CN1917890B - 用于软骨感染性病况的组合物和方法 - Google Patents
用于软骨感染性病况的组合物和方法 Download PDFInfo
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- CN1917890B CN1917890B CN2005800044526A CN200580004452A CN1917890B CN 1917890 B CN1917890 B CN 1917890B CN 2005800044526 A CN2005800044526 A CN 2005800044526A CN 200580004452 A CN200580004452 A CN 200580004452A CN 1917890 B CN1917890 B CN 1917890B
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- manganese
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- methionine
- cystine
- cysteine
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Abstract
本发明公开了用于提高需要的动物中的软骨灵活性的方法，其包括对所述哺乳动物给用提高软骨灵活性的有效量的含硫氨基酸和锰。
Description
前言
几乎所有的关节都有软骨。动物体内的软骨在提供灵活性、在压力下的可压缩性、缓冲、拉伸强度、关节活动范围和关节内移动的平滑性方面具有重要性。具有软骨的关节的例子包括指和趾、颈、膝、臀、肩等等。动物可以患有其中软骨被不利地感染从而导致关节的灵活性、可压缩性降低的许多病况，并且经常引起关节和/或关节周围组织的全面炎症。从而，这些动物将显著丧失关节功能并且经历疼痛。需要用于治疗、预防或改善这种病况的新的组合物和方法。
发明内容
因此，本发明包括用于改善关节健康状态的组合物和方法。因此，在不同的实施方案中，本发明提供用于减少动物中软骨异常的方法，其包括对动物给用有效量的至少一种含硫氨基酸和锰。
其它实施方案提供预防动物中软骨组织退变的方法，其包括对动物给用有效量的至少一种含硫氨基酸和锰。
本发明的其它方面提供适合于对动物进行系统给用的组合物，其包括与载体结合的有效量的至少一种含硫氨基酸和锰。
本发明其它的适用领域可从下文提供的详细说明而变得显而易见。应该理解，详细说明和具体实施例虽然表示本发明的示例性实施方案，但是其不用于限制本发明的范围。
详细描述
以下关于不同实施方案和实施例的说明本质上只是示例性的，并不以任何方式构成对本发明、其申请、或其应用的限制。
本发明提供用于改善动物并且特别是伴侣动物如犬和猫的关节健康状态的组合物和方法。在阅读本文中对本发明的描述时必须考虑以下的在非限制性原则下的定义。
在本文中对参考文献的引用不构成对那些参考文献作为现有技术或与本文公开的本发明的专利性有任何相关性的承认。对前言中引用的参考文献的内容的任何讨论只是用于提供由参考文献的作者提出的论断的一般性描述，其不构成对这种参考文献的内容的准确性的承认。说明书的描述一节中引用的所有参考文献都被全文并入本文作为参考。
对于阐述本发明的实施方案的具体实施例的描述，只是用于说明性目的而不是构成对本发明范围的限制。此外，对于所述特征的多个实施方案的叙述并非意在排除具有其它另外特征的其它实施方案，或并非意在排除具有所述特征的不同组合的其它实施方案。
