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Publication numberCN101951879 A
Publication typeApplication
Application numberCN 200880123524
PCT numberPCT/US2008/084515
Publication date19 Jan 2011
Filing date24 Nov 2008
Priority date30 Nov 2007
Also published asCA2706880A1, EP2219595A1, EP2219595B1, EP3047844A1, US8394782, US8513216, US8853184, US20090143331, US20100004198, US20130209532, US20140349959, WO2009073437A1
Publication number200880123524.2, CN 101951879 A, CN 101951879A, CN 200880123524, CN-A-101951879, CN101951879 A, CN101951879A, CN200880123524, CN200880123524.2, PCT/2008/84515, PCT/US/2008/084515, PCT/US/2008/84515, PCT/US/8/084515, PCT/US/8/84515, PCT/US2008/084515, PCT/US2008/84515, PCT/US2008084515, PCT/US200884515, PCT/US8/084515, PCT/US8/84515, PCT/US8084515, PCT/US884515
InventorsA·泰泽尔, C·S·马德, D·斯特姆普利斯
Applicant阿勒根公司
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
Polysaccharide gel formulation
CN 101951879 A
Abstract
Described herein are polysaccharide gel formulations including at least one inhibitor of polysaccharide degradation and methods of making the same. The methods described herein involve the steps of providing at least one polysaccharide and incorporating at least one inhibitor of degradation into the polysaccharide. In some embodiments, the incorporating step comprises 1 ) mixing the at least one inhibitor with the at least one polysaccharide at a highly hydrated state thereby encapsulating the at least one inhibitor in a polysaccharide network, and 2) dehydrating the polysaccharide network thereby controlling release kinetics or final swell ratio. In another embodiment, the incorporating step comprises 1) encapsulating at least one inhibitor into a biocompatible or biodegradable vessel and 2) combining the polysaccharide and the vessel into a gel formulation. The polysaccharide gel formulations described herein can be used for a variety of cosmetic applications.
Claims(20)  translated from Chinese
  1. 一种包含至少一种多糖和至少一种多糖降解抑制剂的多糖凝胶制剂,所述多糖选自透明质酸、纤维素、壳聚糖、o‑硫酸化的HA、葡聚糖、硫酸葡聚糖、硫酸软骨素、硫酸皮肤素、硫酸角蛋白、肝素、硫酸肝素和藻酸盐,所述多糖降解抑制剂选自糖胺聚糖、抗氧剂、黄酮类化合物、蛋白质、脂肪酸和它们的结合物。 A polysaccharide gel formulation comprising at least one polysaccharide and at least one inhibitor of polysaccharide degradation, the polysaccharides are selected from hyaluronic acid, cellulose, chitosan, o- sulfated HA, dextran, sulfate, Portugal polysaccharide, chondroitin sulfate, dermatan sulfate, keratin sulfate, heparin, heparin sulfate and alginate, a polysaccharide degradation inhibitor is selected from glycosaminoglycans, antioxidants, flavonoids, proteins, fatty acids and their conjugate.
  2. 2.权利要求1的制剂,其中所述多糖是交联的。 2. The formulation of claim 1, wherein said polysaccharide is crosslinked.
  3. 3.权利要求1的制剂,其中所述至少一种多糖为透明质酸。 3. The formulation of claim 1, wherein said at least one polysaccharide is hyaluronic acid.
  4. 4.权利要求1的制剂,其中所述糖胺聚糖选自肝素、硫酸肝素、硫酸皮肤素、硫酸软骨素、ο-硫酸化的透明质酸、亚麻仁苷和苦杏仁苷。 Formulation according to claim 1, wherein the glycosaminoglycan is selected from heparin, heparan sulfate, dermatan sulfate, chondroitin sulfate, ο- sulfated hyaluronic acid, linseed and amygdalin glycosides.
  5. 5.权利要求4的制剂,其中所述糖胺聚糖为硫酸软骨素。 5. The formulation of claim 4, wherein said glycosaminoglycan is chondroitin sulfate.
  6. 6.权利要求5的制剂,其中所述硫酸软骨素以约1重量%至约40重量%的浓度存在。 6. The formulation of claim 5, wherein said chondroitin sulfate at a concentration of about 40% to about 1% by weight by weight.
  7. 7.权利要求1的制剂,其中所述抗氧剂选自抗坏血酸、褪黑激素、维生素C、维生素E和它们的结合物。 7. The formulation of claim 1, wherein the antioxidant is selected from ascorbic acid, melatonin, vitamin C, vitamin E, and combinations thereof.
  8. 8.权利要求1的制剂,其中所述黄酮类化合物选自四羟黄酮、芹菜素、福橘素、槲皮素、 山萘酚、杨梅素、漆黄素、异鼠李素、藿香黄酮醇、鼠李秦素、橙皮素、柚皮素、圣草酚、高圣草素、紫杉醇、二氢槲皮素、二氢山萘酚、鞣酸、单宁、浓缩单宁、可水解单宁和它们的结合物。 Formulation according to claim 1, wherein said compound is selected from four flavonoid quercetin, apigenin, blessing orange pigment, quercetin, kaempferol, myricetin, Fisetin isorhamnetin, Agastache flavonoids alcohol, buckthorn Qin, hesperetin, naringenin, eriodictyol, homoeriodictyol, paclitaxel, dihydroquercetin, dihydro kaempferol, tannic acid, tannic and concentrated tannins, hydrolysable tannins and combinations thereof.
  9. 9.权利要求8的制剂,其中所述黄酮类化合物为鞣酸。 9. The formulation of claim 8, wherein said flavonoid is tannic acid.
  10. 10.权利要求9的制剂,其中所述鞣酸以约0. 0001至约1重量%的浓度存在。 10. The formulation of claim 9, wherein said tannic acid in a concentration of from about 0.0001 to about 1% by weight.
  11. 11.权利要求1的制剂,其中所述蛋白质为血清透明质酸酶抑制剂。 11. The formulation of claim 1, wherein the protein is a serum hyaluronidase inhibitor.
  12. 12.权利要求1的制剂,其中所述脂肪酸为饱和Cich22脂肪酸。 12. The formulation of claim 1, wherein the fatty acid is a saturated fatty acid Cich22.
  13. 13.权利要求1的制剂,还包含生物相容的或可生物降解的容器,其中所述抑制剂在所述容器之中或者是所述容器的一部分,其中所述容器为脂质体、胶束或聚合的小囊。 13. The formulation of claim 1, further comprising a biocompatible or biodegradable vessel wherein said inhibitor into said container or is a part of said container, wherein said container is a liposome, gum beam or polymerized vesicle.
  14. 14.权利要求1的制剂,其中所述抑制剂为所述制剂提供提高的流变性质,使得与交联的多糖凝胶制剂相比给予所述制剂需要更小的挤出力。 14. The formulation of claim 1, wherein said inhibitor provides improved rheological properties of the formulation, such that the cross-linked polysaccharide gel formulation as compared to administering the formulation requires less extrusion force.
  15. 15. 一种制备降解时间增加的多糖凝胶制剂的方法,包括步骤:提供至少一种选自透明质酸、纤维素、壳糖、ο-硫酸化的HA、葡聚糖、硫酸葡聚糖、硫酸软骨素、硫酸皮肤素、硫酸角蛋白、肝素、硫酸肝素和藻酸盐的多糖,并在所述多糖中掺入至少一种选自糖胺聚糖、抗氧剂、黄酮类化合物、蛋白质和脂肪酸多糖降解的抑制剂。 15. A polysaccharide gel method for preparing a formulation increased degradation time comprising the steps of: providing at least one compound selected from hyaluronic acid, cellulose, sugar shell, ο- sulfated HA, dextran, dextran sulfate , chondroitin sulfate, dermatan sulfate, keratin sulfate, heparin, heparin sulfate and polysaccharide alginate, and incorporated in the polysaccharide is at least one selected from glycosaminoglycans, antioxidants, flavonoids, polysaccharide protein and fatty acid degradation inhibitor.
  16. 16.权利要求15的方法,其中所述掺入步骤包括1)在高水合状态下将所述至少一种抑制剂与所述至少一种多糖混合,从而将所述至少一种抑制剂封装于多糖网络中,以及2)水合所述多糖网络,从而控制释放动力学或终膨胀率。 16. The method of claim 15, wherein said introducing step comprises 1) said at least one inhibitor is mixed with at least one polysaccharide at high hydration state, whereby said at least one inhibitor is encapsulated in polysaccharide network, and 2) the hydrated polysaccharide network thereby controlling release kinetics or final expansion.
  17. 17.权利要求15的方法,其中在掺入所述至少一种多糖降解抑制剂前使用交联剂交联所述至少一种多糖,所述交联剂选自1,4_ 丁二醇二缩水甘油醚(BDDE)、1,2_双(2,3_环氧丙氧基)乙烯、1- (2,3-环氧丙基)-2,3-环氧环己烷和它们的结合物。 17. The method of claim 15, wherein prior to incorporation of said at least one inhibitor of polysaccharide degradation of at least one polysaccharide the crosslinking agent used, the crosslinking agent is selected from butanediol diglycidyl 1,4_ glycidyl ether (BDDE), 1,2_ bis (2,3_ epoxypropoxy) ethylene, 1- (2,3-epoxypropyl) -2,3-epoxycyclohexane and combinations thereof thereof.
  18. 18.权利要求15的方法,其中所述掺入步骤包括1)将所述至少一种抑制剂封装至一个生物相容的或可生物降解的容器中,以及2)将所述至少一种多糖和所述容器结合成一种凝胶制剂中。 Method 15 encapsulating the at least one inhibitor to a biocompatible or biodegradable vessel in, and 2) the at least one polysaccharide of claim 18, wherein said introducing step comprises 1) and the container are combined into a gel formulation.
  19. 19. 一种降解时间增加的多糖凝胶制剂,包含交联的透明质酸和鞣酸,其中所述鞣酸以约0. 0001%至约的浓度存在。 19. A method of increasing the degradation time of the polysaccharide gel formulation, contains a cross-linked hyaluronic acid and tannic acid, wherein said tannic acid in a concentration of about 0.0001% to about existence.
  20. 20. 一种降解时间增加的多糖凝胶制剂,包含交联的透明质酸和硫酸软骨素,其中所述硫酸软骨素以约至约40%的浓度存在。 20. A method of increasing the degradation time of polysaccharide gel formulation comprising a crosslinked hyaluronic acid and chondroitin sulfate, wherein the chondroitin sulfate from about to about 40% concentration.
Description  translated from Chinese

多糖凝胶制剂 Polysaccharide gel formulation

[0001] 发明人 [0001] Inventors

[0002] D.斯特姆普利斯、CS马德和A.泰泽尔 [0002] D. Sturm Pulis, CS Madrid and Taize Er A.

