CN105473146A - 含有吡罗昔康和透明质酸的用于治疗骨关节炎的液态药物组合物 - Google Patents
含有吡罗昔康和透明质酸的用于治疗骨关节炎的液态药物组合物 Download PDFInfo
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- CN105473146A CN105473146A CN201480033415.7A CN201480033415A CN105473146A CN 105473146 A CN105473146 A CN 105473146A CN 201480033415 A CN201480033415 A CN 201480033415A CN 105473146 A CN105473146 A CN 105473146A
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- 229960002702 piroxicam Drugs 0.000 title claims abstract description 49
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 39
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Abstract
本发明涉及一种用于治疗骨关节炎的药物组合物,其中,该药物组合物含有特定配比的吡罗昔康或其药学上可接受的盐和透明质酸或其药学上可接受的盐,该组合物可同时对抗炎作用和镇痛作用产生协同效应。本发明提供了一种用于骨关节炎治疗的药物组合物,其中,该组合物含有0.25-10.0重量%的吡罗昔康或其药学上可接受的盐和0.5-5.0重量%的透明质酸或其药学上可接受的盐,其中吡罗昔康或其药学上可接受的盐和透明质酸或其药学上可接受的盐的重量比为1:1-1:3。本发明的液态药物组合物对炎症和疼痛同时具有优异的治疗效果,从而提供具有治疗骨关节炎的协同效应的关节内液态注射剂。
Description
技术领域
本发明涉及含有特定配比的吡罗昔康和透明质酸的用于治疗骨关节炎(退行性关节炎)的药物组合物,该药物组合物能够对抗炎作用和镇痛作用同时表现出协同效应。
背景技术
由于关节的结构变化和对关节软骨的损伤,因此,被称为退行性关节炎的骨关节炎(osteoarthritis)是一种可引起严重的疼痛、关节运动障碍和其它症状的疾病(DiDomenica等,2005)。因为通过放射线检查来评价骨关节炎的生理状态(包括软骨损失程度和骨头变化程度),因此清楚地定义骨关节炎是非常困难的(Ayral等,2005),但是,其一般定义为“以软骨损失和滑囊、关节、关节周围骨头的结构变化为特征的状态”(Altman1987;Altman等,1990)。对实际的退行性关节炎患者的膝关节的评价表明,他们具有保护关节或韧带和由关节组成的骨头的软骨的伤害或损伤,而导致软骨组织不可逆的破坏。该软骨组织不可逆的破坏会导致关节活动度的损失,从而可阻碍日常活动且引起炎症和疼痛。特别地,膝骨关节炎是老人群的重要的健康问题,其可导致日常活动(例如爬楼梯、从坐姿到站立及行走)中的疼痛和身体功能障碍。另外,其还可以引起关节运动障碍、疼痛障碍、肌肉松弛障碍、关节弯曲变形障碍及膝内翻变形障碍、挛缩障碍和可显著影响生活质量的身体功能障碍等临床症状(Kim等,2011)。
骨关节炎治疗中当前的治疗目标是避免治疗的副作用,同时,抑制疼痛,提高关节的功能和提高生活质量。骨关节炎的基本治疗方法包括非药理方法和药理方法。非药理方法包括减少体重、下肢肌肉强化锻炼、物理治疗,药理方法包括药物治疗例如口服乙酰氨基酚(acetaminophen)或非甾体抗炎药(non-steroidalanti-inflammatorydrugs,NSAIDs),关节腔内注射类固醇或透明质酸钠,以及关节置换术等手术方法(Diracoglu等,2009;Iwamono等,2007;Tunay等,2010)。