软骨由不断进行分解和更换的活组织组成。然而，损伤、关节应力、和老化过程可以危害软骨组织，经常在已经存在大量损害之前还没有任何明显迹象。软骨为由65％-80％的水组成的物质。其余的部分由三种其它重要的化合物组成：胶原蛋白、软骨细胞和蛋白多糖。胶原蛋白赋予软骨以减震性和弹性，而蛋白多糖为更大的分子，其赋予软骨以响应运动进行拉伸和然后回弹的能力。然而，与所有物质一样，胶原蛋白和蛋白多糖会老化。软骨细胞清除老化的蛋白多糖和胶原蛋白并且产生新的蛋白多糖和胶原蛋白。这四种要素一起协作以保证软骨在关节中是健康的、平滑的、和运动时无痛性的。当这些要素中的任一个劣化时，软骨可发生退变并且开始发展成骨关节炎。
骨关节炎主要感染关节软骨，关节软骨是沿着关节内的骨布置的光滑的反光表面。软骨的功能是提供减震性和在关节滑动时减少摩擦。骨关节炎产生软骨的变薄和损害，对软骨造成破坏，其将变得粗糙和被侵蚀。随着骨彼此摩擦，软骨和骨进一步受到损害，在关节的一侧萎陷超过另一侧时产生畸形。当软骨丢失较大时，当所牵涉的关节在使用时，甚至在静止时，存在严重疼痛。
骨关节炎是含滑液(synobial)关节的缓慢进行性病症，其影响超过一岁犬群体的约20％。(Johnston S.A.Orthoarthritis.VeterinaryClinics of North America；Small Animal Practice199727：699-720。)这种关节病症的特征在于关节软骨组分的合成和退变之间平衡的丧失，产生随后的关节软骨侵蚀、软骨下的骨的改型、骨赘形成和不同程度的滑膜炎。在伴侣动物中观察到的继发性骨关节炎的一些最常见的原因是前十字韧带断裂、分离性骨软骨炎、成碎片的冠状突和髋发育异常。(Martinez S.A.，Coronados M.G.Acquired conditions that lead toosteoarthritis in a dog.Veterinary Clinics of N orth America：SmallAnimal Practice1997；27：759-775。)软骨感染性病况的其它例子包括但不限于骨软骨病、滑膜炎、细菌化脓性关节炎、骨关节病、银屑病、软骨下囊性病变、physitis、角形肢畸形(angular limb deformities)和骰状骨畸形。大多数的大型犬随着它们的老化发展形成关节炎。由于它们增加的重量和/或遗传学性倾向，大型犬品种更易患上关节炎。大型犬并非是处于关节炎和其它软骨病况危险下的仅有的动物。关节炎和其它退变性关节病在犬中是常见的，但是这种病况已经表现出在猫中流行。(Hardie E.M.等人，JAVMA220(5)2002，628-632。)处在危险下的其它动物包括但不限于所有的犬、猫、马、山羊、绵羊、猪、牛、人、鸟(包括火鸡和鸡)等等。
已经使用多种物质用于改善如上所述的这些病况。所述物质包括在治疗关节炎时使用氨基葡萄糖、软骨素(chondroitin)和硫酸软骨素增补剂。氨基葡萄糖为蛋白多糖的组分，其在软骨中保持流动性。软骨素为另一种蛋白多糖的组分。紫贻贝(Perna canaliculuss)为葡糖胺聚糖(GAG)的丰富来源。令人遗憾的是，这些GAG在口服时吸收很差。贻贝可有益于关节炎的治疗，但是观察的益处可能更多地是来自于其天然的抗炎作用，而不是葡糖胺聚糖的直接吸收。肌酸在葡萄糖转化为肌肉能量时起到重要作用，并且可能有助于改善肌肉力量和使得年长宠物感觉更精力旺盛。二甲基砜(methylsulfonylmethane，MSM)具有抗炎作用，其延缓关节炎进展并缓解疼痛。当然，典型地用于人类的其它物质也可用于宠物，包括阿司匹林、抗炎药如布洛芬、COX-2抑制剂和其它医药组合物。
在本发明的不同实施方案中，用于改善、治疗、预防和/或有时缓解上述病况的组合物和方法包括给用含硫氨基酸和锰。这种病况的说明性例子包括骨关节炎、类风湿性关节炎、骨软骨病、退变性关节病、滑膜炎、细菌化脓性关节炎、骨关节病、银屑病等等。