[0003] 相关专利申请的交叉引用 Cross [0003] REFERENCE TO RELATED PATENT APPLICATION

[0004] 本申请要求以2007年11月30日提交的美国临时专利申请60/991,473为优先权基础,该临时申请的整个公开文本以引用的方式纳入本文。 [0004] This application claims priority to U.S. Provisional Patent November 30, 2007 filed application 60 / 991,473 as a priority, the entire disclosure of the provisional application is incorporated herein by reference.

技术领域 Technical Field

[0005] 整体上公开了用于增加多糖凝胶寿命的应用于美容和医疗中的制剂,以及制备其和使用其的方法。 [0005] discloses a process for increasing the overall life of the polysaccharide gel is applied in cosmetic and medical preparations, as well as their preparation and method of use thereof.

背景技术 Background

[0006] 多糖是相对复杂的糖。 [0006] The polysaccharide is relatively complex sugar. 多糖是由糖苷键连接在一起的许多单糖组成的聚合物。 Polysaccharides are polymers of many monosaccharides joined together by a glycosidic bond formed. 因此,多糖是较大并经常有支链的大分子。 Thus, the polysaccharide is larger and often branched macromolecules. 多糖(尤其是透明质酸(HA))已被应用于美容和医疗中。 Polysaccharide (especially hyaluronic acid (HA)) have been used in cosmetic and medical. 例如,这类聚合物已被用作软组织填充中的填充剂。 For example, such polymers have been used as fillers in soft tissue augmentation.

[0007] HA停留于细胞外空间,其作用是填充空间、稳定结构以及作为具有独特延展性物理性质和极好生物相容性的细胞保护分子。 [0007] HA stay in the extracellular space, its role is to fill the space, structural stability as well as cytoprotective molecule with unique physical properties of ductility and excellent biocompatibility. HA基质有极端的粘弹性,而又保持高水平的水合。 HA viscoelastic matrix extreme, while maintaining a high level of hydration. 在皮肤含水量和真皮组织中HA水平之间存在强相关。 Between the skin and the moisture levels of HA dermal strong correlation. 已知当人皮肤老化时,HA含量和代谢发生改变。 Known that when human skin aging, HA content and metabolic changes. 随着这些改变,皮肤的机械性质有明显劣化。 With these changes, the mechanical properties of the skin significantly deteriorated. 在年轻皮肤和细胞间基质中存在强HA网络之间似乎存在关联。 There seems to be a strong correlation between the presence of HA network of young skin and intercellular matrix.

[0008] 不幸地是,非交联多糖链以及交联多糖链例如HA会通过不同通路降解(如酶降解、自由基降解);从而限制该聚合物的体内寿命。 [0008] Unfortunately, the non-crosslinked polysaccharide chains and crosslinked polysaccharide chain through different pathways such as HA degradation (such as enzymatic degradation, radical degradation); thus limiting the lifetime of the polymer in vivo. 因此,开发在体内降低天然分解速率并增加产物持久性的方法和组合物是重要的。 Therefore, it is important to develop in vivo and reduce the natural rate of decomposition increases product durability methods and compositions. 对通过抗降解而具有增加的寿命的多糖制剂仍有未被满足的需求。 By anti-degradation of polysaccharide preparation with increased life expectancy is still unmet demand.

发明内容 DISCLOSURE

[0009] 本文描述了在体内寿命增加或降解时间增加的多糖凝胶(例如透明质酸,HA)制剂。 [0009] This paper describes the increase in life expectancy or increased degradation time in vivo polysaccharide gel (such as hyaluronic acid, HA) preparations. 该降解时间的增加由掺入作为降解抑制剂的分子提供。 Increase the degradation time is provided by the incorporation of a molecular degradation inhibitors. 此外,本发明提供了用于封装这些制剂以在体内维持延长的寿命或降解时间的方法。 Further, the present invention provides methods for encapsulating these formulations to sustain a prolonged longevity or in vivo degradation time in. 本发明还涉及可应用于药物或美容用的凝胶制品。 The present invention also relates to pharmaceutical or cosmetic can be applied to a gel products.

[0010] 在一个实施方案中,本文描述了一种包含至少一种多糖和至少一种多糖降解抑制剂的多糖凝胶制剂,所述多糖选自透明质酸、纤维素、壳聚糖、O-硫酸化的HA、葡聚糖、硫酸葡聚糖、硫酸软骨素、硫酸皮肤素、硫酸角蛋白、肝素、硫酸肝素和藻酸盐,所述多糖降解抑制剂选自糖胺聚糖(glycos iaminoglycan)、抗氧剂、黄酮类化合物、蛋白质、脂肪酸和它们的结合物。 [0010] In one embodiment, described herein comprising at least one polysaccharide and at least one inhibitor of polysaccharide degradation of polysaccharide gel formulation, the polysaccharide is selected from hyaluronic acid, cellulose, chitosan, O - sulfated HA, dextran, dextran sulfate, chondroitin sulfate, dermatan sulfate, keratin sulfate, heparin, heparin sulfate and alginate, a polysaccharide degradation inhibitor is selected from glycosaminoglycans (glycos iaminoglycan), antioxidants, flavonoids, proteins, fatty acids and combinations thereof. 在一个实施方案中,所述多糖是交联的。 In one embodiment, the polysaccharide is crosslinked. 在一个实施方案中,所述至少一种多糖为透明质酸。 In one embodiment, the at least one polysaccharide is hyaluronic acid.

[0011] 在一个实施方案中,所述糖胺聚糖选自肝素、硫酸肝素、硫酸皮肤素、硫酸软骨素、 [0011] In one embodiment, the glycosaminoglycan is selected from heparin, heparan sulfate, dermatan sulfate, chondroitin sulfate,

4ο-硫酸化的透明质酸、亚麻仁苷(Linamarin)和苦杏仁苷(Amygdalin)。 4ο- sulfated hyaluronic acid, linseed glycosides (Linamarin) and amygdalin (Amygdalin). 在另一个实施方案中,所述糖胺聚糖为硫酸软骨素,并且以约1重量%至约40重量%的浓度存在。 In another embodiment, the glycosaminoglycan is chondroitin sulfate, and a concentration of about 40% to about 1% by weight by weight.

[0012] 在一个实施方案中,抗氧剂选自抗坏血酸、褪黑激素、维生素C、维生素E和它们的结合物。 [0012] In one embodiment, the antioxidant is selected from ascorbic acid, melatonin, vitamin C, vitamin E, and combinations thereof.

[0013] 在一个实施方案中,所述黄酮类化合物选自四羟黄酮、芹菜素、福橘素、槲皮素、山萘酚、杨梅素、漆黄素、异鼠李素、藿香黄酮醇、鼠李秦素、橙皮素、柚皮素、圣草酚、高圣草素、紫杉醇、二氢槲皮素、二氢山萘酚、鞣酸、单宁、浓缩单宁、可水解单宁和它们的结合物。 [0013] In one embodiment, the selected four flavonoid quercetin, apigenin, blessing orange pigment, quercetin, kaempferol, myricetin, Fisetin isorhamnetin, Agastache flavonoids alcohol, buckthorn Qin, hesperetin, naringenin, eriodictyol, homoeriodictyol, paclitaxel, dihydroquercetin, dihydro kaempferol, tannic acid, tannic and concentrated tannins, hydrolysable tannins and combinations thereof. 在另一个实施方案中,所述黄酮类化合物为鞣酸,并且以约0.0001重量%至约1重量%的浓度存在。 In another embodiment, the flavonoid is tannic acid, and at a concentration of about 1% to about 0.0001 wt% by weight.

[0014] 在一个实施方案中,所述蛋白质为血清透明质酸酶抑制剂。 [0014] In one embodiment, the protein is a serum hyaluronidase inhibitor. 在另一个实施方案中, 所述脂肪酸为饱和Cich22脂肪酸。 In another embodiment, the fatty acid is a saturated fatty acid Cich22.

[0015] 在一个实施方案中,所述制剂还包含生物相容的或可生物降解的容器(vessel), 其中所述抑制剂在所述容器之中或者是所述容器的一部分,其中所述容器为脂质体、胶束或聚合的小囊。 [0015] In one embodiment, the formulation further comprises a biocompatible or biodegradable vessel (vessel), wherein said inhibitor into said container or is a part of said container, wherein said Container as liposomes, micelles or polymerized vesicle. 在另一个实施方案中,所述抑制剂为所述制剂提供提高的流变性质,使得与交联的多糖凝胶制剂相比给予所述制剂需要更小的挤出力。 In another embodiment, the inhibitor provides improved rheological properties of the formulation, such that the cross-linked polysaccharide gel formulation as compared to administering the formulation requires less extrusion force.

[0016] 在一个实施方案中,本文描述了一种生产降解时间增加的多糖凝胶制剂的方法, 包括步骤:提供至少一种选自透明质酸、纤维素、壳聚糖、ο-酸化的HA、葡聚糖、硫酸葡聚糖、硫酸软骨素、硫酸皮肤素、硫酸角蛋白、肝素、硫酸肝素和藻酸盐的多糖,并在所述多糖中掺入至少一种选自糖胺聚糖、抗氧剂、黄酮类化合物、蛋白质和脂肪酸的多糖降解抑制剂。 [0016] In one embodiment, described herein, a method of producing an increased degradation time of the polysaccharide gel formulation, comprising the steps of: providing at least one compound selected from hyaluronic acid, cellulose, chitosan, ο- acidified HA, dextran, dextran sulfate, chondroitin sulfate, dermatan sulfate, keratin sulfate, heparin, heparin sulfate and alginate polysaccharides, and incorporating at least one compound selected from glycosaminoglycans gathered in the polysaccharide polysaccharide sugar, antioxidants, flavonoids, protein and fatty acid degradation inhibitor.

