CN101801363A - 胆固醇调节药物 - Google Patents
胆固醇调节药物 Download PDFInfo
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- CN101801363A CN101801363A CN200880017092A CN200880017092A CN101801363A CN 101801363 A CN101801363 A CN 101801363A CN 200880017092 A CN200880017092 A CN 200880017092A CN 200880017092 A CN200880017092 A CN 200880017092A CN 101801363 A CN101801363 A CN 101801363A
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- medicine
- mouse
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- formaldehyde
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Classifications
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/115—Formaldehyde
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
本发明涉及药物，并能用于制造一种使胆固醇水平正常化的药物制剂。本发明的目的是开发一种生理可接受的胆固醇调节药物，它无毒并且不会使生物体上瘾。制造所述药物的方法包括使用2-6重量份36.5-40％浓度的甲醛水溶液，并加入994-998重量份注射浓度为0.85-0.95％的等渗氯化钠溶液，形成一种0.07-024％浓度的甲醛水溶液。该药物应储存在15-35℃中。
Description
该项发明属于医学范畴，并且可以被用于制造调节胆固醇水平的药物。
血液中的胆固醇水平是病人脂质代谢的重要指标。使用胆固醇降低疗法可以在治疗一些疾病时(比如动脉粥样硬化、缺血性心脏病等)使心血管发病的死亡率降低30-40％。血液中胆固醇的水平与冠状动脉疾病之间存在着直接的联系。
已知的调节胆固醇药物是建立在植物药物的基础上。其中含有伸筋草(Licopodium)、碘化金(Aurum iodatum)、碳酸钡(Barium carbonicum)、大蒜种子(Allium sativum)(见俄罗斯联邦专利证书№2162333，MΠΚA61Κ35/78，2001年1月27日公布)，使用C12稀释时用同样的比例。
该药物是顺势疗法药剂的混合体，每一种药剂按照自己的功效被用于其中，包括治疗肺动脉高压、动脉粥样硬化、慢性肝病、尿路结石、肥胖等疾病的药剂。使用该复方药物替代了以往的多种药物一起服用，那样通常会掩盖患者在治疗过程中的反应，最终导致干扰制定出合理的治疗方案。
已知该药物具有调节胆固醇的作用，是植物药剂(见俄罗斯联邦专利证书№2152221，MΠΚA61Κ35/78，2000年7月10日公布)，含有猪毛菜的干萃取物作为活性成分。
使用以猪毛菜为基础的植物药剂等同于使用各种不同的化合物，因为在专利证书的描述中已经指出，该药物的活性成分中包括了黄酮类化合物、多糖、类胡萝卜素、甾醇、皂甙、脂类化合物、氨基酸、各种微量元素。该药物中含有的多种成分等同于同时服用多种药物，正如上面提到的一样，同时服用多种药物不能够清晰地反映出治疗效果。除此之外，该药物中活性成分的含量在0.25-99.9％(重量)，这也是低水平药剂标准。