在本发明的不同实施方案中，可将含硫氨基酸和锰对动物，优选需要这种给用的动物，以多种方法中的任一种方法给用，如口服、非肠道等等，虽然优选口服给用。在一些实施方案中，氨基酸和锰可以湿或干的膳食给用，或者结合在任何膳食组分中或者通过例如喷雾或沉淀而结合在组分表面上。在某些实施方案中，氨基酸和锰本身可作为营养餐存在，或存在于零食、增补剂、治疗剂、或在膳食的液体部分如水或另外的流体中。氨基酸和锰可作为粉末、固体、或作为包括凝胶的液体给用。如果期望，氨基酸和锰可以在药学剂型如胶囊、片剂、囊片、注射器等中口服给用，并且氨基酸和锰可作为粉末或液体如凝胶用于这种剂型。可以与氨基酸和锰一起使用任何通常的药学载体，如水、葡萄糖、蔗糖等等。虽然举例说明的是氨基酸和锰在一起的情况，但是氨基酸和锰可以分别给用，即，例如一个在膳食中给用而另一个在液体或单位剂型中给用。通常，氨基酸和锰应该至少相伴地给用，并且优选在相同的载体中。当在食物中给用时，含硫氨基酸和锰可以作为化合物在正常的食物组分内给用，或者作为两者的组合给用。
有多种含硫氨基酸及其衍生物适用于本发明。这些包括D-甲硫氨酸、L-甲硫氨酸、DL-甲硫氨酸、D-半胱氨酸、L-半胱氨酸、DL-半胱氨酸、D-胱氨酸、L-胱氨酸、DL-胱氨酸、S-腺苷甲硫氨酸、甜菜碱、甲硫氨酸外消旋混合物的β-羟基类似物、和所述氨基酸的所述混合物等等。可以将含硫氨基酸本身提供给动物、或者可以天然地存在于膳食物质中，如鱼粉、玉米面筋粉、家畜食物、酪蛋白、锰甲硫氨酸(螯合物)等等。
如某些实施方案中如上所述，含硫氨基酸和锰可以处在对动物提供的任何食物中。这种食物的例子为提供全体动物营养物、治疗剂、增补剂等等的常规膳食。在一些实施方案中，氨基酸和锰可以在液体中或药学剂型如胶囊、片剂、丸剂、液体剂或甚至通过注射器给用的非肠道形式中提供。最重要的方面在于为动物提供有效量的活性剂以减少异常。优选的给用途径为口服并与食物结合。
如本文中使用的，术语“膳食”是指由动物定期摄取的食物或饮品。伴侣动物的膳食可以是还可为动物提供足够营养的任何适合的宠物食物配方。例如，用于本发明的典型的犬用膳食可以包含约10到30％的脂肪、约22到44重量％的蛋白质和约10％的总膳食纤维。在另一个例子中，典型的猫用食物可以包含约10到30重量％的脂肪，和约30到45重量％的蛋白质。然而，不需要这些或其它营养物的具体比例或百分比。营养物是帮助维持生命的任何食物成分。以下是在伴侣动物的健康中起重要作用的营养物的例子：
表1.伴侣动物膳食的典型组分
| 蛋白质 | 身体组织如肌肉、血液、皮肤、器官、毛发、和指甲的主要成分 |
| 碳水化合物 | 为身体的组织提供能量 |
| 脂肪 | 脂肪吸收、储存和运输维生素、为皮肤和毛皮增加水分、使得健康的宠物食物味道美妙和提供能量。 |
| 水 | 对于存活来说最关键的营养物。 |
| 维生素 | 帮助维持动物的代谢。 |
| 矿物质 | 为健康皮毛、适当的骨骼支撑和发育所必需的。矿物质通常在宠物食物组分中是丰富的。 |
锰可以不同的形式提供给动物，包括硫酸锰(II)、一氧化锰(II)、二氧化锰(II)、碳酸锰(II)、二氯化锰(II)、蛋白质锰盐、锰螯合物、一氧化锰、锰甲硫氨酸等等。
产生本发明的效果应该使用的氨基酸和锰的量可以显著不同。所有的重量％基于足够满足动物的营养需要的日常膳食的干物质组成进行计算。氨基酸的最低量为超过约1.2重量％，优选超过约1.5重量％，更优选超过约1.8重量％。锰的最低量为超过约50ppm，优选超过约75ppm，更优选超过约100ppm。例如，可以将具体的量在日常基础上用于通常的营养物食物定量配给中、或者在日常基础上将相同的日用量配给在治疗剂或增补剂中提供给动物。另外，只要提供有效量的含硫氨基酸和锰，可以采用这些方法或任何其它剂量给用方法的组合。最大量为任何的有效减少软骨异常而很少(可接受的程度)或没有毒性的量。对于氨基酸来说，这种量的例子，在与对于最低量相同的基础上，包括不超过约2.6重量％、2.3重量％、和2.0重量％。锰的这种量的例子，在与最低量相同的基础上，包括不超过约200ppm、优选约175ppm，更优选约150ppm。