[0017] 在所述方法的一个实施方案中,掺入步骤包括1)在高水合状态下将所述抑制剂与所述多糖混合,从而将所述抑制剂封装于多糖网络中,以及2)使所述多糖网络脱水,从而控制释放动力学或终膨胀比。 [0017] In one embodiment of the method, the incorporation step includes 1) hydrated state at a high mixing the inhibitor with the polysaccharide, thereby encapsulating the inhibitor in a polysaccharide network, and 2) said polysaccharide network dehydration, thereby controlling the release kinetics or final swell ratio.

[0018] 在所述方法的另一个实施方案中,在掺入所述至少一种多糖降解抑制剂前使用交联剂交联所述至少一种多糖,所述交联剂选自1,4_ 丁二醇二缩水甘油醚(BDDE)、1,2-双(2,3-环氧丙氧基)乙烯、1- (2,3-环氧丙基)-2,3-环氧环己烷和它们的结合物。 [0018] In another embodiment of the method, at least one polysaccharide degrading the incorporation of at least one polysaccharide before crosslinking agent crosslinking the inhibitor, the crosslinking agent is selected from 1,4_ butanediol diglycidyl ether (BDDE), 1,2- bis (2,3-epoxypropoxy) ethylene, 1- (2,3-epoxypropyl) -2,3-epoxycyclohexyl alkyl and combinations thereof.

[0019] 在所述方法的一个实施方案中,所述掺入步骤包括1)将一种抑制剂封装至一个生物相容的或可生物降解的容器中,以及2)将所述至少一种多糖和所述容器结合至一种凝胶制剂中。 [0019] In one embodiment of the method, the incorporation step comprises 1) encapsulating an inhibitor to the container of a biocompatible or biodegradable in, and 2) the at least one polysaccharide and the vessel binds to a gel formulation.

[0020] 在一个实施方案中,本文描述了一种降解时间增加的多糖凝胶制剂,其包含交联的透明质酸和鞣酸,其中所述鞣酸以约0. 0001%至约的浓度存在。 [0020] In one embodiment, the paper describes a degradation time increased polysaccharide gel formulation comprising a crosslinked hyaluronic acid and tannic acid, wherein the concentration of tannic acid from about 0.0001% to ca. exist.

[0021] 在一个实施方案中,本文描述了一种降解时间增加的多糖凝胶制剂,其包含交联的透明质酸和硫酸软骨素,其中所述硫酸软骨素以约至约40%的浓度存在。 [0021] In one embodiment, the paper describes a degradation time increased polysaccharide gel formulation comprising a cross-linked hyaluronic acid and chondroitin sulfate, wherein the chondroitin sulfate is about 50 to about 40% of the concentration exist.

[0022] 本文还描述了包含多糖凝胶制剂、可药用载体和活性成分的药物组合物。 [0022] Also described herein contain polysaccharide gel formulation, the pharmaceutical composition may be a pharmaceutically acceptable carrier and an active ingredient. 在一个实施方案中,所述活性成分选自抗痒剂、抗蜂窝组织剂、抗瘢痕剂、抗炎症剂、抗氧剂、维生素、增湿剂和它们的结合物。 In one embodiment, the active ingredient is selected from anti-itch agents, anti-cellulite agents, anti-scarring agents, anti-inflammatory agents, antioxidants, vitamins, moisturizers and combinations thereof.

附图说明 Brief Description

[0023] 图1以曲线图示出使用量热试验得到的含硫酸软骨素A(CSA)的多糖凝胶的酶降解程度。 [0023] Figure 1 graphically illustrates the degree of degradation of the enzyme obtained using a calorimeter test containing chondroitin sulfate A (CSA) polysaccharide gel.

[0024] 图2以曲线图示出使用量热试验得到的含鞣酸(TA)的多糖凝胶的酶降解程度。 [0024] 2 graphically illustrates experimentally derived using a calorimeter polysaccharide gel containing tannic acid (TA) the extent of enzymatic degradation of FIG.

[0025] 图3以曲线图示出使用可溶性HA试验得到的有或无CSA的多糖凝胶的酶降解程度。 [0025] FIG. 3 graphically illustrates the extent of enzymatic degradation of soluble HA test obtained with or without CSA polysaccharide gel.

[0026] 图4以曲线图示出使用可溶性HA试验得到的有或无TA的多糖凝胶的酶降解程度。 [0026] FIG. 4 graphically illustrates the degree of degradation of the enzyme obtained using soluble HA test with or without TA polysaccharide gel.

[0027] 图5以曲线图示出CSA对多糖凝胶的挤出力的效应。 [0027] FIG. 5 graphically illustrates the effect of extrusion force CSA's polysaccharide gel. 具体实施方式 DETAILED DESCRIPTION

[0028] 本文描述了通过掺入作为降解抑制剂的分子提供的在体内寿命增加或降解时间增加的多糖凝胶(例如透明质酸,HA)制剂。 [0028] As described herein by incorporating molecular degradation inhibitor provides increased longevity or degradation time in vivo increasing polysaccharide gel (e.g. hyaluronic acid, HA) formulations. 在一些实施方案中,所述多糖凝胶是交联的。 In some embodiments, the polysaccharide gel is crosslinked. 此外,本发明还涉及用于封装这些制剂以在体内维持延长的寿命或降解时间的方法。 Further, the present invention also relates to a body for encapsulating these formulations to sustain a prolonged longevity or degradation time in the method. 本发明还涉及可应用于药物或美容用的凝胶制品。 The present invention also relates to pharmaceutical or cosmetic can be applied to a gel products.

[0029] 本发明的一个方面涉及包含至少一种多糖和至少一种多糖降解抑制剂的多糖凝胶制剂。 [0029] One aspect of the invention relates to compositions comprising at least one polysaccharide and at least one inhibitor of polysaccharide degradation of polysaccharide gel formulation. 本发明还涉及通过掺入降解抑制剂增加多糖凝胶的降解时间。 The present invention also relates to increasing the degradation by the incorporation of an inhibitor of degradation of a polysaccharide gel time. “多糖”是指超过两个单糖分子的聚合物,其中所述单糖可以相同或不同。 "Polysaccharide" means more than two molecules of a monosaccharide polymer, wherein the monosaccharide may be the same or different. 本发明的多糖可以是交联的或非交联的。 Polysaccharide of the present invention may be crosslinked or non-crosslinked. 本文使用的多糖可以为,但不限于HA、纤维素、壳聚糖、ο-硫酸化的HA、葡聚糖、硫酸葡聚糖、硫酸软骨素、硫酸皮肤素、硫酸角蛋白、肝素、硫酸肝素和藻酸盐。 The polysaccharide used herein may be, but is not limited to HA, cellulose, chitosan, ο- sulfated HA, dextran, dextran sulfate, chondroitin sulfate, dermatan sulfate, keratin sulfate, heparin sulfate, heparin and alginate.

[0030] 抑制剂为通过靶向并中和具体降解机制如酶降解和自由基降解发挥作用的分子。 [0030] inhibitors such as enzymatic degradation and the role of radical degradation of molecules by targeting and neutralizing specific degradation mechanisms. 呈现抑制活性的分子包括但不限于糖胺聚糖(GAG)(例如肝素、硫酸肝素、硫酸皮肤素、硫酸软骨素、ο-硫酸化的HA、亚麻仁苷和苦杏仁苷)、抗氧剂(例如抗坏血酸、褪黑激素、维生素C和维生素E)、蛋白质(例如血清透明质酸酶抑制剂)和脂肪酸(例如饱和Cltl-C22脂肪酸)。 Exhibit inhibitory activity of molecules include, but are not limited to glycosaminoglycans (GAG) (such as heparin, heparin sulfate, dermatan sulfate, chondroitin sulfate, ο- sulfated HA, linseed and amygdalin glycosides), antioxidants (such as ascorbic acid, melatonin, vitamin C and vitamin E), proteins (such as serum hyaluronidase inhibitor) and fatty acids (such as saturated Cltl-C22 fatty acids).

[0031] 抑制剂的分子量一般比交联的多糖聚合物具有更小的数量级。 [0031] Inhibitors generally higher than the molecular weight of the crosslinked polysaccharide polymer having a smaller magnitude. 由于抑制剂大小较小且扩散性较高,它们在体内倾向于快速吸收,这有可能限制其性能。 Due to the small size of the inhibitor and high diffusivity, they tend to rapidly absorbed in the body, which may limit its performance. 一种在体内增加这类分子的局部半衰期的方法是,将它们化学接枝于所述多糖聚合物网络并且将它们同时递送。 An increase in partial half-life of such molecules in vivo methods is that they are chemically grafted to the polysaccharide polymer network and deliver them simultaneously. 该方法的一个缺点是,结合的分子可呈现比未结合的分子显著更低的活性。 A disadvantage of this method is that the bound molecule can be unbound molecules exhibit ratio significantly lower activity. 在本发明的多糖凝胶制剂中,所述抑制剂的浓度可以是约0. 0001重量% -约99重量%,约0. 001 重量% -约75重量%,约0.01重量% -约60重量%,约1重量% -约50重量%,约1 重量% -约40重量%,约1重量% -约30重量%,约1重量% -约20重量%,约10重量% -约20重量%,约20重量% -约30重量%,0. 0001重量% -约0. 01重量%,约0. 0001 重量% -约0. 1重量%,约0. 0001重量% -约1重量%,约0. 001重量% -约1重量%,约0.01重量% -约1重量%,约1重量% -约10重量%。 Polysaccharide gel formulations of the present invention, the concentration of the inhibitor may be about 0.0001% by weight - about 99% by weight, from about 0.001% by weight - about 75 weight percent, from about 0.01% by weight - about 60 weight % to about 1% by weight - about 50%, about 1% by weight - about 40 wt%, about 1% by weight - about 30%, about 1% by weight - about 20%, about 10% - about 20 wt % to about 20% by weight - about 30%, 0 0001% by weight - about 0.01 wt% to about 0.0001 wt% - about 0.1% by weight, from about 0.0001 wt% - about 1% , about 0.001% by weight - about 1% by weight, about 0.01% by weight - about 1%, about 1% by weight - about 10% by weight.

