CN111084782A - 一种治疗糖尿病并发症的药物组合物 - Google Patents
一种治疗糖尿病并发症的药物组合物 Download PDFInfo
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- CN111084782A CN111084782A CN202010048871.6A CN202010048871A CN111084782A CN 111084782 A CN111084782 A CN 111084782A CN 202010048871 A CN202010048871 A CN 202010048871A CN 111084782 A CN111084782 A CN 111084782A
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- diabetic
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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- A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
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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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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Abstract
本发明涉及医药领域，提供了一种功效成分有且仅有维生素B1和甲钴胺及羟苯磺酸钙的用于治疗糖尿病并发神经和血管病变的组合物。
Description
技术领域
本发明涉及医药领域的一种药物组合物。
背景技术
糖尿病是一组以高血糖为特征的代谢性疾病，高血糖则是由胰岛素分泌缺陷或其生物作用受损或两者兼有而引起。糖尿病人长期存在的高血糖，导致各种组织，特别是眼、肾、心脏、血管、神经的慢性损害和功能障碍等并发症。糖尿病本身并不可怕，但可怕的是其一系列并发症如糖尿病足，糖尿病眼底病变、糖尿病周围神经炎、糖尿病肾病及糖尿病心血管病变等。糖尿病的治疗首先是要控制好血糖以尽量避免或减缓并发症的产生，其次，直接针对并发症的预防和治疗措施也非常重要。目前常以甲钴胺（维生素B12的一种活性形式）治疗糖尿病周围神经炎，并以羟苯磺酸钙治疗糖尿病微血管病变包括视网膜病变及肾小球硬化。甲钴胺的作用机理可能是其进入神经元细胞器，参与脑细胞和脊髓神经元胸腺嘧啶核苷的合成，促进叶酸的利用和核酸代谢，促进轴突运输功能和轴突再生，促进卵磷脂合成和神经元髓鞘形成。因维生素B1亦可促进神经细胞膜髓鞘磷脂合成，故在甲钴胺应用于临床前，维生素B12联合维生素B1被临床医师广泛应用于临床治疗各种周围神经损伤，如此，完全可以期待甲钴胺联合VB1治疗糖尿病相关神经病变比VB12联合VB1有更好地疗效，经查，确实也有维生素B1联合甲钴胺治疗糖尿病周围神经病变疗效好于单用甲钴胺的报导（河南医学研究２０１８年２月第２７卷第３期P503，ＨＥＮＡＮＭＥＤＩＣＡＬＲＥＳＥＡＲＣＨＦｅｂ．２０１８，Ｖｏｌ．２７，Ｎｏ．３，P503）。此外，尚有研究指出，羟苯磺酸钙联合甲钴胺治疗糖尿病神经病变效果好于单独使用甲钴胺，因为他改善了甲钴胺只能营养神经但不能改善微循环的不足（北方药学2015年第12卷第1期P94；《中国实用医药》2015年第21期）。实际上，神经病的神经病变本就与微血管病变有着密切关系，主要表现为毛细血管基底膜增厚，血管内皮细胞增生，透明性变，同时糖蛋白沉积导致微小血管管腔狭窄，从而导致神经组织映血缺氧。更为巧妙的是，钙剂本就是VB12的吸收助剂（IF-B12复合物与回肠末端黏膜上皮细胞的cubilin受体结合过程是钙依赖性的，补充钙剂可逆转糖尿病治疗药物二甲双胍对VB12的吸收影响）。也就是说，羟苯磺酸钙既以血管保护剂存在，也以VB12吸收助剂存在。而且，作为一种钙剂，羟苯磺酸钙尚有着溶解性好、吸收率高的特点，分子量小于常用钙剂葡萄糖酸钙，含钙量比葡萄糖酸钙高。此外，Thornalley等人对26名1型糖尿病和48名2型糖尿病患者的血浆维生素B1水平进行测定并发现，和非糖尿病人群相比，血浆维生素B1水平分别下降了76%和75%（P<0.001）。与此相对应的是，和非糖尿病人群相比，1型糖尿病和2型糖尿病患者维生素B1的肾排泄分别增加了4倍和3倍（P<0.001），维生素B1肾清除分别增加了24倍和16倍（P<0.001），而维生素B1的分级排泄则分别增加了25倍和15倍（P<0.001）。