WO2017198224A1 - 一种瑞马唑仑的药物组合物 - Google Patents

一种瑞马唑仑的药物组合物 Download PDF

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WO2017198224A1
WO2017198224A1 PCT/CN2017/085141 CN2017085141W WO2017198224A1 WO 2017198224 A1 WO2017198224 A1 WO 2017198224A1 CN 2017085141 W CN2017085141 W CN 2017085141W WO 2017198224 A1 WO2017198224 A1 WO 2017198224A1
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hydroxyethyl starch
remiazolam
composition
solution
composition according
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杨晓容
陈钟威
卢韵
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Jiangsu Hengrui Medicine Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
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    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

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  • the present invention is in the field of pharmaceutical preparations, and in particular relates to a composition comprising remimagazole and a pharmaceutically acceptable salt thereof.
  • Remiazolam is a sedative superior to the similar products currently in use, with rapid onset and failure, stable sedation, short recovery time, short half-life, inactive metabolites, predictable pharmacokinetics, and wide therapeutic window
  • the potential for interaction between drugs is low, and flumazenil can reverse the sedative effect and will not calm again. It was developed to obtain a new drug that combines the active activities of midazolam and propofol while discarding related defects. According to the results of the study, remiazolam is superior to these two products already on the market and is a breakthrough new chemical entity that is highly likely to become the new gold standard in the field of sedation/anaesthesia.
  • CN101501019A discloses benzenesulfonate and its polymorphs, and discloses a series of possible compositions thereof, but does not disclose how to obtain a stable composition; CN103221414A discloses remarazol The p-toluenesulfonate and its polymorph, but no composition thereof are disclosed.
  • CN103202815A discloses a lyophilized formulation of remamazepine containing mannitol or glycine, but the concentration of remiazolam in such a solution before or after lyophilization Lower, the relative proportion of excipients is higher, and a large amount of solution is required for clinical use, which is very inconvenient.
  • CN104968348A discloses a combination of a benzodiazepine compound and at least one hygroscopic excipient, in particular lactose and/or dextran, but the excipient lactose is an animal-derived excipient due to possible residual impurities therein. Protein, there is a certain safety risk when injected in large quantities.
  • Rimamazol is hydrolyzed in aqueous solution as well as in long-term storage to produce inactive impurities as shown in formula (II), so it is necessary to provide a stable composition of remiazolam.
  • It is an object of the present invention to provide a composition comprising remimagazole or a pharmaceutically acceptable salt thereof and hydroxyethyl starch.
  • the hydroxyethyl starch may be selected from any model, such as hydroxyethyl starch 200/0.5, hydroxyethyl starch 130/0.4, preferably hydroxyethyl starch 130/0.4.
  • composition of the present invention is allowed to stand at 50 ° C for 7 days to increase the amount of impurities present in the form of the compound of the formula (II) or its salt by no more than 0.15%; or to leave the compound of the formula (II) or its salt at 50 ° C for 14 days.
  • the amount of impurities present in the form does not increase by more than 0.3%, preferably 0.2%, more preferably not more than 0.2%.
  • the composition does not contain mannitol or gan Amino acid.
  • the ratio of remiazolam or a pharmaceutically acceptable salt thereof to hydroxyethyl starch is not particularly limited, and in a preferred embodiment of the present invention, remiazolam or a pharmaceutically acceptable thereof
  • the weight ratio of salt to hydroxyethyl starch is from 1:0.1 to 1000, preferably from 1:1 to 1:50, more preferably from 1:1 to 1:20, most preferably from 1:1 to 1:10.
  • the composition is a lyophilized formulation.
  • a monosaccharide may also be added to the compositions of the present invention.
  • the monosaccharide may be selected from the group consisting of glucose, fructose, galactose, mannose, galactose, glucosamine and the like.
