CN105979931A - 液体形式的益智药“pantocalcin” - Google Patents
液体形式的益智药“pantocalcin” Download PDFInfo
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Abstract
本发明涉及一种表现出混合的益智性质和广泛的活性的药品，该药品对γ‑氨基丁酸(GABA)系统有影响，并且可以用于医学、精神神经学实践和制药工业。本发明的技术效果在于提高了活性物质在液体形式的药剂中的含量(高达40％)，这是通过改善活性物质的感官性质、通过降低能够增加液体形式的药剂的粘度的物质在其中的含量以及增加水含量来提供降低液体形式的药剂的粘度的能力来实现的。
Description
本发明涉及一种表现出混合型益智性质的药物产品，该药物产品具有广谱的影响GABA(γ-氨基丁酸)系统的作用，并且可用于精神神经医学实践和制药工业。
本发明确保能够制造用于儿童精神病学和神经病学的便利的液体药物形式。此外，其具有较高的生物利用度。
高泛酸钙被用于患有智力缺陷、智力发育不全、延缓言语发展的儿童，以及患有癫痫，特别是在多形性攻击(polymorphous attack)或癫痫小发作时的儿童(联合治疗，有时单独治疗)。
基于GABA的益智药(Aminolon)是本领域已知的，其对中枢神经系统的机能活动有显著的影响；然而，GABA透过血脑屏障不佳，因此这阻碍了Aminolon在临床条件下治疗中枢紊乱的应用(参见文献“V.M.Kopelevich,Uspekhi Khimii,48(7),1979,p.1273-1296”)。
益智药剂Pyracetam也是本领域已知的，其是用于在健康患者和(特别是)患有与多种疾病并发的失调的患者中治疗以下疾病的药物的第一种药剂，所述疾病例如，教育和记忆过程障碍、认知功能障碍(参见文献“T.A.Voronina,S.B.Seredinin.Exper.and Clin.Pharmacology,61(4),1998,p.3-8”)。
这种药剂的劣势在于其应用存在一定的限制，即：这种药剂可能不能用于治疗小孩(年龄低于8岁的)，该药剂不表现出抗惊厥活性，而且，它增加了预备惊厥的风险，这限制了其在各种阵发性状况下治疗患者的实践中的使用。
表现出益智活性的药物组合物是本领域已知的(俄罗斯联邦专利No.2145213,IPC A61K9/20,公开时间：2000年10月2日)，其包含活性物质、佐剂和包衣。该药物组合物包含作为活性物质的γ-氨基丁酸、作为佐剂的糖和润滑剂、和由碱性碳酸镁、面粉和糖组成的包衣，其成分比(以重量％计)如下：核：γ-氨基丁酸，84-94；糖，5-15；润滑剂，0.8-1；包衣：碱性碳酸镁，10-50；面粉，10-30；糖40-80。
片剂形式的益智药剂Pantogam是本领域已知的，其为高泛酸的钙盐(Pantogam.在精神神经病学中20年的使用经验(Twenty-YearExperience of Use in Psychoneurology).-M.:PP"Patent",1998)
片剂形式的益智药剂Pantocalcin是本领域已知的(制造者–OJSC"Valenta Pharm",Reg.No:P N001397/01)，其包含作为活性物质的高泛酸钙(Pantogam或高泛酸的钙盐)，0.25克或0.5克；佐剂：羟基碳酸镁、硬脂酸钙、滑石、土豆淀粉。
这些药剂被用于治疗患智力缺陷(延缓的智力发育)和智力发育不全的儿童以及患延迟言语发展的儿童。这些药剂被用于联合治疗或(在某些情况中)单独治疗患癫痫的儿童。在伴有延迟智力过程的癫痫的情况中，将PantogamTM与抗惊厥药物联合施用给成年人。同样，可以施用这些药剂来治疗儿童和成年人的排尿障碍，例如遗尿和日间尿失禁。
这些药剂的劣势在于它们仅仅被制造为0.25克和0.5克的片剂形式。当儿童每日剂量为0.75克至3克时，儿童每天应服用3至12片(取决于年龄和诊断)。由于该药剂被施用给年龄为2个月至15岁的儿童，因此，考虑到药剂的医学指示，有时给年幼的儿童以及(有时)年长的儿童施用必需的剂量是困难的。由于该药剂具有苦味，这种情况甚至更加困难。
最近开发的类似物(原型)为包含Pantogam(高泛酸的钙盐)和佐剂的益智药PANTOGAM(俄罗斯联邦专利No.2177783,IPCA61K9/08,公开时间：2002年10月1日)，其特征在于其为糖浆剂，并且包含甘油、山梨糖醇、柠檬酸、阿斯巴甜、芳香精华和苯甲酸钠作为佐剂，其组分比如下，以重量％计：
此组合物的劣势在于活性物质的含量相当低(不超过20％)，其需要每天口服数次，并且该药剂的液体形式(糖浆剂)具有高粘度，这使得很难定量配制出该药剂，并限制其应用于年龄超过3岁和更大的儿童。此外，由于当糖浆剂的Pantogam含量高于10重量％时，其感官特性急剧劣化(不允许将该药剂用于儿童)，因此原型药剂PANTOGAM(PIK-FARMA LLC生产)的活性物质(Pantogam)的含量不超过10重量％。