可以将聚合透明质酸或其药学上可接受的盐用作退行性关节炎或类风湿性关节炎的注射液治疗剂,可以将其直接注入受影响的部分,例如膝关节、肩关节等。据报道,将粘弹性(Visco-elasticity)高分子物质直接注入到关节腔中可以缓解由于软骨组织损失而导致的关节运动时的冲击感,还可以帮助润滑作用,因此不仅可减轻关节疼痛和实现功能的正常化,而且,还可以改善关节炎导致的功能障碍和抑制疼痛(徐正卓,透明质酸的临床意义和应用,韩国家庭医学杂志2002;23(9):1071-1079;李东哲、白承熙、孙旭镇等。透明质酸对膝骨关节炎的影响,韩国膝关节协会杂志2002;14(2):213-221;宋永旭。骨关节炎的药理治疗,韩国医师协会杂志2003;46(11):958-964;鲁成淑、李再俊、黄成美等。关节内透明质酸钠对具有膝骨关节炎的患者的疗效,韩国痛症学会杂志2004;17(2):170-174)。
吡罗昔康为苯并噻嗪衍生物系列的非甾体抗炎药,可通过抑制前列腺素的合成而产生抗炎作用,由于其优异的镇痛、抗炎作用以及较长的血浆半衰期,因此,目前其可用于治疗退行性关节炎。目前将其用作口服剂、肌肉注射剂、外用贴剂或凝胶。
日本专利申请公开号1992-18022公开了由吡罗昔康和水溶性聚合物、透明质酸、表面活性剂组成的稳定的吡罗昔康组合物。该组合物含有0.1-0.5w/v%的吡罗昔康和0.03-0.05w/v%的透明质酸。但是,其是将透明质酸、水溶性聚合物及表面活性剂用作赋形剂以稳定吡罗昔康,而透明质酸并不是这种组合物的有效成分。
在美国专利申请号5,095,037中,将透明质酸钠和包括吡罗昔康的非甾体抗炎药(Non-SteroidalAnti-InflammatoryDrugs)联合给药至关节炎动物模型并评价其累积或协同抗炎效果。结果表明将吲哚美辛(indomethacin)、双氯芬酸、或布洛芬与透明质酸钠联合给药可以在角叉菜胶(carrageenan)诱导的足水肿动物模型中产生累积或协同作用,但4mg/kg吡罗昔康和4mg/kg透明质酸钠联合给药的效果甚微。另外,通过角叉菜胶引发的红肿部位为足垫(foodpad),其显著不同于实际受骨关节炎影响的身体的其它部分,例如膝关节、手指末梢、腕掌骨(carpometacarpus)、近端关节、跖趾间关节、腕(wrist)、髋、腰椎、颈椎和脚踝。此外,其机理也不同于实际骨关节炎,因此,这不适合于评价NSAID和透明质酸联合给药对骨关节炎的治疗效果。
如上所述,从现有技术中不可预期的是,对于含有吡罗昔康和透明质酸的组合物的抗炎作用及镇痛作用,这样的组合物可以对骨关节炎的治疗产生累积或协同效果。
但是,本发明人将吡罗昔康或其药学上可接受的盐和透明质酸或其药学上可接受的盐按特定配比结合,发现该结合可同时对抗炎作用和镇痛作用产生协同效应,并因此对骨关节炎的治疗非常有效,本发明人进行了各种实验而完成了本发明。
发明内容
技术问题
本发明的目的在于提供一种用于治疗骨关节炎的药物组合物,其中,该药物组合物含有特定配比的吡罗昔康或其药学上可接受的盐和透明质酸或其药学上可接受的盐,该组合物可同时对抗炎作用和镇痛作用产生协同效应。
技术方案
为实现上述目的,本发明提供了一种用于骨关节炎治疗的药物组合物,该药物组合物含有0.25-10.0重量%的吡罗昔康或其药学上可接受的盐和0.5-5.0重量%的透明质酸或其药学上可接受的盐,其中含有的吡罗昔康或其药学上可接受的盐与透明质酸或其药学上可接受的盐的重量比为1:1-1:3。
下面,对本发明进行更详细的说明。
本发明提供了一种液态药物组合物,基于组合物总重量,该组合物含有0.25-10.0重量%的吡罗昔康或其药学上可接受的盐和0.5-5.0重量%的透明质酸或其药学上可接受的盐,且分别优选为含有0.33-3.0重量%的吡罗昔康或其药学上可接受的盐和1.0-3.0重量%的透明质酸或其药学上可接受的盐,其中,吡罗昔康或其药学上可接受的盐与透明质酸或其药学上可接受的盐的重量比为1:1-1:3。
将根据本发明的液态药物组合物优选制成注射剂型,而且,将其关节内注射给药以治疗骨关节炎。
在本发明中,吡罗昔康药学上可接受的盐是指所有吡罗昔康的有机或无机加成盐,其浓度是对患者相对无毒无害的且其副作用不会降低吡罗昔康盐化合物的优异效果。这样的盐可以使用无机酸和有机酸作为游离酸,可接受的无机酸包括盐酸、溴酸、硝酸、硫酸、高氯酸、磷酸,这样的有机酸包括柠檬酸、醋酸、乳酸、马来酸、富马酸、葡萄糖酸、乙醇酸、琥珀酸、酒石酸、半乳糖醛酸、亚甲基双羟萘酸(embonicacid)、谷氨酸、天冬氨酸、草酸、D-苹果酸或L-苹果酸、甲磺酸、乙磺酸、4-甲苯磺酸、水杨酸、苯甲酸和丙二酸。另外,这些盐可以为碱金属盐(例如钠盐、钾盐)及碱土金属盐(例如钙盐、镁盐)。