已知的调节胆固醇水平的化学药剂主要是烟酸及其衍生物、胆汁酸螯合物、纤维素酸的衍生物(贝特类)(见《内脏器官疾病治疗/实践指导资料》，作者：A.H.奥克洛科夫，明斯克市，最高学府出版社，维捷布斯科市，白俄罗斯医学书籍出版社-1996年，第三卷，第一部分，19-41页)。
但是使用烟酸会导致一些副作用，比如破坏肝功能、加重慢性胃炎、胃溃疡，还可能造成血糖升高、皮肤充血，以及血液中的尿酸水平升高。
使用螯合物进行治疗时会产生以下副作用，比如呕吐、胀气、便秘、腹泻。还有可能使甘油三酯水平升高，以及破坏吸收脂溶性维生素(A、D、K)和叶酸。
使用贝特类(比如非诺贝特、吉非贝齐等)的副作用是造成肌肉损伤、胆道结石，还可能引发白细胞减少症、血小板减少症、贫血。
使用пробукол会造成室性心律失常、消化不良、肝功能恶化。
与申请药物最为相近的降胆固醇药物是洛伐他汀(同义词：雷克拉等)，该药物可以调节代谢，含有化学活性成分以及目标添加剂(见《俄罗斯药物制剂手册》，莫斯科，阿斯特拉制药服务出版社，2000年，Б-364-Б-365页)。
活性成分是他汀类药物，有[IS-(Iα(R*)，3α，7β，8β(2S*，4S*)，8αβ]1，2，3，7，8，8α，8二甲基3.7六氢，2-(四氢)-4-羟基-6-氧代-2H-吡喃-2基。药物的作用是抑制胆固醇的合成。当洛伐他汀进入机体之后代谢形成β-羟基，它是3羟基-3甲基辅酶A还原酶的竞争抑制剂。
药物中的目标添加剂中含有乳糖、胶化淀粉、微晶体纤维素、丁基氢氧苯甲醚、靛蓝(E132)、硬脂酸镁。
使用他汀类药物的不足之处在于需要长期使用，其中也包括洛伐他汀。除此之外，使用他汀类药物还可能对肝脏、肌肉、胃肠道造成负面影响，以及引起睡眠障碍和头痛。反复使用这种药物还会降低疗效(快速抗药反应)(见Cromwell W.C.Ziajka P.E.Developmentof tachyphylaxis among patients taking HMG CoA reductase inhibitors./Am J.Cardiol 2000；86：1123-1127//翻译文章刊登在CONSILIUM medicum杂志上，2001年，第三卷，№2，P.И.叶拉金翻译，《得到3羟基-3甲基辅酶A还原酶抑制剂的患者的快速抗药反应发展》)。另外，他汀类药物属于排他性生命素。
这项药物发明的目的是制造出生理接收的胆固醇调节药物，而且药物没有毒副作用，也不会引起机体的抗药性。
为了解决这些问题，该药物的活性成分中含有36.5-40％浓度的甲醛水溶液，作为目标添加剂该药物中含有注射浓度为0.85-0.95％的等渗氯化钠溶液，以下是重量关系：
36.5-40％浓度的甲醛水溶液 -2-6
浓度为0.85-0.95％的等渗氯化钠溶液 -994-998
在发明人已知的专利和科技信息中没有依靠提高受体亲和力来调节胆固醇水平的药物。
已经知道，甲醛是细胞代谢的自然产物(见Hunter B.K.et al.Formaldehyde metabolismby Escherichia coli.Carbon and solvent deuterium incorporation into glycerol，1，2-propanedioland 1，3-propanediol.//Biochemistry.-1985.-v.24.№15.-p.4148-4155)。甲醛在醇、氨基酸中的真核生物的物质交换过程中形成，它有时形成在自由状态的细胞中，有时和其它代谢物相关联，首先是四氢叶酸和谷胱甘肽。目前已知可以把甲醛作为免疫调节剂使用(见俄罗斯联邦专利证书№2077882，MпкA61к31/115，1997年4月27日公布)。