研究者认为，糖尿病患者的维生素B1缺乏可能会降低微血管细胞对高糖的耐受，使其容易受到糖毒性的损伤，因而罹患微血管并发症的风险增加。为了明确维生素B1缺乏和糖尿病微血管病变之间的关系，Adaikalakoteswari等人对943名尿白蛋白正常的糖尿病患者进行随访，观察早期糖尿病肾病患者血浆维生素B1水平及肾维生素B1清除的情况。结果发现，随访期间有109人出现微量白蛋白尿，其中52人被纳入该研究，包括25名肾功能进行性丧失的患者和27名肾功能相对稳定的患者。研究结果表明，微量白蛋白尿和早期肾功能衰退患者血浆维生素B1与非糖尿病人群相比显著降低，其中合并早期肾功能衰退的微量白蛋白尿患者血浆维生素B1水平又显著低于肾功能正常的糖尿病患者（P<0.001）；合并早期肾功能衰退和微量白蛋白尿的患者尿维生素B1浓度和尿维生素B1排泄高于白蛋白尿正常的患者（P<0.001/P<0.001）及肾功能稳定的患者（P<0.02/P<0.05）。Logistic回归分析显示，尿维生素B1水平独立于糖化血红蛋白，与早期肾功能衰退相关。上述实验结果证实在维生素B1缺乏和糖尿病微血管病变之间的确存在某种程度的关联，并且糖尿病患者在肾小球滤过率正常时已经存在肾清除维生素B1功能紊乱，因此，维生素B1缺乏可能是糖尿病肾病的早期标志【吉林大学学报（医学版）Ｊｏｕｒｎａｌ ｏｆ Ｊｉｌｉｎ Ｕｎｉｖｅｒｓｉｔｙ（Ｍｅｄｉｃｉｎｅ Ｅｄｉｔｉｏｎ）Ｖｏｌ．４０ Ｎｏ．６ Ｎｏｖ．２０１４】。这与羟苯磺酸钙作为血管保护剂的机理有所不同。羟苯磺酸钙的药理作用为通过调节微血管壁的生理功能，减少阻力，降低血浆粘稠度和血小板的高聚集性，从而防止血栓形成，并能提高红细胞柔韧性，间接增加淋巴的引流而减轻水肿，还可抑制血管活性物质(组胺、5-羟色胺、缓激肽、透明质酸酶、前列腺素)对微血管引起的高通透作用，改善基底膜胶原的生物合成。如此，也可期待VB1联合羟苯磺酸钙能够对糖尿病患者的血管病变能有比单用羟苯磺酸钙更好的治疗作用。基于VB1和甲钴胺及羟苯磺酸钙三者间相辅相成的作用机制以及糖尿病血管和神经并发症之间的关联关系，将VB1和甲钴胺及羟苯磺酸钙研发制作成治疗糖尿病并发症的固定组合物不管是在药理上还是在患者的用药依从性上都具有显见的意义，经查，目前无类似产品面市，也无相关专利授权和申请。
发明内容
本发明创造提供了一种功效成分有且仅有维生素B1和甲钴胺及羟苯磺酸钙的组合物，三种功效成分在药理药效上相辅相成并相得益彰，且减少了病人需要一次使用多种药物的麻烦，增强了患者依从性；组分中羟苯磺酸钙既作为功效成分存在，也作为另一组分甲钴胺的吸收助剂存在。的当然的，产品不排除甚至必然含有一些其他药品制造领域常用非功效性辅料如乳糖、淀粉、乙醇、水、硬脂酸镁、羧甲基纤维素钠、羧甲基纤维素钙、滑石粉、羟乙基纤维素、羟丙基纤维素等、防腐剂、抗氧化剂等。
以上的组分与辅料可以使用药品生产制造领域常用和普通的工艺与方法制作成片剂、胶囊、颗粒、干混悬剂、散剂、注射剂等常用剂型和形态，释放形式包括普通速释、缓释、控释、胃溶释放、肠溶释放、分散释放、咀嚼释放等，从携带的便利性及患者依从性角度考虑，以口服固体剂型为优选。
组合物中VB1日使用剂量范围为10mg-60mg/d（参照已批准药物说明书及Thornalley等人的研究），甲钴胺日使用剂量范围为0.5mg-1.5mg/d（参照已批准药物说明书），羟苯磺酸钙日使用剂量为1.0g-1.5g/d（参照已批准药物说明书）；以上日使用剂量可设计为一次或两至三次的服用剂量，每次使用剂量又可拆分为1至数片（粒、瓶、袋）的制剂剂量以便满足不同服用剂量的需求。优选的，以日服用2—3次为佳。
实施例（非限制性）1：胶囊或片，规格：每片（粒）20mg VB1， 0.5mg甲钴胺，羟苯磺酸钙0.5g ，每次服用1片，每日服用2—3次。
实施例（非限制性）2：胶囊或片，规格：每片（粒）10mg VB1， 0.25mg甲钴胺，羟苯磺酸钙0.25g ，每次服用1—2片，每日服用2—4次。
Claims (4)
1.一种药物组合物，其特征在于产品主要功效成分有且仅有维生素B1和甲钴胺及羟苯磺酸钙三种（但可以包括用于制剂成型的其他非功效性辅料）。
2.如权利要求1所述的产品，其用途仅限于糖尿病并发血管和神经病变的治疗。
3.如权利要求1所述的产品以片剂、胶囊、颗粒、散剂、溶液剂、混悬剂、注射剂等形态存在，其释放方式包括普通速释、缓释、控释、胃溶释放、肠溶释放、分散释放等。
4.如权利要求1所述的产品，其组分中维生素B1的日使用剂量范围为10mg-60mg，甲钴胺的日使用剂量范围为0.5mg-1.5mg，羟苯磺酸钙的日使用剂量范围为1.0g-1.5g。
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