本发明的不同实施方案包括用于改善伴侣动物中的软骨的方法。在这种实施方案中，该方法包括为动物喂食包括基于每天干物质组成为至少50ppm的量的锰和至少1.2重量％的量的含硫氨基酸的膳食。在其它实施方案中，该方法包括为动物喂食包括基于每天干物质组成为至少100ppm的量的锰和至少1.8重量％的量的含硫氨基酸的膳食。在其它实施方案中，该方法包括为动物喂食包括基于每天干物质组成为约50ppm到约200ppm的量的锰和约1.2重量％到约2.6重量％的量的含硫氨基酸的膳食。
在本发明的不同实施方案中，伴侣动物膳食包括增加的锰和含硫氨基酸，其改善伴侣动物的关节的健康状态。在本发明的一些实施方案中，将锰和含硫氨基酸加入到伴侣动物的食物中。在这种实施方案中，可以在加工伴侣动物食物的过程中加入锰和含硫氨基酸，然后将其进行包装并且提供给消费者。这种加工可以包括挤出、装罐、烘烤等等，或本领域中已知的生产宠物食物的任何其它方法或工艺。在这些方法中，锰和含硫氨基酸可由天然来源如动物或植物成分提供，或者锰和含硫氨基酸可由合成来源提供，或者锰和含硫氨基酸可由天然和合成来源的混合物提供。在本发明的其它实施方案中，锰和含硫氨基酸可以是要被喂食给伴侣动物的胶囊形式。在本发明的其它实施方案中，锰和含硫氨基酸可以是粉末或结晶形式，其可以被加入到动物的食物中或直接用于对动物喂食。在本发明的不同实施方案中，伴侣动物膳食包括锰和含硫氨基酸和其它需要的营养组分。在本发明的不同实施方案中，伴侣动物为犬。在其它实施方案中，伴侣动物为猫。在某些实施方案中，伴侣动物为马。
软骨健康状态的一个度量为视觉上可观察到的软骨上的异常的量。观察软骨异常的其它方法包括MRI、计算机化X射线断层照相法和射线照相法。异常程度越高，则全面的关节弱化程度越深，使得其更易感染病况或加重现有病况。这些病况特别地包括关节炎(包括骨关节炎和类风湿性关节炎)、骨软骨病、退变性关节病、滑膜炎、细菌化脓性关节炎、骨关节病、和银屑病。可视觉上观察到的软骨异常包括全面病变、侵蚀、和异常生长。
实施例1
使用正在生长的猪(80实验单位)作为试验模型，用于测定甲硫氨酸和锰对软骨异常的影响。猪最初为约35kg。每头猪分别圈养在5.2ft2的围栏中，不限量供应食物和水。对猪喂食试验食物60天到近似最终重量为约130kg。
在屠宰产肉时，收集右股骨的远端并且评价肉眼可见损害和组织病理学。将右股骨的远端保存在甲醛中并且储存在室温下用于肉眼观察。评价关节的存在于关节面上的病变总数(包括临床病变、软骨侵蚀和异常生长形态)。肉眼可见损害通过组织病理学表征进行证实。从股骨内髁的腹侧承重面取得组织切片。在2X和10X显微照片上进行评价，以测定细胞计数和证实软骨到软骨下的骨的病理学损害。
表2.实验食物的组成
表3.实验食物-第一批的解析分析
表4.实验食物-第二批的解析分析
表5.营养物对软骨异常的影响
如上述数据所示，增加的含硫氨基酸和锰的组合在统计学上减少了通过视觉观察到的软骨异常的数目(例如病变和侵蚀)，如样品3所示。样品1和样品2都没有在统计学上表现出显著的异常减少。样品1的锰含量高，但是含硫氨基酸含量大致与对照相同。样品2的含硫氨基酸含量高，但是锰含量大致与对照相同。
使用正在生长的猪(80实验单位)作为试验模型，用于测定甲硫氨酸和锰对软骨异常的影响。猪最初为约35kg。每头猪分别圈养在5.2ft2的围栏中，不限量供应食物和水。对猪喂食试验食物60天到近似最终重量为约130kg。
实施例2
表6-对血清基质金属蛋白酶和胶原蛋白合成的影响