  • the lyophilized preparation of the present invention is reconstituted with water to the volume before lyophilization, and is determined according to the method of the Chinese Pharmacopoeia 2010 edition two appendix VI H, the pH of the solution is 2-7, more preferably 2-5. Most preferably 2 to 4.
  • the lyophilized formulation of the present invention can be reconstituted using various aqueous diluents to provide solutions for injection, such as water for injection, physiological saline, aqueous 5% dextrose, and the like, which are widely known in the art.
  • the ratio of the hydroxyethyl starch to the monosaccharide is not particularly limited, and in a preferred embodiment of the present invention, the weight ratio of the hydroxyethyl starch to the monosaccharide is from 1:9 to 9:1, more preferably 1:5. 5:1, most preferably 1:3 to 3:1.
  • the concentration of remazolium (in terms of free base) in the solution obtained by lyophilization or reconstitution with an aqueous diluent is about 0.5 to 30 mg/ml, preferably 1 to 20 mg/ml. It is particularly preferably 2 to 15 mg/ml.
  • the pharmaceutically acceptable salt of remiazolam may be a benzenesulfonate, a p-toluenesulfonate, an isethionate or the like.
  • the solution for injection can be reconstituted to obtain a clear solution after slight shaking, and the reconstitution time is less than 3 min, more preferably less than 2 min, most preferably less than 1.5 min; long time after dissolution or dilution Stabilization does not precipitate drug crystals.
  • the present invention provides a method of inhibiting degradation of remimalam or a pharmaceutically acceptable salt thereof to a compound of formula (II) or a salt thereof, the method comprising adding a hydroxy group as described above Ethyl starch or hydroxyethyl starch and monosaccharide.
  • hydroxyethyl starch, monosaccharides, and combinations thereof are capable of inhibiting the degradation of remazolam or a pharmaceutically acceptable salt thereof to a compound of formula (II) or a salt thereof, thereby further solving The problem of stability; hydroxyethyl starch, monosaccharide and combinations thereof are much stronger than the known glycine, mannitol, lactose and other common excipients.
  • the present invention provides a method of preparing a composition comprising remiazolam and a pharmaceutically acceptable salt thereof, which is simple in operation, good in reproducibility, and easy to industrialize.
  • the method includes the following steps:
  • the method further comprises the step of lyophilizing the solution obtained in step 3).
  • the product needs to have good stability, and the composition provided by the present invention exhibits excellent stability after drying, and the reconstitution rate does not change after standing.
  • the pharmaceutical preparation of the present invention is usually obtained by the following steps:
  • the solution is lyophilized.
  • Two bottles of the product were reconstituted with 2.0 ml of water for injection, reconstituted with a 5 ml syringe and a suitable needle, and the time required for the solid to completely dissolve was recorded.
  • the lyophilized products of the respective examples were reconstituted rapidly, and the appearance, the reconstitution time, and the appearance of the solution after reconstitution did not change significantly during storage at a high temperature of 50 ° C, and the CNS7054 related substance grew slowly, showing excellent stability.
  • the prescription for further addition of monosaccharides showed better stability.
  • Example II lactose prescription (A01P310 prescription) published in CN104968348A and the example 6 glycine prescription of CN103202815A, and prepare a remazole lyophilized powder needle by freeze-drying a sample disclosed in the patent at a high temperature of 50 ° C.
  • the stability was investigated under the conditions, and the results are shown in Table 1. Further, the lactose and glycine prescription lyophilized product and the lyophilized product of Example 4, Example 7 and Example 10 were respectively reconstituted with water for injection, and the stability of the solution at room temperature was examined. The results were compared. The results are shown in Table 3.
  • Table 1 The results of Table 1, Table 2 and Table 3 show that the stability of the rimazolam composition lyophilized product of the present invention at high temperature and the stability of the solution after reconstitution are superior to the patent prescription, especially remarazol and A combination of hydroxyethyl starch and a monosaccharide.