对胆固醇水平的调节作用机制建立在发明人发现的甲醛的功能之上，包括超标准突变机制，该机制导致调节胆固醇水平的受体亲和力提高。
我们通过实验证明，在生物体外注入甲醛会导致生长转化因子水平降低，从而引起细胞凋亡或者程序性细胞死亡。细胞凋亡参与到了心脏冠状动脉的粥样硬化发病机制中(见《细胞凋亡在动脉粥样硬化、心肌缺血、心力衰竭发展中的作用/心力衰竭》，作者：Γ.И.斯托洛扎科夫，Д.Б.乌捷舍夫，2000年，第一卷，№4)。在动脉粥样硬化的发病机制中的一个重要观点被认为是内皮细胞的功能被破坏。目前人们理解的内皮细胞功能障碍是神经递质之间不平衡，这种神经递质可以保证所有的内皮依赖过程处于正常状态(见《内皮细胞的临床意义与修正》，作者：Д.B.切尔卡伸，-htt:/www.Cardiolog.ru)，这其中也包括属于彻底硬化的细胞因子的生长转化因子(见Cooper M.E.，Rumbler Y.，Komers R.et.al.-Diabets.-1994.-№43.-P.1221-1228)。
这样一来，凋亡的细胞不只是血管壁的异常细胞，还有其它组织的细胞，包括肝脏细胞、甲状腺细胞、肾上腺细胞。最终恢复器官功能，包括恢复可以保障分裂脂质的酶的活性，以及使血蛋白的物理化学状态处于正常水平，最终使血液中的胆固醇水平趋于正常。
甲醛水溶液是一种透明无色的液体，有独特的刺鼻气味，可以在任何对比关系的情况下与水和酒精混溶。
甲醛属于醛类的代表，是具有刺激气味的无色气体，分子量是30.03，在气温是20摄氏度时密度为0.815，熔点是92摄氏度，沸点是19.2摄氏度。甲醛可以很好地溶于水和酒精，很容易聚合，聚合过程中在水环境里会形成多聚甲醛，在非水环境中(丁烷、己烷)会形成聚甲醛。
注射用等渗氯化钠溶液是有咸味的无色透明液体，无菌溶液。
氯化钠是立方晶体或者是白色的晶体粉末，有咸味，无气味，溶于水(1∶3)。
该申请药物是透明的无色液体，无气味，略有咸味。
该药物按以下方式进行制作。取浓度是36.5-40％的医用甲醛溶液重量部分的2-6，添加到无菌的浓度为0.85-0.95％的氯化钠注射溶液中，重量部分的998-994，直到获得浓度为0.07-0.24％的甲醛溶液。该药物需要在阴暗处保存，温度保持在15-35摄氏度。
示例1：取0.2毫升浓度为37％的医用甲醛溶液，将其加入到99.8毫升的浓度为0.9％(或者0.95％)的无菌氯化钠等渗溶液中。仔细混合溶液混合物，最终得到药物中的甲醛浓度是0.074％(重量百分比)。
示例2：取0.6毫升浓度为37％的医用甲醛溶液，将其加入到99.4毫升的浓度为0.9％(或者0.95％)的无菌氯化钠等渗溶液中。仔细混合溶液混合物，最终得到药物中的甲醛浓度是0.222％(重量百分比)。
示例3：取0.6毫升浓度为40％的医用甲醛溶液，按照上面“示例2”中的描述制作药物。甲醛的最终浓度是0.24％(重量百分比)。
示例4：取3毫升浓度为40％的医用甲醛溶液，将其加入到997毫升的浓度为0.95％的无菌氯化钠等渗溶液中。仔细混合溶液混合物，最终得到药物中的甲醛浓度是0.12％(重量百分比)。
为了证明该申请药物不具有毒性作用，在老鼠身上进行了实验。
在实验中使用了56只重量在18-24克的远亲繁殖的雌雄两性的ICR老鼠。老鼠在标准条件的动物饲养场生活，老鼠处于同样的饲养条件之下，按照规定的食谱进食，自由饮水进食。
从给老鼠注射完药剂之后，对老鼠进行了14昼夜的观察。对它们的整体状况、运动活力、行为、对刺激的反应、反射进行了评估。在整个实验过程中需要不断地为老鼠称重，试验中规定了所需食物和水的重量。对在研究过程中死亡的老鼠进行了解剖，对它们的内脏器官进行了评估，确定了相对系数(大脑、肝脏、心脏、脾脏、肾脏、肾上腺、睾丸、卵巢)。观察期过后存活下来的老鼠被用颈椎脱位法杀死，进行了解剖，并且评估了老鼠内脏器官状态的宏观病理改变。