此外，到目前为止还没有滴剂形式的高泛酸制剂。
本发明的技术效果为，高泛酸制剂为滴剂形式，并且液体药剂的活性物质的含量(高达40％)增加，这是由于其感官性质得到改善，并且提供了降低液体形式的药剂的粘度的可能性(由于降低了增加其粘度的物质的量，并且增加了其水含量)。
实现该技术效果是由于根据本发明的包含高泛酸的钙盐和佐剂的液体益智药是滴剂的形式，并且包含苯甲酸、糖精钠、橙色香料、1M的盐酸和Trilon B作为佐剂，所述组分的比例(重量％)如下：
术语“滴剂”指的是溶解在水或其它溶剂中的液体形式的药剂，并且按照滴剂施用剂量。
术语“糖浆剂”指的是溶解在浓缩的碳水化合物浆中的液体形式的药剂。浓缩的糖浆的目的是用来改善药剂的感官性质。
在加入感官性物质以前，本发明所要求保护的药剂溶液具有涩口和令人不愉快的味道，并且带有明显的苦味。在本申请的浓缩物中，将Trilon B加入药剂组合物有助于封闭苦味受体并且消除所述苦味。
在比较甜味剂(其为碱金属的盐)味道的细微差别，并在舌头上发现钙受体之后，申请人得出结论：药剂的涩味与舌头中钙受体上的钙离子(当活性物质钙盐发生2级离解时，在Pantocalcin溶液中形成了钙离子)的影响有关。
将Trilon B加入药剂组合物主要改变了药剂感官性能，使其味道更好，而粘度没有显著改变。此外，除了改变涩味的“强度”之外，Trilon B的加入完全消除了所述苦味(这一切似乎表明高浓度Pantocalcin溶液的苦的感觉与苦味受体的有限的特异性相关，这使得对浓缩物质的作用的响应不特异于该受体)。
色谱-质谱研究表明所有的Trilon B都与钙离子结合。由于溶解度的限制，不能进一步增加溶液中的Trilon B的浓度。尽管如此，通过添加一定的矫正剂，我们已经成功地实现了使40％Pantocalcin溶液具有适宜的味道。
通过添加1M的盐酸溶液使溶液的pH降低到pH＝5，这确保了防腐剂(苯甲酸)的作用效率更高并且增加了表面张力，因此，这使得该药剂溶液的每一滴的重量最佳化(提高)。
以下给出了所要求保护的药剂的示例性组合物1-3。
实施例1.“Pantocalcin，滴剂”药剂的组成，重量％：
实施例2.“Pantocalcin，滴剂”药剂的组成，重量％：
实施例3.“Pantocalcin，滴剂”药剂的组成，重量％：
实施例4.制备本发明药剂的溶液的工艺
为了在储存过程中实现药剂的最大稳定性，并在制造该药剂的过程中使其对设备的作用最小化，在这两个阶段中溶解该药剂是合理的。
在第一阶段，将水供给至反应器中，然后加入一部分Pantocalcin物质(其重量比水的重量高20％)并搅拌直至完全溶解。此外，加入剩余部分的Pantocalcin物质和1摩尔的盐酸，搅拌直至完全溶解。按照以下顺序加入其它组分：橙色香料-溶解；Trilon B-溶解；糖精钠-溶解；苯甲酸-溶解。
因此，由上述教导明显得知，本发明成功地实现了所述技术效果，即：由于感官性能改善，所述液体形式的药剂具有较高的活性物质含量(高达40％)，并且由于增加其粘度的物质的量较低以及水含量较高，所述液体形式的药剂的粘度较低。
Claims (2)
1.一种高泛酸的钙盐的液体制剂，其表现出益智活性，并且所述液体制剂包含有效量的所述高泛酸的钙盐和佐剂，其特征在于所述液体制剂为滴剂的形式，并且包含苯甲酸、糖精钠、橙色香料、1M的盐酸和Trilon B作为佐剂，所述组分的比例以重量％计如下：
2.根据权利要求1所述的液体制剂用于治疗各种病因的神经和认知障碍的应用。
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| RU2014101564 | 2014-01-20 | ||
| RU2014101564/15A RU2542419C1 (ru) | 2014-01-20 | 2014-01-20 | Ноотропное средсто "пантокальцин" в жидкой форме |
| PCT/RU2015/000014 WO2015108449A1 (ru) | 2014-01-20 | 2015-01-16 | Ноотропное средство "пантокальцин" в жидкой форме |
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| RU2181757C2 (ru) * | 2000-03-07 | 2002-04-27 | Тюменская государственная медицинская академия | Состав для стабилизации липидов |
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