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Abstract

本发明提供了一种瑞马唑仑的药物组合物。具体而言，本发明提供了一种药物组合物，其包含瑞马唑仑或其药学上可接受的盐和羟乙基淀粉和/或单糖组合物。本发明提供的组合物中瑞马唑仑干燥后的重构时间短，方便临床用药，且具有良好的稳定性。

Description

一种瑞马唑仑的药物组合物 技术领域
本发明属于药物制剂领域，具体涉及包含瑞马唑仑及其药学上可接受的盐的组合物。
背景技术
瑞马唑仑(Remimazolam)化学名：(4S)-8-溴-1-甲基-6-(2-吡啶基)-4H-咪唑[1，2-a][1，4]苯并二氮卓-4-丙酸甲酯，结构式如式(I)所示，该化合物由GSK公司设计，PAION公司开发，代号CNS7056，为一种超速效的镇静、麻醉药，作用于GABAA受体，经组织酯酶代谢，分裂成无活性的代谢产物CNS7054，结构式如式(II)所示。
Figure PCTCN2017085141-appb-000001
瑞马唑仑是一种优于目前正在使用的同类产品的镇静剂，起效和失效迅速，镇静作用稳定，恢复时间短，半衰期短，代谢产物无活性，药代动力学可预测，治疗窗广，药物间相互作用的潜在性较低，氟马西尼可逆转镇静作用，不会再次镇静。其开发目的是为获得一种集合咪达唑仑和异丙酚的积极活性，而摒弃相关缺陷的新型药物。根据研究结果，瑞马唑仑优于这两种已上市销售的产品，是一种突破性的新化学实体，极有可能成为镇静/麻醉领域的新型金标准。
CN101501019A公开了瑞马唑仑的苯磺酸盐和其多晶型，并公开了其一系列可能制成的组合物，但是没有公开如何获得一种稳定的组合物；CN103221414A公开了瑞马唑仑的对甲苯磺酸盐和其多晶型，但没有公开其组合物。
目前瑞马唑仑还未上市，CN103202815A公开了一种含有甘露醇或甘氨酸的瑞马唑仑冻干制剂，但是此类制剂在冻干前溶液或重建后的溶液中，瑞马唑仑的浓度较低，辅料相对比例较高，临床使用需要大量溶液，十分不便。
CN104968348A中公布了苯二氮杂卓类化合物和至少一种吸湿性赋形剂，特别是乳糖和/或葡聚糖的组合物，但赋形剂乳糖为动物来源辅料，由于其中可能残留的杂蛋白，大量注射时存在一定的安全性风险。
瑞马唑仑在水溶液中以及长期储存中会水解产生如式(II)所示的无活性的杂质，因此提供一种稳定的瑞马唑仑的组合物非常有必要。
发明内容
本发明的目的是提供一种含瑞马唑仑或其药学上可接受的盐与羟乙基淀粉的组合物。
所述的羟乙基淀粉可以选自任意型号，例如羟乙基淀粉200/0.5、羟乙基淀粉130/0.4，优选羟乙基淀粉130/0.4。
本发明的组合物在50℃条件下放置7天以式(II)化合物或其盐形式存在的杂质增长不超过0.15％；或在50℃条件下放置14天以式(II)化合物或其盐形式存在的杂质增长不超过0.3％，选0.2％，更优选不超过0.2％。
Figure PCTCN2017085141-appb-000002
在本发明优选的实施方案中，所述的组合物中不含有甘露醇或甘 氨酸。
本发明的组合物中，瑞马唑仑或其药学上可接受的盐与羟乙基淀粉的比例没有特别限制，在本发明优选的实施方案中，瑞马唑仑或其药学上可接受的盐与羟乙基淀粉的重量比为1∶0.1～1000，优选的1∶1～1∶50，更优选的为1∶1～1∶20，最优选1∶1～1∶10。
在本发明优选的实施方案中，所述的组合物为冻干制剂。
在更为优选的实施方案中，本发明的组合物中还可以加入单糖。所述的单糖可以选自葡萄糖、果糖、半乳糖、甘露糖、氨基半乳糖、氨基葡萄糖等。
本发明的冻干制剂，用水重构至冻干前的体积，并根据中国药典2010年版二部附录VI H项下的方法测定，该溶液的pH为2～7，更优选的为2～5，最优选的为2～4。
本发明的冻干制剂可以使用各种水性稀释剂重构后得到用于注射的溶液，所述的水性稀释剂是本领域广泛公知的，例如注射用水、生理盐水、5％葡萄糖水溶液等。
羟乙基淀粉与单糖的比例没有特别的限制，在本发明优选的实施方案中，羟乙基淀粉与单糖的重量比例为1∶9～9∶1，更优选的为1∶5～5∶1，最优选的为1∶3～3∶1。
在本发明的组合物中，冻干前溶液或使用水性稀释剂复溶后得到的溶液中瑞马唑仑(以游离碱计)浓度约为0.5～30mg/ml，优选1～20mg/ml，特别优选2～15mg/ml。