用Litchield和Wilcoxon概率分析方法确定了毒性指标。
将含有0.2毫升的浓度为37％的甲醛溶液和99.8毫升的浓度为0.9％的氯化钠溶液的药剂，一次性按照5毫升/公斤，25毫升/公斤和50毫升/公斤的剂量进行肌肉注射。在整个观察过程中对老鼠进行了三次称重(分别是注射后的第1、7、14昼夜)。
研究结果显示，在以5.0毫升/公斤的剂量进行药剂注射之后，没有发现老鼠在整体状况和行为上的任何变化。在整个观察期内没有老鼠死亡。所有老鼠体重增加的动态值都在标准范围之内。雄性老鼠和雌性老鼠在整体状况和行为上没有区别。
在给老鼠注射了25毫升/公斤剂量的药剂之后，也发现了接近上述的场景。不论是雄性老鼠，还是雌性老鼠，整体状况、行为、进食进水、体重增长动态值都处在标准范围之内。
在注射了剂量为50.0毫升/公斤药剂的老鼠中出现了短暂的(一分钟以内)轻微兴奋，在这之后老鼠的状态恢复正常，在其它老鼠实验组中没有明显的不同。
在观察期结束后(14昼夜)用颈椎脱落方法将老鼠杀死，进行了解剖和内脏器官的宏观评估，在这之后把老鼠的内脏清除，进行称重，并确定内脏器官的相对指数。研究确定，在所有实验组中的器官的相对重量没有区别，都处于标准范围之内。没有发现局部反应(渗透、充血、脱毛等)。
按照成药制剂浓度的十倍剂量进行了注射试验，也即是说药剂中含有2毫升浓度为37％的甲醛溶液和98毫升的浓度为0.9％的氯化钠溶液。
对ICR的老鼠(雄性和雌性)进行了剂量分别为6、12.5、25毫升/公斤肌肉药剂注射。
在注射之后的头5-6个钟头发现老鼠出现了中度的兴奋抑制和反应抑制。逐渐增加了呼吸频率，并且心跳加快。但是在注射药剂之后的第一个昼夜中没有出现老鼠死亡。在注射药剂之后的第四个昼夜，一只老鼠由于呼吸停止而死亡，这只老鼠被注射了25毫升/公斤剂量的药剂。
所有的实验老鼠在注射药剂之后都出现了肌肉硬结的局部反应。实验结束时，在给老鼠进行注射的皮肤表面开始脱毛，这里形成了密集渗透。
研究表明，最初的药剂毒性剂量没有实质影响到老鼠的体重增长。这些指标在雄性和雌性老鼠中没有超出所允许的范围。
在实验的最后老鼠被杀死，进行了宏观研究，它们的内脏器官被称重，并且计算出了相对系数。
实验结果表明，两性老鼠在被注射了10倍于治疗剂量的药剂之后，在实验结束时，其大脑、心脏、肝脏、脾脏、肾脏、肾上腺、睾丸(卵巢)的相对重量与老鼠的正常值没有实质性区别。
这样一来，获得的结果表明，申请的药剂具有很低的毒性。
治疗方法如下。肌肉注射，剂量为5毫升，间隔7、21、30、60天。
胆固醇水平的研究样本是早晨从病人尺静脉中采集的静脉血样本。
根据赫尔辛基宣言的要求、国际道德标准、人体试验的质量与计划科学标准、白俄罗斯共和国卫生法、白俄罗斯共和国卫生部2000年8月18日下达的第254号文件《关于药物制剂的临床试验》，在白俄罗斯共和国国家传染病院(明斯克市)进行了该药剂的临床试验。
在药物开始作用之后，经过7、28、35、65天确定了治疗效果。胆固醇的标准水平是5.2毫摩/升以内(见《内脏器官疾病治疗/实践指导资料》，作者：A.H.奥克洛科夫，明斯克市，最高学府出版社，维捷布斯科市，白俄罗斯医学书籍出版社-1996年，第三卷，第一部分，19-41页)，临界水平是5.2-6.2毫摩/升，超过6.2毫摩/升属于高水平。
胆固醇水平的修正结果显示在表格1中。
表格1.
修正效果(n＝20人)
在35和65天之后，与原始的水平相比较，统计的显著性差异是p＜0.05。
中度和重度高胆固醇血症的治疗结果显示在表格2和3中。
表格2.
中度高胆固醇血症的治疗结果
表格3.