[0032] 本发明的另一方面涉及一种生产降解减少的多糖凝胶制剂的方法,包括提供一种多糖,并在所述多糖中封装一种降解抑制剂。 [0032] Another aspect of the present invention relates to a method for producing a polysaccharide gel formulation to reduce degradation comprising providing a polysaccharide and encapsulating the one kind of polysaccharide degradation inhibitor.

[0033] 非交联多糖链以及交联多糖链会通过不同途径降解(如酶降解、自由基降解),这经常会限制该聚合物在体内的寿命。 [0033] non-crosslinked polysaccharide chains and crosslinked polysaccharide chains degrade via different routes (such as enzymatic degradation, radical degradation), which often limits the life of the body of the polymer. 因此,开发在组织中降低天然分解速率并增加产物持久性的方法是重要的。 Therefore, to reduce the natural rate of decomposition in the development of tissue and a method to increase the product durability is important.

[0034] 获得多糖持续时间增加的一种方法是,将抑制剂分子封装于多糖聚合物网络本身中或者至所述网络中的大容器中,这将使得降解抑制剂被局部(注入部位)、持续且可控的释放。 A method [0034] to increase the duration of the polysaccharide obtained is the inhibitor molecules encapsulated in polysaccharide polymer network itself or to the network of a large container, which will cause degradation inhibitor is locally (injection site), sustained and controlled release. 这还将能够避免天然降解机制。 It will also be able to avoid the natural degradation mechanisms. 本发明的封装方法可在数周的时间向所述多糖聚合物网络持续供应降解抑制剂。 Packaging method of the present invention may be a continuous supply of degradation inhibitor in a few weeks to the polysaccharide polymer network. 在另一些实施方案中,在数月的时间提供降解抑制剂的持续供应。 In other embodiments, in a few months time to provide a continuous supply of degradation inhibitor. 一种封装方法是,通过吸附或者通过封装过程将所述降解抑制剂封装于所述多糖聚合物网络中。 An encapsulation method by adsorption or by encapsulation process will degrade the inhibitor package on the polysaccharide polymer network. 在后一种情况中,所述抑制剂被允许以高水合状态与所述多糖网络混合,然后对所述网络脱水以控制所述释放动力学(例如所述聚合物的终膨胀率)。 In the latter case, the inhibitors are allowed to mix with the high hydrated state polysaccharide network, then the network to control the release kinetics of dehydration (e.g. expansion ratio of the final polymer). 高水合状态对应于低于约20mg/ml的HA浓度。 High hydration state corresponds to less than HA concentration of about 20mg / ml of.

[0035] 可通过调节pH或者使所述多糖网络部分脱水而控制所述终膨胀率。 [0035] or by adjusting the pH of said polysaccharide network partially dehydrated while controlling the final expansion. 可将所述收缩的网络的大小调节成颗粒,与所述多糖凝胶混合并递送至所述注入部位。 The size of the contraction may be adjusted to a network particles, mixed with the polysaccharide gel and delivered to the implantation site. 所述装载抑制剂的多糖颗粒的缓慢再水合可提供其活性内容物的持续且可控的递送。 The slow re-hydration inhibitors loaded polysaccharide particles can provide sustained and controlled delivery of their active content.

[0036] 本发明的另一方面涉及一种包含多糖和多糖降解抑制剂的多糖凝胶制剂,所述多糖凝胶制剂还包含生物相容的或可生物降解的容器,其中所述抑制剂在所述容器之中或者是所述容器的一部分。 [0036] Another aspect of the present invention relates to a polysaccharide gel formulation comprising a polysaccharide and an inhibitor of polysaccharide degradation, the polysaccharide gel formulation further comprises a biocompatible or biodegradable vessel wherein the inhibitor among the part of the container or the container. 这类容器可以由非共价或共价连接的自组装分子例如脂质体、胶束和聚合化小囊组成。 Self-assembling molecules such containers can be connected by a non-covalent or covalent such as liposomes, micelles and vesicles polymerized composition.

[0037] 脂质体是一种由一个或多个双层膜组成的小囊,所述双层膜由含混合脂质链的天然来源的磷脂(例如卵磷脂酰乙醇胺)形成,或者由纯表面活性物质组分如二油酰磷脂酰乙醇胺(DOPE)形成。 [0037] Liposomes are composed of one or more of the vesicle bilayer membrane composed of a bilayer membrane formed of a lipid-containing natural sources mixed chain phospholipids (e.g. lecithin, phosphatidylethanolamine), or of pure surfactant component such as dioleoyl phosphatidyl ethanolamine (DOPE) is formed. 脂质体(通常但非限定性地)包含一个水性溶液核心;包含非水性材料的脂质结构称为胶束。 Liposomes (usually, but not limiting to) an aqueous solution comprising a core; lipid structure comprising a non-aqueous material known as micelles. 胶束是分散于胶体流体中的表面活性分子的聚集体。 Micelles are dispersed in a fluid colloidal aggregates of surfactant molecules. 水性溶液中的典型胶束可形成聚集体,具有与周围溶剂接触的亲水“头部”区域,隔离所述胶束中央的疏水“尾部”区域。 A typical micelle aqueous solution can form aggregates, in contact with the surrounding solvent hydrophilic "head" region, isolating the micelle central hydrophobic "tail" region. 这种类型的胶束被称为正相胶束(水包油胶束)。 This type of micelle is known as normal phase micelle (oil-in-water micelle). 逆胶束的头部基团在中央,尾部伸展向外(油包水胶束)。 Reverse micellar head group in the center, the tail extending outward (water in oil micelles). 胶束通常近似球形,然而,还有可能为椭圆体、圆筒和双层。 Generally spherical micelles, however, there may be an ellipsoid, cylinder and double. 胶束的形状和大小随其表面活性分子的分子几何结构以及溶液条件例如表面活性物质浓度、温度、PH和离子强度变化。 Micelle shape and size with the molecular geometry of its surfactant molecules and solution conditions such as surfactant concentration, temperature, PH and ionic strength changes. 胶束的形成过程被称为胶粒形成,并根据脂质的多态性形成多种脂质相性质的一部分。 Micelle formation process is called micelles formed, and a part of the nature of the formation of a variety of lipid phase based on lipid polymorphism.

[0038] 本发明的另一方面涉及一种制备降解减少的多糖凝胶制剂的方法,包括步骤:1) 提供一种多糖,2)将一种抑制剂掺入至一种生物相容的或可生物降解的容器中,以及3)将所述多糖和容器结合成一种凝胶制剂中。 [0038] Another aspect relates to a process for producing a polysaccharide gel formulation to reduce degradation of the method of the present invention, comprises the steps of: a) providing a polysaccharide, 2) the incorporation of an inhibitor to a biocompatible or biodegradable vessel and 3) combining said polysaccharide and vessel into a gel formulation. 该封装方法因此将所述抑制剂掺入至生物相容的和可生物降解的容器中,所述容器可与所述多糖同时递送。 This packaging method therefore inhibitor incorporated into the biocompatible and biodegradable container, the container can be delivered simultaneously with the polysaccharide. 这类容器可由非共价或共价连接的自组装分子(例如胶束、脂质体和聚合的小囊)组成。 Such containers may be non-self-assembling molecules covalently or covalently linked (eg micelles, liposomes and polymeric capsule) composition. 本文使用的术语自组装描述这样的过程,即其中已存在组分的无序体系形成一个有组织的结构或模式,无外部指导的情况下在所述组分自身中形成特定的局部相互作用。 The term used herein to describe the self-assembly process, i.e., wherein the component already exists disordered system formed an organized structure or pattern, without external guidance of the case of forming a specific interaction of the local component itself.

[0039] 所提出的制剂的另一优点是所述终产品流变性质的调整能力的增加。 [0039] Another advantage of the proposed formulation is to increase the ability to adjust the rheological properties of the final product. 交联多糖凝胶一般具有高粘度,需要相当大的力挤压通过细针。 Crosslinked polysaccharide gels typically have high viscosity, requires considerable force is extruded through a fine needle. 非交联多糖通常被用作润滑剂,以有利于该挤压过程。 Non-crosslinked polysaccharide is generally used as a lubricant to facilitate the extrusion process. 然而,尤其在HA皮肤填充剂中,非交联HA对所述终产物在体内的持久性没有贡献。 However, especially in HA dermal fillers, the non-crosslinked HA of the final product does not contribute to the persistence in vivo. 事实上,越多交联HA被非交联HA替换以调整所述皮肤填充剂的流变性质(为获得固定的总HA浓度),所述产品的降解抗性将会越低。 In fact, the more cross-linked HA is replaced in order to adjust the rheological properties of the dermal filler non-crosslinked HA (in order to obtain a fixed total HA concentration), the resistance to degradation products will be lower. 另外,根据所提出的制剂,亦为降解抑制剂的非交联GAG (例如硫酸软骨素、ο-硫酸化的透明质酸)可用于延长所述终产物的寿命并改善其流变性质。 Further, according to the proposed formulation, degradation inhibitors also non-crosslinked GAG (e.g. chondroitin sulfate, ο- sulfated hyaluronic acid) can be used to extend the life of the final product and to improve the rheological properties.

[0040] 本文描述的多糖可以是交联的或非交联的。 [0040] polysaccharide described herein may be cross-linked or non-crosslinked. 交联剂可用于交联本说明书的多糖。 Crosslinking agents can be used to crosslink polysaccharide present specification.