本发明中，瑞马唑仑的药学上可接受的盐可以是苯磺酸盐、对甲苯磺酸盐，羟乙磺酸盐等。
本发明提供的组合物制剂经干燥后，加入注射用溶剂后轻微振摇即可重构得到澄清溶液，重构时间小于3min，更优选小于2min，最优选小于1.5min；溶解或稀释后长时间静置不会析出药物晶体。
另一方面，本发明还提供了一种抑制瑞马唑仑或其药学上可接的盐降解为式(II)所示化合物或其盐的方法，所述方法包括加入如前所述的羟乙基淀粉或加入羟乙基淀粉和单糖。
Figure PCTCN2017085141-appb-000003
本发明意外地发现，羟乙基淀粉、单糖及其组合物均能够抑制瑞马唑仑或其药学上可接的盐降解为式(II)所示化合物或其盐，从而进一步地解决了稳定性的问题；羟乙基淀粉、单糖及其组合为对该种降解产物的抑制作用大大地强于已知的甘氨酸、甘露醇、乳糖等常见辅料。
再一方面本发明还提供了一种制备含瑞马唑仑及其药学上可接受的盐的组合物的方法，该方法操作简单、重现性良好，易于产业化。所述方法包括如下步骤：
1)将羟乙基淀粉及任选的其它辅料(如单糖)溶解于水性稀释剂中，调节pH值至2-4，
2)加入瑞马唑仑或其盐，调节pH值至2-4，
3)加入水性稀释剂至最终体积。
优选所述方法还包括将步骤3)所得溶液冻干的步骤。
为达到较低的储存成本，产品需具有良好的稳定性，本发明提供的组合物制剂干燥后表现出了优异的稳定性，且放置后复溶速率未发生变化。
具体实施方式
以下实施例是为了阐述发明，并不以任何方式限制本发明的范围。
实施例1至11
本发明的药物制剂通常通过下面的步骤制得：
1.称取处方量的羟乙基淀粉130/0.4(含单糖在该步骤添加)，搅拌溶解在至少一种水性稀释剂中，水性稀释剂为处方量的80％左右，水温控制在0-30℃，测定溶液的pH值，根据需要，使 用pH调节剂对溶液pH值进行调整，pH控制在2-4。
2.称取处方量的瑞马唑仑，搅拌溶解在上述溶液中，完全溶解后测定溶液的pH值，根据需要，使用pH调节剂对溶液pH值进行调整，pH控制在2-4。
3.加入水性稀释剂至最终体积，将溶液继续搅拌至混合均匀。
4.将上述的溶液过滤除菌。
5.将溶液进行冷冻干燥。
Figure PCTCN2017085141-appb-000004
Figure PCTCN2017085141-appb-000005
冷冻干燥：
6ml瓶灌装2ml药液，半加塞后按如下程序冻干。
冻干程序：
Figure PCTCN2017085141-appb-000006
Figure PCTCN2017085141-appb-000007
考察实施例1-11产品冻干后的冻干品外观、重构时间、重构后溶液外观、水分、有关物质，并分别在高温50℃条件下进行稳定性考察。
检验方法：
1、重构时间
用2.0ml注射用水，使用5ml注射器和合适的针头复溶重构2瓶制品，记录固体完全溶解所需时间。
2、复溶后外观
记录重构后溶液的外观。
3、水分
通过卡尔.费歇尔(Karl Fischer)滴定测定水分，通过消耗滴定液的体积计算出水分含量，结果由仪器显示。
4、有关物质
采用HPLC方法检测，产品最主要的降解杂质为CNS7054(即式(II)化合物)。
结果见表1与表2。
各实施例的冻干制品重构迅速，在高温50℃储存过程中外观、重构时间、重构后溶液外观未发生明显变化，CNS7054有关物质增长缓慢，表现出优良的稳定性。进一步添加单糖的处方表现出更佳的稳定性。
实施例12
参照CN104968348A专利中公布的实施例II乳糖处方(A01P310处方)及CN103202815A的实施例6甘氨酸处方，并用专利中公布的对一个工艺进行冻干样品制备瑞马唑仑冻干粉针，在高温50℃条件下进行稳定性考察，结果见表1。此外，将乳糖与甘氨酸处方冻干品与实施例4、实施例7和实施例10冻干品分别用注射用水重构后，进行室温溶液稳定性考察，结果进行对比，结果见表3。
表1、表2和表3结果表明，本发明中的瑞马唑仑组合物冻干品在高温下稳定性以及重构后的溶液稳定性均优于专利处方，尤其是瑞马唑仑与羟乙基淀粉和单糖的组合物。
Figure PCTCN2017085141-appb-000008
Figure PCTCN2017085141-appb-000009
表3重构后溶液稳定性结果
Figure PCTCN2017085141-appb-000010