例如,酸加成盐可包括醋酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、右旋樟脑磺酸盐、柠檬酸盐、乙二磺酸盐、乙醇盐、甲酸盐、富马酸盐(fumarate)、葡庚糖酸盐、葡糖酸盐、葡萄糖醛酸盐、六氟磷酸盐、海苯酸盐(hibenzate)、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘化物/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘二甲酸(naphthalate,)、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、亚甲基双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、糖酸盐(saccharate)、硬脂酸盐、琥珀酸盐、酒石酸盐、甲苯磺酸盐、三氟醋酸盐、铝盐、精氨酸盐、苄星盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、乙醇胺盐、钾盐、钠盐、氨丁三醇盐和锌盐,优选地,使用碱金属盐、胺类及精氨酸和赖氨酸等氨基酸盐。可使用由这些药学上可接受的盐产生的吡罗昔康盐来引发上述组合物的制备,可替代地,当将吡罗昔康溶解于溶剂中时,可以在制备过程中途将上述盐逐滴加入。充分搅拌后,可形成吡罗昔康盐。
另外,本发明含有透明质酸、透明质酸药学上可接受的盐或透明质酸和透明质酸的药学上可接受的盐的混合物。透明质酸药学上可接受的盐包括无机盐如透明质酸钠、透明质酸镁、透明质酸锌、透明质酸钴,以及有机盐如透明质酸四丁铵(tetrabutylammoniumhyaluronate)。在某些情况下,可使用这些盐中的两者或多种的组合。在本发明中,对透明质酸的分子量没有特殊的限制,但优选地平均分子量为500,000-10,000,000。
根据本发明的液态药物组合物含有0.25-10.0重量%的吡罗昔康和0.5-5.0重量%的透明质酸,且分别优选含有0.33-3.0重量%的吡罗昔康和1.0-3.0重量%的透明质酸,而且,相应地,吡罗昔康与透明质酸的重量比为1:1-1:3。在该比例以上或以下,均难以获得对骨关节炎的累积或协同治疗效果。
吡罗昔康或其盐可占全部注射液的0.25-10.0重量%。在浓度为0.25重量%以下时,治疗效果最小,而浓度为10.0重量%以上时,则需要过量的增溶剂,有可能导致增溶剂的漂浮或吡罗昔康的沉淀。
另外,液态组合物可以含有透明质酸或其盐,以透明质酸的浓度计,透明质酸或其盐可以为全部溶液的0.5-5.0重量%。如果透明质酸的浓度为0.5重量%或者0.5重量%以下,治疗效果甚微;而在5.0重量%水平以上时,因组合物的粘性急剧增加会导致难以填充预充式注射器或安瓿容器(ampoulecontainer)且难以将该组合物给药给患者身体的受影响部分。
透明质酸和吡罗昔康的液态注射制剂的液态组合物的优选pH值为5.5-8.5,更优选为7.0-8.5。pH值在5以下,当冷藏或室温贮存时,吡罗昔康的物理稳定性降低,可能会引起沉淀,而pH值水平在8.5以上下,透明质酸变的不稳定且关节内给药可能会导致局部刺激而引起疼痛、浮肿、炎症和其它副作用。
发明的有益效果
本发明提供了一种对骨关节炎治疗效果具有协同效应的来自液态组合物的关节内液态注射制剂,该液体组合物含有0.25-10.0重量%的吡罗昔康或其药学上可接受的盐和0.5-5.0重量%的透明质酸或其药学上可接受的盐,其中,吡罗昔康或其药学上可接受的盐与透明质酸或其药学上可接受的盐的重量比为1:1-1:3。
附图说明
图1示出了在诱导骨关节炎的大鼠模型中炎症减少效果的示意图,其中,吡罗昔康和透明质酸的比例为(a)1:4;(b)1:3;(c)1:2;(d)1:1;(e)2:1及(f)3:1;
图2示出了在诱导骨关节炎的大鼠模型中疼痛减少效果的示意图,其中,吡罗昔康和透明质酸的比例为(a)1:4;(b)1:3;(c)1:2;(d)1:1;(e)2:1及(f)3:1。
最优实施方式
下面,结合实施例对本发明进行具体说明,以帮助更好地理解本发明。但本发明的实施例可变形为各种其他形式,且不应该被理解为对本发明的范围的限制。本发明提供实施例的目的是描述本发明以帮助本领域技术人员更好地理解本发明。
<实施例1>本发明含有吡罗昔康和透明质酸的液态组合物的制备