7所述交联剂可以是已知适合于多糖或其衍生物经由羟基交联的任意试剂。 The crosslinking agent 7 may be adapted to any agent known in the polysaccharide or a derivative thereof crosslinked via hydroxyl groups. 合适的交联剂包括但不限于,例如1,4_ 丁二醇二缩水甘油醚(或者1,4_双(2,3_环氧丙氧基)丁烷或1, 4_双缩水甘油氧丁烷,它们通常都被称为BDDE)、1,2-双(2,3_环氧丙氧基)乙烯和1_(2, 3_环氧丙基)-2,3_环氧环己烷。 Suitable crosslinking agents include, but are not limited to, e.g., 1,4_-butanediol diglycidyl ether (or 1,4_ bis (2,3_ epoxypropoxy) butane or 1, 4_ double glycidoxy butane, which are usually referred to as BDDE), 1,2- bis (2,3_ epoxypropoxy) ethylene and 1_ (2, 3_ epoxypropyl) -2,3_ epoxycyclohexyl alkyl. 本发明的范围还涵盖使用不止一种交联剂或不同交联剂。 The scope of the present invention also contemplates the use of more than one agent or different cross-linking agents. 在一个实施方案中,所述交联剂包含BDDE或者由BDDE组成。 In one embodiment, the crosslinking agent comprises BDDE composition or of BDDE.

[0041] 皮肤填充剂可用于治疗轻度至重度面部皱纹和褶皱如法令纹(那些从鼻子扩展至嘴角的细纹)。 [0041] The dermal filler for the treatment of mild to severe facial wrinkles and folds such as nasolabial folds (those that extend from the nose to the mouth of fine lines). 皮肤填充剂可以为包括HA的凝胶植入物,HA是一种增强皮肤弹性的天然复合糖,提供一种平滑且柔软的外表。 HA dermal fillers may include gel implants, HA is an enhanced skin elasticity of natural complex carbohydrates, providing a smooth and soft appearance. 它是生物相容的,可补充身体的天然HA——其随衰老而耗尽。 It is biocompatible, it can supplement the body's natural HA-- its depleted with aging.

[0042] 皮肤凝胶可经注射器注入至面部的真皮中部至深处。 [0042] skin gel may be injected with a syringe to the middle of the face to the deep dermis. 真皮是表皮之下的皮肤层, 含结缔组织、神经末梢、汗腺和油脂腺、以及血管。 The dermis is the layer of skin below the epidermis, containing connective tissue, nerve endings, sweat glands and oil glands, and blood vessels. 皮肤填充剂可通过提升及增加治疗区域的皱纹和褶皱的体积而改善皮肤外表。 Dermal fillers can enhance and increase the volume of the treatment of wrinkles and folds region and improve skin appearance.

[0043] 本发明的另一方面涉及一种美容用的组合物,包含本发明的多糖凝胶制剂、美容用的载体和活性成分。 [0043] Another aspect relates to a cosmetic composition, the polysaccharide gel formulation comprising the present invention, the cosmetic carrier and an active ingredient of the present invention. 所述美容用的活性成分可包括但不限于抗氧剂、维生素和增湿剂。 The cosmetic active ingredients may include, but are not limited to antioxidants, vitamins, and moisturizers.

[0044] 本文使用的形容词“美容用的”是指改善表皮外表或者遮盖缺陷。 [0044] As used herein, the adjective "cosmetic" means to improve the appearance of the skin or hide defects. 一般而言,美容用的组合物可用于提高表皮的美观,而不是提高表皮的功能方面。 In general, the compositions may be used to improve the cosmetic appearance of the skin, rather than improve the skin's function. 更通常地,美容用的组合物被配制用途健康和美学处理法,或者用于改变身体如角质表面的个性化外表,例如皮肤、 毛发、指甲等。 More generally, the compositions are formulated cosmetic and aesthetic purposes health treatment, or for changing the appearance of the body such as personalized horny surface, such as skin, hair, nails and so on.

[0045] 本文使用的“可美容用载体”是指适合应用于角质表面或身体其他区域的物质。 [0045] As used herein, "cosmetically acceptable carrier" refers to a substance suitable for horny surface or other body regions. 在应用时,可美容用载体与皮肤和其他角膜表面基本上无不良反应。 In the application, cosmetically acceptable carrier and skin and other corneal surface is substantially no adverse reactions. 例如,美容用载体可采取以下形式:脂肪乳剂或非脂肪乳剂、乳状悬液、油包乳剂或水包油型、洗剂、凝胶或胶冻剂、 胶状或非胶状水性溶液剂或油溶液剂、糊剂、气溶胶、可溶解片剂或者棒剂。 For example, the cosmetic carrier may take the following forms: fat emulsions or fat emulsions, suspensions emulsions, water-in-oil emulsion or oil-in, lotions, gels or jellies, jelly or non-aqueous solution or colloidal oil solutions, pastes, aerosols, dissolvable tablet or stick form.

[0046] 本文使用的“制剂”和“组合物”可互换使用,是指在一块呈现给定目的的成分的结合物。 [0046] As used herein, "preparation" and "composition" are used interchangeably to refer to the combination of a presentation given purpose components. 这类术语是本领域普通技术人员公知的。 Such terms are to those of ordinary skill in the art.

[0047] 本文使用的“载体”、“惰性载体”和“可用的载体”可互换使用,是指可以与本发明公开的多糖凝胶结合以提供所需组合物的载体。 [0047] As used herein, "vector", "inert carrier" and "acceptable carrier" are used interchangeably to refer to the present disclosure may be combined to provide a polysaccharide gel carrier of the desired composition. 本领域普通技术人员应了解许多熟知的载体可用于制备具体的治疗性药物和/或美容用组合物。 Those of ordinary skill in the art to understand many of the well-known vectors can be used to prepare specific therapeutic drugs and / or cosmetic compositions.

[0048] 本发明的另一方面涉及一种药物组合物,所述药物组合物包含所述多糖凝胶制剂、药用载体和活性成分。 [0048] Another aspect of the present invention relates to a pharmaceutical composition, said pharmaceutical composition comprising the polysaccharide gel formulation, a pharmaceutically acceptable carrier and an active ingredient. 本文使用的活性成分包括但不限于药物。 As used herein, the active ingredients include, but are not limited to drugs. 药物一般可定义为用于疾病的治疗、治愈、预防或诊断的或者用于另外增强身体健康或精神健康的化学物质。 Drugs are generally defined as for the treatment, cure, prevention or diagnosis or for additional enhanced physical or mental health of the chemicals.

[0049] 可以包括在本发明药物组合物中的活性成分的实例有抗痒剂、抗蜂窝组织剂、抗瘢痕剂、抗炎症剂。 [0049] In the pharmaceutical compositions may comprise the active ingredient of the present invention, examples of anti-itch agents, anti-cellulite agents, anti-scarring agents, anti-inflammatory agent. 抗痒剂可包括甲基磺酰甲烷、碳酸氢钠、炉甘石、尿囊素、高岭土、薄荷油、茶树油和它们的结合物。 Anti-itch agents can include methyl sulphonyl methane, sodium bicarbonate, calamine, allantoin, kaolin, peppermint, tea tree oil, and combinations thereof. 抗蜂窝组织剂可包括福斯高林(forskolin)、黄嘌呤化合物,例如但不限于咖啡因、茶碱、可可碱、氨茶碱和它们的结合物。 Anti-cellulite agents may include, xanthine compound forskolin (forskolin), such as, but not limited to, caffeine, theophylline, theobromine, theophylline, and combinations thereof. 抗瘢痕剂可包括IFN-Y、氟尿嘧啶、乳酸/羟基乙酸共聚物、甲基化的聚乙二醇、聚乳酸、聚乙二醇和它们的结合物。 Anti-scarring agent may comprise IFN-Y, fluorouracil, lactic acid / glycolic acid copolymer, methylated polyethylene glycol, polylactic acid, polyethylene glycol, and combinations thereof. 抗炎症剂可包括地塞米松、泼尼松龙、皮质酮、布地奈德、雌激素、柳氮磺吡啶、美沙拉嗪和它们的结合物。 Anti-inflammatory agents can include dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, mesalamine, and combinations thereof.

[0050] 多糖例如HA天然出现在身体的多种组织中,例如但不限于皮肤、软骨和玻璃体液。 [0050] naturally occurring polysaccharide such as HA in various tissues of the body, such as, but not limited to, skin, cartilage and vitreous humor. 因此,它十分适合于靶向这些组织的生物医学应用。 Therefore, it is very suitable for biomedical applications targeting these organizations. HA可用于眼科手术中(即角膜移 HA can be used in eye surgery (ie cornea shift

8植、白内障手术、青光眼手术和修复视网膜脱离的手术)。 8-sik, cataract surgery, glaucoma surgery and repair of retinal detachment surgery). HA还可用于治疗膝的骨关节炎。 HA can also be used to treat osteoarthritis of the knee. 这类治疗被称为黏弹性补充疗法,以注入膝关节中的过程给予,被认为可补充关节液的粘度,从而润滑关节,缓冲关节并产生镇痛效应。 Such treatment is called viscoelastic replacement therapy, to inject the knee in the process of giving, it is believed to supplement the viscosity of synovial fluid, which lubricates the joint, cushioning joints and analgesic effects. 还已经提出,HA对软骨细胞具有积极的生物化学效应。 It has also been proposed, HA on cartilage cells have positive biochemical effects. 最近提出可口服HA,但需证明其有效性。 Recently proposed to oral HA, but need to prove its effectiveness. 现如今,有一些初步的临床研究表明, 口服HA对骨性关节炎有积极效应。 Now, there are some preliminary clinical studies have shown that oral HA osteoarthritis have a positive effect.

