丹曲林的水性组合物 |
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