向约350ml磷酸盐缓冲液(pH值为7.4)中添加5.58g吡罗昔康钾和适量的增溶剂,然后在30℃下搅拌1小时将混合物溶解,再添加磷酸盐缓冲液至最终体积为500ml。利用注射器过滤器进行灭菌之后,然后添加5.0g透明质酸钠。随后利用高架混合器在30-40℃的温度下搅拌12小时以作为最后步骤来制备组合物。
<实施例2和3>本发明含有吡罗昔康和透明质酸的液态组合物的制备
使用与上述实施例1相同的方法制备含有吡罗昔康和透明质酸的液态组合物,但是含量却如下表1中所示,并将其分别作为实施例2和实施例3。
<比较例1至3>本发明含有吡罗昔康和透明质酸的液态组合物的制备
使用与上述实施例1相同的方法制备含有吡罗昔康和透明质酸的液态组合物,但是组成和含量却如下表1中所示,并将其分别作为比较例1至比较例3。
<对照组1至7>含有吡罗昔康的液态组合物的制备
使用与上述实施例1相同的方法制备吡罗昔康液态组合物,但是组成和含量却如下表1中所示,并将其分别作为对照组1至7。
表1
[表1]
Pi:吡罗昔康钾
HA:透明质酸钠
<实验例1>在Mono-iodoacetate诱导的骨关节炎模型中的抗炎症效力评价
对于本评价,将从(株)大韩BIOLINK公司购买的8周龄雄性SD大鼠在清净区域(研究所新馆地下二层动物饲养室)内稳定四周,其中,清净区域中温度维持在23±2℃,相对湿度维持在40-60%,换气次数维持在10次/小时以上,氨浓度维持在20ppm或20ppm以下,平均照度为150-300lux,噪音水平维持在60或60以下响度单位(phon),且光照和黑暗循环维持在12小时。实验开始时,Mono-iodoacetate(下称MIA)中以3mg/30ul/只向右侧关节腔内给药。在给药一天后,测量大鼠的关节直径,并将它们分组,使得各组具有相同的平均关节直径。形成组后,将适当的药物给药给各组一次,并在MIA给药的第三天测量关节的直径,其结果示于图1中。
<试验日程>
Day0-测量关节直径;诱导骨关节炎
Day1-测量关节直径,进行药物给药
Day3-测量关节直径
<试验组>
炎症程度评价:将关节的因炎症性变化引起的浮肿用作炎症严重性的指标。将关节直径作为端点,使用电子数显卡尺(Mitutoyo,Japan)测量关节的直径。
关节肿胀=绝对值(右关节直径–左关节直径)
如图1所示,在比较例1(Pi:HA=1:4)中表现出协同的抗炎效应,但比较例2(Pi:HA=2:1)及比较例3(Pi:HA=3:1)在抗炎效果方面没有表现出协同作用。
如上所述,与仅给药吡罗昔康或者仅给药透明质酸的对照组相比,本发明的实施例1(Pi:HA=1:1)、实施例2(Pi:HA=1:2)、实施例3(Pi:HA=1:3)均表现出减少炎症的协同效应。
<实验例2>在Mono-iodoacetate诱导的骨关节炎模型中的镇痛效力评价
对于本评价,将从(株)大韩BIOLINK公司购买的8周龄雄性SD大鼠在清净区域(研究所新馆地下二层动物饲养室)内稳定四周,其中,清净区域中温度维持在23±2℃,相对湿度维持在40-60%,换气次数维持在10次/小时以上,氨浓度维持在20ppm或20ppm以下,平均照度为150-300lux,噪音水平维持在60或60phon以下,且光照和黑暗循环维持在12小时。实验开始时,Mono-iodoacetate(下称MIA)中以3mg/30ul/只向右侧关节空间内给药。在给药一天后,测量大鼠的平衡重量,并将大鼠分组,使各组具有相同的平均平衡重量。形成组之后,将适当的药物给药给各组一次,并在MIA给药的第三天测量平衡重量,其结果示于图2中。
<试验日程>
Day0-测量平衡重量,诱导骨关节炎
Day1-测量平衡重量,药物给药
Day3-测量平衡重量
<试验组>
疼痛程度评价:作为以疼痛程度评价的方法采用最广为使用的重量分布(%)。在计算重量分布中,将大鼠放在双足平衡测痛仪(Incapacitancemeter)上,获得当后肢脚掌在测量板之上5秒内每个后肢的平均重量,并通过下式进行计算:
重量分布(%)=100*右侧肢体重量/(左侧肢体重量+右侧肢体重量)
所有结果均以平均值±SEM表示,而为了确定实验结果的显著性,利用SigmaStat的T检验(studentt-test)对各组之间进行统计处理评价。
如图2所示,仅比较例2(Pi:HA=2:1)表现出疼痛减少的协同效应,但比较例1(Pi:HA=1:4)和比较例3(Pi:HA=1:3)在疼痛减少方面并没有表现出协同效应。
如上所述,与仅给药吡罗昔康或者仅给药透明质酸的对照组相比,本发明的实施例1(Pi:HA=1:1)、实施例2(Pi:HA=1:2)、实施例3(Pi:HA=1:3)均表现出疼痛减少的协同效应。