[0051] 由于HA的高生物相容性极普遍存在于组织的细胞外基质中,它可在组织工程研究中用作生物材料支架。 [0051] Due to the high biocompatibility of HA very prevalent in the extracellular matrix tissue, which can be used as biological scaffolds in tissue engineering. 在一些癌症中,HA水平与恶性和预后不良很好地相关。 In some cancers, HA levels and poor prognosis malignant correlate well. 因此,HA 经常被用作前列腺和乳腺癌的肿瘤标记物。 Thus, HA is frequently used as the prostate and breast tumor markers. 它还可以被用于监视疾病的进展。 It can also be used to monitor the progression of the disease. HA还可在手术后使用,以诱导组织愈合,特别是在白内障手术后。 HA can also be used after surgery to induce tissue healing, particularly after cataract surgery. 现在的伤口愈合模型提出,更大的HA 聚合物出现于愈合的早期阶段以物理地为白细胞腾出空间,所述白血病介导免疫反应。 Wound healing model now proposed, greater HA polymer at an early stage of healing appeared to physically make room for white blood cells, the leukemia-mediated immune response.

[0052] 药物组合物可任选地包含一种或多种试剂,例如但不限于乳化剂、湿润剂、甜味剂或风味剂、渗透佐剂、防腐剂、缓冲剂、抗氧剂、黄酮类化合物。 [0052] The pharmaceutical compositions may optionally contain one or more agents, such as, but not limited to, emulsifiers, wetting agents, sweetening or flavoring agents, penetration adjuvants, preservatives, buffers, antioxidants, flavonoid compounds. 可用于本发明的药物组合物中的渗透佐剂包括但不限于盐,例如乙酸钠、氯化纳、氯化钾;甘露醇或甘油;以及其他可药用的渗透佐剂。 The pharmaceutical compositions of the present invention may be used in the permeation adjuvants include, but are not limited to salts, such as sodium acetate, sodium chloride, potassium chloride; mannitol or glycerin; and other pharmaceutically acceptable permeation adjuvants. 可用于本文公开的药物组合物中的防腐剂包括但不限于苯扎氯铵、三氯叔丁醇、硫柳汞、乙酸苯汞和硝酸苯汞。 Can be used in pharmaceutical compositions disclosed herein include, but are not limited to, the preservative benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. 用于调节PH的多种缓冲剂和方法可用于制备药物组合物,包括但不限于乙酸盐缓冲物、柠檬酸盐缓冲物、磷酸盐缓冲物和硼酸盐缓冲物。 Various buffers and means for adjusting the PH may be used in the preparation of pharmaceutical compositions, including but not limited to acetate buffer material, citrate buffer, phosphate buffer and borate buffer composition thereof. 类似地,可用于药物组合物中的抗氧剂是本领域中熟知的,包括例如焦亚硫酸钠、硫代硫酸钠、乙酰半胱氨酸、丁羟茴醚和丁羟甲苯。 Similarly, a pharmaceutical composition of antioxidants are known in the art, including, for example, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxy toluene. 黄酮类化合物是植物中出现的化合物,已知它们具有不同的有利生物化学和抗氧剂效应。 Flavonoids are compounds occurring in plants, are known to have different biochemical and antioxidant effects advantageously. 黄酮类化合物的亚类包括:黄酮、黄酮醇、 黄烷酮和黄烷酮醇。 Subclass of flavonoids include: flavones, flavonols, flavanones and flavanonols. 黄酮类化合物的实例包括:四羟黄酮、芹菜素、福橘素、槲皮素、山奈酚、杨梅素、漆黄素、异鼠李素、藿香黄酮醇、鼠李秦素、橙皮素、柚皮素、圣草酚、高圣草素、 紫杉醇、二氢槲皮素、二氢山奈酚、鞣酸、单宁、浓缩单宁和可水解单宁。 Examples of flavonoids include: four quercetin, apigenin, blessing orange pigment, quercetin, kaempferol, myricetin, Fisetin isorhamnetin, Agastache flavonols, buckthorn Qin, hesperetin, grapefruit mesothelin, eriodictyol, homoeriodictyol, paclitaxel, dihydroquercetin, dihydro kaempferol, tannic acid, tannins, concentrated tannins and hydrolyzable tannins. 应理解,药理学领域中已知的这些和其他物质可包括在本发明的药物组合物中。 It should be understood pharmacology of those known in the art and other materials may be included in pharmaceutical compositions of the present invention. 参见,例如Remington' s Pharmaceutical Sciences Mac Publishing Company,Easton,PA,. 16 片反,1980。 See, e.g., Remington 's Pharmaceutical Sciences Mac Publishing Company, Easton, PA ,. 16 片 trans, 1980.

[0053] 在下文使用实施例描述了本发明的一些优点,这些实施例记载了依照本文描述的方法制备HA填充凝胶剂,依照现有技术制备HA填充凝胶剂以及针对这些样品进行的降解试验。 [0053] In the embodiments described hereinafter using some of the advantages of the present invention, those embodiments in accordance with the method described herein describes a HA filling gels prepared in accordance with prior art HA filling gels prepared for these samples as well as the degradation of test.

[0054] 本文中使用的分子量(Mw)是指一个分子中原子的原子总重量。 [0054] As used herein, molecular weight (Mw) of the total weight refers to the atom in a molecule atom. 例如,甲烷(CH4) 的分子量是16. 043g/mol,原子量为碳=12. Ollg/mol,氢=1.008g/mol。 For example, methane (CH4) is the molecular weight of 16. 043g / mol, the atomic weight of carbon = 12. Ollg / mol, hydrogen = 1.008g / mol. 道尔顿(Da)是重量单位,等于12O重量的1/12,1百万Da可记作lMDa。 Dalton (Da) is a unit of weight equal to the weight of 1 12O / 12, 1 one million Da may be credited to lMDa.

[0055] 实施例1 [0055] Example 1

[0056] 依照本发明公开的内容制备HA填充凝胶剂 [0056] HA filling gels prepared in accordance with the present disclosure

[0057] 将HA浓度为24mg/mL、交联度为约6%且G,为约180的1_5克多糖填充物(JUVEDERMŪ 24HV, (Allergan Inc.,Irvine,California))与补充有10_200mg硫酸软骨素A (CSA-Mw = 5,000-120,OOODa)的1000 μ 1磷酸盐缓冲盐水(PBS)溶液(ρΗ约7)混合。 [0057] The HA concentration of 24mg / mL, the degree of crosslinking is about 6%, and G, is about 180 1_5 g polysaccharide filler (JUVEDERMŪ 24HV, (Allergan Inc., Irvine, California)) with sulfuric acid supplemented with 10_200mg chondroitin sulfate A (CSA-Mw = 5,000-120, OOODa) of 1000 μ 1 phosphate buffered saline (PBS) solution (ρΗ about 7) were mixed. 将所述混合物进行机械勻化。 The mixture is mechanically homogenized.

[0058] 实施例2 [0058] Example 2

[0059] 通过现有技术的方法制备HA填充凝胶剂 [0059] HA filling gels prepared by the method of the prior art

[0060] 将HA浓度为24mg/mL、交联度为约6%且G,为约180的1_5克多糖填充物(JUVEDERMŪ 24HV)与1000 u 1的PBS混合,使终HA浓度与实施例1中的相同。 [0060] The HA concentration of 24mg / mL, the degree of crosslinking is about 6%, and G, mixed with the PBS 1000 u 1 1_5 of about 180 grams of polysaccharide filler (JUVEDERMŪ 24HV), to a final concentration of HA Example the same 1. 将所述混合物进行机械勻化。 The mixture is mechanically homogenized.

[0061] 实施例3 [0061] Example 3

[0062] 依照本发明公开的内容制备另一种透明质酸填充凝胶剂 [0062] Another preparation of hyaluronic acid gel filled in accordance with the present disclosure

[0063] 将HA浓度为24mg/mL、交联度为约6%且G,为约170的1_5克基于HA的多糖填充物(JUVEDERMŪ 30)与补充有l_20mg 鞣酸(TA-MW = 800-4, OOODa)的50 yl 的PBS 溶液(PH约7)混合。 [0063] The HA concentration of 24mg / mL, the degree of crosslinking is about 6%, and G, is about 170 1_5 Albuquerque to HA polysaccharide filler (JUVEDERMŪ 30) and supplemented with l_20mg tannic acid (TA-MW = 800 -4, OOODa) in PBS for 50 yl of (PH about 7) were mixed. 将所述混合物进行机械勻化。 The mixture is mechanically homogenized.

[0064] 实施例4 [0064] Example 4

[0065] 通过现有技术的方法制备另一种透明质酸填充凝胶剂将HA浓度为24mg/mL、交联度为约6%且G,为约170的1-5克基于HA的多糖填充物(JUVEDERMŪ 30)与50 yl的PBS混合,使终HA浓度与实施例3中的相同。 [0065] Another preparation of hyaluronic acid gel filled by the prior art method will HA concentration of 24mg / mL, the degree of crosslinking is about 6%, and G, of about 170 HA polysaccharides 1-5 in Albuquerque filler (JUVEDERMŪ 30) was mixed with 50 yl of PBS, to a final concentration of HA same as in Example 3. 将所述混合物进行机械勻化。 The mixture is mechanically homogenized.

[0066] 实施例5 [0066] Example 5

[0067] 依照本发明公开的内容制备透明质酸填充凝胶剂 [0067] Preparation of hyaluronic acid gel filled in accordance with the present disclosure

[0068] 将1克透明质酸钠纤维(NaHA,Mw = 0. 5_3MDa)与5_10g的1 %氢氧化钠溶液混合,并放置所述混合物1-5小时以进行水合。 [0068] One gram of sodium hyaluronate fibers (NaHA, Mw = 0. 5_3MDa) mixed with 1% sodium hydroxide solution 5_10g and placing the mixture for 1-5 hours hydration.

[0069] 将50-200毫克1,4_ 丁二醇二缩水甘油醚(BDDE)加入至NaHA凝胶剂中,并将所述混合物进行机械勻化。 [0069] 50-200 mg of the 1,4_ butanediol diglycidyl ether (BDDE) are added to the NaHA gel and the mixture is mechanically homogenized.

[0070] 然后,将所述混合物至于40-70°C的烤箱中1-4小时。 [0070] Then, as for the mixture of 40-70 ° C oven for 1-4 hours.