在90天期限结束时收获血清样品，用于测定基质金属蛋白酶活性(MMP-13)和2型胶原蛋白合成活性。如上述数据所示，增加的含硫氨基酸和锰的组合通过如样品5中所示的酶MMP-13和2型胶原蛋白合成活性的改善而改善软骨。
本文中所述的实施例和其它实施方案是示例性的，其并非意在限制本发明的装置、系统、组合物、材料、和方法的全部范围。可在本发明的范围内对具体的实施方案、装置、系统、组合物、材料和方法进行等效变化、改进、变体，基本上得到类似的结果。这种变化、改进、或变体不应被认为是偏离本发明的精神实质和范围。本文中引用的所有专利、以及本文中讨论的所有的公开、文章、手册、和产品资料都被全文并入本文作为参考。
Claims (20)
1.一种包含基于干物质组成至少1.2重量％含硫氨基酸及其衍生物和至少50ppm锰的组合物在制造用于改善动物中软骨异常的药物中的用途，其中所述含硫氨基酸及其衍生物选自D-甲硫氨酸、L-甲硫氨酸、DL-甲硫氨酸、D-半胱氨酸、L-半胱氨酸、DL-半胱氨酸、D-胱氨酸、L-胱氨酸、DL-胱氨酸、甜菜碱、甲硫氨酸的β-羟基化物、及其混合物，且其中所述锰作为硫酸锰(II)、二氧化锰(II)、碳酸锰(II)、二氯化锰(II)、蛋白质锰盐、锰螯合物、一氧化锰或锰甲硫氨酸提供。
2.权利要求1的用途，其中所述动物不是人类。
3.权利要求2的用途，其中所述动物为伴侣动物。
4.权利要求1的用途，其中所述动物为人类。
5.权利要求1的用途，其中所述氨基酸选自D-甲硫氨酸、L-甲硫氨酸、DL-甲硫氨酸、D-半胱氨酸、L-半胱氨酸、DL-半胱氨酸、D-胱氨酸、L-胱氨酸和DL-胱氨酸。
6.权利要求1的用途，其中所述组合物包含至少1.5重量％的所述氨基酸。
7.权利要求1的用途，其中所述组合物包含基于干物质组成至少100ppm的锰。
8.权利要求1的用途，其中所述组合物包含基于干物质组成1.2-2.6重量％的所述氨基酸和50-200ppm的锰。
9.权利要求8的用途，其中所述软骨异常选自骨关节炎、类风湿性关节炎、骨软骨病、退变性关节病、滑膜炎和细菌化脓性关节炎。
10.权利要求9的用途，其中组合物另外包含选自以下的至少一种物质：氨基葡萄糖、软骨素、二甲基砜、肌酸、抗氧化剂、及其混合物。
11.权利要求9的用途，其中组合物另外包含硫酸软骨素。
12.权利要求1的用途，其中所述组合物包含基于干物质组成1.5-2.3重量％的所述氨基酸和75-175ppm的锰。
13.用于改善动物中软骨异常的组合物，该组合物包括基于干物质组成：
1.2-2.6重量％的至少一种含硫氨基酸，所述氨基酸选自D-甲硫氨酸、L-甲硫氨酸、DL-甲硫氨酸、D-半胱氨酸、L-半胱氨酸、DL-半胱氨酸、D-胱氨酸、L-胱氨酸、DL-胱氨酸、甜菜碱、甲硫氨酸的β-羟基化物、及其混合物；和
50-200ppm的锰。
14.权利要求13的组合物，其中所述氨基酸选自D-甲硫氨酸、L-甲硫氨酸、DL-甲硫氨酸、D-半胱氨酸、L-半胱氨酸、DL-半胱氨酸、D-胱氨酸、L-胱氨酸、DL-胱氨酸及其混合物。
15.权利要求13的组合物，其包含基于干物质组成1.5-2.3重量％的所述氨基酸和75-175ppm的锰。
16.权利要求13的组合物，其另外包括选自以下的至少一种物质：氨基葡萄糖、软骨素、二甲基砜、肌酸、抗氧化剂、及其混合物。
17.权利要求13的组合物，其另外包括硫酸软骨素。
18.权利要求13的组合物，其另外包括蛋白质、脂肪和碳水化合物。
19.权利要求13的组合物，其中所述组合物为犬用食物的组分。
20.权利要求13的组合物，其中所述组合物为猫用食物的组分。
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| EP1982706A1 (en) * | 2007-04-18 | 2008-10-22 | DSMIP Assets B.V. | Use of hydroxytyrosol for the treatment of cartilage injury |