由此可以看出,较之对照组,本发明在抗炎和镇痛作用方面具有协同效应,因此,本发明作为抗炎镇痛药物组合物是有用的。
Claims (12)
1.一种用于治疗骨关节炎的药物组合物,该药物组合物含有吡罗昔康或其药学上可接受的盐和透明质酸或其药学上可接受的盐,其中,所述药物组合物含有0.25-10.0重量%的吡罗昔康或其药学上可接受的盐和0.5-5.0重量%的透明质酸或其药学上可接受的盐,且吡罗昔康或其药学上可接受的盐与透明质酸或其药学上可接受的盐的重量比为1:1-1:3。
2.根据权利要求1所述的药物组合物,其中,吡罗昔康或其药学上可接受的盐的浓度为0.33重量%-3.0重量%,且透明质酸或其药学上可接受的盐的浓度为1.0重量%-3.0重量%。
3.根据权利要求1所述的药物组合物,其中,所述药物组合物的pH值为5.5-8.5。
4.根据权利要求3所述的药物组合物,其中,药物组合物的pH值为7.0-8.5。
5.根据权利要求1所述的药物组合物,其中,吡罗昔康的药学上可接受的盐选自由盐酸、溴酸、硝酸、硫酸、高氯酸、磷酸、柠檬酸、醋酸、乳酸、马来酸、富马酸、葡萄糖酸、乙醇酸、琥珀酸、酒石酸、半乳糖醛酸、亚甲基双羟萘酸、谷氨酸、天冬氨酸、草酸、D-苹果酸或L-苹果酸、甲磺酸、乙磺酸、4-甲苯磺酸、水杨酸、苯甲酸、丙二酸的碱金属盐(钠盐和钾盐)以及碱土金属盐(钙盐和镁盐)组成的组。
6.根据权利要求5所述的药物组合物,其中,吡罗昔康的药学上可接受的盐为钾盐。
7.根据权利要求1所述的药物组合物,其中,透明质酸的药学上可接受的盐选自由透明质酸钠、透明质酸镁、透明质酸锌、透明质酸钴和透明质酸四丁铵组成的组。
8.根据权利要求7所述的药物组合物,其中,透明质酸的药学上可接受的盐为钠盐。
9.根据权利要求7所述的药物组合物,其中,透明质酸的药学上可接受的盐为两种盐的混合物。
10.根据权利要求1所述的药物组合物,其中,透明质酸为透明质酸和透明质酸的药学上可接受的盐的混合物。
11.根据权利要求1所述的药物组合物,其中,将所述药物组合物制备成注射剂型的形式。
12.根据权利要求11所述的药物组合物,其中,将所述药物组合物给药至关节腔中。
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1078388A (zh) * | 1992-02-20 | 1993-11-17 | 诺法姆康公司 | 应用透明质酸和nsaids治疗疾病 |
CN1084064A (zh) * | 1992-02-20 | 1994-03-23 | 诺法姆康公司 | 含有透明质酸的制剂 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
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CA1340994C (en) * | 1989-09-21 | 2000-05-16 | Rudolf Edgar Dr. Falk | Treatment of conditions and disease |
US5639738A (en) * | 1992-02-20 | 1997-06-17 | Hyal Pharmaceutical Corporation | Treatment of basal cell carcinoma and actinic keratosis employing hyaluronic acid and NSAIDs |
US6017900A (en) * | 1991-07-03 | 2000-01-25 | Hyal Pharmaceutical Corporation | Topical composition containing hyaluronic acid and nsaids |
US6114314A (en) * | 1992-02-21 | 2000-09-05 | Hyal Pharmaceutical Corp. | Formulations containing hyaluronic acid |
US5420124A (en) * | 1994-01-12 | 1995-05-30 | Kim; Young S. | Stable, painless piroxicam potassium injectable composition |