[0071] 将所形成的交联水凝胶用当量的氢氯酸(HC1)中和并在PBS(pH ^ 7)中膨胀。 [0071] The crosslinked hydrogel formed expanded in PBS (pH ^ 7) with the equivalents of hydrochloric acid (HC1) and neutralized.

[0072] 加入10-200毫克CSA (Mw = 5,000-120,OOODa),并将所述水凝胶进行机械勻化。 [0072] Add 10-200 mg of CSA (Mw = 5,000-120, OOODa), and the hydrogel is mechanically homogenized.

[0073] 实施例6 [0073] Example 6

[0074] 依照现有技术的方法制备透明质酸(HA)填充凝胶剂 [0074] Preparation of hyaluronic acid (HA) gel padding method according to the prior art

[0075] 将1克NaHA (Mw = 0. 5_3MDa)与5_10g的1 %氢氧化钠溶液混合,并放置所述混合物1-5小时以进行水合。 [0075] One gram of NaHA (Mw = 0. 5_3MDa) mixed with 1% sodium hydroxide solution 5_10g and placing the mixture for 1-5 hours hydration.

[0076] 将50-200毫克BDDE (与实施例5中HA :交联剂摩尔比相同)加入至NaHA凝胶剂中,并将所述混合物进行机械勻化。 [0076] 50-200 mg of the BDDE (Example 5 HA: the same molar ratio of the crosslinking agent) was added to the NaHA gel and the mixture is mechanically homogenized.

[0077] 然后,将所述混合物至于40-70°C的烤箱中1-4小时。 [0077] Then, as for the mixture of 40-70 ° C oven for 1-4 hours.

[0078] 将所形成的交联水凝胶用当量的氢氯酸(HC1)中和并在PBS(pH ^ 7)中膨胀,使得终HA浓度与实施例5中的相同。 [0078] The cross-linked hydrogel formed with equivalents of hydrochloric acid (HC1) and and expanded in PBS (pH ^ 7) such that the final concentration of HA same as in Example 5. 将所得到的水凝胶进行机械勻化。 The resulting hydrogel is mechanically homogenized.

[0079] 实施例7 [0079] Example 7

[0080] 酶降解研究(量热试验) [0080] enzymatic degradation studies (calorimeter test)

[0081] 使用Morgan-Elson量热测定评估实施例1和2中制备的HA填充凝胶剂对酶降解的抗性。 [0081] The Morgan-Elson calorimetry to assess HA filling gels in Examples 1 and 2 prepared in resistance to enzymatic degradation. 将该测定用于在酶降解之前和之后估计HA链的平均分子量。 This assay was used before and after enzymatic degradation estimated average molecular weight of HA chain.

[0082] 将透明质酸酶(0. l-10mg)加入至HA样品中,在37°C下维持10-250分钟,然后加入0. lml的0. 8M四硼酸钾溶液并在100°C下加热10分钟。 [0082] The hyaluronidase (0. l-10mg) was added to the HA sample, maintain 10-250 minutes at 37 ° C, then added 0. lml of 0. 8M solution of potassium tetraborate and 100 ° C under heating for 10 minutes. 将所述样品补充3ml的10重量% 对二甲氨基苯甲醛的乙酸溶液,并在37°C下孵育10-120分钟。 10 wt% of the sample add 3ml of acetic acid solution of dimethylaminobenzaldehyde and incubated at 37 ° C for 10 to 120 minutes. 将降解之后和之前585nm下光密度(0D)的变化用于对每个样品中的降解程度进行定量。 After the change before degradation and 585nm optical density (0D) for quantitative extent of degradation of each sample.

[0083] 显示于图1的在依照本发明的方法和依照现有技术制备的填充凝胶剂上进行的测量结果(酶降解试验结果(量热测定))表明,通过本发明公开的方法制备的凝胶剂的0D值(实施例1 :0. 774-25. 184mg/ml CSA)低于通过现有技术的方法制备的凝胶剂的0D值(实施例2 :Omg/ml CSA)。 [0083] shown in Figure 1. In accordance with the method of the present invention and measurement results according to the prior art filling gels were prepared (the enzymatic degradation test results (Calorimetry)) showed that the preparation method of the present invention disclosed 0D value of gelling agent (Example 1:.. 0 774-25 184mg / ml CSA) is lower than the value 0D prepared by the method of the prior art gelling agent (Example 2: Omg / ml CSA). 再者,0D值的降低与CSA浓度成比例。 Furthermore, lowering the concentration of CSA 0D value proportional. 由于0D值代表了降解的程度,这些结果表明依照本发明的方法制备的凝胶剂呈现比依照现有技术方法制备的凝胶剂高3-75%的酶降解抗性。 Since 0D value represents the degree of degradation, these results suggest that gels prepared according to the method of the present invention exhibits than gels prepared according to the prior art high resistance to enzymatic degradation of 3-75%.

[0084] 类似于补充CSA的凝胶剂的情况,如图2中所示,通过本发明的方法制备的补充有TA的凝胶剂的0D值(实施例3 :0. 063-1. 000mg/mL TA)低于通过现有技术的方法制备的凝胶剂的0D值(实施例4 :0mg/mL TA)。 [0084] Like the case of gels complement the CSA, as shown in Figure 2, the supplement prepared by the method of the present invention include a gelling agent 0D TA values (Example 3:.. 0 063-1 000mg / mL TA) is lower than the value 0D prepared by the method of the prior art gels (Example 4: 0mg / mL TA). 再者,0D值的降低与TA浓度成比例。 Moreover, reducing the value 0D proportional to the concentration of TA. 由于0D值代表了降解的程度,这些结果表明依照本发明的方法制备的凝胶剂呈现比依照现有技术方法制备的凝胶剂高15-90%的酶降解抗性。 Since 0D value represents the degree of degradation, these results indicate that gels prepared in accordance with the method of the present invention exhibits than gels prepared according to the prior art method 15-90% higher enzymatic degradation resistance. 还可以看出,TA具有比CSA更高的抑制活性,这是因为TA以低1个数量级的量获得与CSA相同的抑制。 Can also be seen, TA has a higher inhibitory activity than CSA, because TA to an order of magnitude lower amount of inhibition obtained with the same CSA.

[0085] 实施例8 [0085] Example 8

[0086] 酶降解研究(可溶性HA测定) [0086] Enzyme (soluble HA assay) degradation

[0087] 为了进一步评估实施例1和2中制备的HA填充凝胶剂对酶降解的抗性,使用了基于SEC-MALS (体积排阻多角度光散射)的可溶性HA测定。 [0087] In order to further assess the implementation HA filling gels prepared in Examples 1 and 2, the resistance to enzymatic degradation, the use of SEC-MALS (multi-angle light scattering size exclusion) soluble HA based assays. 可使用该测定通过评估每个样品中含有的可溶性HA的百分数(定义为可通过0. 2-1. Oym滤器的凝胶部分)对降解进行定量。 You can use this to assess the percentage of each sample was determined by soluble HA containing (defined as by 0. 2-1. Gel portion Oym filter) degradation was quantified. 降解之前和之后可溶性HA的量变化可用于定量每个样品中的降解程度。 Before and after the amount of soluble degradation of HA can be used to change the degree of degradation of each sample quantification.

[0088] 使用装配有Wyatt光散射和折射指数单元的Agilent体积排阻色谱系统进行SEC-MALS试验。 [0088] equipped with an Wyatt light scattering and refractive index cells Agilent Size Exclusion Chromatography SEC-MALS system test. 将透明质酸酶(0. l-10mg)加入至HA样品中,在37°C下维持10-250分钟, 然后加入0. lml 0.8M四硼酸钾溶液并在100°C下加热10分钟。 The hyaluronidase (0. l-10mg) was added to the HA samples maintained at 37 ° C for 10-250 minutes, followed by addition of 0. lml 0.8M potassium tetraborate solution and heated at 100 ° C for 10 minutes. 将所述样品于PBS中稀释, 过滤通过0. 2-1. 0 um滤器并注入至SEC-MALS系统中。 The samples were diluted in PBS, filtered through a 0. 2-1. 0 um filter and injected into the SEC-MALS system. 酶解之前和之后可溶性HA含量以及它们的差显示于图3中。 Before and after enzymatic hydrolysis of soluble HA content as well as their difference is shown in Figure 3.

[0089] 显示于图3中的结果(酶降解试验结果(SEC-MALS测定))表明,不含CSA的样品的酶降解后的可溶性HA含量显著更高。 [0089] The results are shown in Figure 3 (enzyme degradation test results (SEC-MALS measurement)) showed that the content of soluble HA-free samples of CSA after enzymatic degradation significantly higher. CSA和非CSA样品之间可溶性HA增加的这种差异与量热降解测定中得到的结果一致,并表明依照本发明的方法制备的凝胶剂显示比依照现有技术制备的凝胶剂更高的降解抗性。 Between the CSA and the non-CSA samples soluble HA increase the amount of the difference in thermal degradation of measurement results obtained consistent, and show that gels prepared in accordance with the method of the present invention display higher than the prior art prepared in accordance with a gelling agent The degradation resistance.

[0090] 类似于补充CSA的凝胶剂的情况,通过本说明书的方法制备的补充TA的凝胶剂的可溶性HA含量(实施例3 :0. 063-1. 000mg/mL TA)低于通过现有技术的方法制备的凝胶剂的可溶性HA含量(实施例4:0mg/mL TA)。 Case [0090] Like supplementary CSA gels were prepared by the methods described in the supplementary TA soluble gelling agent HA content (Example 3:.. 0 063-1 000mg / mL TA) below the pass the soluble HA content of the prior art methods for preparing the gels (Example 4: 0mg / mL TA). 这些结果与总结于图4中的量热方法相符。 These results are summarized in Figure 4 in an amount consistent with the thermal method. 再者,还可以看出,TA的抑制活性比CSA高1个数量级。 Furthermore, it can be seen, TA inhibitory activity than an order of magnitude higher CSA.