Claims (12)

  1. 一种药物组合物，含有瑞马唑仑或其药学上可接受的盐以及羟乙基淀粉。
  2. 根据权利要求1所述的组合物，其中所述的羟乙基淀粉选自羟乙基淀粉200/0.5和羟乙基淀粉130/0.4中的一种或两种。
  3. 根据权利要求1所述的组合物，其中所述的瑞马唑仑或其药学上可接受的盐与羟乙基淀粉的重量比为1：0.1～1000，优选的为1:1～1:50，更优选的为1:1～1:20，最优选1:1～1:10。
  4. 根据权利要求1所述的组合物，还含有单糖，优选所述单糖选自葡萄糖、果糖、半乳糖、甘露糖、氨基半乳糖、氨基葡萄糖中的一种或几种。
  5. 根据权利要求4所述的组合物，其中所述的羟乙基淀粉与单糖的重量比例为1:9～9:1，更优选的为1:5～5:1，最优选的为1:3～3:1。
  6. 根据权利要求1所述的组合物，所述组合物为溶液形式，其中瑞马唑仑或其盐的浓度以瑞马唑仑碱计为0.5～30mg/ml，优选1～20mg/ml，更优选2～15mg/ml。
  7. 根据权利要求1至6任一项所述的组合物，其中所述的瑞马唑仑的盐选自苯磺酸盐、对甲苯磺酸盐和羟乙基磺酸盐中的一种。
  8. 根据权利要求1至5任一项所述的组合物，其中所述组合物为冻干制剂。
  9. 根据权利要求8所述的组合物，其中所述冻干制剂的冻干前溶液或复溶后溶液中瑞马唑仑或其盐的浓度以瑞马唑仑碱计为0.5～30mg/ml，优选1～20mg/ml，更优选2～15mg/ml。
  10. 权利要求1至5任一项所述的组合物的制备方法，包括如下步骤：
    1)将羟乙基淀粉或羟乙基淀粉和单糖溶解于水性稀释剂中，
    2)加入瑞马唑仑或其盐，
    3)加入水性稀释剂至最终体积。
  11. 根据权利要求10所述的制备方法，还包括将步骤3)所得溶液冻干的步骤。
  12. 根据权利要求10所述的制备方法，其中还包括将步骤1)、2)、3)中任意一步或多步中所得溶液的pH调节至2-4的步骤。
PCT/CN2017/085141 2016-05-20 2017-05-19 一种瑞马唑仑的药物组合物 Ceased WO2017198224A1 (zh)

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CN104546675A (zh) * 2014-12-25 2015-04-29 海南卫康制药(潜山)有限公司 一种艾司唑仑组合物冻干片及其制备方法
CN104968348A (zh) * 2012-05-22 2015-10-07 Paion英国有限公司 包含短效苯二氮杂*类化合物的组合物

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CN104968348A (zh) * 2012-05-22 2015-10-07 Paion英国有限公司 包含短效苯二氮杂*类化合物的组合物
CN104546675A (zh) * 2014-12-25 2015-04-29 海南卫康制药(潜山)有限公司 一种艾司唑仑组合物冻干片及其制备方法

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