KR101304085B1 (ko) * | 2008-03-04 | 2013-09-05 | 라브리스 바이올로직스 인코포레이티드 | 염증성 통증의 치료 방법 |
JP2009298741A (ja) * | 2008-06-16 | 2009-12-24 | Teikoku Seiyaku Co Ltd | 消炎鎮痛外用剤 |
KR101005079B1 (ko) * | 2008-10-23 | 2010-12-30 | 금오공과대학교 산학협력단 | 유착방지막 용도의 생분해성 나노섬유시트 및 그 제조방법 |
CA2835016A1 (en) * | 2011-05-30 | 2012-12-06 | Novozymes Biopharma Dk A/S | Spray drying of high molecular weight hyaluronic acid |
KR101383941B1 (ko) * | 2012-03-09 | 2014-04-10 | 동아에스티 주식회사 | 피록시캄 또는 약제학적으로 허용되는 그의 염과 히알루론산 또는 약제학적으로 허용되는 그의 염의 안정한 액상 조성물 및 그 제조방법 |
-
2013
- 2013-06-13 KR KR1020130067792A patent/KR101439032B1/ko active IP Right Grant
-
2014
- 2014-05-27 CN CN201480033415.7A patent/CN105473146A/zh active Pending
- 2014-05-27 EP EP14811288.1A patent/EP3007702A4/en not_active Withdrawn
- 2014-05-27 WO PCT/KR2014/004745 patent/WO2014200211A1/en active Application Filing
- 2014-05-27 US US14/897,571 patent/US20160106774A1/en not_active Abandoned
- 2014-05-27 JP JP2016519430A patent/JP2016521741A/ja active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1078388A (zh) * | 1992-02-20 | 1993-11-17 | 诺法姆康公司 | 应用透明质酸和nsaids治疗疾病 |
CN1084064A (zh) * | 1992-02-20 | 1994-03-23 | 诺法姆康公司 | 含有透明质酸的制剂 |
Non-Patent Citations (1)
Title |
---|
JOSÉ ILLNAIT等: "Effects of D-002, a Product Isolated from Beeswax, on Gastric Symptoms of Patients with Osteoarthritis Treated with Piroxicam: A Pilot Study", 《JOURNAL OF MEDICINAL FOOD》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107840897A (zh) * | 2016-09-18 | 2018-03-27 | 中南大学湘雅医院 | 一种用于治疗骨关节炎的透明质酸镁盐及其制备方法和应用 |
Also Published As
Publication number | Publication date |
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WO2014200211A1 (en) | 2014-12-18 |
EP3007702A4 (en) | 2016-12-28 |
EP3007702A1 (en) | 2016-04-20 |
KR101439032B1 (ko) | 2014-09-05 |
JP2016521741A (ja) | 2016-07-25 |
US20160106774A1 (en) | 2016-04-21 |
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