[0091] 实施例9 [0091] Example 9

[0092] 连续挤压力试验 [0092] continuous extrusion pressure test

[0093] 为了评估实施例5和6中制备的透明质酸填充凝胶剂的流变性质,在每个样品上进行了连续挤压力试验。 [0093] In order to evaluate 5 and rheological properties of hyaluronic acid, prepared in Example 6 gel filled implemented on each sample continuous extrusion pressure test. 挤压力试验可用于确定CSA是否可通过作为润滑剂而有利于所述挤压过程。 Extrusion pressure test may be used to determine whether the CSA extrusion process by acting as a lubricant in favor.

[0094] 使用带有30G针头的5ml注射器在Ins tron仪器上进行挤压力试验。 5ml syringe [0094] use with 30G needle on Ins tron instrument squeeze pressure test. 将0. 5ml 每个样品以50mm/分钟的恒定速率挤出。 To 0. 5ml of each sample at a constant rate of 50mm / min extrusion. 所记录的力的峰值是挤压容易程度的定量。 The peak force recorded is the ease of extruding quantified. 两个样品的压力与压缩伸长的函数绘于图5中。 Two samples of pressure elongation and compression functions are plotted in Figure 5.

[0095] 图5中的结果表明,对通过本文描述的方法制备的凝胶剂记录到的挤压力低于对通过现有技术的方法制备的凝胶剂的记录到的挤压力。 [0095] FIG. 5 results show that the gel prepared by the method described herein is recorded into the extrusion pressure is lower than recorded by the prior art methods for the preparation of the gel to the pressing force. 挤压力的这种差异是流动时的凝胶硬度差异的特征,并且表明通过本文描述的方法制备的凝胶剂中含有的CSA发挥有利于流动的润滑剂的功能。 This difference is characterized by the pressing force of the flow of the difference between the hardness of the gel, and the gel showed that prepared by the methods described herein contained in the CSA play in favor of the lubricant flow function.

[0096] 除非另有指出,在说明书及权利要求书中使用的表示成分数量、性质例如分子量、 反应条件等的所有数值,应理解为在所有情形中都以词语“约”进行修饰。 [0096] Unless otherwise indicated, all numbers in the number represents a component in the specification and claims the use of properties such as molecular weight, reaction conditions, etc., should be understood as all cases are in the word "about" modified. 因而,除非另有指明,说明书及所附权利要求书中所提到的数值参数均为约数,其可随本发明想要获得的所需性质而变。 Thus, unless otherwise indicated, the description and the appended claims the numerical parameters mentioned in the book are about the number of requirements, which may vary depending on the desired properties of the present invention is intended to get the change. 至少,并不试图限制将等同原则用于解释权利要求书的范围,每个数值参数至少应根据所报道的有意义的数字的值,并应用常规的近似方法来理解。 At least, it does not attempt to limit the scope of the principle of equivalents used to interpret the claims, each numerical parameter should at least according to the figures reported in meaningful value, and using conventional methods of approximation to understand. 尽管陈述本发明的宽泛范围的数值范围和参数为约数,但对具体实施例中提到的数值作尽可能精确的报道。 Despite the broad scope of the present invention stated numerical ranges and parameters about the number, but the numerical values mentioned in the specific implementation reports as accurate as possible. 但是,任何数值都内在地包含一定的由它们各自的测试过程所存在的标准偏差而必然导致的误差。 However, any value inherently contains certain standard deviation by their respective testing process exists and will inevitably lead to errors.

[0097] 在描述本发明时(尤其是在所附的权利要求书中)使用的词语“一”、“一个”、“该” 以及类似的指代,应理解为包括单个和多个,除非文中另有指出,或与上下文意思明显相悖。 [0097] In describing the present invention (especially in the book in the appended claims) used the words "a", "an" and "the" and similar referents should be understood to include the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. 文中引述值的范围仅意在作为一种对落在所述范围内的每个单独值各个提及的简便方法。 Scope quoted values are only intended as a simple method for each separate value falling within the range mentioned in each. 除非文中另有指出,每个单独值均被纳入说明书中,如同单独引述一般。 Unless otherwise indicated herein, each individual value are included in the specification as a single quote in general. 文中所述的所有方法可以任何合适的顺序实施,除非文中另有指出或与上下文意思明显相悖。 All methods described herein can be in any suitable order unless otherwise indicated herein or clearly contradicted by context. 文中使用的任何及所有实例,或示例性语言(如,“例如”)仅意在更好地阐明本发明,并不对本发明所要求保护的范围进行限制。 Any and all examples, or exemplary language used herein (eg, "such as"), is intended merely to better illuminate the invention, the invention is not to limit the scope of protection required. 说明书中任何语言均不应被理解为表示对于实施本发明所必需但不要求保护的要素。 No language in the specification should be construed as showing the embodiment of the present invention, but the protection of the essential elements is not required.

[0098] 文中所公开的发明的可选择要素或实施方案的分组不应被理解为限制性的。 [0098] Alternatively grouping elements or embodiments of the invention disclosed herein should not be construed as limiting. 每个组要素可单个被提及和被要求,或者与该组内的其它要素或文中出现的其它要素的任意组合的形式被提及和被要求。 Each set of elements may be mentioned and the individual requirements or mentioned in any combination with other elements or other elements of the text that appears within the group and were asked. 可以预见,出于简便和/或可专利性的原因,一个或多个要素可被囊括于组内,或自组内删除。 Can be expected, for convenience and / or patentability reasons, one or more elements may be include in the group, to or deleted from the group. 当出现任何这类囊括或删除时,说明书应被认为包含所修改的组,从而满足随附权利要求书中使用的所有马库什组的书面说明。 When any such covers or deleted, the instructions shall be deemed to contain the modified group to meet written all Markush groups used in the appended claims instructions.

[0099] 本发明的某些实施方案在文中作了描述,包括发明人已知的实施本发明的最佳方式。 [0099] Certain embodiments of the present invention are described in the text, including the best mode known to the inventors of carrying out the invention. 当然,所述实施方案的变型对本领域技术人员而言,在其阅读前面的说明后将会变得很清楚。 Of course, variations of the embodiments of the present skilled in reading the foregoing description it will become very clear. 发明人预期本领域技术人员可以适当地使用所述变型,并且发明人也想使本发明以与文中所具体描述的不同的方式来实施。 The inventors expect skilled in the art can be suitably used the variant, and the inventors of the present invention also want a different manner specifically described herein to implement. 因此,本发明包括适用的法律所许可的所附权利要求中记载的主题的所有变化及等同方式。 Accordingly, the present invention includes a topic permitted by applicable law set forth in the appended claims and all changes and equivalents. 此外,上述要素在其所有可能的变型中的任意组合均涵盖于本发明之内,除非文中另有指出或与上下文含义明显相悖。 Also, any combination of these elements in all possible variations are encompassed within the present invention, unless otherwise indicated herein or clearly contradicted by context meaning.

[0100] 此外,说明书通篇提到了多篇专利及出版物文献。 [0100] In addition, throughout the specification refers to number of patents and publications Document. 上述文献及出版物中的每一篇的全文均通过引用的方式纳入本说明书。 The above-mentioned documents and publications full text of each of which are incorporated herein by reference.

[0101] 最后,应理解的是,文中所公开的发明的实施方案是本发明原理的示例说明。 [0101] Finally, it should be understood that the embodiments of the invention disclosed herein is an example of the principles of the present invention is illustrated. 可使用的其它变化方案也在本发明的范围内。 Other variations may also be used within the scope of the invention. 因此,例如,但不限于,可根据本文教导而使用本发明的替代构型。 Thus, for example, but not limited to, the teachings herein can be used in accordance with an alternative configuration of the present invention. 因而,本发明不限于具体示出及描述的方案。 Thus, the present invention is not limited to the specific program are shown and described.

[0102] 本文公开的具体实施方案可使用语言“由......组成”或“基本由......组成” [0102] Specific embodiments disclosed herein may be using language "composed by the ......" or "consisting essentially of ......"

在权利要求书中进一步进行限制。 The book claims further restrictions. 当用于权利要求中时,不管是初始提交或者是后加的每 When used in the claims, regardless of the initial submission or after adding each

次修改时,及物术语“由......组成”不包括权利要求中未指定的任何要素、步骤或成分。 When the time changes, and physical terms "...... composition" does not include any element of a claim is not specified, step, or ingredient.

及物术语“基本由......组成”将权利要求的范围限制到指定的物质或步骤,以及那些不 Transitivity term "consisting essentially of ......" limits the scope of the claims to the specified steps or materials and those that do not

重大影响基本特征和新特征的物质或步骤。 A significant impact on the basic and novel characteristics of the substance or steps. 所要求的本发明的实施方案在本文中固有地或明确地被记载或实现。 Embodiments of the present invention is required or expressly described herein or implement inherently.

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Classifications
International ClassificationA61K8/60, A61K8/73, A61K8/04, A61Q19/08, A61K9/10, C08B37/00, A61K9/00, A61Q19/00, A61K31/738
Cooperative ClassificationA61L27/505, A61L27/26, A61K47/26, A61K8/60, C08L5/08, A61K47/38, A61K47/42, A61K8/73, A61K8/731, C08K5/053, A61K2800/522, A61K8/042, A61K8/602, A61K31/738, C08L2205/02, A61K31/727, A61K31/737, C08B37/0072, A61K31/715, A61K8/492, A61K31/717, C08J2305/08, A61Q19/08, A61K47/36, A61K31/728, A61K8/678, A61K31/721, A61K8/735, C08J3/075, A61K8/676, A61K8/736, A61K47/183
European ClassificationA61K31/728, A61K8/60A, A61K47/38, A61K31/717, A61K31/737, A61K47/18B, A61K8/73, A61K8/67L, A61K47/42, A61K8/73L, A61K8/73C, A61K31/727, A61K8/04A, A61K8/60, A61K31/715, A61K8/67H, A61K47/36, A61Q19/08, A61K8/49C2C, A61K31/721, A61K8/73P, A61K31/738, C08L5/08, C08J3/075, C08B37/00P2F
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