| BR112013016217A2 (pt) | 2010-12-23 | 2018-05-15 | Hills Pet Nutrition Inc | composições alimentares para animais domésticos e métodos para perda e manutenção de peso. |
| WO2019164892A1 (en) * | 2018-02-20 | 2019-08-29 | University Of Florida Research Foundation, Inc. | Composition and method for treating osteoarthritis with manganese dioxide nanoparticles |
| CN114698751B (zh) * | 2022-04-29 | 2023-08-22 | 华南师范大学 | 一种利用s-腺苷甲硫氨酸促进鱼类肌肉生长的饲料、制备方法及其应用 |
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| US6492349B1 (en) * | 1993-03-31 | 2002-12-10 | Nutramax Laboratories, Inc. | Aminosugar and glycosaminoglycan composition for the treatment and repair of connective tissue |
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| JP2002516866A (ja) * | 1998-06-04 | 2002-06-11 | ニュートラマックス ラボラトリーズ，インコーポレイテッド | 結合組織を治療し修復するためのアミノ糖、グリコサミノグリカンおよびｓ−アデノシルメチオニン組成物 |
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| US20030224071A1 (en) * | 1999-08-20 | 2003-12-04 | Howard Murad | Pharmaceutical compositions and methods for managing connective tissue ailments |
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| AU2005212363B2 (en) | 2010-12-23 |
| WO2005077386A1 (en) | 2005-08-25 |
| US20050176674A1 (en) | 2005-08-11 |
| AU2005212363A1 (en) | 2005-08-25 |
| EP1720558A1 (en) | 2006-11-15 |
| RU2006132348A (ru) | 2008-03-20 |
| JP2007524684A (ja) | 2007-08-30 |
| CN1917890A (zh) | 2007-02-21 |
| RU2389485C2 (ru) | 2010-05-20 |
| BRPI0507491A (pt) | 2007-07-10 |
| CA2553748A1 (en) | 2005-08-25 |
| CA2553748C (en) | 2015-07-14 |
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