重度高胆固醇血症的治疗结果
该申请药剂可以使血液中的胆固醇水平恢复正常，而且没有毒性作用，也不会引起机体的抗药性。
Claims (1)
1.该药物具有调节胆固醇的作用，含有化学活性成分和目标添加剂，其特征在于作为活性成分该药物含有36.5-40％浓度的甲醛水溶液，作为目标添加剂该药物中含有注射浓度为0.85-0.95％的等渗氯化钠溶液，以下是重量关系：
36.5-40％浓度的甲醛水溶液 -2-6
浓度为0.85-0.95％的等渗氯化钠溶液 -994-998
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU2007125298 | 2007-07-04 | ||
| RU2007125298/15A RU2352331C1 (ru) | 2007-07-04 | 2007-07-04 | Средство, обладающее холестеринорегулирующим действием |
| PCT/RU2008/000203 WO2009005396A1 (ru) | 2007-07-04 | 2008-04-02 | Средство, обладающее холестеринорегулирующим действием |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012101801544A Division CN102727472A (zh) | 2007-07-04 | 2008-04-02 | 一种制剂在制备调节胆固醇药物中的应用 |
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| CN101801363A true CN101801363A (zh) | 2010-08-11 |
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| CN200880017092A Pending CN101801363A (zh) | 2007-07-04 | 2008-04-02 | 胆固醇调节药物 |
| CN2012101801544A Pending CN102727472A (zh) | 2007-07-04 | 2008-04-02 | 一种制剂在制备调节胆固醇药物中的应用 |
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| CN2012101801544A Pending CN102727472A (zh) | 2007-07-04 | 2008-04-02 | 一种制剂在制备调节胆固醇药物中的应用 |
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| US (2) | US20100144889A1 (zh) |
| EP (1) | EP2172195B1 (zh) |
| JP (1) | JP5095818B2 (zh) |
| CN (2) | CN101801363A (zh) |
| BR (1) | BRPI0810283A2 (zh) |
| RU (1) | RU2352331C1 (zh) |
| WO (1) | WO2009005396A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101925351B (zh) * | 2008-02-09 | 2013-07-24 | 谢尔盖·季什金 | 细胞抑制组合物 |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TR202000720A2 (tr) * | 2020-01-17 | 2021-07-26 | Aslan Yavuz Haberdar | Kardi̇yovasküler ve serebrovasküler hastaliklarin tedavi̇si̇ i̇çi̇n bi̇r bi̇leşi̇m üreti̇m yöntemi̇ |
| RU2765467C1 (ru) | 2021-07-12 | 2022-01-31 | Владислав Николаевич Ласкавый | Средство для коррекции митохондриальной дисфункции |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2077882C1 (ru) * | 1995-11-21 | 1997-04-27 | Владислав Николаевич Ласкавый | Иммуномодулирующее средство |
| RU2077887C1 (ru) * | 1996-04-11 | 1997-04-27 | Владимир Владимирович Цыганков | Порошкообразный биогенный препарат из окостенелых оленьих рогов и пищевая добавка на его основе |
| RU2100027C1 (ru) * | 1997-03-21 | 1997-12-27 | Чумаян Саида Пайлаковна | Королевский эликсир "астхик"-м, обладающий антиинфекционными и нормализующими системные функции организма свойствами |
| RU2146533C1 (ru) * | 1998-08-19 | 2000-03-20 | Ласкавый Владислав Николаевич | Способ профилактики туберкулеза молодняка крупного рогатого скота |
| US7919130B2 (en) * | 2005-10-26 | 2011-04-05 | Hae-Soo Kwak | Method for crosslinking β-cyclodextrin for cholesterol trapping and regeneration thereof |
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- 2008-04-02 CN CN200880017092A patent/CN101801363A/zh active Pending
- 2008-04-02 US US12/451,459 patent/US20100144889A1/en not_active Abandoned
- 2008-04-02 CN CN2012101801544A patent/CN102727472A/zh active Pending
- 2008-04-02 BR BRPI0810283-0A patent/BRPI0810283A2/pt not_active Application Discontinuation
- 2008-04-02 EP EP08753904A patent/EP2172195B1/en not_active Not-in-force
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101925351B (zh) * | 2008-02-09 | 2013-07-24 | 谢尔盖·季什金 | 细胞抑制组合物 |
Also Published As
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|---|---|
| US8497259B2 (en) | 2013-07-30 |
| US20100144889A1 (en) | 2010-06-10 |
| EP2172195A1 (en) | 2010-04-07 |
| JP5095818B2 (ja) | 2012-12-12 |
| RU2352331C1 (ru) | 2009-04-20 |
| JP2010529190A (ja) | 2010-08-26 |
| BRPI0810283A2 (pt) | 2020-08-04 |
| EP2172195A4 (en) | 2010-09-01 |
| CN102727472A (zh) | 2012-10-17 |
| US20120252903A1 (en) | 2012-10-04 |
| WO2009005396A1 (ru) | 2009-01-08 |
| EP2172195B1 (en) | 2012-06-20 |
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